Download 2013 ADA Posters 386-1338.indd - American Diabetes Association

CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE
CATEGORY
MONITORING AND SENSING
training. A linear patient-specific state-space model, combined with generic
compartment models describing the insulin pharmacokinetics and the glucose
rate of appearance from the gut, was identified from the CGM and meal and
insulin data, using the subspace method N4SID, to describe the post-prandial
impact of these inputs. The CIR of each patient was calculated by taking the
ratio between the summarized amounts of carbohydrates and bolus insulin
over the entire study period, and compared to the CIR estimates using the 500rule and the model, with a correlation of 0.5 and 0.8, respectively.
The results suggest that the suggested method could be used as a means
to improve the estimates of CIR from a limited set of data.
858-P
The Impact of a Video Phone Reminder System on Glycemic Control
in Older Adults With Type 2 Diabetes Mellitus (T2DM) in a Retirement Home
LUCIA NOVAK, SUSAN WALKER, STEPHANIE FONDA, VIRGINIA SCHMIDT, ROBERT VIGERSKY, Bethesda, MD
Interactive behavior change technologies (IBCT) - web portals connecting
patients to their providers and personal health information, web-based care
management programs, and mobile phone applications - have been shown
to be helpful for improving outcomes in diabetes. We have shown that daily,
diabetes-related video-based tips and reminders, sent to patients’ mobile
phones, were associated with a clinically significant improvement in A1C
(Bell AM et al. J Diab Sci Tech 6:310-319, 2012). We have developed a similar
intervention for older adults residing in the Armed Forces Retirement Home
in which the tips were tailored to the specific needs of this population and
produced by providers familiar to the subjects. We conducted a prospective,
randomized pilot study in subjects ages 70-89 with T2DM for 4-30 years.
They were randomized to usual care (UC) or to UC plus receiving daily 1530 second video message (VM) on a bedside phone for 6 months. A1C was
measured at baseline and quarterly for up to 12 months. We found that 4 of
5 VM subjects and only 1 of 4 UC subjects improved their A1C at 3 months.
The trend continued at 6 and 9 months but dropouts prevented analysis at 12
months (Figure). These data suggest that video tips and reminders about self
care management behavior may improve glycemic control in people with DM
in retirement home settings.
Supported by: The European Union
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860-P
Effect of Different Plasma Insulin Concentrations (PI) on Interstitial Glucose (IG): Implications for Continuous Glucose Monitoring
(CGM)
Supported by: United States Army Medical Research and Materiel Command
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—
GLUCOSE MONITORING AND SENSING
Guided Audio Tour: Utility of Continuous Glucose Monitoring (Posters: 859-P
to 866-P), see page 15.
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859-P
Model-Based Estimates of the Post-Prandial Response to Carbohydrate and Insulin and of the Carbohydrate-to-Insulin Ratio
FREDRIK STÅHL, ROLF JOHANSSON, ERIC RENARD, Lund, Sweden, Montpellier,
France
The Carbohydrate-to-Insulin Ratio (CIR) is a measure of how many units
of rapid acting insulin to administer to match the digested amount of
carbohydrates, and this metric is commonly used in optimizing both the
Multi-Dose Injection (MDI) and insulin pump regime of insulin dependent
diabetes patients (IDDM). To estimate the value for a specific patient,
a heuristic rule of dividing 500 by the Total Daily Insulin (TDI) has been
suggested. This so-called 500-rule often produces poor estimates, and to
improve these estimates a model-based approach is suggested.
In total, 90 patient IDDM data sets were collected in a three day hospitalized
trial. The patients were equipped with Continuous Glucose Measurement
systems (Abbott Freestyle), received standardized meals for breakfast, lunch
and dinner (45, 70 and 70 gram), and the amount of bolus and basal doses were
noted. 47 (27 pump, 20 MDI, age 42 [22-68], BMI 24.5 [16.8-35.9], HbA1c 7.8
[5.6-9.7], TDI 42 [6-82]) of the 90 data sets fulfilled quality inclusion criteria
(no missing meals/insulin doses in the record, no gaps in the CGM data).
For each patient data set, a segment of 24 hours was selected for model
ADA-Funded Research
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Supported by: European Union (252085); Ministry of Science (DPI2011-28112C04-01)
For author disclosure information, see page 829.
Guided Audio Tour poster
A217
POSTERS
Current CGM accuracy during hypoglycemia is still poor. This might be
explained by insulin-induced changes of the plasma-to-interstitium glucose
dynamics, not considered by CGM calibration algorithms.
The aim of the present study was to assess the role, if any, of different PI on IG.
Fourteen subjects with type 1 diabetes (36.5±10.5 years, HbA1c 7.9±0.4%)
were evaluated under conditions of hyperinsulinemic eu- and hypoglycemia.
Following an insulin-feedback period to standardize initial plasma glucose
(PG), each subject underwent two randomized crossover clamps with either
a primed 0.3mU/kg/min (low insulin, LIS) or 1mU/kg/min (high insulin, HIS)
insulin infusion. A hypoglycemic plateau of 45 minutes was achieved after a
euglycemic phase, recovering later euglycemia (Figure).
Each subject wore two CGM monitors per study (Paradigm VEO, Medtronic,
CA). Due to different sensor sensitivities, the raw CGM signal (nA) was
normalized (CGMn) with the median pre-clamp values before statistical
analysis (ANOVA).
Despite much greater mean PI concentrations in HIS vs LIS (58.8±1.9
vs 24.7±1.4µU/ml), neither PG (79.5±4.8 vs 80.2±4.3 mg/dl, p=0.13) nor IG
expressed as CGMn (0.83±0.14 vs 0.84±0.13, p=0.95) were significantly
different (Figure).
In summary, differences of PI in the physiological range do not affect IG
concentrations. Other factors responsible for poor CGM accuracy under
hypoglycemia should be investigated.
Clinical Diabetes/
Therapeutics
PAOLO ROSSETTI, FRANCISCO JAVIER AMPUDIA-BLASCO, FÀTIMA BARCELÓRICO, JUAN F. ASCASO, JORGE BONDIA, Gandia, Spain, Valencia, Spain
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
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MAGE and CONGA were calculated from 12-14 days of continuous glucose
monitoring. Cell adhesion molecules ICAM1 and VCAM were measured in
plasma by ELISA. GV was significantly higher in patients with MiVC (n=17)
while their HbA1C, ICAM1 and VCAM were comparable to patients without
complications. No correlation of GV and ICAM1 or VCAM was observed
in patients with MiVC, however, in the patients without MiVC, ICAM1
correlated with SD (r=0.66, p=0.007), MAGE (r=0.64, p=0.01) and CONGA
(r=0.78, p<0.001) while VCAM correlated with MAGE (r=0.56, p=0.031).
Although GV was higher in patients with MiVC, it correlated with ICAM1
and VCAM independently on the presence of MiVC. In our study, GV was
associated with endothelial dysfunction prior to the development of MiVC.
This may indicate a potential role of GV for the future development of MiVC
in Type 1 diabetes and requires further research.
861-P
Glucose Differences in Patients With Type 1 Diabetes Who Continue versus Discontinue CGM Use
POSTERS
Clinical Diabetes/
Therapeutics
SAMUEL L. ELLIS, ROBERT B. MCQUEEN, DAVID MAAHS, KAVITA V. NAIR,
HEATHER D. ANDERSON, ANNE M. LIBBY, JON D. CAMPBELL, Aurora, CO
There is limited data on the clinical effectiveness supporting the use
of continuous glucose monitors (CGM). We recognize there is a high
discontinuation rate of CGM use in adult patients with type 1 diabetes within
the first 6 months, but limited data evaluates the reasons why patients selfdiscontinue CGM and the effects of self-discontinuation on glucose control.
We retrospectively identified adult T1D patients at the Barbara Davis
Center who first initiated CGM from 2006 to 2011. We conducted surveys
on these patients to determine who self-discontinued CGM use during the
first year of use and the most commons reasons for this. Adherence to CGM
was estimated from survey recall and defined as average number of days/
month of CGM use during follow-up. Change in A1c was calculated as the
difference between the baseline value and lowest follow-up value while
patients used CGM.
A total of 66 patients completed the CGM survey. Baseline mean (SD) age
for CGM users was 39 (12) years; duration of diabetes was 23 (12) years; and
A1c was 7.47%. The most common CGM product was DexCom (42%). A total
of 23 (35%) CGM users self-discontinued use within the first year. The most
common reasons patients self-discontinued CGM were accuracy, numerous
alarms, skin reactions/sensor discomfort and cost. CGM users who selfdiscontinued within the first year were most likely to do so within 6 months
(>70%). While using CGM those individuals who self-discontinued had
minimal A1c reduction compared to those who continued (0.63% vs 0.32%;
p=0.07). The within group changes were significant for both the continuers
and self-discontinuers p< 0.0001 and p=0.017, respectively.
Further research needs to be done to improve adherence to CGM so
patients can achieve maximal clinical benefits.
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862-P
Supported by: Charles University
Specificity and Precision Assessment of a Long Term, Fully Implantable Continuous Glucose Monitoring (CGM) System
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CARRIE LORENZ, WENDOLYN QUINTANILLA, COLLEEN MDINGI, SRINIVASAN
RAJARAMAN, MARK MORTELLARO, Germantown, MD
CGM use has been shown to be associated with improvements in A1C.
Currently available CGM systems, which use enzymes for glucose signaling,
are approved for short durations of use (≤ 7 days). Senseonics, Inc. has
developed a CGM system intended for up to 180 days of use that utilizes an
abiotic glucose transducer rather than an enzyme. Specificity of the abiotic
recognition system for glucose over potentially interfering substances has
been assessed in vitro (PBS). No mono-saccharide was observed to interfere
over physiologically relevant concentrations and no signal response was
observed for di-saccharides (e.g., sucrose, maltose) over any concentration
tested.
Glucose measurement precision of the CGM system has been assessed
in vitro and in vivo. Precision was characterized in pH 7.4 PBS buffer at
32°C and 37°C across 3 glucose levels using 53 CGM sensors from 3
different production lots. Percent coefficient of variation (% CV) for glucose
concentrations > 75 mg/dL were below 3% and standard deviations (SD) for
concentrations < 75 mg/dL were below 3 mg/dL. In vivo glucose precision
of the CGM system was characterized using data obtained from a 28 day
human clinical trial on a subset of 4 human subjects each inserted with 2
sensors (1 in each arm) read continuously and simultaneously for 3 days. All
sensors were recalibrated twice per day and display blinded. An overall in
vivo percent absolute relative difference (PARD) of 6.0% and % CV of 4.5%
was obtained.
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864-P
The Impact of Continuous Glucose Monitoring (CGM) on Low Interstitial Glucose Values and Low Blood Glucose Values Assessed by
Point of Care Glucose Meters (POC-GM)
NORBERT HERMANNS, BEATRIX SCHUMANN, BERNHARD KULZER, THOMAS
HAAK, Bad Mergentheim, Germany
The impact of CGM on the duration of periods with low glucose measured
in interstitial fluid is well known. But studies showing an impact of CGM
on low blood glucose values, measured by POC-GM are rare. This crossover study examines the impact of CGM on duration of periods spent in low
interstitial glucose range (70 mg/dl) as well as on the proportion of low blood
glucose (BG) values measured by POC-GM (Glukometer 3000, Bio Sensor
Technology, Germany)and time until detection of low BG by use of POC-GM.
41 type 1 diabetic patients (age 42.0 ±11.3 yrs, diabetes duration 15.3
±10.1; A1c 8.2 ±1.4%) used the DEXCOM 7 Plus CGM system twice; once
participants were blinded against the results and in the other study phase
(Open GCM) patients received real-time glucose values and current glucose
trends, used the CGM data to determine their insulin dose, and were alerted
if hypoglycaemic or hyperglycaemic glucose ranges were approached. In
addition, BG was routinely measured 6 times a day by POC-GM. The order of
study phases was randomized. The time spent in a hypoglycaemic glucose
range (< 70 mg/dl) was reduced by open CGM from 180.6 ±125 to 125 ± 89.2
minutes per day (p=.005). Also time spent in the euglycemic glucose range
was increased from 946 ±176 to 1023 ±168 minutes per day (p=.003). Open
CGM reduced the proportion of low BG measurements by POC-GM from
10.3 ±7.6% to 7.4 ±5.8% (p=.039), whereas the euglycemic POC readings
was increased from 68.3 ±12.1% to 73.7 ±12.1% (p=.007). The time until a
hypoglycaemic BG value was detected by POC-GM was significantly (p.028)
shortened by 33.1 (95% CI 3.8 -62.3) minutes.
These results demonstrate that CGM used for insulin dosing and
hypoglycaemia alerts not only diminishes low interstitial glucose values but
also reduces the proportion of low BG measured by POC-GM. In addition
the time for the detection of a hypoglycaemic episode by POC-GM was
significantly shortened.
863-P
Glycemic Variability Is Associated With Markers of Endothelial
Dysfunction: Cell Adhesion Molecules ICAM-1 and VCAM in Type 1
Diabetes Without Complications
MARTIN PRAZNY, JAN SOUPAL, MARTIN FAJMON, JAN SKRHA JR., JAN KVASNICKA, JAN SKRHA, Prague, Czech Republic
Glycemic variability (GV) is probably associated with vascular complications
in patients with diabetes. However, it is not clear whether increased GV
directly contributes to their development. In this study we compared GV
with markers of endothelial dysfunction in Type 1 diabetic patients with
and without microvascular complications (MiVC). Thirty-two patients
were included (age 44 ± 13 yrs, HbA1C 70 ± 9 mmol/M, no macrovascular
complications). Glucose standard deviation (SD), coefficient of variation (CV),
Supported by: DexCom, Inc.
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For author disclosure information, see page 829.
A218
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
Guided Audio Tour: Blood Glucose Monitoring (Posters: 867-P to 874-P), see
page 15.
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BRADLEY C. LIANG, TALY ENGEL, CYRUS A. ROUSHAN, STACIE HALLER-WICH,
XIAOLONG LI, MEGAN E. LITTLE, KEITH NOGUEIRA, ASHLEY SULLIVAN, JOHN B.
WELSH, JEROME S. FISCHER, RAJIV SHAH, FRANCINE R. KAUFMAN, SCOTT W.
LEE, Northridge, CA, San Antonio, TX
LAURENCE B. KATZ, LUPE R. MILLER, RANDEE A. RANDOLL, RIAD G. DIRANI,
GANG LI, West Chester, PA, Milpitas, CA
This study is a retrospective evaluation of the 7-day performance of a
novel subcutaneous amperometric glucose oxidase-based glucose sensor. Its
design utilizes high-density circular array electrodes on a flexible polyimide
substrate over which an enzymatic layer and protective membranes are
deposited. Electrodes and membranes were optimized for responsiveness,
linearity, and signal consistency. The sensor is 9 mm in length (implant volume
0.17 mm3) with mechanical properties that minimize wear-induced tissue
inflammation. Data were analyzed with a prototype real-time continuous
glucose monitoring (CGM) algorithm.
Twenty subjects with type 1 or type 2 diabetes were enrolled into a singlesite feasibility study. Each subject wore either 1 or 2 of the glucose sensors
on the abdomen connected to iPro2 recording devices (Medtronic) over two
7-day wear periods. Blood glucose (BG) concentration was measured using
Contour NEXT Link meters (Bayer); collected points were used for both
calibration and accuracy determination. Subjects performed 3 frequent
sampling tests (on days 1, 3-4, and 6-7), each consisting of 12 or more BG
samples over a period of 3 hours.
Sensor data were analyzed with the real-time calibration algorithm
configured to select calibration points twice daily. Sensor data were
evaluated against all collected BG points at times recorded by the meter
(2333 evaluation points over 266 sensor days). The mean absolute relative
difference (MARD) between sensor and reference values was 11.80%
(14.37%, 10.02%, and 11.43% on days 1, 3-4, and 6-7) with just 1 of the 43
sensors (2.33%) having a calculated MARD >20%. The mean functional life
was 6.17 d, 84.14% of readings met ISO15197:2003 accuracy criteria, and
98.29% were in Clarke Error Grid zones A+B.
The system provided consistent and accurate readings when compared
to a BG meter reference. Such improvements in the accuracy and reliability
of Medtronic’s next-generation CGM system are part of the technology
evolution required to support development of the Artificial Pancreas.
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Improving glycemic control in patients with diabetes is challenging for
patients and their healthcare providers (HCPs). Tools that allow rapid
evaluation of blood glucose (BG) patterns by HCPs during short office visits
and provide insight to patients between visits to enable positive changes
may support these efforts. This study evaluated HCP experience with a BG
meter under development (OneTouch®Verio™) which uses pattern recognition
and other automatic messages to provide patients with insight into their BG
results.
The accuracy and time for 64 HCPs to identify high and low BG patterns
according to meter algorithms in 5 simulated logbooks containing 30 days of
BG data was compared to using meters containing identical data. In addition,
HCPs were given a demonstration of possible automatic meter messages
patients may see when testing on their own, and asked if these messages
may help their patients manage their BG.
HCPs took more time to find patterns using a logbook (4.0 min; 3.7-4.3
min, 95% Confidence Interval) compared to using the meter (1.0 min; 0.91.1 min) (p<0.001). The total error rate for finding patterns using a logbook
compared to patterns in the meter was 26.0% (18-34%, p<0.0001) for all low
and high patterns. Most (70%) of the HCPs felt using the meter was easier
than reviewing a logbook. Between 77-97% of the HCPs found high value in
the features of the meter and felt that insights provided by the automatic
messages may help their patients improve management of BG between
office visits. Ninety-two percent (92%) of the HCPs had a favorable level of
satisfaction to the meter and 89% would recommend it to all their patients;
91% to their patients on insulin.
In summary, using the new OneTouch® Verio™ meter was 4 times faster
and more accurate than using logbooks to help HCPs identify BG patterns.
Based on responses to a survey, HCPs liked the meter and would recommend
it to their patients.
866-P
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Relationship between Glycemic Variability and Blood Pressure
Variability in Diabetic Patients With Hypertension: Jikei Variability
of ABPM and CGM Study
HUGH D. TILDESLEY, ADAM S. WHITE, MARY-ELLEN CONWAY, STUART A.
ROSS, AUGUSTINE M. LEE, HAMISH G. TILDESLEY, JEREMY H.M. CHAN, ADEL
B. MAZANDERANI, Vancouver, BC, Canada, Hamilton, ON, Canada, Calgary, AB,
Canada, Hanover, NH, Nashville, TN, St. George’s, Grenada
Although recent studies have reported that both glycemic variability
(GV) and blood pressure (BP) variability contribute to the development of
cardiovascular disease, little is known about the relationship between GV
and BP variability in diabetic patients with hypertension. We evaluated GV,
BP variability and progression of arteriosclerosis using continuous glucose
monitoring (CGM), ambulatory blood pressure monitoring (ABPM) and Cardio
Ankle Vascular Index (CAVI). ABPM and CGM underwent at same time for
straight 2 days (48 hours). Hypertension was defined as diastolic blood
pressure systolic blood pressure [SBP] ə130 mmHg or, [DBP] ə80 mmHg
or were taking antihypertensive medicine. Variability was estimated by
Coefficient of variation (CV: Standard Deviation/average ambulatory BP
or glucose). This was a prospective study. 64 adult diabetic patients with
hypertension were enrolled in this study (mean: Age 53±12 years, BMI
26.7±3.8kg/m2, HbA1c 8.2±1.6%, diabetes duration 9.2±3.6 years, Patients
takingα-Glucosidase inhibitor or glinide or using rapid acting insulin were
excluded). The mean 24-h blood glucose level (mg/dl) and CV (%) were
144.2±36.8 and 21.2±8.8. The mean 24-h BP level (mmHg) and CV (%) were as
follows, Systolic:126.6±14.6 and 10.8±2.6, Diastolic: 78.0±9.9 and 12.9±3.6.
CAVI was 8.1±1.3 (normal range: <8.0). There were significant correlations
with GV and 24-h systolic pressure (Pearson’s r=0.30, P=0.02), daytime
systolic BP variability (Pearson’s r=0.31, P=0.04) and pulse pressure (Pearson’s
r=0.41, P=0.002). There was no relationship between GV and diastolic BP.
Interestingly, we observed a strong correlation between pulse pressure and
CAVI by correlation analysis (Pearson’s r=0.478, P<0.001). We conclude that
increased systolic BP variability and pulse pressure together related to GV
and that both might finally lead to development of cardiovascular disease.
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868-P
A Review of the Effect of Internet Therapeutic Intervention in Patients With Type 1 and Type 2 Diabetes
MASAYA SAKAMOTO, HIROFUMI SUZUKI, HIROYUKI IUCHI, KENNOSUKE
OHHASHI, TAKESHI HAYASHI, RIMEI NISHIMURA, KATSUYOSHI TOJO, KAZUNORI UTSUNOMIYA, Tokyo, Japan
ADA-Funded Research
867-P
A Novel Blood Glucose Meter that Provides Real-Time Automatic
Messaging: Benefi ts to HCPs and Patients
It is now our standard of care to offer an Internet Based Glucose
Monitoring System. We reviewed the first 409 patients registered, of whom
388 patients had baseline and follow-up A1C.
Patients were instructed to send their results every two weeks to their
endocrinologist for review and feedback. A1C and laboratory results were
requested at 3 month intervals.
We compared baseline values to follow-up, results summarized in table 1.
Regardless of type or treatment, all groups improved A1C.
Frequent reporters showed greater drops in A1C shown in table 2. The
observed difference in drops of frequent vs. infrequent reporters were found
to be significant across all groups (p < 0.05).
Type 1 patients with A1C at goal reported sporadically. When we excluded
patients with A1C at goal, the difference in frequent reporters vs. infrequent
reporters was significant.
Table - 1 PAIRED SAMPLES T-TEST BASELINE AND 6 MONTHS
TYPE
N BASELINE (SD) 6 MONTHS (SD)
ALL USERS
388
8.20 (1.27)
7.87 (1.15)
TYPE 1 * excluding A1C < 6.9
115
8.12 (1.38)
7.93 (1.17)
ALL TYPE 2
256
8.36 (1.35)
7.91 (0.98)
TYPE 2 - OHA’S
116
8.15 (0.98)
7.67 (1.29)
TYPE 2 - INSULIN +/- OHA’S
140
8.53 (0.82)
8.12 (0.91)
P VALUE
2.86 E -9
0.0064
1.04E-9
1.26 E -5
1.13 E -5
For author disclosure information, see page 829.
Guided Audio Tour poster
A219
POSTERS
Clinical Evaluation of a Prototype 7-Day CGM System
865-P
Clinical Diabetes/
Therapeutics
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
these limits). Three POCT systems for professional use and the three lots
of the system for self-monitoring had more than 95% of the measurement
results within these more restrictive limits.
This study demonstrated that BG systems for self-monitoring which have
to fulfil strict requirements prior to market introduction can achieve similar
system accuracy as POCT systems for professional use.
Table 2 - PAIRED T-TEST BY FREQUENCY (Frequent = >Once a month, Infrequent = <Once a month)
TYPE
N REPORTING BASELINE (SD)6 MONTHS (SD) P VALUE
TYPE 1 *excluding A1C < 7.4 44 FREQUENT 8.07 (0.84) 7.85 (1.02) 0.035
TYPE 1 *excluding A1C < 7.4 71 INFREQUENT 8.14 (1.15) 7.98 (1.00) 0.043
TYPE 2 - OHA’S
35 FREQUENT 8.03 (1.25) 7.48 (0.85) 0.0018
TYPE 2 - OHA’S
81 INFREQUENT 8.21 (1.42) 7.75 (1.27) 0.00074
TYPE 2 - INSULIN +/- OHA’S 41 FREQUENT 8.42 (1.40) 7.86 (1.39) 0.00007
TYPE 2 - INSULIN +/- OHA’S 99 INFREQUENT 8.57 (1.42) 8.22 (1.08) 0.0013
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Supported by: Sanofi
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GREGORY G. FOTIEO, CHRISTOPHER S. WENDEL, JAYENDRA H. SHAH, ELENA V.
PLUMMER, ALLISON E. MURATA, HEATHER C. BRISLEN, GERALD A. CHARLTON,
GLEN H. MURATA, Albuquerque, NM, Tucson, AZ, Phoenix, AZ
869-P
The purpose of this study was to determine if HbA1c is better correlated
with mean glucose or the area under the curve (AUC) derived from a 7-point
glucose profile. Sixty-nine patients from the VA Southwest Health Care
Network participated in this study. Subjects provided a blood sample for
HbA1c and then measured their blood glucoses before and 2 hours after 3
daily meals and at bedtime for 3 consecutive days. A 7-point profile was
constructed for each subject from the average reading for each time of day
and average sampling intervals. AUC was defined as the total area under
the glucose versus time plot. Mean glucose was defined as the average of
the 7 profile values. The fractional contribution of each reading to AUC was
derived from the expression: reading * (mean of adjacent sampling periods)/
AUC. The mean (SD) age of the subjects was 64.5 (7.8) years, all were men,
and 40% belonged to an ethnic minority. Simple linear regression showed a
positive correlation between HbA1c and mean glucose (r=0.338; P=0.007).
However, more of the variance in HbA1c was explained by regressing HbA1c
against AUC (r=0.375; P=0.002). After adjusting for multiple comparisons,
no differences were found between the pre-breakfast reading (PRB) and all
other values or the bedtime reading (BED) and all other values. Moreover, no
differences were found between the fractional contributions of PRB and BED
to AUC [0.233 (0.044) vs 0.244 (0.046), respectively; P=NS]. However, their
contributions to AUC were each more than twice that of any other reading
(P<0.001 in all cases). Among diabetic veterans, AUC is somewhat better
correlated with HbA1c than mean glucose derived from glucose profiles.
More importantly, AUC provides information on the relative importance of
readings by giving greater weight to those that bracket longer time intervals.
Our study supports the concept that protein glycation is a function of glucose
concentration and exposure time and suggests that choosing treatment
targets should be based upon sampling times as well as glucose values.
JAE HYOUNG CHO, HUN SUNG KIM, SEUNG HYU YOO, CHANG HEE JUNG, WOO
JE LEE, CHUL YOUNG PARK, JOONG YEOL PARK, SUNG WOO PARK, HO YOUNG
SON, KUN HO YOON, Seoul, Republic of Korea
POSTERS
Clinical Diabetes/
Therapeutics
Large Scale Study of the Internet-Based Diabetes Management
System With an Automatic Data Uploading Device for Type 2 Diabetes Patients in Korea
Objective: To improve the quality of diabetes control, we developed an
Internet based interactive communication system with an automatic data
uploading device and investigated its effectiveness on controlling the
changes in HbA1c levels and blood pressure.
Research Design and Methods: We conducted a large-scale, multi-center,
randomized clinical trial involving 484 patients who visited the outpatient
clinic at the Seoul St. Mary’s Hospital, Seoul Asan Hospital and Samsung
Kangbook Hospital for 6 months. Intervention group (n=244) were treated
with the management system for 24 weeks, and the control group (n=240)
received the usual outpatient management over the same period. HbA1c ,
blood pressure and other laboratory tests were performed at the beginning
of the study, at 3 month and the end of the study.
Results: There was no significant differences between the two groups
with respect to age, sex, diabetes duration, BMI, blood pressure, HbA1c and
other laboratory data. At the end of the study . On follow-up examination
24 weeks later, HbA1c level were significantly decreased from 7.86± 0.69 to
7.55 ± 0.86% within intervention group (p<0.001) compared to 7.81 ± 0.66
to 7.70 ± 0.88% within control group. A subgroup with baseline HbA1c more
than 8% and good compliance achieved a big reduction of HbA1c by 0.8 ±
1.05%, compared to a small reduction of 0.37 ± 0.82% in a subgroup with
bad compliance.
Conclusions: This new internet-based diabetes management system with
an automatic data uploading device resulted in a significant reduction of
HbA1c during the study period and patients with good compliance showed
a more reduction of HbA1c. We propose that such the system can be a new
method for improving diabetes control.
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871-P
Correlating HbA1c With Glucose Profiles: A Comparison of Two
Methods
Supported by: Roche Diagnostics Corporation
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872-P
The Impact of Age on Interventions to Improve Glycemic Control in
Diabetes Patients on Multiple Daily Insulin Injection (MDI) Therapy:
Results from the Automated Bolus Advisor Control and Usability
Study (ABACUS)
870-P
Evaluating System Accuracy of Blood Glucose Monitoring Systems
for Point of Care Testing
IAIN CRANSTON, DAVID A. CAVAN, RALPH ZIEGLER, KATHARINE BARNARD,
CHRISTOPHER G. PARKIN, WALTER KOEHLER, BETTINA PETERSEN, MATTHIAS
A. SCHWEITZER, ROBIN S. WAGNER, Portsmouth, United Kingdom, Bournemouth,
United Kingdom, Muenster, Germany, Southampton, United Kingdom, Boulder City,
NV, Mannheim, Germany, Indianapolis, IN
GUIDO FRECKMANN, ANNETTE BAUMSTARK, MANUELA LINK, STEFAN PLEUS,
CORNELIA HAUG, JOCHEN SIEBER, Ulm, Germany, Frankfurt, Germany
Point of care testing (POCT) is performed with blood glucose (BG)
monitoring systems for professional use only and with systems designated
for self-monitoring of BG. These systems are often used interchangeably,
thus raising the question for comparability of measurement quality.
In this study, we evaluated the accuracy of a BG system for self-monitoring
(BGStar, Sanofi) and six different, commonly used systems for professional
use (HemoCue Glucose 201+, HEMOCUE AB; StatStrip, nova biomedical;
ACCU-CHEK Inform II, Roche Diagnostics; BIOSEN C_line, EKF-diagnostic;
HITADO SUPER GL compact, Dr. Müller Gerätebau; GLUKOMETER PRO,
BST Bio Sensor Technology). Investigational procedures were performed
following the international standard ISO 15197. Measurement results from
capillary blood samples of 100 subjects were analyzed by calculating the
percentage of results within ±10%/±15% or within ±10 mg/dL/±15 mg/dL of
the reference measurement results for BG concentrations above or below
100 mg/dL, respectively. Glucose oxidase was used as comparison method
(YSI 2300 STAT Plus, YSI Life Sciences, USA). From each BG monitoring
system two devices and one lot of reagents were used, except BGStar, for
which three reagent lots were evaluated separately.
For all evaluated systems 99% to 100% of the measurement results were
within ±15 mg/dL or ±15% of the reference method results. When applying
more restrictive limits of ±10 mg/dL or ±10% larger differences between
the evaluated systems were observed (81.5% to 97.5% of the results within
Managing younger patients with diabetes is often problematic. We
assessed the impact of bolus advisor use in patients who participated in
the ABACUS trial, a 26-week, prospective, randomized, controlled, multinational study that enrolled 218, poorly controlled MDI-treated diabetes
patients (202 type 1, 16 type 2) with mean (SD) baseline A1C 8.9 (1.2)%,
age 42.4 (14.0) years and BMI 26.5 (4.2) kg/m2. Baseline age of patients was
stratified to 18-30 years (n=53) or > 30 years (n=165), with younger adults
having higher A1C values than older patients (9.3 [1.6]% vs. 8.7 [1.0]%, p <
0.05) and shorter duration of diabetes (11.8 [6.3] years vs. 19.6 [11.6] years,
p < 0.01). Patients randomized to the control group (CNL) used a standard
blood glucose meter and calculated bolus insulin dosages manually; patients
randomized to intervention group (EXP) used the Accu-Chek Expert meter
with an automated bolus advisor to calculate insulin dosages. Among the
100 EXP patients who completed the study, bolus advisor use was associated
with a significantly higher percentage of patients achieving the primary goal
of > 0.5% A1C reduction than CNL patients (n=93): 56.0% vs. 34.4%, p <
0.01. Although older patients (> 30 years) in both groups were more likely
to achieve the primary outcome than younger patients (49% vs. 33%), more
younger EXP than CNL patients achieved > 0.5% A1C reductions: 53% vs.
15%, p < 0.05. The mean age of those who achieved the goal within the
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ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
with the instructions for use and with the ISO accuracy testing protocol in
a clinical setting.
EXP group was lower compared with those who did not: 42.4 (12.8) years vs.
44.3 (14.2) years. However, within the CNL group, the mean age was higher
among those who achieved the A1C goal compared with those who did not:
49.4 (13.7) years vs. 41.4 (13.9) years. This suggests that while bolus advisor
use is beneficial in both age groups, it may be especially useful in younger
adults, a population in which glycemic control is often difficult to achieve.
Supported by: Sanofi
875-P
Use of an Automated Bolus Advisor Reduces Glycemic Variability
in Poorly Controlled Diabetes Patients Treated With Multiple Daily
Insulin Injection (MDI) Therapy: Results from the Automated Bolus
Advisor Control and Usability Study (ABACUS)
Supported by: Roche Diagnostics GmbH
873-P
LESLIE J. KLAFF, RONALD L. BRAZG, KRISTEN HUGHES, ANN M. TIDEMAN, HOLLY C. SCHACHNER, PATRICIA STENGER, SCOTT PARDO, NANCY DUNNE, JOAN
LEE PARKES, Renton, WA, Tarrytown, NY
Calculating insulin dosages is challenging for most diabetic patients on
MDI therapy. We examined the effect of bolus advisor use on glycemic
variability (GV) as measured by mean amplitude of glucose excursions
(MAGE) in a subset of patients enrolled in the ABACUS trial, a 26-week,
prospective, randomized, controlled, multi-national study of poorly
controlled, MDI-treated patients, with mean (SD) baseline A1C 8.9 (1.2)%.
Patients randomized to the control group (CNL) used a standard blood
glucose meter and calculated bolus insulin dosages manually; intervention
patients (EXP) used the Accu-Chek Expert meter with an automated bolus
advisor. Ninety-three patients (90 type 1 diabetes) wore a continuous
glucose monitoring (CGM) device for 3 days at 3 time periods. Only EXP
patients showed significant reductions in mean MAGE: -20.2 (41.1) mg/dL
/ -1.1 (2.3) mmol/L, p < 0.01, vs. -2.9 (32.1) mg/dL / -0.2 (1.8) mmol/L, p = NS.
In patients with baseline A1C of 7.5-9.0%, improvement was even greater
in EXP than CNL patients: -23.2 (35.3) mg/dL / -1.3 (2.0) mmol/L, p < 0.01,
vs. -5.3 (33.2) mg/dL / -0.3 (1.8) mmol/L, p = NS. In patients who achieved ≤
0.5% A1C improvement, EXP by not CNL patients showed significant MAGE
reductions: -15.3 (29.3) mg/dL / -0.9 (1.6) mmol/L, p < 0.05, vs. 1.1 (35.8) mg/
dL / 0.1 (2.0) mmol/L, p = NS; a similar trend was seen in those who achieved
> 0.5% A1C reductions. Changes in MAGE correlated with SD of glucose
values (r = 0.87) and were independent of education level, diabetes duration,
duration of MDI or gender. The percentage of blood glucose values < 50
mg/dL / 2.7 mmol/L was < 2% in both groups throughout the study. Use of
the Accu-Chek Expert meter may reduce GV by facilitating more accurate
dosage calculations without increasing the risk of hypoglycemia.
This study compared the accuracy of the CONTOUR® NEXT BGMS with 5
other BGMSs (Accu-Chek® Aviva Nano, Freestyle Lite®, OneTouch® Ultra®
2, OneTouch® Verio™ Pro, and Truetrack®). Subjects (N = 146) were ≥18 years
and had diabetes. Subjects’ glucose levels were safely lowered or raised
to provide a wide range of glucose values. Study staff tested fingerstick
samples on the 6 BGMSs. Extreme glucose values were achieved by blood
sample glucose modification. The primary endpoint was comparison of the
mean absolute difference (MAD) from the reference value (YSI) in the low
glucose range (<70 mg/dL). In this sub-analysis, a comparison was done
using mean absolute relative difference (MARD) between the BGMSs and
YSI values in the low range and across the entire range for both modified
and unmodified samples. For all samples, in the low glucose range and
across the entire range (21-496 mg/dL), CONTOUR® NEXT had a statistically
significantly lower MARD than all the other BGMSs (Table 1). In unmodified
samples, in the low glucose range, CONTOUR® NEXT had a lower MARD
than all BGMSs and was significantly lower (P <0.05) except for Freestyle
Lite®. In unmodified samples over the entire range, CONTOUR® NEXT had
a statistically significantly lower MARD than all the BGMSs. In conclusion,
when compared with other BGMSs, CONTOUR® NEXT demonstrated the
lowest mean deviation from the reference value in the low and overall
glucose range (MARD) with modified and unmodified samples.
Supported by: Roche Diagnostics GmbH
876-P
Low Glucose Suspend Systems: CGM Signal Attenuation Detection
to Reduce Undesirable Pump Suspensions
NIHAT BAYSAL, FRASER CAMERON, BRUCE A. BUCKINGHAM, DARRELL M. WILSON, H. PETER CHASE, DAVID MAAHS, B. WAYNE BEQUETTE, Troy, NY, Stanford,
CA, Aurora, CO
&
Low glucose suspend (pump shut-off) algorithms use continuous glucose
monitor (CGM) signals to predict when glucose values are likely to violate
a hypoglycemic threshold, and therefore shut-off the continuous insulin
infusion pump. In in-patient and out-patient studies we have shown that our
Kalman-filter based pump shut-off algorithm reduces the risk of overnight
hypoglycemia by 50%, with an 11 mg/dL increase in mean blood glucose.
Unfortunately there are a number of false hypoglycemic predictions that
cause the pump to shut-off unnecessarily; many of these false detections
are due to pressure-induced sensor attenuations (PISA) that can occur, e.g.,
when someone rolls over their sensor while in bed.
We compare 3 different methods for mitigating the effect of PISAs to avoid
undesirable pump shut-offs. Method 1 prevents suspensions when the CGM
readings drop faster than 8 mg/dL/min, and prevents suspensions above 230
mg/dL. Method 2 adds to these rules the removal of CGM readings that are
part of a sharp, exponential decay from a rising or gently falling glucose
trajectory and the following exponential restoration. Method 3 removes
readings between sharp declines and two consecutive second derivatives.
We test the effectiveness of the mitigation against the base Kalman filter
algorithm applied to the original dataset and to a “fixed” version where the
PISAs (total of 282 CGM readings) were manually removed. The dataset
consists of 60 nights (~6000 readings at 5 min intervals) of outpatient CGM
data from pump shut-off studies. On the original and “fixed” datasets the
base algorithm suspended for 1020 and 920 readings, respectively, so there
were 100 readings or 500 min of undesired pump suspensions from PISAs.
When the three methods are run on the original dataset 3/15/25% of these
undesired pump suspensions were removed. These results show that the
874-P
Current Blood Glucose Meters Perform in Compliance With New
Draft ISO Guidelines
MARCUS BORCHERT, CARINA HENGESBACH, FILIZ DEMIRCIK, CHRISTINA
SCHIPPER, THOMAS FORST, ANDREAS PFÜTZNER, PETRA B. MUSHOLT, Mainz,
Germany
ISO15197 accuracy performance criteria have to be met by devices for
blood glucose measurement: 95 % of readings have to be within ±15 mg/dL
for values < 75 mg/dL, and within ±20 % for values ≥100 mg/dL. The currently
reviewed new draft ISO guideline suggests stricter accuracy acceptance
criteria (95 % of readings have to be within ±15 mg/dL for values < 100 mg/
dL, and within ±15 % for values ≥100 mg/dL). We studied the compliance
six blood glucose meters with the new guideline by performing a post-hoc
analysis of data obtained from an ISO-conform clinical accuracy performance
study. This study had been performed with 106 patients, clinically presenting
with blood glucose levels distributed over the entire measurement range
and in line with the glucose distribution requirements as demanded by the
ISO guideline. The YSI 2300 STAT Plus™ analyzer (glucose-oxidase) served as
reference method. All tested meters were in compliance with the current ISO
criteria. The following meters met the new criteria: Accu-Chek Aviva (95.6
%/99.1 %), BG*Star (99.3 %/97.5 %), iBG*Star (98.5 %/97.5 %), FreeStyle
Freedom Lite (95.6 %/96.5 %), and OneTouch Ultra2 (95.6 %/96.3 %). One
meter failed the low blood glucose range criteria (Contour: 90.4 %/97.5 %).
Almost all branded blood glucose meters, including BG*Star and iBG*Star
met the new draft ISO15197 acceptance criteria, when tested in accordance
ADA-Funded Research
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RALPH ZIEGLER, DAVID A. CAVAN, IAIN CRANSTON, KATHARINE BARNARD,
CHRISTOPHER G. PARKIN, WALTER KOEHLER, BETTINA PETERSEN, MATTHIAS
A. SCHWEITZER, ROBIN S. WAGNER, Muenster, Germany, Bournemouth, United
Kingdom, Portsmouth, United Kingdom, Southampton, United Kingdom, Boulder City,
NV, Mannheim, Germany, Indianapolis, IN
Clinical Diabetes/
Therapeutics
&
Comparative Accuracy Evaluation of Six Blood Glucose Monitoring
Systems (BGMSs)
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
application of a PISA detection algorithm would prevent unnecessary pump
suspensions when CGM signals are attenuated.
BG, number of BG >180 mg/dl, and with higher total insulin requirement (U/
day), all p<0.001 (Table). The number of hypoglycemic events (<70mg/dL)
were inversely related to the admission HbA1c level (p= 0.046). There were no
association between admission HbA1c and hospital complications.
In summary, this analysis indicates that the admission HbA1c value is a
useful marker in predicting inpatient glycemic control and hypoglycemic
events in non-ICU patients with T2D. Future randomized controlled studies
should take the admission HbA1c into consideration for selecting the
starting insulin dose in patients with T2D.
Supported by: JDRF (22-2011-647)
877-P
Use of an Automated Bolus Advisor Improves Glycemic Control
With Increased Treatment Satisfaction in Poorly Controlled Diabetes: Results from the Automated Bolus Advisor Control and Usability Study (ABACUS)
POSTERS
Clinical Diabetes/
Therapeutics
DAVID A. CAVAN, RALPH ZIEGLER, IAIN CRANSTON, KATHARINE BARNARD,
JACQUELINE RYDER, CLAUDIA VOGEL, CHRISTOPHER G. PARKIN, WALTER KOEHLER, BETTINA PETERSEN, MATTHIAS A. SCHWEITZER, ROBIN S. WAGNER,
Bournemouth, United Kingdom, Muenster, Germany, Portsmouth, United Kingdom,
Southampton, United Kingdom, Langen, Germany, Boulder City, NV, Mannheim,
Germany, Indianapolis, IN
A1C <7% A1C 7-9% A1C >9% p-value
Admission BG, mg/dl
156± 53 192± 63 280± 99 p<0.001
Mean daily BG,
148±35 161±29 183±36 p<0.001
mg/dl
BG >180 mg/dl during treatment, %
53%
70%
91% p<0.001
# units of insulin/day, U/day
26±13 33±15
38±16 p<0.001
# units of insulin/day, U/kg/day
0.3±0.1 0.3±0.2 0.4±0.2 p<0.001
Patients BG<70 mg/dl, n (%)
18 (18%) 16 (17%) 8 (8%) p=0.046
We conducted a study to assess the impact of using an insulin bolus
advisor on glycemic control in patients treated with multiple daily insulin
injection (MDI) therapy. The ABACUS trial, a large, 26-week, prospective,
randomized, controlled, multi-national study, enrolled 218 poorly controlled
MDI-treated patients with diabetes (202 type 1, 16 type 2), with mean (SD)
baseline A1C 8.9 (1.2)%, age 42.4 (14.0) years, BMI 26.5 (4.2) kg/m2 and 17.7
(11.1) years duration of diabetes. Patients randomized to the control group
(CNL) used a standard blood glucose meter and manual bolus calculation;
patients randomized to the intervention group (EXP) used the Accu-Chek
Expert meter with an automated bolus advisor to calculate insulin dosages.
Glucose data were downloaded and used for therapy parameter adjustments
in both groups. A total of 193 patients (CNL, n=93; EXP, n=100) completed
the study. Significantly more EXP than CNL patients achieved > 0.5% A1C
reduction: 56.0% vs. 34.4% (p < 0.01). (Figure) Improvement in treatment
satisfaction (DTSQ scale) was significantly greater in EXP patients: 11.4
(6.0) vs. 9.0 (6.3); p<0.01. Percentage of blood glucose values <50 mg/dL
/ 2.7 mmol/L was <2% in both groups during the study. Use of the AccuChek Expert meter resulted in improved glycemic control and treatment
satisfaction without increasing severe hypoglycemia.
879-P
The Association between Self-Monitoring Blood Glucose and Glycemic Control in Insulin Treated Patients With Type 2 Diabetes
MIYUKI FURUYA, YUKO HATAJI, HIROHITO KUWATA, YUSUKE ARAI, SATOSHI
MATSUNAGA, SHINTARO OKAMURA, TSUYOSHI MASHITANI, MASAKO KITATANI, SHIGEKI IKUSHIMA, YASUAKI HAYASHINO, SATORU TSUJII, HITOSHI
ISHII, TENRI COHORT STUDY GROUP, Tenri, Japan
The aim of this study is to investigate whether frequency and timing of
SMBG are related to glycemic control in insulin-treated patients with type
2 diabetes. We obtained data of 1496 patients [average age, 66.1 years;
42.0% of females] with insulin-treated type2 diabetes from a registry that
registered all outpatients with diabetes visiting the Diabetes Center at the
Tenri Hospital, Japan.The patients answered the questionnaires regarding
the frequency, number of measurements per day and the timing of SMBG.
We evaluated the association between the frequency and HbA1c values using
linear regression analyses. Furthermore, we proceeded to subgroup analysis
by the number of insulin injections (1, 2, 3, >or 4 daily injections or CSII). Next,
patients were categorized into two groups based on the timing of SMBG,
group A (n=1231): patients who perform only pre-prandial testing, group B
(n=263); patients who perform not only pre-prandial but also postprandial
testing at least once a week. We compared HbA1c value in both groups. On
average, patients performed 1.8 measurements of SMBG per day. Mean
HbA1c were 8.1, 8.2, 8.0, 7.7, 7.6 and 7.5% for groups of the frequency of
SMBG: none, rarely, once/day, twice/day, 3 times/day and 4 times or more/
day, respectively. Higher frequency of measurements was associated with
lower HbA1c levels (p<0.0001), and there were no changes in these findings
no matter what times patients shot insulin in the day. Mean HbA1c was 7.8%
in the group A and 7.8% in the group B (p=NS). There were no differences
between the groups in glycemic control by the timing of SMBG. The crosssectional survey showed higher frequency of SMBG testing was associated
with better glycemic control regardless of the number of insulin injections
in patients with type 2 diabetes. Meanwhile we did not observe significant
association between the timing of SMBG and glycemic control.
880-P
Supported by: Roche Diagnostics GmbH
Laboratory Study for Evaluation of the Influence of Temperature
and Humidity on Blood Glucose Measurements With BGStar and
iBGStar
878-P
Value of Admission Hemoglobin A1c (HbA1c) in Predicting Inpatient
Glycemic Control and Clinical Outcome in Non-ICU Patients With
Type 2 Diabetes
PETRA B. MUSHOLT, CARINA HENGESBACH, FILIZ DEMIRCIK, CHRISTINA
SCHIPPER, THOMAS FORST, ANDREAS PFÜTZNER, Mainz, Germany
Dynamic electrochemistry performs multiple measurements under different
electrochemical conditions for one reading. It applies a mathematical
algorithm for correction of confounding factors, based on the different kinetics
involved in the signal generation of confounding factors. This laboratory
study investigated the impact of temperature and humidity on blood glucose
meters employing dynamic electrochemistry (BGStar and iBGStar, Sanofi)
in comparison to 3 competitive blood glucose meters (Contour, Bayer; One
Touch Ultra 2 and OneTouch Verio Pro, Lifescan). Ten meters and 3 strip lots
per type were conditioned to the selected temperature (12°, 25°, 38°) and
humidity (<25 %, 50-60 %, 80-90 %) in an approved Climate Cabinet for 1 h
prior to the performance of the measurements. Heparinized blood samples
were manipulated to contain 3 different levels of blood glucose (60-90 mg/dL,
150-200 mg/dL, 250-350 mg/dL). Normal oxygen pressure was confirmed and
glucose was tested with the reference method (YSI Stat 2300). Samples were
FRANCISCO PASQUEL, SAIRA ADEEL, FARNOOSH FARROKHI, ISABEL ANZOLA,
LIMIN PENG, DAWN SMILEY, GUILLERMO E. UMPIERREZ, Atlanta, GA
Clinical guidelines recommend measuring HbA1c on admission to assist
tailoring insulin therapy in the hospital and after discharge in non-ICU patients
with T2D; however, the predictive value of admission HbA1c on inpatient
glycemic control and outcomes has not been determined. Accordingly, we
analyzed medical records of 296 general medicine and surgery patients (age:
58±12 yrs, admission BG: 212±92 mg/dl, HbA1c: 8.6±2.5%) treated with basal
bolus regimen starting at 0.4 U/kg/day if BG was between 140-200 mg/dl
and 0.5 U/kg/day if BG was between 200-400 mg/dl, given half as glargine
once daily and half as glulisine before meals. Patients were divided into
three groups according to HbA1c value: <7% (n=99), 7-9% (n=92), and >9%
(n=105). Higher HbA1c directly correlated with admission BG, hospital daily
&
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mean interstitial glucose (MG) and glucose variability (GV) in the risk of
hypoglycemia in patients with type 1 diabetes (T1D). Continuous glucose
monitoring using CGMS® system, was performed in 130 T1D patients, with
diabetes duration of 17,1±8,6 years, in intensive insulin therapy (49.8±17.9
UI per day). MG (in mg/dL), GV (SD of MG, in mg/dL), time per day spent
in hypoglycemia (HT), interstitial glucose ≤70mg/dl, in hours, and episodes
of nocturnal hypoglycemia (NH), hypoglycemia between midnight and 8
a.m., in %, were assessed. Patients were divided in group I (n = 84) with
HbA1C≤7,5% and group II (n = 46) with HbA1C>7,5%. Statistical analysis
was performed using SPSS, version 21.0. Group I presented a significantly
lower MG (139.2±25.9 vs173.1±33.2mg/dL, p<0,05) and GV (58.4±18.8
vs. 70.3±18.6mg/dL, p<0,05) and more HT (1,85±1.68 vs. 1,30±1.04 hours
p<0,05). NH episodes weren’t significantly different between groups (8.7 vs.
5.8%). HT was positively correlated with GV (r=0.23, p=0.01) and negatively
with HbA1C and MG (r=-0.23 and r=-0.36; p=0.01). NH was correlated with
MG (r= - 0.24, p<0.05). In multivariate analysis, GV and MG were associated
with TH (β= 0.22 and β= -0.15, p < 0.01, respectively), independent of
HbA1c, diabetes duration and insulin dose; NH was only associated with
MG (OR=0.9, p< 0.05). NH was associated with 16-fold increased risk of
asymptomatic hypoglycemia (OR:16.9; p<0.01). In conclusion, patients
with high HbA1C still remain at risk of hypoglycemia. Glucose variability
independently predicts daily time duration spent in hypoglycemia. At night,
hypoglycemia only correlates with MG, suggesting daily fluctuations are
probably due to inadequate insulin coverage of the meals. Higher MG during
night can eventually reduce risk of asymptomatic hypoglycemia.
Supported by: Sanofi
881-P
Prediction of Plasma Glucose via Exhaled Breath Analysis in Obesity and Type 2 Diabetes
STACY R. OLIVER, HEATHER SOPHER, MATTHEW K. CARLSON, SIMONE MEINARDI, DONALD R. BLAKE, PIETRO R. GALASSETTI, Irvine, CA
The life-threatening cardiovascular complications of obesity (OW)
and type 2 diabetes (T2D) are linked to glycemic control, currently based
on invasive, blood-based testing of plasma glucose. Breath analysis is
increasingly considered an alternative, non-invasive, painless methodology
for glycemic testing, able to improve patients’ compliance/ metabolic
control. Its practical therapeutic applications, though, remain limited.
We hypothesized that accurate breath-based glucose predictions can be
obtained with gas clusters specific for each patient group.
We studied 17 T2D (10M) and 12 OW (6M) subjects over 4 h in basal,
hyperglycemic (220 mg/dL) and euglycemic-hyperinsulinemic conditions.
At 12 time points ~100 volatile organic compounds (VOC) were quantified
by gas chromatography on room and breath samples, and matched with
plasma glucose. Gas-based glycemic predictions were generated by least
squares regression on several VOC clusters. The strongest correlations
between measured and predicted glucose values were seen using acetone,
butanone, EtONO2, 2- and 3-PeONO2, and 2-BuONO2 in OW (r = 0.88, range
0.66-0.97), and acetone, MeONO2, methanol, propane, 2-PeONO2, and
ethanol, in T2D (r = 0.902, range 0.73-0.99).
Our data show how accuracy of breath-based metabolic tests increases
by tailoring gas profiles to specific dysmetabolic conditions, and confirm the
growing potential of breath analysis for non-invasive diagnosis/metabolic
monitoring in diabetes.
883-P
Safety and Accuracy Evaluation of San MediTech’s Real-Time Continuous Glucose Monitoring (RT-CGM) Device
HUASHI ZHANG, DAN WANG, WENBEI CHEN, JING WU, IRVINE, CA
To evaluate the safety and accuracy of the San MediTech’s Real-Time
CGM device with the comparison of the capillary and the venous blood
glucose reference values, respectively.Twenty Subjects (4 Type I and 16
Type II diabetes mellitus) were enrolled with Beijing Jian Heng Diabetes
Hospital from June, 2012 to October, 2012.Each patient wore two SMT’s
RT-CGM devices. Each day 7 capillary glucose values were measured with
the glucose meter (Bayer Breeze2, Germany) On Day 3 and Day 5, eight
venous blood glucose references were measured for each subjects once
every 30 min during a 4hr period. The total numbers of the capillary and the
venous blood glucose reference values used for the accuracy study are 1118
pairs (<4.4mmol/L:4.2%;4.4-13.3mmol/L:65.3%; > 13.3mmol/L:30.5%) and
495 pairs (< 4.4mmol/L:4.8%;4.4-13.3mmol/L:56.6%;> 13.3mmol/L:38.6%),
respectively.All the subjects finished and no safety adverse event was
observed. The MARD (mean absolute relative difference) values of SMT’s
RT-CGM device compared with the capillary and venous references values
are 16.8% and 15.9%, respectively. The Clarke error grid analysis plot of
the SMT’s RT-CGM values VS the capillary blood glucose references is
shown in Figure 1.The combined A zone and B zone percentage is 96.8%.
More importantly, for the hypo glycemic range (1.7-4.4 mmol/L, n=47 pairs),
the SMT’s RT-CGM device has the MARD as 26.4% and the combined A+B
percentage as 76.6%.
Supported by: NIH (1UL1RR031985), (K24DK085223)
882-P
HbA1C, Glucose Variability and Hypoglycemia Risk in Patients With
Type 1 Diabetes Mellitus
DANIELA F. GUELHO, LUÍSA BARROS, CARLA BAPTISTA, ISABEL PAIVA, SOFIA
GOUVEIA, JOANA SARAIVA, CAROLINA MORENO, LUÍSA RUAS, MANUELA
CARVALHEIRO, FRANCISCO CARRILHO, Coimbra, Portugal
Supported by: America-Asia Diabetes Research Foundation
Many diabetic patients experience high variability in glucose
concentrations which is associated with a risk of hypoglycemia. The aim of
this study was to compare the predictive value of hemoglobin A1C (HbA1C),
ADA-Funded Research
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briefly equilibrated to the cabinet conditions and measured within the cabinet
(via small door inlets). Mean values and standard deviations for each meter
type/sample combination were calculated, and the mean absolute relative
deviation (MARD) and precision were determined. MARD was found to be
5.3±2.7 % for BGStar and 6.5 ± 4.0 % for iBGStar (Contour: 5.3±0.8 %, Ultra2:
8.6±0.3 %, Verio Pro: 4.0±0.1 %). Deviations were slightly higher under dry
condition and at cold temperature. Cold temperature also led to more frequent
devices errors. Mean precision was 3.4±1.9 % for BGStar and 3.7±1.6 % for
iBGStar (Contour: 3.1±0.1 %, Ultra2: 3.3±1.2 %, Verio Pro: 2.9±0.2 %). With
a general imprecision of 3-4 CV% and an inaccuracy well below 10 DEV%,
iBGStar and BGStar performed in line with current standards of patient self
blood glucose monitoring. Generally, measurements should not be performed
at cold ambient temperature conditions.
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
POSTERS
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
884-P
886-P
Glycemic Variability Is Associated With Subclinical Atherosclerosis in Chinese Type 2 Diabetic Patients
Differences between Continuous Glucose Monitoring (CGM) Systems may Influence Frequency of CGM Usage
JIAN ZHOU, YIFEI MO, MEI LI, YUQIAN BAO, XIAOJING MA, DI LI, WEI LU,
CHENG HU, WEIPING JIA, Shanghai, China
JAMES CHAMBERLAIN, DANA DOPITA, EMILY GILGEN, Salt Lake City, UT
Realization of the clinical benefits of continuous glucose monitoring (CGM)
in diabetes management is dependent upon the frequency at which patients
use their CGM devices. To determine whether frequency of sensor use is
related to CGM technology, in general, or differences between available
CGM systems, we surveyed 81 type 1 adult diabetes patients with at least
one year of CGM experience. The 8-item survey was offered to patients on
an “as seen” basis; all patients completed the survey; 43 patients (all on
insulin pumps) used the Medtronic MiniLink REAL-Time CGM (ML) and 38
patients (25 on insulin pumps) used the Dexcom SEVEN PLUS (SP) device.
Results showed that 19% of ML users wore their CGM device “almost daily”
compared with 76% of SP patients; 65% if ML users wore their device ≤
1 week per month compared with 3% of SP users. (Table) Most “almost
daily” ML users reported “improved bG” as their main reason for frequent
use. The most common reason for frequent SP users was “liked knowing
bG values at all times”. Thirty-one percent of ML users reported ‘CGM did
not seem accurate” as the main reason for less frequent use. Reasons for
infrequent use among SP patients showed no pattern. More than 92%
(n=35) of SP patients reported they would purchase the same CGM system
again compared with 44% (n=19) of ML patients. Differences in perceptions
of performance and usability may strongly influence frequency of CGM use,
which can impact clinical outcomes.
The contribution of glycemic variability to macrovascular complications
remains unclear. We therefore investigated the association between
glycemic variability and cervical and/or intracranial atherosclerosis in
Chinese type 2 diabetic patients.
We conducted a cross-sectional study in 216 type 2 diabetic patients
with a hemoglobin A1c of 8.3 ± 1.7% and a median diabetes duration of 9.0
years. The standard deviation of blood glucose values (SDBG) and the mean
amplitude of glycemic excursion (MAGE) were calculated from continuous
glucose monitoring system data for assessing glycemic variability while
24h mean blood glucose (MBG) was calculated for measuring overall
blood glucose level. Magnetic resonance angiography (MRA) was used to
detect cervical and/or intracranial plaque, and ultrasonography was used
to quantify carotid intima-media thickness (IMT) as an index of subclinical
atherosclerosis.
One hundred and fifty-three patients (70.8%) presented with cervical
and/or intracranial lesions on MRA among 216 patients in the study. Elder
age, increased systolic blood pressure, increased MBG and elevated low
density lipoprotein cholesterol were independent contributors to plaque
formation. In patients without stenosis (n = 63), SDBG (r = 0.412, P = 0.001)
and MAGE (r = 0.365, P = 0.005) were both correlated with carotid IMT
and these relationships remained significant in multiple linear regression
analysis (multiple R2 = 0.314 for the model including SDBG and multiple R2 =
0.268 for the model including MAGE). However, SDBG and MAGE were not
significantly different among patients with different stenosis degrees.
Taken together, our study suggests that glycemic variability is associated
with subclinicalatherosclerosis in Chinese type 2 diabetic patients.
885-P
Use of an Automated Bolus Advisor Is Associated With Improved
Competence in Carbohydrate Counting in Patients Treated With
Multiple Daily Insulin Injections (MDI): Results from the Automated
Bolus Advisor Control and Usability Study (ABACUS)
DAVID A. CAVAN, IAIN CRANSTON, RALPH ZIEGLER, KATHARINE BARNARD,
JACQUELINE RYDER, CLAUDIA VOGEL, CHRISTOPHER G. PARKIN, WALTER KOEHLER, BETTINA PETERSEN, MATTHIAS A. SCHWEITZER, ROBIN S. WAGNER,
Bournemouth, United Kingdom, Portsmouth, United Kingdom, Muenster, Germany,
Southampton, United Kingdom, Langen, Germany, Boulder City, NV, Mannheim,
Germany, Indianapolis, IN
887-P
24-Hour Glucose Spectra Evaluation of Continuous Ambulatory
Peritoneal Dialysis Patients
QIN TAN, JIANBIN LIU, JUAN LIU, YANBING LI, Guangzhou, China
We assessed the carbohydrate (CHO) counting competency of 218 patients,
treated with multiple daily insulin injection (MDI) therapy, who participated
in the Automated Bolus Advisor Control and Usability Study (ABACUS), a
large, 26-week, multi-national, prospective, randomized, controlled trial
that evaluated the use of an automated bolus advisor in poorly controlled
MDI-treated type 1 diabetes and type 2 diabetes patients with baseline
A1C 8.9 (1.2)%. At entry, patients were asked to assess the carbohydrate
content (grams) of 10 standardized meals (using life-size photographs),
from which the mean meal error (MME), an indicator of accuracy, and mean
meal absolute error (MMAE), an indicator of variability were calculated.
All patients then received refresher training and carbohydrate reference
materials prior to randomization. Patients randomized to the control group
(CNL) used a standard blood glucose meter and calculated bolus insulin
dosages manually; patients randomized to the intervention group (EXP) used
the Accu-Chek Expert meter with an automated bolus advisor to calculate
insulin dosages. Patients were followed for six months, with regular
reviews by their healthcare team. The carbohydrate counting assessment
was repeated at the end of the study and showed significant improvement
in MMAE (15.2 [9.0] grams to 12.4 [7.3] grams, p < 0.01) and a trend towards
improvement in MME (1.0 [10.1] grams to 0.3 [7.1] grams, p = NS) in the EXP
group but no change in CNL patients. This suggests that use of a bolus
advisor may improve competency in carbohydrate counting by providing
frequent feedback on patient accuracy in estimating the carbohydrate
intake. Thus, automated bolus advisors may serve as educational tools that
can improve the effectiveness of diabetes self-management in patients
treated with MDI.
Glucose-based peritoneal dialysis(PD) solution is commonly used in
patients with diabetes undergoing continuous ambulatory peritoneal
dialysis (CAPD), but how it affects glucose fluctuation during PD remains
unknown. The aim of our study was to investigate 24-hour blood glucose
profile and fluctuation following peritoneal exchange (PE) in patients
undergoing CAPD with glucose-based PD solution evaluated by CGMS.
Forty-two patients receiving CAPD were enrolled, of whom 22 subjects with
diabetic nephropathy (DN group) and 20 were free of diabetes (NDN group).
Data of 30 healthy volunteers (control group) was also analyzed. Compared
to control group, patients in DN group presented higher blood glucose value
and blood glucose fluctuations value (all p<0.05). Patients in DN group also
presented similar changes as well as the increment following PEcompared
with NDN group (all p<0.05). However, there were no significant difference
of these CGMS parameters between NDN group and control group (P>0.05).
(Fig.1) For the NDN group, the increment following PE was higher with the
use of 2.5%peritoneal solution than 1.5% peritoneal solution (2.13±2.02 vs
2.76±1.51, P=0.005).But there was no significant difference of the impact on
blood glucose level with the use of 1.5% or 2.5% peritoneal solution in the
DN group(all p>0.05). CAPD with glucose-based PD solution may impose
disturbance to glucose homeostasis in patients with ERD, with a more
significant impact in those with DN.
Supported by: Roche Diagnostics GmbH
&
For author disclosure information, see page 829.
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
of 2.8 times per day; however, daily frequency of advice sought decreased
significantly (-0.2/day, p < 0.01) during the course of the study. Older patients
tended to use the bolus advisor more often than younger patients: 2.9 vs.
2.3, p < 0.05. There was no difference in bolus advice use between patients
who achieved > 0.5% A1C reductions (n= 56) vs. those who achieved ≤ 0.5%
A1C reduction (n=44). However, patients with baseline A1C 7.5-9.0% used
the bolus advisor more often throughout the study than patients with higher
glycemic levels (A1C > 9.0%): 3.1/day vs. 2.2/day, (p < 0.01) The number of
times patients accepted the bolus advice sought was similar between age
groups, with 2.5/day for all patients. When modifications to bolus advice
were made, patients were nearly twice as likely to reduce insulin (0.2/day)
vs. increasing insulin (0.1/day), with no difference between the age groups.
These results demonstrate that patients frequently sought bolus advice.
Further, improvements in A1C were seen despite the small decrease in use
over time, suggesting that patients placed a high level of trust in their bolus
advisor, learned from experience about their insulin-to-meal response and,
thus, required slightly less frequent bolus advice over time.
888-P
Pilot Study to Assess the Efficacy of a Continuous Glucose MonitorBased Semi-Automated Basal Assessment Management Protocol
ROGER MAZZE, ELLIE STROCK, MATTHEW MURPHY, RICHARD M. BERGENSTAL, Minneapolis, MN
ANDREJ ORSZAG, LEIF E. LOVBLOM, HOLLY TSCHIRHART, PETER PICTON, JOSEPH A. CAFAZZO, BRUCE A. PERKINS, Toronto, ON, Canada
Few studies use a systematic, evidence-based approach to decisionmaking when comparing SMBG or CGM guided decisions with routine care.
We undertook a randomized controlled 36-week study in which patients
with type 2 diabetes were assigned to routine care (Controls) or care guided
by Staged Diabetes Management (SDM) clinical pathways employing
scheduled episodic testing (SMBG) or continuous monitoring (CGM).
All subjects wore blinded CGM to produce AGPs which include glucose
exposure, variability, stability, and percent hypoglycemia. Sixty patients
were enrolled. There was a 1:2 F:M ratio, with average age 60+/-8.6 years
and duration 15+/-7 years. There was a significant (p<0.0001) improvement
in HbA1c from baseline to end of study for the SMBG (N=18) (8.2 to 7.1%) and
CGM (N=24) (8.4 to 7.4%) groups and no significant change for the controls
(N=18) (8.0 to 7.7%). Forty-seven patients had sufficient blinded CGM data
to produce glucose profiles. Shown in Figure 1 is the change in glucose
exposure (SMBG or CGM p<0.004, Controls NS) for the three groups. The
CGM group experienced a significant reduction in hypoglycemia (p<0.05)
while the other groups did not. Change in glucose variability was not
significant, while change in stability was (p<0.02) for SMBG and CGM.
There is an urgent need for clinical protocols to guide adjustment of
overnight basal rates in current clinical practice. We aimed to evaluate
a continuous glucose monitoring (CGM)-based semi-automated basal
assessment algorithm on overnight glycemic stability, overnight hypoglycemia incidence and glycemic control.
We developed and piloted an algorithm that interpreted CGM data from
overnight fasting protocols and recommended basal rate changes based on
glucose excursions. Subjects uploaded data online using sensor-augmented
insulin pumps (Medtronic 754 pumps and Carelink Personal, Medtronic Inc.)
for evaluation by the algorithm after each of 5 overnight fasts conducted
over 4-10 weeks. The algorithm was designed to be conservative and
iterative: it made hourly basal rate changes that did not exceed 10% at each
iteration. The Standard Deviation of CGM values from midnight to 7 am
(SD12-7am) over 3 baseline and follow-up nights, hypoglycemia incidence
(defined by CGM values <4.0 mmol/L) and A1c were compared by paired
sign-rank tests.
Twenty subjects (male/female 7/13) with mean age 38±13y and A1c
7.6±0.8 percent underwent the 5 iterations of basal assessments over 7±3
weeks. SD12-7am did not change from baseline to follow-up (1.57±0.8 and
1.63±0.8 mmol/l, p=0.35). Qualitatively, however, mean glucose values
were lower between 2 to 3 am at baseline compared to follow-up and
3-night hypoglycemia incidence declined from 1.6±1.8 to 0.5±0.7 episodes
(p=0.01). Despite attenuation of overnight declines in mean blood glucose
and a decrease in hypoglycemia incidence, the A1c improved from 7.6±0.8
to 7.4±0.9 (p=0.03).
Despite not demonstrating improvements in the overnight measures
of glycemic variability, we observed significant decline in hypoglycemia
incidence and short-term improvement in A1c. Future research must focus
on clinical applicability of CGM-based basal adjustment algorithms.
889-P
Usage of a Bolus Advisor: Results from the Automated Bolus Advisor Control and Usability Study (ABACUS)
RALPH ZIEGLER, DAVID A. CAVAN, IAIN CRANSTON, KATHARINE BARNARD,
CHRISTOPHER G. PARKIN, IRIS VESPER, MATTHIAS A. SCHWEITZER, ROBIN S.
WAGNER, Muenster, Germany, Bournemouth, United Kingdom, Portsmouth, United
Kingdom, Southampton, United Kingdom, Boulder City, NV, Mannheim, Germany,
Indianapolis, IN
The use of SDM to guide clinical decision-making based on SMBG or
CGM produced significant improvement in glycemic control assessed by
AGP when compared to routine care.
Adjusting insulin doses according to blood glucose and carbohydrate intake
is challenging for most diabetic patients on multiple daily insulin injection
(MDI) therapy. We examined usage of the Accu-Chek Expert meter with an
automated bolus advisor in patients enrolled in the Automated Bolus Advisor
Control and Usability Study (ABACUS), a 26-week, prospective, randomized,
multi-national study. Data from 105 poorly controlled diabetic patients (98
type 1, 7 type 2), with mean (SD) baseline A1C 8.9 (1.1)%, age 42.7 (13.5) years
were analyzed. Patients used their bolus advisor for 73.5% of all possible
bolus opportunities. No differences in age, gender or type of diabetes were
seen. At the beginning of the study, patients sought bolus advice an average
ADA-Funded Research
&
891-P
Performance Evaluation of a Continuous Glucose Monitoring System Under Conditions Similar to Daily Life
STEFAN PLEUS, CORNELIA HAUG, MANUELA LINK, EVA ZSCHORNACK, GUIDO
FRECKMANN, Ulm, Germany
This study aimed at evaluating the new generation of a continuous
glucose monitoring (CGM) system under daily life-like conditions.
The DexCom™ G4 CGM system was used with two sensors in parallel by
10 type 1 diabetes subjects for the whole sensor lifetime (approx. 7 days).
For author disclosure information, see page 829.
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A225
POSTERS
890-P
Randomized, Controlled 36 Week Study of Clinical Decision-Making Employing SMBG and CGM With Analysis by Ambulatory Glucose Profile (AGP)
Clinical Diabetes/
Therapeutics
Supported by: Roche Diagnostics GmbH
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
diabetes types and ages (currently over 18 years). At the beginning of the
trial, each subject was calibrated. The measurements taken throughout the
trial were based on this calibration. Subjects participated in the trials for
up to 6 months, in order to verify the calibration validity period (6 months).
Moreover, feedback regarding device usability and user satisfaction was
analyzed.
Clarke Error Grid pulled data analysis of 89 subjects (5050 points) over 6
months of operation shows 96% of the points in the clinically accepted A+B
zones and ARDmean of 32%. No degradation in performance was noticed as
a function of time elapsed from calibration. Feedback shows that 96% of
the subjects found the device comfortable; 75% found the device easy to
operate, 85% expressed willingness to use the device regularly and 80%
declared they will use the device more frequently than the invasive one.
GlucoTrack is technically available to use. Its key benefits include 6
months of operation without re-calibration and ability to perform numerous
spot measurements with acceptable accuracy. Furthermore, it provides
pain-free and inexpensive use, without the need to be continuously worn.
These advantages can lead to better blood glucose monitoring adherence
and tighter glucose control.
Supported by: Roche Diagnostics GmbH
POSTERS
Clinical Diabetes/
Therapeutics
The sensors were applied during study day 1 and removed during study
day 8. Performance was assessed by calculation of mean absolute relative
deviation (MARD) between CGM readings and paired capillary blood glucose
(BG) readings (approx. 15 duplicate measurements per day and per subject)
and precision absolute relative deviation (PARD), i.e. differences between
the paired CGM readings of the first and the second sensor worn by each
subject. Additionally, MARD was separately calculated for BG readings
below 70 mg/dL, between 70 and 180 mg/dL and above 180 mg/dL.
Total MARD of the sensors used in this study was 10.4%. The MARD
for BG below 70 mg/dL was 13.6% (8.3% of BG readings), when BG was
between 70 and 180 mg/dL 10.8% (69.5% of BG readings) and for BG above
180 mg/dL 8.0% (22.2% of BG readings). PARD was 7.3% for the complete
experiments (n=10), improving from 12.9% and 9.2% on days 1 and 2,
respectively, to 5.3% and 5.9% on days 7 and 8, respectively.
In this study, the evaluated CGM system showed good overall MARD
compared to results reported for other commercially available CGM systems.
In the hypoglycemic range, where CGM performance is often reported to be
low, the CGM system achieved comparably good MARD. Overall PARD was
7.3% with a marked improvement during the course of the study from mean
PARD 12.9% on day 1 to mean PARD 5.9% on day 8.
894-P
Poorly Controlled Patients on Multiple Daily Insulin Injections
(MDI) Often Improperly Use Insulin Therapy Parameters for Manual Bolus Calculations: Results from the Automated Bolus Advisor
Control and Usability Study (ABACUS)
892-P
WITHDRAWN
ROBIN S. WAGNER, RALPH ZIEGLER, DAVID A. CAVAN, IAIN CRANSTON, KATHARINE BARNARD, CHRISTOPHER PARKIN, WALTER KOEHLER, IRIS VESPER,
MATTHIAS A. SCHWEITZER, Indianapolis, IN, Muenster, Germany, Bournemouth,
United Kingdom, Portsmouth, United Kingdom, Southampton, United Kingdom,
Boulder City, NV, Mannheim, Germany
Diabetes patients on MDI therapy utilize insulin to carbohydrate ratios
(I:CHO), insulin sensitivity factors (ISF), target range and blood glucose
(bG) values to determine appropriate insulin doses. Clinicians use resultant
insulin doses and bG values to adjust I:CHO and ISF. We examined use of
I:CHO and ISF by control (CNL) patients enrolled in the ABACUS trial, a 26week, prospective, randomized, controlled, multi-national trial. Patients
randomized to the CNL group used a standard blood glucose meter
and calculated bolus insulin dosages manually; patients randomized to
intervention group (EXP) used the Accu-Chek Expert meter with a bolus
advisor to calculate insulin dosages. Diary data from 96 CNL patients (87
type 1, 9 type 2) with baseline A1C 8.8 (1.2)% were analyzed. Patientrecorded bolus calculations were checked to determine if the stated I:CHO
and ISF rules were used in a mathematically correct manner for each
bolus calculation. Patients calculated an average of 4.0 (1.0) boluses per
day with no change in frequency during the study. Patients correctly used
their I:CHO and ISF rules 1.4 (1.1) and 0.8 (0.7) times per day, respectively.
Patients incorrectly used I:CHO and ISF rules 1.7 (0.9) and 2.3 (1.0) times
per day, respectively. There was no change in correct or incorrect usage
of either parameter during the study; only 34.4% (n=32) achieved the
study goal of >0.5% reduction in A1C. The results demonstrate that
these MDI patients did not use their parameters correctly for most
bolus dose calculations. This may be due to mathematical errors and/
or a lack of trust in their parameters; in which case, patients may have
found unknown “compensatory mechanisms”. Although this may explain
improvements in those who achieved the A1C goal, this behavior could
have a negative impact on therapy adjustment if clinicians are unaware
of these discrepancies.
Supported by: Roche Diagnostics GmbH
895-P
893-P
Presenting a Truly Non-Invasive Glucose Monitor for Home Use
Sample Handling Is of Critical Importance for Successful Performance of Laboratory Investigations With Blood Glucose Meters
Employing Dynamic Electrochemistry
AVNER GAL, ILANA HARMAN-BOEHM, EUGENE NAIDIS, YULIA MAYZEL, NETA
GOLDSTEIN, KEREN HORMAN, Ashkelon, Israel, Beer Sheva, Israel
GlucoTrack® is a Non-Invasive device for self-monitoring of blood glucose
at home, or home-alike environment, combining 3 technologies: Ultrasonic,
Electromagnetic and Thermal. The device comprises user friendly Main
Unit (MU) and sensors per each technology, located at a Personal Ear Clip
(PEC). The PEC is clipped externally to the earlobe for less than a minute, to
conduct a real-time spot measurement, after individual calibration. Glucose
readings are heard and displayed on the smartphone sized MU with a color
touch screen, designed for diabetics needs. The PEC must be replaced every
6 months, to be followed by a calibration.
GlucoTrack performances were evaluated in various clinical trials
simulating home-alike environment, for subjects of diverse genders, BMI,
SANJA RAMLJAK, DAVID C. KLONOFF, PETRA B. MUSHOLT, ELLEN AMBERS,
THOMAS FORST, FILIZ DEMIRCIK, ANDREAS PFÜTZNER, Mainz, Germany, San
Mateo, CA, San Jose, CA
Laboratory proficiency testing is a frequent procedure in many hospitals
prior to introduction of new blood glucose meters for in-house use and
recommendation to patients. Glucose meters optimized for patient use
may fail when tested with laboratory procedures previously used with
older meter technologies. Meters employing dynamic electrochemistry (DE)
appear to be sensitive to laboratory errors. This study tested the impact
of sample handling by experienced and inexperienced personnel on the
results of an accuracy and hematocrit (HCT) interference test performed
&
For author disclosure information, see page 829.
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with iBGStar vs. YSI Stat 2300. Venous heparinized whole blood was
immediately aliquoted after draw, and manipulated to contain 3 different
blood glucose concentrations (50-80 mg/dL, 120-180 mg/dL, and 250-330
mg/dL) and 3 different HCT levels (30 %, 45 %, and 60 %). Each sample
was tested 4 times with 4 devices. Mean absolute relative deviation
(MARD) was calculated for all samples. Sample preparation was done
independently under observation by three groups: a team very experienced
with DE laboratory testing (A), a group experienced with other meters but
not DE (B), and a team entirely inexperienced with meter testing (C). Team
A ensured physiological pO2 and gentle sample preparation. Team B did not
consider pO2 and used laboratory equipment for effective mixing. Team C
did everything manually, but also ignored pO2. MARD was 4.3 % with team
A, 9.2 % with team B and 5.2 % with team C. Team B had much higher
readings in particular at low glucose levels and team C produced 100% of
“sample composition” errors with high HCT levels. Laboratory proficiency
testing of DE devices should only be performed by trained and experienced
experts taking into consideration that the sample handling in the laboratory
had a major impact on the accuracy results. Normal hospitals should rather
evaluate modern devices like iBGStar with patients and in accordance with
the instructions for use.
Methods: Pooled, retrospective, descriptive analysis of 160 eligible CGM
profiles from T2DM patients with drug treatment over ≥6 months recorded
in RCTs in our center (GLA=78; M=82). CGM (Medtronic) was performed
for 72h to measure interstitial glucose (iG). AUC-24h, standard deviation of
mean iG (SD-iG), mean average glucose excursions (MAGE), and day-to-day
variation of glucose lowering effect between day 2 and 3 of CGM were
calculated as difference for each couple (day 2 and 3) every 5 minutes of
glucose profile. Threshold for HE was <3.0 mmol/L iG.
Results: Characteristics of patients for GLA and M treatment were: age
64.0/64.0yrs; BMI: 29.7/30.0 kg/m²; diabetes duration: 4.9/4.7 yrs; A1C:
6.1/6.4%. CGM results: mean iG at day 2: 6.8/7.0 mmol/L (ns); fasting iG:
6.0/6.8mmol/L (p=0.002) AUC-24h: 1936/2005 mmol/L/24h (ns); SD-iG:
1.66/1.40 mmol/L (ns); MAGE: 4.3/3.7 mmol/L (ns). No difference in dayto-day variability was found between groups (mean difference iG: 0.03/0.03 mmol/L (ns) with coefficient of variation: 73.5/75.0 %, ns). Overall HE
duration was similar with GLA and M (18.5/10.1 min/24h, ns).
Conclusion: Pooled CGM data from early stage T2DM showed no
significant difference in glycaemic variability and hypoglycaemia risk with
insulin glargine compared to metformin therapy even at A1C control <6.5%.
Comparison of Inpatient Glycemic Control by Continuous Glucose
Monitoring (CGM) and Capillary Point-Of-Care (POC) Testing in
General Medicine Patients With Type 2 Diabetes Treated With
Basal Bolus Insulin Regimen
Interest of Continuous Glucose Monitoring to Improve Glycemic
Control in Patients With Type 2 Diabetes and End-Stage Renal Disease Treated by Basal-Bolus Insulin Regimen
LORI KÉPÉNÉKIAN, AGNIESZKA SMAGALA, LAURENT MEYER, OLIVIER IMHOFF,
AICHA SISSOKO, LIVIU SERB, THIERRY KRUMMEL, FRANÇOIS DOREY, DOMINIQUE FLEURY, JEAN-PIERRE LE FLOCH, FRANÇOIS CHANTREL, LAURENCE KESSLER, Strasbourg, France, Colmar, France, Mulhouse, France, Valenciennes, France,
Villecresnes, France
ANA M. GOMEZ, GUILLERMO E. UMPIERREZ, PABLO ASCHNER, FELIPE HERRERA, CLAUDIA P. RUBIO, OSCAR MUÑOZ, Bogotá, Colombia, Atlanta, GA
Point-of care testing with capillary glucose finger-stick tests is the
universally accepted method of glucose monitoring in the hospital. No
previous studies have compared the efficacy of CGM in the management
of hyperglycemia in general medicine patients with T2D. Accordingly,
this prospective randomized study compared glycemic control by CGM
(Sofsensor iPro 2, Medtronic) to bedside POC testing in non-ICU patients
treated with basal bolus regimen for ≥ 3 days. Both patients and hospital
staff were blinded to the CGM data. POC testing measurements were
performed before meals, 2-h after meals, at bedtime and 3 AM. The primary
outcomes were differences in daily BG, and number of hypoglycemia (<70
mg/dl) and hyperglycemia (>180 mg/dl) events between groups.
A total of 40 insulin-naïve patients (age: 65.8±8 yr, DM duration 14.7±9 yr,
admission BG: 251±9 mg/dl, A1C: 9.7±2.4%, ±SD) were treated with glargine
and glulisine at a starting total dose of 0.4 U/kg/day if BG was between
140-200 mg/dl and 0.5 U/kg/day if BG was between 200-400 mg/dl, given
half as glargine once daily and half as glulisine before meals. We observed
no difference in daily BG after the 1st day of treatment by CGM and POC
testing (176.2±33.9 vs. 176.6±33.7 mg/dl, p=0.828). There were 10 patients
with BG<70 mg/dl recognized by both methods, but CGM detected higher of
number of events (55 vs. 12, p=0.0001) than POC testing, with 40% occurring
between breakfast and dinner and 60% between dinner and 6 A.M. A total
of 26.3% of hypoglycemia were asymptomatic and most (86.7%) were only
identified by CGM. The proportion of BG >180 mg/dl was 36.8% by CGM and
42.1% by POC, p=0.828.
In summary, the use of CGM recognized increased number of hypoglycemic
events compared to POC testing. Our study indicates potential benefit of
using real-time CGM in the hospital to detect hypoglycemia in a more timely
fashion compared to POC testing.
Patients with type 2 diabetes and end-stage renal disease (ESRD) are
at high cardiovascular risk. Optimal glucose level control is determinant to
reduce morbi-mortality but is difficult to obtain because of haemodialysis
session. The continuous glucose monitoring (CGM) could be an useful tool
to optimize glycemic control in this population.
We conducted a pilot prospective multicenter study to evaluate the
contribution of CGM on glucose level control after 3 months of treatment
with basal long-acting insulin once daily and rapid-acting insulin 3 times
daily (detemir-aspart) in haemodialyzed patients with type 2 diabetes.
CGM (Navigator ®, Abbott) was performed during 54 hours including 2
haemodialysis consecutive sessions at 0, 1 and 3 months with determination
of the mean CGM glucose value, maximal glucose excursions and MAGE.
Insulin was adapted by the CGM values. Comparisons were performed
using ANOVA for repeated measures.
The analysis concerned 28 patients: 19 males and 9 females, age 65.7±9.4
yr, BMI 33.3±6.6 kg/m², diabetes duration: 22.8±9.8 yr, haemodialysis
duration: 3.6±2.5 yr, coronary disease: 39%, amputation: 14%. After 3
months, the mean CGM glucose value significantly decreased from 176±35
to 160±37 mg/dL (p=0.05). The frequency of hyperglycaemia > 180 mg/dL
significantly decreased from 41.3±21.9 to 30.1±22.4 % (p<0.05) without
significant increase of hypoglycaemia. There was no modification of MAGE.
Insulin requirements increased significantly from 70±51 to 82±77 IU/d
(p<0.001) without significant change in body weight.
CGM coupled to basal-bolus insulin regimen detemir-aspart improves
glycemic control, without increasing hypoglycemia, in type 2 diabetes
patients with ESRD at high cardiovascular risk.
Supported by: Abbott Laboratories; Novo Nordisk, Inc.
899-P
Accuracy of Blood Glucose Meters Employing Dynamic Electrochemistry in Comparison to Other Devices
897-P
Hypoglycaemic Episodes and Glycaemic Variability in Ealy Stage
Type 2 Diabetes Patients Treated With Monotherapy Insulin
Glargine and Metformin, Using Continuous Glucose Monitoring
FILIZ DEMIRCIK, PETRA B. MUSHOLT, JOCHEN SIEBER, FRANK FLACKE, THOMAS FORST, ANDREAS PFÜTZNER, Mainz, Germany, Frankfurt, Germany
Dynamic electrochemistry (DE) provides mathematical algorithms to
correct for a variety of interfering conditions, including hematocrit (HCT).
HCT values can vary widely in community patient populations (25-60 %)
and may be further influenced by daily activities, e.g. exercise etc. This
laboratory study investigated the accuracy of four DE devices (BGStar and
iBGStar, Sanofi; Wavesense Jazz, AgaMatrix; Wellion Linus, Wellion) in
comparison to three other devices (GlucoDock, Medisana; OneTouch Verio
Pro, LifeScan; FreeStyle InsuLinx, Abbott-Medisense) in blood samples
with varying HCT concentrations. Venous heparinized whole blood was
immediately aliquoted after draw, and manipulated to contain 3 different
blood glucose concentrations (60-90 mg/dL, 155 mg/dL, and 310 mg/dL) and
5 different HCT levels (25 %, 35 %, 45 %, 55 %, and 60 %). The samples
CARSTA KOEHLER, FRANK SCHAPER, FRANK PISTROSCH, ELENA HENKEL, CAREN HOFFMANN, JULIANE STEINER, RONNY STAUDTE, WOLFGANG LANDGRAF,
SUSANNE BILZ, CONSTANZE SCHONER, MARKOLF HANEFELD, Dresden, Germany, Frankfurt, Germany
Aim: Among antidiabetic treatments which can lower HbA1c to target
insulin is discussed to show greatest hypoglycaemia risk (HR) and glycaemic
variability (GV). In routine daily SMBG profiles asymptomatic hypoglycaemic
episodes (HE) are often unrecognized and underreported. Continuous glucose
monitoring (CGM) was used to assess GV and duration of HE in early type 2
diabetes patients (T2DM) well controlled for A1C under daily life conditions
with monotherapy of insulin glargine (GLA) or metformin (M).
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A227
POSTERS
898-P
896-P
Clinical Diabetes/
Therapeutics
Supported by: sanofi-aventis
Supported by: Sanofi
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
were confirmed to have normal pO2 and were measured in parallel 6 times
with three devices and three strip lots of each meter and twice with YSI Stat
2300 (reference method). Precision and mean absolute relative deviation
(MARD) from reference was calculated. Stability to HCT influence was
assumed, when less than 10 % difference occurred between the highest
and lowest mean glucose deviations in relation to HCT concentrations
(HIF: HCT Interference Factor). Five of the investigated meters showed
HCT stability: BGStar (Precision/MARD/HIF: 3.1%/8.3%/4.6%), iBGStar
(3.6%/8.8%/6.6%), Wavesense Jazz (4.5%/8.9%/4.1%), Wellion Linus
(3.6%/5.0%/8.5 %), and OneTouch Verio Pro (2.7%/6.4%/6.2%). The two
other meters were influenced by HCT (FreeStyle InsuLinx: 4.0%/7.5%/17.8%;
GlucoDock: 2.8%/7.4%/46.5%). In this study, all meters employing dynamic
electrochemistry were shown to have a high accuracy and precision and to
reliably correct for potential hematocrit influence on the meter results.
901-P
Online Prediction of Abnormal Glycemia Events for Type 1 Diabetes
Using Empirical Models and Confidence Limits
CHUNHUI ZHAO, WENQING LI, LUPING ZHAO, Hangzhou, China, Hong Kong,
China
Accurate glucose predictions can be used to provide early warnings of
impending abnormal glycemia events. Before taking any action to correct
the future violations, a measure of the reliability of the predictions is
important and necessary to assess the uncertainty of the predicted values.
To address this problem, data-driven empirical models are developed based
on continuous glucose measurements for glucose prediction in this paper.
An error bound in the form of prediction intervals is calculated to evaluate
the prediction errors based on history predictions. Also, it is updated
real time based on the most recent predictions. The hypoglycemia and
hyperglycemia are thus judged using the combination of predictions and
the confidence limits.
The above method is investigated by a combination of confidence limits
and empirical models based on two groups of ambulatory subjects and two
groups of in silico subjects using the FDA-accepted UVa/Padova metabolic
simulator for online short-term (0-60min) glucose prediction. The different
online alarming types of abnormal glycemia events are illustrated in Figure
1 where four classes of alarming degrees are defined. The results indicate
that the use of confidence limits for reality check of glucose prediction
provides a useful quantitative measure of the forecasted alarming events
and can make the early warnings of impending abnormal glycemia events
more reliable.
Supported by: Sanofi
900-P
POSTERS
Clinical Diabetes/
Therapeutics
Effectiveness of Continuous Glucose Monitoring for Type 1 Diabetes in Clinical Practice
ROBERT B. MCQUEEN, SAM L. ELLIS, DAVID M. MAAHS, HEATHER D. ANDERSON, ANNE M. LIBBY, KAVITA V. NAIR, SATISH GARG, JONATHAN D. CAMPBELL, Aurora, CO
There is little evidence on the use of continuous glucose monitoring
(CGM) in clinical practice and its effect on change in A1c for adults with type
1 diabetes (T1D). We estimated the adherence and change in A1c with CGM
use when compared to self-monitoring of blood glucose (SMBG) alone.
We retrospectively identified 66 adult T1D patients at the Barbara
Davis Center who first initiated CGM from 2006 to 2011 and 67 controls
using SMBG. 12 months prior to index date was the baseline period with
a maximum follow-up of 9-months post index. Adherence to CGM was
estimated from survey recall and defined as average number of days/
month of CGM use during follow-up. Change in A1c was calculated as the
difference between the baseline value and lowest follow-up value.
Baseline mean (SD) age in years for CGM vs. SMBG was 39 (12) vs. 32
(12) (p<0.05); duration of diabetes in years was 23 (12) vs. 15 (10) (p<0.05);
and A1c was 7.47% vs. 7.67% (p=0.30). N=32 (48%) used CGM < 21 days/
month. Reasons for low adherence included cost, high frequency of alarms,
and discomfort. The between group mean difference in change in A1c,
adjusted for demographics, was -0.12% (p = 0.36), whereas the subgroup
with a baseline A1c ≥ 7.5% and users of CGM ≥ 21 days/month was -0.49%
(p = 0.10) [Fig 1].
These clinical practice CGM data suggest a trend towards decreasing
A1c for adults with T1D, especially in patients with higher baseline A1c and
higher CGM adherence. More data are needed on how to efficiently target
CGM therapy in clinical practice.
Supported by: NSFC (61273166)
902-P
Opportunities to Enhance Recruitment of Youth With Type 1 Diabetes (T1D) into Continuous Glucose Monitoring (CGM) Trials
KAITLIN C. GAFFNEY, LISA K. VOLKENING, MARIAH M. BARSTOW, CHRISTINA
L. SULLIVAN, MICHELLE L. KATZ, LORI M. LAFFEL, Boston, MA
Consistent CGM use improves A1c and reduces severe hypoglycemia
but few T1D youth sustain CGM use and derive glycemic benefit. Research
provides opportunities to understand CGM use but requires enrollment
of unselected samples to enhance generalizability. To understand youth
recruitment into CGM trials, we assessed characteristics and enrollment
outcomes of eligible T1D youth approached to participate in a 2-year RCT
comparing CGM use with and without a behavioral intervention. Eligibility
criteria included ages 8-17y, T1D for ≥1y, A1c 6.5-10%, daily insulin ≥0.5 U/
kg, BG monitoring ≥4x/d, and no current CGM use. At routine visits, study
staff approached patients deemed eligible by prior EHR review to explain
the study and obtain written informed consent/assent. Following the
recruitment visit, we categorized patients as agreed, thinking, or declined.
Over 13 months, we approached 408 eligible patients (50% male, mean
A1c 8.0±0.8%): 105 (26%) agreed, 47 (12%) were thinking, and 256 (63%)
declined. Decliners were older (13.5y) and had longer T1D duration (7.2y)
&
For author disclosure information, see page 829.
A228
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—GLUCOSE MONITORING AND SENSING
than both agreers (12.7y, 5.9y; each p=.01) and thinkers (12.7y, 6.8y; each
p=.01). Pump use was more common in agreers (86%) than thinkers (77%)
and decliners (74%) (each p=.05). Sex and A1c did not differ by recruitment
status. Most (55%) decliners cited wearing CGM as reason for refusal;
youth <15y declined more often due to CGM than youth ≥15y (61% Vs 41%,
p=.004). Almost 60% (241) agreed or declined at first encounter; of the
remaining 167, 21% later agreed, 51% later declined, and 28% (47) remained
thinkers. Thinkers were 3.5 times more likely to agree if they made a
decision within 1 month of initial visit (p=.003). Recruitment for CGM trials
in T1D youth requires substantial resources and should focus on providing
up-to-date information on CGM devices, attention to realities of sensor
placement for younger patients, and aggressive follow-up within 1 month of
initial invitation to maximize enrollment.
Table 1. MARD Comparisons to the CONTOUR PLUS BGMS
Overall glucose range Low glucose range High glucose range
n=314
n=93
n=113
YSI 27-460 mg/dL
YSI < 80 mg/dL
YSI > 180 mg/dL
Meter system
MARD
MARD
MARD
mg/dL
mg/dL
mg/dL
3.35
3.43
3.26
CONTOUR®PLUS
Accu-Chek® Performa
4.95*
4.55
6.0*
5.84*
6.42*
5.58*
Accu-Chek® Active
OneTouch® SelectSimple
10.32*
12.87*
9.43*
14.69*
17.11*
13.49*
FreeStyle Freedom™
* CONTOUR®PLUS MARD
YSI-YSI glucose
statistically significantly
analyzer, YSI Inc.
lower in this range.
Yellow Springs, OH
Supported by: 5R01DK089349
903-P
A Comparison of Internet Monitoring With Continuous Glucose
Monitoring in Insulin-Requiring Type 2 DM
SHAILA V. KOTHIWALE, VEERAPPA A. KOTHIWALE, PURVI V. BHARGAVA, Belgaum, India
We compared the effects of Real-Time Continuous Glucose Monitoring
(RT-CGM) with an Internet Blood Glucose Monitoring System (IBGMS)
on Hemoglobin A1C levels (A1C) in patients with type 2 diabetes mellitus
(T2DM) treated with insulin in a randomized study.
57 patients with T2DM were randomly assigned to one of two groups.
Group one had the results of their self-monitoring of blood glucose (SMBG)
monitored every two weeks using an IBGMS. Group two utilized RTCGM and were monitored every two weeks. Both groups used a secure
website to upload data and to receive feedback from an endocrinologist.
A1C and laboratory test results were collected at 0 and 6 months. Baseline
parameters were not significantly different. After a 6 month follow up, both
IBGMS and RT-CGM demonstrated significant within-group improvements
in A1C, and are summarized in Table 1. IBGMS and RT-CGM did not show
significantly different A1C levels at baseline and 6 months (p > 0.05). Daily
insulin dosages for both within and between group data after 6 months
were not found to be significantly different from baseline. The use of both
IBGMS and RT-CGM significantly improved A1C levels in patients with
T2DM treated with insulin in a randomized trial over a six month period.
Periodontal diseases are chronic infectious diseases characterized
by microbial plaque which provoke a host response and may induce an
elevated chronic systemic inflammatory state, contributing to increased
insulin resistance and worsening of glycaemic control over time in Type 2
diabetes mellitus patients. Hence the present randomized control trial was
conducted in 50 type 2 diabetic patients for a period of three months to
investigate the effect of conventional non-invasive periodontal therapy
on glycaemic control. The demographic status, Body Mass Index(BMI),
lifestyle, oral hygiene practices, HbA1c and Community Periodontal
Index(CPI) were recorded at baseline and three months. The patients were
randomly assigned into study group and control group. The conventional
non-invasive periodontal therapy included scaling and root planning to
eliminate microbial plaque in the study group whereas no periodontal
therapy was rendered in the control group.
In results , paired t test for HbA1c showed a decrease in mean of
0.63±0.47 % with p-value <0.000 in the study group and control group
showed an increase in mean of 0.03±0.08% with p=0.2 at three months.
Karl Pearson’s correlation coefficient showed a positive correlation for CPI
scores and HbA1c with r=0.4006,p=0.0472 from baseline to three months
in the study group.
The findings of the present study concluded that non-invasive periodontal
treatment resulted in the reduction of clinical parameters of periodontal
infection with the improvement in glycaemic levels. Knowledge regarding
this inter-relationship should be imparted to the patients for their oral hygiene
maintenance and metabolic control.Thus, periodontal treatment could be an
integral component of a holistic diabetic patient care programme.
Table 1. Measurements in A1C over study period.
Group
Baseline
6 month
P = Baseline versus
(SD)
Follow-up (SD) 6-month follow-up.
RT-CGM
8.80 (1.37)
7.49 (0.70)
0.0001
IBGMS
8.79 (1.25)
7.96 (1.30)
0.0170
P = RT-CGM versus IBGMS 0.496
0.081
—
904-P
906-P
Comparative Accuracy Evaluation of 5 Blood Glucose Monitorng
Systems (BGMSs)
Impact of 3-Day Glycemic Profile Use in Poorly Controlled Diabetes
Patients on Multiple Daily Insulin Injection (MDI) Therapy: Results
from the Automated Bolus Advisor Control and Usability Study
(ABACUS)
NANCY DUNNE, MARIA T. VIGGIANI, SCOTT PARDO, CYNTHIA ROBINSON,
MARY E. WARCHAL-WINDHAM, HOLLY SCHACHNER, JOAN LEE PARKES, Tarrytown, NY
KATHARINE BARNARD, DAVID A. CAVAN, RALPH ZIEGLER, IAIN CRANSTON,
CHRISTOPHER PARKIN, WALTER KOEHLER, IRIS VESPER, MATTHIAS A. SCHWEITZER, ROBIN S. WAGNER, Southampton, United Kingdom, Bournemouth,
United Kingdom, Muenster, Germany, Portsmouth, United Kingdom, Boulder City,
NV, Mannheim, Germany, Indianapolis, IN
This study compared the accuracy of the CONTOUR®PLUS BGMS, as
measured by mean absolute relative difference (MARD), with 4 other
BGMSs (Accu-Chek® Performa, Accu-Chek® Active, FreeStyle Freedom™,
OneTouch® SelectSimple™). Study staff tested fingerstick samples on 5
BGMSs from 106 subjects ≥ 18 years of age. Extreme glucose values were
achieved by blood sample glucose modification. The primary endpoint was
comparison of the MARD from the reference value (YSI) in the overall tested
glucose range. Other endpoints were MARD in the low glucose (< 80mg/dl)
and high glucose (> 180 mg/dl) ranges. CONTOUR®PLUS had a statistically
significant lower MARD across the entire tested range (27-460 mg/dL) as
measured by YSI, as well as in the high range compared to the other BGMSs
(Table 1). In the low glucose range CONTOUR®PLUS had a lower MARD
than all other BGMSs which was statistically significant except for AccuChek® Performa (Table 1). In conclusion, the primary endpoint of this study,
assessing accuracy in the overall glucose range using MARD, was met;
CONTOUR®PLUS had a statistically significant lower MARD, one indicator
of accuracy.
ADA-Funded Research
&
We examined the effect of using 3-day, 7-point profiles in patients treated
with multiple daily insulin injection (MDI) therapy. Data were drawn from
194 patients enrolled in the ABACUS trial, a large, 26-week, prospective,
randomized multi-national study of poorly controlled, MDI-treated people
with T1DM and T2DM, with mean (SD) baseline A1C 8.9 (1.2)%. All patients
were asked to perform 7-point blood glucose (bG) testing (pre-/postprandial,
at bedtime) for 3 consecutive days prior to randomization and prior to 3
additional clinic visits. We compared bG levels obtained on profile days
with values from non-profile days. All patients had significantly (p < 0.01)
lower mean bG values (Table) and a higher percentage of bG values within
target range (70-180 mg/dL / 3.9-10 mmol/L) on more profile days than nonprofile days. Glycemic variability (MAGE) was significantly (p < 0.01) lower
with significantly fewer bG values in the hypoglycemic range (< 50 mg/dL /
2.8 mmol/L) and hyperglycemic range (> 300 mg/dL / 16.7 mmol/L) on most
For author disclosure information, see page 829.
Guided Audio Tour poster
A229
POSTERS
Effect of Non-Invasive Periodontal Therapy on Glycaemic Control
In Type 2 Diabetes Mellitus Patients—A Randomized Control Trial
Clinical Diabetes/
Therapeutics
905-P
HUGH D. TILDESLEY, ADAM S. WHITE, ANTHONY M. WRIGHT, JEREMY H.S.
CHAN, ADEL B. MAZANDERANI, TRICIA TANG, STUART A. ROSS, AUGUSTINE
M. LEE, HAMISH G. TILDESLEY, Vancouver, BC, Canada, Victoria, BC, Canada,
Nashville, TN, St. George’s, Grenada, Calgary, AB, Canada, Hanover, NH
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
profile days compared with non-profile days. No significant between-group
differences were seen in these parameters. Performing periodic 3-day,
7-point bG profiles may be an effective stand-alone intervention to optimize
glycemic control.
+0.02±0.23g/L if initial ascending arrow (n=36); p=0.008 by ANOVA. Similar
differences in capillary glucose levels outcomes were observed for the 222
patients with initially correct interstitial glucose levels between 0,80 and
1.60g/L, p=0.003 by ANOVA. From these observations, 10/32 had a final
capillary glucose level lower than 0,80g/L after a descending arrow; 16/162
after a stable arrow and 0/28 after an ascending arrow (p<0.0001 by χ2).
For a patient with a “normal” interstitial glucose level, the trending
arrow is a good indication of hypoglycemia risk 15 minutes later: never
if ascending; 10 % if stable and 30 % if descending. This argues for the
interest of CGMS in the prevention of hypoglycemia in real life situations.
Table. Comparison of bG values on profile days vs. non-profile days (Intentto-Treat cohort, n=194)
Profile Days
Baseline
Visit 5
Visit 7
Visit 9
Mean bG on
Profile Days
(mg/dL / mmol/L)
173.7 (39.6) / 9.7 (2.2)
175.1 (39.1) / 9.7 (2.2)
173.9 (38.7) / 9.7 (2.2)
176.0 (37.1) / 9.8 (2.1)
Mean bG on
Non-Profile Days
(mg/dL / mmol/L)
181.9 (42.4) / 10.1 (2.4)
183.5 (40.6) / 10.2 (2.3)
184.8 (40.7) / 10.3 (2.3)
179.8 (39.6) / 10.0 (2.2)
P Value
< 0.01
< 0.01
< 0.01
NS
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—
INSULINS
Guided Audio Tour: New Insulin Therapeutics (Posters: 909-P to 914-P),
see page 19.
907-P
&
JOHN S. MELISH, Honolulu, HI
POSTERS
Clinical Diabetes/
Therapeutics
Impact of Rest and Activity on Glucose Pharmacodynamic Using
CGM
Modeling Continuous Glucose Monitoring (CGM) data from mealrelated glucose tolerance testing can provide a pharmacokinetic picture
of glucose metabolism glucose uptake and disposal. This study applies a
pharmacokinetic model (Melish, 2011 and 2012) to a published CGM study
(Manohar, C., et al. Diabetes Care 35:2459, 2012) of interstitial fluid dynamic
responses to a standardized meal containing 50 g glucose in age and
weight match controls (n=12) and Type 1 diabetics (n=12) while at rest and
after low-intensity exercise. One meal/day was followed by rest and two
meals were followed by activity on three separate days. Areas under the
curve above baseline were compared and in both groups were reduced by
measured activity. Boluses of insulin were used in all meals in the diabetic
patients. The analysis applied to this data assumes a linear uptake/time
of glucose from mixed gastric contents and applies a pharmacokinetic
analysis to the glucose concentration curves generated following either
mild activity or rest. The grouped results include volume of distribution (Vd,
(dL)), fraction/min glucose disappearance (Kd (min-1)), glucose remaining
after glucose extraction, dietary glucose (PHGR (mg)), and dietary glucose
clearance (Cldiet (dL/min)). Control healthy patients showed increase Kd,
Vd, Cl compared with Type 1 patients. Activity was associated with a 22%
increase in Vd in controls; no change was seen with Type 1 patients.
Pharmacokinetic Data
Subjects
Control (rest)
Control (active)
Type 1 (rest)
Type 1 (active)
Kd
0.00711
0.00702
0.00570
0.00516
Vd
107
130
76
76
PHGR
37502
36826
39256
36584
909-P
Demonstration of the Additive Effect of IDeg and IAsp in Adipocytes
ANDERS R. SØRENSEN, ERICA NISHIMURA, AAGE VØLUND, Måløv, Denmark,
Charlottenlund, Denmark
In the IDegAsp formulation, insulin degludec (IDeg) and insulin aspart
(IAsp) are combined while still retaining the distinct ultra-long basal
acting and fast acting properties of each analogue. Thus, it is important to
establish the nature of interactions between IDeg and IAsp as well as with
endogenous human insulin (HI), which is being produced in many people
with diabetes requiring insulin therapy.
Insulin dependent de novo lipogenesis (DNL), determined as insulin
stimulated incorporation of tritium labelled glucose into lipid in primary rat
adipocytes, was used to assess the functional interaction of IDeg, IAsp and
HI. All three produced full dose-response curves in this system, but with
different EC50 values. Possible interactions could be antagonism (less lipid
is produced), or synergism (more lipid is produced), or the effects could be
additive. The dose response surfaces obtained by incubating combinations
of two ligands were examined (see example in figure below). This was done
by using the four parameter logistic model with a reformatted expression for
the ligand concentrations in order to accommodate for potency difference
and possible interaction between ligands. The results revealed additivity of
all possible combinations.
From these studies it can be concluded that HI, IAsp and IDeg act
independently through the insulin receptor to produce the lipogenic
response in adipocytes, indicating that in IDegAsp, the effects of IDeg and
IAsp would also be additive.
Cldietl
0.76
0.91
0.43
0.39
908-P
Can Trending Arrows in Continuous Monitoring Systems Predict
Glycemia Below 0,80g/l ?
CONCEPCION GONZALEZ, ELISA MAURY, ISABELLE BARCOS, HENRI GIN, VINCENT RIGALLEAU, Pessac, France
Real-time continuous glucose monitoring system (CGMS) has been
shown to help improve HbA1c levels in patients with Type 1 diabetes, but
its preventive effect on hypoglycemia is not established. We assessed
whether the CGMS trending arrows predict subsequent blood glucose level
lower than 0,80g/L.
Thirty three patients with type 1 diabetes were admitted for education in
the use of CGMS Medtronic (n=23) or Navigator (n=10). They were requested
to note at time 0: the interstitial glucose level, the direction of the arrow
(ascending, stable, descending), the capillary glucose level and the same
parameters 15 minutes later to check whether the arrow had predicted the
glucose level course (Time 15 min-Time 0).
The patients (age: 42±12 years; diabetes duration: 22±12 years; HbA1c:
8.4±1.3%) collected 386 observations (one observation = one arrow plus
2 successive interstitial and capillary glucose levels). Interstitial Glucose
levels at time 0 and 15 minutes later correlated with capillary glucose
levels (R1=0.81 and R2=0.78 p<0.0001) but were lower (p<0.0001). For
the 386 observations, initial descending arrows (n=47) were associated
with decreasing capillary glucose levels (-0.15±0.28g/L) whereas capillary
glucose course were -0.01±0.23g/L if initial stable arrow (n=303) and
Supported by: Novo Nordisk, Inc.
&
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which decreased within two weeks. No differences were seen between
arms in adverse events or standard safety parameters.
In conclusion, addition of Lira to IDeg once daily + Met improved longterm glycemic control, with weight loss and less hypoglycemia compared
with addition of a single daily dose of IAsp with the largest meal.
910-P
Telematic Support for Therapeutic Decision and Remote Monitoring by PDA Phone or Voice Server Improves HbA1c in Patients With
Type 2 Diabetes Starting a Basal Insulin Therapy: The TELEDIAB2
Study
Supported by: Novo Nordisk, Inc.
MICHAËL JOUBERT, SYLVIA FRANC, AHMED DAOUDI, CEDRIC FAGOUR, BEATRIX BOUCHERIE, ERIC BENAMO, MICHEL RODIER, LISE DUFAITRE, BRUNO
GUERCI, HÉLÈNE AFFRES, LUCY CHAILLOUS, ANNIE CLERGEOT, DURED DARDARI, OLIVIER DUPUY, HELEN MOSNIER-PUDAR, DIDIER CHARITANSKI, LUC
MILLOT, CATHERINE GILET, BÉATRICE ROCHE, DOMINIQUE HOULBERT, YVES
REZNIK, PIERRE-YVES BENHAMOU, GUILLAUME CHARPENTIER, Caen, France,
Evry, France, Fort de France, France, Avignon, France, Nimes, France, Marseille,
France, Nancy, France, Kremlin Bicêtre, France, Nantes, France, Besançon, France,
Saint Mandé, France, Paris, France, Dreux, France, Saint-Etienne, France, Montargis,
France, Clermont Ferrand, France, Alencon, France, Grenoble, France
&
We previously reported that LY2605541 (LY), a novel basal insulin
analog with a prolonged duration of action, has a preferential hepatic
effect compared with regular human insulin (HI), when both were infused
via peripheral vein (0.5 and 0.1 nmol .kg-1.h-1 for LY and HI, respectively)
such that similar glucose infusion rates (GIRs) were required to maintain
euglycemia. The current study examined two additional LY delivery rates
to determine if the hepato-preferential action is dose-specific. Chronicallycatheterized overnight-fasted conscious dogs underwent clamp studies
with portal infusion of glucagon at a basal rate and peripheral venous
infusions of somatostatin, LY at 0.25 (n=4) or 0.375 (n=5) nmol.kg-1.h-1
(with 0.25 and 0.375 nmol/kg priming doses, respectively), and glucose to
maintain euglycemia. Net hepatic glucose output was reduced from basal in
the HI group during the clamp, but there was no net hepatic glucose uptake
(NHGU). In contrast, the LY groups switched to NHGU, reaching rates of
0.3±0.3 and 1.8±0.3 mg.kg-1.min-1 within 5 h with LY 0.25 and 0.375 nmol,
respectively (P<0.001 for 0.375 nmol vs HI). The ratio of increase in nonliver glucose uptake relative to change in net hepatic glucose balance
from basal, calculated at a time when GIRs were ≈3.5 mg.kg-1.min-1 in all
groups, was high in HI (1.17±0.38), reflecting a predominant effect on the
non-hepatic tissues with less impact on the liver. In contrast, the LY groups’
ratios were 0.39±0.33 (0.25 nmol; P=0.07 vs HI), -0.01±0.13 (0.375 nmol;
P<0.01 vs HI), and -0.01±0.08 (in the previously-reported 0.5 nmol group;
P<0.01 vs HI), indicating that stimulation of glucose disposal was greater in
the liver relative to non-hepatic tissues such as muscle. Similarly, the ratio
of change from basal in tracer-determined glucose uptake vs endogenous
glucose production was 1.4 (HI) vs 0.72, 0.45, and 0.55 (LY: 0.25, 0.375, and
0.5 nmol). In conclusion, at current and previous doses tested, LY has a clear
hepato-preferential action.
Supported by: Eli Lilly and Company
Supported by: Novo Nordisk, Inc.
&
Comparison of Addition of Liraglutide to Insulin Degludec Plus
Metformin vs. Addition of a Single Dose of Rapid-Acting Insulin
Analog to Largest Meal in Type 2 Diabetes
BRIAN G. TOPP, JEANNE S. GEISER, DANNY K.W. SOON, TIM HEISE, M. DODSON MICHAEL, SCOTT J. JACOBER, JOHN M. BEALS, VIKRAM P. SINHA, Indianapolis, IN, Neuss, Germany
CHANTAL MATHIEU, HELENA W. RODBARD, BERTRAND CARIOU, YEHUDA
HANDELSMAN, ATHENA PHILIS-TSIMIKAS, ANN MARIE OCAMPO FRANCISCO,
AZHAR RANA, BERNARD ZINMAN, Leuven, Belgium, Rockville, MD, Nantes,
France, Tarzana, CA, La Jolla, CA, Søborg, Denmark, Toronto, ON, Canada
LY2605541 (LY) is a novel basal insulin analog with a large hydrodynamic
size that slows absorption and reduces clearance. The effects of LY’s large
size on tissue distribution and mechanism of action remain unclear. We
developed a tissue distribution model for LY and Insulin glargine (G) and
performed simulations (sims) of recently completed Phase 1 and Phase
2 clinical trials using a mathematical model of metabolic regulation.
Due to secretion into the portal vein and first pass clearance at the liver,
endogenous insulin is 2-4 fold higher at the liver than muscle. G is predicted
to diffuse relatively rapidly from plasma to liver and muscle resulting in
a 1:1 ratio. LY is predicted to diffuse rapidly from plasma to the liver via
fenestrated vessels but to diffuse slowly across the tight capillary junctions
in the muscle resulting in a 4:1 ratio. As a result the primary tissue of
action is predicted to be muscle for G and liver for LY. Physiologic based
pharmacodynamic simulations incorporating this tissue distribution model
were consistent with Phase 1 and Phase 2 data. Following a single injection
in healthy volunteers, G (0.8 U/kg) is predicted to display 228 mg/min of
glucose infusion during a euglycemic clamp (data: 263 ± 105 mg/min). A
single dose of LY (2.2 U/kg) is predicted to display a glucose infusion rate
of 144 mg/min (data: 161 ± 49 mg/min). Following 14 days of dosing (1.0 U/
kg) in virtual patients with T2D, LY is predicted to display glucose infusion
rates of 210 mg/min during a euglycemic clamp (data: 250 ± 36 mg/min). At
the end of 12 weeks of titrate-to-target dosing in virtual patients with type
2 diabetes, predicted changes in A1C (sims: -0.6 ± 0.5, -0.5 ± 0.5% for G, LY)
(data: -0.7 ± 0.8, -0.7 ± 0.7% for G, LY), and hypoglycemic events (sims: 0.40,
Previous studies have evaluated the efficacy and safety of adding a
glucagon-like peptide-1 (GLP-1) analog to basal insulin or vice versa in type
2 diabetes. In this treat-to-target trial, subjects who completed 104 weeks
on insulin degludec (IDeg) once daily plus metformin (Met) with HbA1c ≥7%
were randomized to either liraglutide (Lira) once daily (N=88) or insulin
aspart (IAsp) with largest meal once daily (N=89) for intensification during
this subsequent 26-week trial.
Mean baseline HbA1c was 7.7% in both arms. IDeg + Lira reduced HbA1c
(−0.74 %-points) and was superior to IDeg + IAsp (−0.39 %-points) at Week
26 (estimated treatment difference [ETD] {IDeg + Lira}−{IDeg + IAsp}: −0.32
%-points [−0.53; −0.12]95%CI; p=0.0024). After 26 weeks, mean HbA1c was
7.0% with IDeg + Lira and 7.3% with IDeg + IAsp. Significantly more subjects
achieved the target HbA1c <7% without confirmed hypoglycemia (plasma
glucose < 56 mg/dL or severe hypoglycemia) and without weight gain with
IDeg + Lira (49.4%) vs IDeg + IAsp (7.2%); estimated odds ratio {IDeg + Lira}/
{IDeg + IAsp}: 13.8 [5.2; 36.3]; p<0.0001.
With lower HbA1c at end of trial, IDeg + Lira subjects had 87% less
confirmed hypoglycemia vs IDeg + IAsp (1.00 and 8.15 events/patient-yr,
respectively; p<0.0001), 86% less nocturnal confirmed hypoglycemia (0.17
and 1.11 events/patient-yr, respectively; p=0.0002), and significant weight
loss (−2.8 kg) vs IDeg + IAsp (+0.9 kg); ETD {IDeg + Lira}−{IDeg + IAsp}: −3.8
kg [−4.7; −2.8]; p<0.0001. IDeg + Lira subjects initially had more nausea,
ADA-Funded Research
&
913-P
Effects of a Novel Basal Insulin, LY2605541, on Hepatic Glucose
Output and Muscle Glucose Uptake: A Physiologic Based Simulation Analysis
911-P
For author disclosure information, see page 829.
Guided Audio Tour poster
A231
POSTERS
MARY C. MOORE, MARTA S. SMITH, VIKRAM P. SINHA, JOHN M. BEALS, M.
DODSON MICHAEL, SCOTT J. JACOBER, ALAN D. CHERRINGTON, Nashville, TN,
Indianapolis, IN
Basal insulin is recommended in type 2 diabetes (T2D) when HbA1c >
7-7.5% despite a combination of antidiabetic agents, and its efficacy relies
on the active titration of insulin dosage. Telemedecine devices may help
optimizing insulin titration and metabolic control in T2D. We evaluated
two telematic support systems, an interactive voice server (IVS) and a
smartphone with a decision support system (DSS) for T2D on the model
of the DIABEO system (DSS for basal insulin titration and educational
coaching functions for postprandial glycemic control). This 4-month, openlabel, parallel-group, multicenter study enrolled 190 adult patients with
T2D (>1 yr), BMI 29.5±4.9 Kg/m2, age 58.7±9.6 yrs, 64% men, diabetes
duration 13.1±7.6 yrs, HbA1c 8.9±1.1% despite oral agents (>6 months).
Patients were randomized to i) a standard follow-up (1 consultation at 4
months) (G1), ii) the daily use of an interactive voice server (IVS) with regular
short phone consultations (G2), iii) the daily use of the smartphone with
regular short phone consultations (G3) for basal insulin Detemir (levemir)
dose titration. The primary endpoint was HbA1c value at 4 months. Insulin
was initiated at a mean dose of 16.5±4.7 U/d with a 4-month titration of
35±23,(G1), 44±35 (G2) and 50±35 U/d (G3). The 4-month HbA1c reduction
was greater in G2 (-1.44%) and G3 (-1.48%) vs. G1 (-0.92%)(p=0.0017, G2 vs
G1 and G3 vs G1), but did not differ between the intervention groups. The
percentage of patients with a normal 08.00h fasting blood glucose level
was higher in G2 and G3 compared to G1 (82.5% and 82.7% vs. 41.8%). No
severe hypoglycemia occurred and the frequency of mild hypoglycemia
was similar in all groups (0.3±0.7per week).
In conclusion, both PDA and IVS improved metabolic control in patients
with T2D with a poor glycemic control thanks to a more active titration of
insulin dose, with no increase of hypoglycemia frequency.
&
912-P
Basal Insulin LY2605541 Has Hepato-Preferential Action Across a
Range of Delivery Rates
Clinical Diabetes/
Therapeutics
&
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
0.23 per wk for G, LY) (data: 0.35, 0.33 per wk for G, LY) were consistent with
data. Overall LY’s large size is predicted to result in hepatic preferential
tissue distribution.
In conclusion, LY treatment compared with GL in patients with T1D
demonstrated lower daily mean blood glucose, less nocturnal hypoglycemia
but more total hypoglycemia, resulting in a need for lower mealtime insulin
doses, which may reflect a more prolonged duration of basal insulin action
or greater suppression of hepatic glucose production.
Supported by: Eli Lilly and Company
&
914-P
Lower Within-Subject Variability in Mean Blood Glucose Concentration With Insulin Degludec vs. Insulin Glargine: A Meta-Analysis
of Patients With T2D
POSTERS
Clinical Diabetes/
Therapeutics
LUIGI F. MENEGHINI, STEWART B. HARRIS, MARC EVANS, SØREN RASMUSSEN, THUE JOHANSEN, THOMAS R. PIEBER, Miami, FL, London, ON, Canada,
Cardiff, United Kingdom, Søborg, Denmark, Graz, Austria
Insulin degludec (IDeg) is a new ultra-long-acting basal insulin shown to
have low day-to-day variability in a euglycemic clamp study. In this post-hoc
meta-analysis of patients with T2D, we compared day-to-day variability in
mean self-measured blood glucose (derived from 9-point profiles; 9P-SMPG)
between IDeg and insulin glargine (IGlar).
This patient-level meta-analysis included all fi ve phase 3a, randomized,
open-label, treat-to-target trials (26 or 52 week) in which once-daily
IDeg and IGlar have been compared. 9P-SMPG profiles comprised
measurements made before and 90 min after the start of breakfast,
lunch and main evening meal, before bedtime, at 4 AM, and before start
of breakfast the next day. Within-subject variability (CV%) in the overall
mean plasma glucose (PG) concentration of the 9P-SMPG profile (area
under the profile) was estimated from profiles recorded at weeks 12, 16,
and 26 (26-week trials) and weeks 12, 16, 26, 40, and 52 (52-week trials),
using a linear mixed model.
Estimated within-subject variability in mean 9P-SMPG was significantly
lower by 7-10% for IDeg vs. IGlar for patients on basal insulin plus OAD
therapy, as well as the subset of previously insulin-naïve patients (Table).
In conclusion, IDeg is associated with significantly lower within-subject
day-to-day variability in mean blood glucose concentration than IGlar in
patients with T2D receiving basal insulin plus OAD therapy.
Supported by: Eli Lilly and Company
&
MARKOLF HANEFELD, RACHELE BERRIA, JAY LIN, RONNIE ARONSON, PATRICE
DARMON, MARC EVANS, LUC VAN GAAL, Dresden, Germany, Bridgewater, NJ,
Flemington, NJ, Toronto, ON, Canada, Marseille, France, Cardiff, United Kingdom,
Edegem, Belgium
Population
Insulin degludec
Insulin glargine
IDeg/IGlar
(IDeg)
(IGlar)
(ratio [95% CI])
n
CV%
n
CV%
T2D (BB)
692
16.0
236
16.3
0.98 [0.93; 1.04]
T2D (BOT)
1370
13.8
789
14.9
0.93 [0.89; 0.96]*
T2D (BOT-IN)
1162
13.8
581
15.2
0.90 [0.86; 0.94]*
n = number of subjects; CV% = coefficient of variation; T2D = Trials 3579,
3672, 3582, 3586 and 3668 (excluding IDeg flexible dosing group); BB = basalbolus therapy (Trial 3582); BOT = basal insulin plus OAD therapy (Trials 3579,
3672, 3586, 3668 (excluding IDeg flexible dosing group); BOT-IN = previously
insulin-naïve patients on BOT therapy (Trials 3579, 3762 and 3586); *p<0.05%
The number of elderly people with T2DM is increasing; therefore, efficacy
and safety of antidiabetic drugs for vulnerable patients is a key question for
individualized treatment. This meta-analysis of 5 Phase 3 lixisenatide (LIXI)
randomized trials (GetGoal-M, -P, -S, -M-Asia, -F1) in 501 elderly patients
(≥65 yrs) with T2DM compared LIXI to placebo (PBO) on top of OADs. Mean
patient characteristics at baseline: age 69.3 yrs, BMI 29.4 kg/m2, diabetes
duration 10.6 yrs, HbA1C LIXI 7.99%, PBO 7.92%; 90.0% of patients on
MET, 44.7% on SU, 16.6% on TZD. LIXI significantly reduced HbA1C vs PBO
(-0.54% [CI: -0.73, -0.36], p<0.00001) and was better than placebo in each
of the following composite endpoints: proportion of patients achieving
HbA1C <7% (49.3 vs 22.8%, p<0.0001); HbA1C <7% and no weight gain
(41.8 vs 18.8%, p<0.0001); HbA1C <7% and no documented symptomatic
hypoglycemia (44.4 vs 22.3%, p<0.0001); HbA1C <7%, no documented
symptomatic hypoglycemia and no weight gain (37.2 vs 18.8%, p<0.0001).
A higher trend for more frequent documented symptomatic hypoglycemia
was seen with LIXI vs PBO (OR: 2.09 [0.88, 4.97] p=0.09) mainly driven by
SU as background medication, and no incidence of severe hypoglycemia in
either group. This post-hoc analysis suggests in elderly patients with T2DM
inadequately controlled on OADs, LIXI significantly improved glycemic
control, particularly in composite assessments that indicate limited risk of
weight gain/hypoglycemia.
Supported by: Novo Nordisk, Inc.
Guided Audio Tour: Novel Agents for Diabetes Treatment (Posters: 915-P
to 921-P), see page 19.
&
916-P
Efficacy and Safety of Lixisenatide in Elderly T2DM Patients: Subanalysis from the GetGoal Program
915-P
Improved Glycemic Control Despite Reductions in Bolus Insulin
Doses With Basal Insulin LY2605541 Compared With Basal Insulin
Glargine in Patients With Type 1 Diabetes
JULIO ROSENSTOCK, RICHARD M. BERGENSTAL, THOMAS BLEVINS, LINDA
MORROW, YONGMING QU, SCOTT J. JACOBER, Dallas, TX, Minneapolis, MN,
Austin, TX, Chula Vista, CA, Indianapolis, IN
LY2605541 (LY) is a novel basal insulin analog with a prolonged duration
of action. The objective of this analysis was to further explore the initial
observation of a reduction in prandial insulin requirements with LY compared
with insulin glargine (GL) for patients with type 1 diabetes (T1D) who
completed a Phase 2 randomized, open-label, 2x2 crossover study (n=108).
At 8 weeks, patients (n=108) treated with LY required significantly less
bolus insulin compared with GL (least-squares mean differences±standard
error [SE] for LY − GL): breakfast (-0.9±0.4 IU; p=0.021), lunch (-1.4±0.4 IU;
p<0.001), dinner (-2.0±0.4 IU; p<0.001), and total daily bolus dose (-4.3±1.5
IU; p=0.005). Figure 1 presents total daily basal and bolus insulin doses
over time by treatment. LY had lower daily mean blood glucose compared
with GL (143.1 mg/dL vs. 151.7 mg/dL; p<0.001) (N=108). The rate of total
hypoglycemia events was higher for LY vs. GL (9.2 vs. 8.1 events/30d;
p=0.074), but the rate of nocturnal hypoglycemia events was lower (0.9 vs.
1.2 events/30d; p=0.007) (n=108 for both).
&
For author disclosure information, see page 829.
A232
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
BIOD-530 vs. U-500R (Study 1) or BIOD-530 vs. IL (Study 2) in miniature
diabetic swine using a crossover study design. Fasted swine were given
0.25 U/kg insulin s.c. and fed. Blood was sampled from -30 to 480 min post
dose. Plasma insulin was measured by insulin ELISA and glucose by YSI. Tmax
(min) and T50%max (min) values were 42±12*, 11±2* for BIOD-530 and 94±17,
27±5 for U-500R in Study 1 and 67±18, 9.7±1.6* for BIOD-530 and 55±8,
21±4 for IL in Study 2, respectively (*p<0.05 vs. U500R or IL). Concentration
vs. time profiles for insulin and glucose are shown in Figure below. The rate
of absorption and onset of action of BIOD-530 are similar to or faster than
IL and more rapid than U-500R. The times for insulin to return to baseline
were similar for BIOD-530, IL and U-500R, while the time for glucose to
return to baseline was faster for IL vs. BIOD-530 and U-500R. If similar
profiles are demonstrated in humans, the rapid absorption of concentrated
insulin BIOD-530 may provide superior meal time glucose control relative to
U-500R for patients with severe insulin resistance.
Supported by: Sanofi
&
917-P
Clinical Diabetes/
Therapeutics
LINDA A. MORROW, MARCUS HOMPESCH, SCOTT J. JACOBER, SIAK LENG
CHOI, YONGMING QU, VIKRAM P. SINHA, Chula Vista, CA, Indianapolis, IN, Singapore, Singapore
In an open-label, randomized Phase 2 crossover T1D substudy, subjects
(n=23) underwent 24-hr Biostator-controlled euglycemic clamps after 8
wks treatment with GL or LY, a novel basal insulin analog with prolonged
duration of action. Clinically titrated basal insulin doses (LY: 16 to 64 U, GL:
19 to 60 U) were administered the morning of the clamp. At baseline, mean
BMI was 26.8 kg/m2 ± 4.2 [SD]; mean A1C was 7.7% ± 1.0. Endpoint dose (U/
kg) was LY: 0.43 ± 0.13, GL: 0.42 ± 0.10. Daily mean BG (mg/dL) was LY: 138 ±
22, GL: 142 ± 22, p=0.64. Mean total and nocturnal hypoglycemia rates/30 d
were LY: 2.7 ± 2.3 and 0.5 ± 0.8, GL: 3.0 ± 2.4 and 0.7 ± 1.1, p=0.11 and 0.43.
Mean glucose infusion rate (GIR) normalized to unit of insulin was less for LY
than GL and persistent over 24 hrs. The GIR profile for LY is consistent with
a peak to trough fluctuation ratio <1.5.
Supported by: NIDDK (R43DK096604)
&
919-P
A Pilot Prospective Case-Control Study to Compare the Efficacy of
Laparoscopic Placement of Gastric Contraction Modulator (TANTALUS II®) versus Supplementary Insulin Treatment in Obese Type
2 Diabetic Patients
SIMON K. WONG, ALICE P.S. KONG, RISA OZAKI, VANESSA NG, HAROLD E. LEBOVITZ, ENDERS K.W. NG, JULIANA C. CHAN, Hong Kong, China, New York, NY
Aims: We evaluated the efficacy of the TANTALUS system, a mealinitiated implantable gastric contractility modulator (GCM) in suboptimally
controlled obese Chinese type 2 diabetic (T2D) patients, who failed oral
antidiabetic drugs (OAD) compared to supplementary insulin (INS) therapy.
Methods: Moderately obese (BMI 25-35kg/m2) T2D patients with HbA1c
>7.5% despite receiving maximal doses of 2 or more OADs were included.
Patients either received laparoscopic implantation of GCM or insulin
therapy. We compared the body weight, waist circumference (WC) and
glycemic control (HbA1C) before and 1 year after intervention. Of the 17
patients recruited, 8 received GCM therapy and 9 received insulin injection.
GCM and INS groups had similar mean (SD) body weight [80.4(10.9)kg vs
86.3(8.5)kg, p=0.17], BMI [29.4(2.1) kg/m2 vs 30.1(2.3)kg/m2, p=0.42] and
HbA1c [9.1(1.0)% vs 9.0(0.7)%, p=0.55] at baseline. The respective mean
(SD) HbA1c reduction at 6 and 12 months in the GCM group was 1.6(1.1)%
and 0.9(1.6)% (p<0.05 within group). The corresponding changes in the
insulin group were 0.3(0.6)% and 0.3(0.7)% (p=0.27 within group) with a
trend of between-group differences (p=0.06). In the GCM group, there was
modest but significant reduction in bodyweight [-3.2(5.2)kg, p=0.04 with
group) and WC [-3.8(4.5)cm, p=0.02] at 12 months. In the insulin group, the
respective changes were 2.4(2.5)kg (p=0.03) and 1.5(2.5)kg (p=0.09) with
significant between-group differences (p<0.05). At 1 year, 2 patients in the
GCM group required rescue insulin therapy but the daily dose was less than
that in the insulin group [0.08(0.04) units/kg vs 0.37(0.20) units/kg, p=0.07).
Conclusion: In difficult-to-treat T2D patients with obesity who fail OADs,
GCM implantation may be a safe and alternative treatment option to insulin
therapy.
Inter-subject GIR variability (SD) was LY: 0.67, GL: 0.53. Eight LY and 1 GL
subjects had minimal GIRs over 24 hrs (defined as <800 mg/kg), indicating
optimal glucose control. Mean total glucose infused (GTOT(0-24);g/kg) was LY:
1.22 ± 0.82, GL: 1.90 ± 1.01, p<0.01. Mean GTOT(0-6) (g/kg) was LY: 0.21 ± 0.22,
GL: 0.41 ± 0.22, p<0.01. Mean GTOT(18-24) (g/kg) was LY: 0.28 ± 0.18, GL: 0.35
± 0.23, p=0.20. LY has a flatter profile than GL, with potentially more stable
and predictable metabolic control. LY may have a novel mechanism of action
as LY GTOT(0-24) is less than GL with similar glycemic control.
Supported by: Eli Lilly and Company
&
918-P
BIOD-530 U-400 Concentrated Recombinant Human Insulin: Pharmacokinetic (PK) and Pharmacodynamic (PD) Profiles in Diabetic
Swine Compared to U-500 Regular Human Insulin (U-500R) and Insulin Lispro U-100 (IL)
RODERIKE POHL, ROBERT HAUSER, MING LI, BRYAN R. WILSON, MARY GUINNESS, MARILYN JACKSON, ALAN KRASNER, ERROL DE SOUZA, Danbury, CT
BIOD-530 is a U-400 formulation of recombinant human insulin, disodium
EDTA and citrate under evaluation as an alternative to U-500 regular human
insulin (Humulin R®) for the treatment of diabetic patients with severe insulin
resistance. In the present studies, we evaluated the PK and PD profiles of
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A233
POSTERS
LY2605541 (LY) Exhibits a Flatter Glucodynamic Profile than Insulin Glargine (GL) at Steady State in Subjects With Type 1 Diabetes
(T1D)
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
&
922-P
920-P
Inhibition of Glucagon Secretion in Rat Pancreatic Islets via Na+
Channels: Mechanism of Anti-Diabetic Effect of Ranolazine
Euglycemic Clamp Profile of New Insulin Glargine U300 Formulation in Patients With Type 1 Diabetes (T1DM) Is Different from
Glargine U100
MING YANG, RUTH CHU, LUIZ BELARDINELLI, ARVINDER DHALLA, Fremont, CA
Ranolazine (RAN), a Na+ channel blocker, has been shown to reduce HbA1c
and glucose levels in pre-clinical and clinical studies, but the mechanism
of this effect is unclear. Pancreatic α-cells express voltage-gated Na+
channels (NaCh), which play a significant role in glucagon secretion. In this
study we determined the effects of RAN and the NaCh blocker tetrodotoxin
(TTX) on glucagon secretion from rat pancreatic islets.
RAN and TTX significantly reduced glucagon secretion in a concentrationdependent manner, with IC50 of 4.0±2 µM and 2.8±2 nM, respectively.
Veratridine, a NaCh activator, concentration-dependently increased
glucagon secretion, causing an 8-fold increase at 100 µM (Fig. A). Veratridine
(30 µM)-induced glucagon secretion was reduced by RAN and TTX, with
IC50 of 2.8 ±1 µM and 3.0±1 nM, respectively (Fig. B and C). Physiologic
stimuli epinephrine and arginine also concentration-dependently increased
glucagon secretion, with EC50 of 2.9±2 µM and 29±8 mM, respectively.
RAN (10 µM) reduced epinephrine (5 µM)- and arginine (20 mM)-induced
glucagon secretion by 61±6 and 44±7%, respectively. qPCR analysis showed
that Nav1.3 is the predominant isoform expressed in rat islets and α-cells.
In summary, RAN inhibits glucagon secretion from rat islets mediated
via blockade of Nav1.3. These data suggest that the anti-diabetic effect of
RAN in vivo may be due to inhibition of glucagon secretion from pancreatic
α-cells.
POSTERS
Clinical Diabetes/
Therapeutics
JOACHIM TILLNER, KARIN BERGMANN, LENORE TEICHERT, RAPHAEL DAHMEN, TIM HEISE, REINHARD H.A. BECKER, Frankfurt, Germany, Neuss, Germany
Insulin glargine U100 (Lantus®, GlarU100) has become a standard of care
as it provides a 24-h basal insulin supply after single-dose subcutaneous
injection. A novel formulation containing 300 U/ml insulin glargine
(GlarU300) is being developed to improve the activity profile. The aim of this
study was to assess the pharmacodynamic and pharmacokinetic properties
of this novel formulation in patients with T1DM. Single SC doses of 0.4, 0.6,
and 0.9 U/kg GlarU300 and 0.4 U/kg GlarU100 administered in 24 patients
with T1DM were compared in this double-blind, randomized, 4-sequence,
crossover study using the automated (Biostator) euglycemic clamp technique
over 36 hours. The mean profiles of serum insulin concentrations (INS), blood
glucose (BG), and smoothed (LOESS factor = 0.06) body-weight-standardized
glucose infusion rate (GIR) were different for the 2 formulations. GlarU100
GIR increased until 11 h and declined thereafter towards 36 h, consistent
with the observation of BG values staying at a euglycemic level (mean
smoothed BG ≤ 105 mg/dl) beyond 24 h during the clamp and then slowly
increasing until the end of the clamp.
GIR profiles for 0.4, 0.6, and 0.9 U/kg GlarU300 increased dose dependently
with a similar shape over the 36 clamp hours showing an increase from 2
h until around 12 h, followed by a slight decline thereafter with ongoing
activity up to 36 h. As compared to GlarU100, GlarU300 showed flatter
profiles with less fluctuation in individual GIRs and provided still full BG
control at 36 h, end of the clamp. All treatments were well tolerated with no
differences in safety-related parameters between treatments. In line with
GIR profiles, INS profiles of GlarU300 increased dose dependently and were
flatter as with GlarU100.
The new insulin glargine U300 formulation provides even longer and
flatter activity and PK profiles as compared to GlarU100.
Supported by: Sanofi
&
923-P
921-P
WITHDRAWN
Insulin Mediated Glucose Disposal Rate Rather than Improvement
of Acute Insulin Response after Intensive Insulin Treatment Is the
Major Contributor to Induce Long-Term Remission of Newly Diagnosed Type 2 Diabetes
HUI WANG, JIAN KUANG, LI YAN, QIFU LI, SHIPING LIU, ZHENGNAN GAO,
WEIGANG ZHAO, FAN ZHANG, YERONG YU, GUOCHUN LUO, GANGYI YANG,
LING LI, GUANGWEI LI, Beijing, China, Guangzhou, China, Chongqing, China,
Changsha, China, Dalian, China, Shenzhen, China, Chengdu, China, Shenyang,
China
Underline mechanisms of transient continuous subcutaneous insulin
infusion (CSII) induced long-term remission in severe newly diagnosed type
2 diabetes (T2DM) remains unclear. Aim of the present study is to explore
major predictors of the remission. Method: 134 newly diagnosed T2DM with
HbA1c 11.1% accepted intensive CSII therapy for 2 weeks, then followed for
at least 2 years. Glucose clamp tests and IVGTT were performed to assess
glucose infusion rate (GIR), acute insulin response (AIR) and acute glucagon
response (AGR) before and after CSII. Multivariate analysis was used
to identify predictors of the remission, which was defined as the HbA1c
less than 7.0% and PG2h less than10 mmol/l without any hypoglycaemic
agents. Results: (1) GIR(6.2 vs. 3.8 mg.kg-1.min-1 p<0.0001), AIR(74.2 vs.
51.6mU.L-1.min,p<0.01) and AGR (1201.6 vs. 1111.3 pg.ml-1.min, p=0.002)
were significantly improved after the CSII compared with it before. (2) The
remission rate was 58.2%, 47.6%, 41.1% and 30.6% at 6, 12, 18 and 24
month after the CSII respectively. Cox model analysis showed that GIR (HR
0.5, p=0.027), AGR (HR 0.99,p=0.04) (but not AIR, HR=0.81,p=0.16) after the
2-week insulin therapy and age at diagnosis of diabetes (HR 1.027, p=0.02)
independently associated with remission. However if the HOMA_IR and
HOMA_β were used instead of GIR and AIR, it was showed that HOMA_IR
before (HR1.58, p=0.018) and after CSII (HR 2.42, p=0.018), HOMA_β (HR
0.365, p<0.0001) after CSII independently associated with the remission.
Of note, among which the HOMA_IR had the biggest contribution to the
remission (R2=0.15, contributed to 50% of the total changes of remission,
whereas the R2 of HOMA_β was 0.05). Conclusion: Insulin sensitivity
before and after the intensive insulin therapy rather than the improvement
of β-cell function is the major contributor of the long-term remission of
newly diagnosed diabetes.
&
For author disclosure information, see page 829.
A234
Guided Audio Tour poster
ADA-Funded Research
926-P
IDegAsp Shows Distinct Prandial and Basal Glucose-Lowering Effects at Steady State in Subjects With Type 1 Diabetes
YUN NING, JENNY JIANG, MICHAEL VAN PETTEN, LUIZ BELARDINELLI, ARVINDER K. DHALLA, Fremont, CA
TIM HEISE, LESZEK NOSEK, HANNE HASTRUP, SURESH CHENJI, OLIVER KLEIN,
HANNE HAAHR, Neuss, Germany, Søborg, Denmark, Bangalore, India
Hyperglucagonemia leads to increased hepatic glucose production and
plays a central role in development of hyperglycemia. Ranolazine (RAN)
is an anti-anginal drug and also has anti-diabetic properties. It inhibits
glucagon release from pancreatic islets, suggesting that it may exert the
anti-hyperglycemic effects via a novel glucagon-lowering mechanism. This
study determined the effect of RAN on glucagon secretion in streptozotozin
(STZ)-induced diabetic rat model. Two weeks after STZ injection (65
mg/kg, i.p.) rats had hyperglycemia (from 83 ± 3 to 367 ± 10 mg/dL) and
hyperglucagonemia (from 126 ± 7 to 219 ± 16 pg/mL). During an oral glucose
tolerance test (oGTT), administration of RAN (30 mg/kg, p.o.) to diabetic
rats 15 min prior to glucose load decreased glucagon levels from 194 ± 21
to 157 ± 19 pg/mL. Glucagon levels were significantly higher in vehicletreated diabetic rats compared with non-diabetic animals (258 ± 24 pg/mL
vs. 130 ± 10 pg/mL) at 15 min post-glucose load. RAN treatment significantly
lowered glucagon levels in diabetic rats (AUC RAN: 408 ± 229 pg/mL*min
vs. vehicle: 1232 ± 206 pg/mL*min, P<0.05). Consistent with the reduction in
glucagon levels, glucose AUC was also significantly lower in RAN-treated
rats (AUC RAN: 9662 ± 546 mg/dL*min vs. vehicle: 13200 ± 1233 mg/dL*min,
P<0.05). To rule out the potential for RAN to interfere with hypoglycemiainduced glucagon release, the effect of RAN was also assessed during
insulin-induced hypoglycemia in normal rats. RAN administration during
the hypoglycemic clamp did not affect the normal glucagon response;
whereas glibenclamide, an insulin secretagogue, significantly prevented
hypoglycemia-induced glucagon release. In summary, data show that RAN
normalized the exaggerated postprandial glucagon response in diabetic
rats without affecting the hypoglycemia-induced glucagon secretion. This
glucagon lowering effect of RAN may be the mechanism of the anti-diabetic
effects of RAN in non-clinical and clinical studies.
Insulin degludec (IDeg)/insulin aspart (IAsp) is a soluble combination of
70% IDeg and 30% IAsp providing both ultra-long-acting basal coverage
and a prandial insulin bolus in a single injection. The pharmacodynamic
properties of IDegAsp at steady state in subjects with T1DM were examined
in a single-centre, multiple-dose trial. To achieve steady state of the basal
component, subjects received once-daily IDeg (0.42 U/kg) for 5 consecutive
days (with separate bolus IAsp as needed for safety and glycaemic control).
On Day 6 a 30-h euglycaemic clamp procedure was performed (Biostator,
glucose target: 100 mg/dL) after a single dose of IDegAsp (0.6 U/kg
comprising 0.42 U IDeg and 0.18 U IAsp). Twenty-two subjects (mean age,
40 y; HbA1c, 7.9%; duration of diabetes, 23 y) were exposed to treatment.
The mean glucose infusion rate (GIR) profile showed a rapid onset of
action and a distinct peak followed by a flat basal action (Fig 1). Median
time to maximum glucose-lowering effect of IDegAsp (tGIRmax) was 2.5 h.
Duration of action (from dosing until blood glucose was consistently >150
mg/dL) extended beyond 30 h in all subjects. In conclusion, at steady state
the glucose-lowering effect of IDegAsp in subjects with T1DM showed a
distinct peak action due to IAsp, and a separate and stable basal action
from IDeg sustained for >30 hours. This profile may constitute a clinical
advance, allowing for the combination of specific meal coverage with full
24-h basal coverage.
925-P
Chronic Dosing of a Liver-Specific Glucokinase Activator (LGKA)
Decreases Fasting Hyperglycemia (HG) by Decreasing Hepatic Glucose Production (HGP) in Zucker Diabetic Fatty Rats (ZDF)
ERIN C. HEALEY, TRACY P. O’BRIEN, GREGORY A. MCCOY, TIFFANY D. FARMER,
DEREK M. ERION, JEFFREY A. PFEFFERKORN, MASAKAZU SHIOTA, Nashville,
TN, Cambridge, MA
Glucokinase plays an important role in regulating hepatic glucose
metabolism and liver selective activation of the enzyme is emerging as a
therapeutic strategy for T2DM. (S)-6-(3-cyclohexyl-2-(4-(trifluoromethyl)1H-imidazol-1-yl) propanamido) nicotinic acid is a potent (EC50: 79±3 nM
for human and 170±7 nM for rat) LGKA that exhibits enhanced distribution
to the liver (liver:plasma = 9) and impaired distribution into the pancreas
(pancreas:plasma = 0.05). ZDF were dosed LGKA at 100 mg/kg (ZDF-G) or
vehicle (ZDF-V) once daily for 6 wks. Blood was collected prior to treatment
(W0) and at 2 (W2), 4 (W4) and 6 wks (W6). A HG clamp study was performed
at W6 on 6-h fasted conscious animals.
The ZDF-G group had a 30% decrease in HG within 2 wks of treatment
compared to ZDF-V without alteration of plasma insulin (INS) and glucagon
(GGN) concentrations. At W6, under the basal condition, ZDF-G decreased
HG (19.0±1.8 vs 21.6±0.7) and also was associated with slightly lower
glucose utilization rates (Rd, µmol/kg/min: 56±5 vs 65±5) and HGP (µmol/kg/
min: 60±5 vs 69±4), compared to ZDF-V. During HG clamp studies in which
plasma glucose (PG) were similar between groups, the ZDF-G had higher
Rd (73±5 vs 56±5) and further decreased HGP (50±8 vs 66±8) that was
associated with reduced gluconeogenesis (29±5 vs 48±6) and higher PG
incorporation into hepatic glycogen (µmol/g: 20.6±3.2 vs 8.0±2.1) compared
to that in ZDF-V.
In ZDF-G, plasma triglyceride (TG) increased by 40% within W2 (mg/ml:
2.8±0.2 vs 2.6±0.3 at W0 to 4.1±0.5 vs 2.3±0.2 at W2, 4.3±0.2 vs 2.8±0.4 at
W4 and 4.3±0.3 vs 2.6±0.4 at W6) without changes in plasma FFAs. The TG
content in liver at W6 (mg/g: 13.1±1.1 vs 14.1±2.6) and muscle (9.0±2.0 vs
12.6±2.4) were similar between groups.
Chronic dosing of LGKA improved hyperglycemia by decreasing gluconeogenesis and increasing glycogen synthesis. LGKA treatment was
associated with increased plasma but not liver or muscle TG.
ADA-Funded Research
&
Supported by: Novo Nordisk, Inc.
927-P
Impact of Short-Acting Insulin Analogs on Biomarkers of Oxidative
Stress and Chronic Systemic Inflammation in Patients With Type 2
Diabetes: Results from a Pilot Study
ANKE PFÜTZNER, THOMAS FORST, MICHAEL MITRI, ANDREAS LÖFFLER, JULIA
HEISE, CLAUDIA FORKEL, ANDREAS PFÜTZNER, Mainz, Germany
This pilot study investigated hypothesis generating data regarding
the impact of short-acting insulin analogs (insulin aspart, IA, and insulin
glulisine, IG) in comparison to regular human insulin (RHI) on biomarkers
of inflammation and oxidative stress during an oral glucose challenge
experiment (OGTT) in patients with type 2 diabetes. Twelve patients were
enrolled into this trial (11 male, 1 female, age: 64±9 yrs., HbA1c: 7.1±0.6 %,
BMI: 31.5±4.9 kg/m²). They were randomized (4/treatment arm) to intensive
insulin therapy with insulin glargine and either IA, IG, or RHI as short-acting
insulin component. An OGGT was performed at baseline and after six months
with assessment of nitrotyrosine, hsCRP and mRNA macrophage activation
markers (IL6, TNFalpha, eNOS, MAPK1) after 0, 1 and 2h. Reduction of HbA1c
to near normal levels, and similar and unchanged glucose excursions during
the OGTT were seen in all three groups. A reduction in nitrotyrosine levels
was seen with both analogs (-33 %), while RHI led to an increase (+31 %,
p<0.05 vs. the combined analogs). IL-6 expression decreased slightly with
IG (-5 %), while it increased with IA (+142%) and RHI (+64 %). TNFalpha
expression decreased in all three groups (IG: -35%, IA: -71%, RHI: -30%).
Vasoprotective eNOS expression increased with IG (+25 %), decreased with
IA (-28 %), and was stable with RHI (+1 %). Growth hormone effect indicating
MAPK1-expression was reduced in all three groups (-16%, -23%, -33%). In
parallel, hsCRP was significantly reduced by -78 % with IG only (IA: -2%,
RHI: - 11%, p<0.05 vs. IG in both groups). In this pilot study, an improvement
of the inflammatory vascular situation could generally be observed with
For author disclosure information, see page 829.
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A235
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924-P
Ranolazine Suppresses Exaggerated Postprandial Glucagon Response in STZ-Induced Diabetic Rats
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
all insulin regimens, while a particular improvement in cardiovascular risk
as indicated by a consistent trend of improvement of all reported markers
was seen with IG only. These results need be confirmed in appropriately
designed larger clinical trials.
proteins suggest that the improvement of endothelial function contributes
to CBF augmentation.
Supported by: Novo Nordisk, Inc.
Supported by: Sanofi
930-P
Optimizing Insulin PK to Improve Glucose Control With a Bionic
Pancreas
928-P
Increased 1,5-Anhydroglucitol Predicts Long-Term Glycemic Remission in Patients With Newly Diagnosed Type 2 Diabetes Treated
With Short-Term Intensive Insulin Therapy
MANASI SINHA, FIRAS H. EL-KHATIB, EDWARD R. DAMIANO, STEVEN J. RUSSELL, Boston, MA
The objective is to correlate insulin lispro time-to-peak plasma levels
after injection (tmax) with anti-insulin antibody (ab) titers in adults and
children with T1DM.
Plasma insulin lispro levels in adult (21-72 yo) and pediatric subjects (1221 yo) with T1DM participating in bionic pancreas trials were measured
every 30 min. Models for pharmacokinetics of insulin lispro were derived
by fitting a summation of the exponential accumulation and decay functions
for each bolus to the measured insulin lispro levels using a least-squares
minimization protocol. The tmax values were derived from the fitted model
for each subject. Antibody titers against regular human insulin were
measured by a competitive binding assay for the 1st adult study and by a
non-competitive binding ELISA assay in the 2nd adult study and pediatric
study. Values were normalized for both assays such that lowest value
measured was normalized to 0 and highest to 1 (Fig).
Insulin lispro tmax varied from 31-191 min (mean 83±43) in adults and
57-138 min (mean 79±24) in pediatric subjects. High tmax values correlated
with high insulin antibody titers measured by both assays.
There was a high degree of variability in the speed of insulin lispro
absorption in both groups. Slow absorption may be mechanistically related
to autoimmunity against insulin. A potential mechanism is binding of insulin
lispro by antibodies in the interstitial fluid after injection, thereby slowing
diffusion out of the injection depot and absorption into the blood.
POSTERS
Clinical Diabetes/
Therapeutics
LIEHUA LIU, XUESI WAN, ZHIMIN HUANG, DONGHONG FANG, HAI LI, AILING
CHEN CHEN, WANPING DENG, YANBING LI, Guangzhou, China
Our previous study showed that in patients with newly diagnosed type 2
diabetes mellitus (T2DM) treated with short-term continuous subcutaneous
insulin infusion (CSII), serous 1,5-anhydroglucitol (1,5 AG) 1 month after the
therapy could predict a 3-month glycemic remission. However, the longterm predictive effect remains to be validated.
We enrolled 61 patients with newly diagnosed T2DM. After anthropometric measurements, fasting plasma glucose (FPG), fasting insulin, 2h
post-prandial glucose(PPG), glycated hemoglobin A1c (A1C) and 1,5 AG
were determined. CSII was used in all patients to achieve and maintain
euglycemia (fasting capillary blood glucose 4.4-6.1mmol/L, postprandial
capillary blood glucose 4.4-7.8mmol/L) for 2 weeks. After the cessation of
CSII, baseline assessments were repeated. The patients were then followed
up monthly for 3 months and every 3 months afterwards with FPG and 2hPG
monitored. 1,5AG were measured at 1-month follow-up. Maintenance of
optimum glycemic control (FPG<7.0mmol/L,2hPG<10mmol/L) for 1 year was
defined as remission.
After the therapy, FPG (11.8±3.0 vs. 6.6±1.7mmol/L,P<0.001), PPG
(17.6±5.7 vs. 8.6±3.0mmol/L, P<0.001) and A1C(11.1±1.7 % vs. 9.5±1.3%,
P<0.001) decreased. 1,5AG elevated significantly over time (baseline,
2.8±3.0mg/L, after CSII, 7.9±3.8 mg/L, 1 month, 9.9±4.4 mg/L, P<0.001).
Logistic regression analysis showed that 1,5 AG at 1-month follow-up
predicted 1-year remission independent of age, BMI, HOMA IR, FPG and
PPG after CSII (OR 1.37,95%CI [1.12,1.69], P=0.03). The area under the curve
of 1,5AG in the receiver operating characteristic curve analysis was 0.84
(95% CI 0.74–0.94, P < 0.001), and the optimal cutoff point was 9.28 mg/L
(sensitivity 81.8%,specificity 75.0%).
We concluded that 1,5 AG 1 month after CSII therapy can be used as a
predictor of long-term remission after short-term intensive insulin therapy
in newly diagnosed T2DM.
929-P
Increase in Microcirculatory Cutaneous Perfusion With Improved
Endothelial Function after Insulin Treatment in Poorly Controlled
Type 2 Diabetic Patients—The INSUVASC Study
MARINOS FYSEKIDIS, KARIM TAKBOU, YAYA JABER, EMMANUEL COSSON,
PAUL VALENSI, Bondy, France
The aim of this study was to examine the changes in cutaneous blood
flow (CBF) at fasting and post-prandially, in poorly controlled type 2 diabetic
(T2D) patients after insulin treatment.
The INSUVASC study was a unicenter pilot, open labeled study. We
included 42 poorly controlled T2D patients (mean age 53.8±9.6 years,
HbA1c 9.0±1.4%). CBF was measured with a laser doppler device for a
6-minute period at rest and for 3 minutes after acetylcholine iontophoretic
administration, at fasting (H0) and one to two hours (H1, H2) after a
standardised breakfast. Vascular sympathetic activity at rest was
evaluated by the 0.1Hz CBF spectral peak. Patients randomly received one
of the three insulin regimens (Aspart (A), Detemir (D) or Aspart combined
with Detemir(AD)) during four weeks.
A total of 34 patients had good quality CBF measurements (A: n=8, D:
n= 14 or AD: n=12) and completed the study. Age, BMI, HbAlc did not differ
at baseline across the groups. CBF changes (expressed as % of the first
baseline value) increased after breakfast, before (H2: 57±14%, p< 0.001) and
after (H2: 83±25%, p=0.005) insulin treatment. After insulin treatment, at
fasting, CBF increased (H0:30±10%, p=0.009), without significant correlation
between CBF and glycaemia, CBF response to acetylcholine improved (area
under the curve, maximum perfusion and vasodilation duration, p<0.05),
and serum VCAM (p=0.021) and E-selectin (p=0.002) decreased. Spectral
analysis showed no increased sympathetic activation and no significant
differences across insulin regimens.
CBF increased at fasting after insulin treatment independently of blood
glucose changes. The lack of sympathetic activity changes, the increase
in acetylcholine stimulated response and the decrease in adhesion glyco-
Supported by: Leona M. and Harry B. Helmsley Charitable Trust; NIH/NIDDK
931-P
A Clinical Utility Index for Selecting an Optimal Insulin Dosing Algorithm for LY2605541
DAVID H. MANNER, JUNXIANG LUO, YONGMING QU, SCOTT BERRY, BRENDA
GAYDOS, SCOTT J. JACOBER, Indianapolis, IN, Austin, TX
Selecting an optimal insulin dosing algorithm is difficult due to multifaceted
dependent outcomes. In a utility-based approach to this issue, a Clinical
Utility Index (CUI) was created by a priori weighing the relative benefit/risk
(via expert input) of 4 components (Figure 1). Individual component value
functions were created and the values multiplied to compute a single utility
value for each dosing algorithm for a novel long-acting basal insulin analog,
LY2605541 (LY). The CUI was then slightly modified and retrospectively
applied to data obtained from a Phase 2 type 2 diabetes trial in which
patients were randomized to 1 of 2 LY dosing algorithms (LY1 or LY2) or
insulin glargine (GL) (Table 1). The overall CUIs for LY1 and LY2 relative to GL
showed that LY2 seemed to perform better than LY1.
The overall CUI results are generally consistent with the interpretation of
the components. Based on this CUI, LY2 is more likely to be a better dosing
algorithm than LY1.
&
For author disclosure information, see page 829.
A236
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
These data suggest that non-critically ill patients with hyperglycemia
receiving steroids require a higher percentage of their insulin TDD as
nutritional insulin to achieve normoglycemia.
Table 1. Clinical Utility Index (CUI) Components and Computed Values for 2
LY Dosing Algorithms Relative to GL Dosing
Components
LY1a
LY2a
GLa
LY1/GL CUI LY2/GL CUI
(n=98)
(n=97)
(n=93)
1. LSmean Change from Baseline in HbA1c (%) (SE) -0.64 (0.07) -0.83 (0.07) -0.64 (0.08)
1.00
1.23
2. Percent of Patients Achieving HbA1c <7%
55.3%
51.7%
48.4%
1.17
1.08
3. LSmean Total Hypoglycemia Rate (Events/
1.74 (0.33) 1.59 (0.31) 1.68 (0.36)
0.91
1.13
Patient/30 Days) (SE)
4. LSmean Time When 50% of Patients Reached
5.00
4.00
3.14
0.77
0.89
Steady-State Dose (Weeks)
CUI
LY1/GL: 0.82, LY2/GL: 1.35
(4 Components)
CUI probabilitiesb for LY2>LY1, LY2=LY1, and LY2<LY1 are 48%, 24%, and
28%, respectively.
CUI
LY1/GL: 1.07, LY2/GL: 1.51
(Components 1-3)
CUI probabilitiesb for LY2>LY1, LY2=LY1, and LY2<LY1 are 46%, 24%, and
30%, respectively.
aBergenstal et al, Diabetes Care 2012;35(11):2140-7.
bBased on 3000 bootstrap samples.
Supported by: NIH
933-P
The Distinct Prandial and Basal Pharmacodynamics of IDegAsp
Observed in Younger Adults are Preserved in Elderly Subjects With
Type 1 Diabetes
Supported by: Eli Lilly and Company
932-P
Insulin Requirements in Non-Critically Ill Hospitalized Patients
With Steroid-Induced Hyperglycemia
ELIAS SPANAKIS, NINA SHAH, KEYA MALHOTRA, TERRI KEMMERER, HSINCHIEH YEH, SHERITA H. GOLDEN, Baltimore, MD
Supported by: Novo Nordisk, Inc.
Steroid administration to hospitalized patients frequently results in
hyperglycemia. Guidelines for glucose management in this setting are
lacking. We conducted a retrospective chart review of all non-critically
ill inpatients with diabetes or hyperglycemia receiving steroids from
1/2009 to 12/2010. Forty-one patients were identified from 514 consults.
Normoglycemia was defined as a patient-day weighted mean blood glucose
[PDWMBG] of 70-180 mg/dL and hyperglycemia as a PDWMBG>180 mg/
dL. Multivariable linear regression was used to compare the insulin total
daily dose (TDD), percentage of TDD given as basal and nutritional insulin,
and TDD/kilogram (kg) body weight between normoglycemic versus
hyperglycemic patients, adjusting for age, sex, race, and diabetes type and
duration.
Twenty-one patients achieved normoglycemia during admission
(PDWMBG=153±16 mg/dL) and 20 patients remained hyperglycemic
(PDWMBG=233±33 mg/dL)(p<0.001). There was no difference in age, sex
distribution, hypoglycemia, or type or duration of diabetes between the
groups; however, those with hyperglycemia were more likely to be Black
(65%) compared to those who achieved normoglycemia (28.5%; p=0.04).
Following multivariable adjustment, compared to hyperglycemic patients,
normoglycemic patients had significantly lower percentage of insulin TDD
(basal + nutritional) given as basal (40%±4% vs 60%±4%; p<0.001) and a
significantly higher percentage given as nutritional (45%±8% vs 19%±8%,
p=0.009). Although not statistically significant, TDD/kilogram (kg) bodyweight
was higher in normoglycemic versus hyperglycemic patients (0.92±0.14 units/
kg versus 0.71±0.14 units/kg; p=0.21). Results were similar in subsidiary
analyses excluding individuals with hypoglycemia during admission.
ADA-Funded Research
&
934-P
Physical Health Status and Nocturnal Hypoglycemia With Insulin
Degludec vs. Insulin Glargine: A 2-Year Trial in Insulin-Naïve Patients With Type 2 Diabetes
HELENA W. RODBARD, BERTRAND CARIOU, BERNARD ZINMAN, YEHUDA HANDELSMAN, MICHAEL L. WOLDEN, AZHAR RANA, CHANTAL MATHIEU, Rockville,
MD, Nantes, France, Toronto, ON, Canada, Tarzana, CA, Søborg, Denmark, Leuven,
Belgium
Insulin degludec (IDeg) is a new basal insulin with an ultra-long and
stable glucose-lowering effect. We compared once-daily IDeg and insulin
glargine (IGlar) (randomized 3:1) both in combination with metformin ± DPP4 inhibitors in an open-label, treat-to-target trial in patients with type 2
diabetes (T2D). Health status was assessed at baseline and 105 weeks using
the Short Form 36 (SF-36 v2) questionnaire. SF-36 scores were analyzed (ITT
population) using ANOVA, with adjustments for relevant covariates. After
an initial 1-yr study period IDeg improved overall SF-36 physical health and
functioning compared to IGlar. This was followed by a 1-yr extension in
which subjects maintained their randomized treatment assignment.
Of 1,030 subjects, 725 entered the extension and 659 (IDeg: 505; IGlar:
154) completed 2 yrs of treatment. At 105 weeks, IDeg was similar to
IGlar with respect to change in A1C from baseline, but was associated
with a significantly greater reduction in FPG (-6.8 mg/dL [-12.6; -1.1] 95% CI,
p=0.02). Rates of overall confirmed hypoglycemia (PG <56 mg/dL, or severe)
were similar between groups, whereas the rate of nocturnal confirmed
For author disclosure information, see page 829.
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Insulin degludec (IDeg)/insulin aspart (IAsp) is a soluble combination
of 70% IDeg and 30% IAsp, providing both ultra-long basal coverage and
a prandial insulin bolus in 1 injection. The pharmacodynamic profiles of
IDegAsp and biphasic IAsp 30 (BIAsp 30) were investigated in a singlecentre, double-blind, two-period, single-dose, crossover trial in elderly (≥65
y) and younger (18-35 y) adults with type 1 diabetes randomly assigned 2 0.5
U/kg single-dose administrations of IDegAsp or BIAsp 30. Following each
dose a 26-h euglycaemic clamp was performed (glucose target: 100 mg/dL).
Fifteen elderly (mean age 68 y, duration of diabetes 34 y, BMI 25.2 kg/m2,
HbA1c 7.5%) and 13 younger (mean age 25 y, duration of diabetes 13 y, BMI
23.2 kg/m2, HbA1c 7.4%) adults were randomised and completed the trial.
Mean 24-hour area under the glucose infusion rate curve (AUCGIR,0-24h,SD)
for IDegAsp was similar for elderly (geometric mean 1794 mg/kg [CV 62%])
and younger (1786 mg/kg [CV 28%]) subjects (mean ratio elderly/younger
adults 1.01, 95% CI: 0.69; 1.47). Prandial coverage (AUCGIR,0-6h,SD) was
comparable between elderly (geometric mean 909 mg/kg [CV 45%]) and
younger adults (1001 mg/kg [CV 25%]). In conclusion, the glucose-lowering
effect of IDegAsp is preserved in elderly subjects with type 1 diabetes (Fig
1), consisting of a distinct peak action due to the prandial IAsp, in addition
to the stable, sustained ultra-long action of IDeg.
Clinical Diabetes/
Therapeutics
THOMAS PIEBER, STEFAN KORSATKO, SIGRID DELLER, HARALD KOJZAR,
CARSTEN ROEPSTORFF, ANNE LOUISE SVENDSEN, HANNE HAAHR, Graz, Austria, Søborg, Denmark
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
hypoglycemia (12:01AM to 5:59AM) was significantly lower (by 43%,
p<0.01) for IDeg.
Consistent with previously reported findings for the initial 1-yr trial
period, the overall physical component score was significantly better with
IDeg vs IGlar after 2-yrs (treatment contrast (TC): 1.1 [0.1; 2.1], p<0.05). This
was largely due to significantly better physical functioning (TC: 1.1 [0.0;
2.3], p<0.05) and bodily pain sub-domain scores (TC: 1.5 [0.2; 2.9], p<0.05).
Consistent with 1-yr data, other SF-36 domain scores showed no significant
differences between groups.
In conclusion, a significantly better physical health status and lower risk
of nocturnal hypoglycemia is maintained for IDeg vs IGlar following the
second year of treatment of insulin-naïve patients with T2D.
The Clinical Characteristics of the groups
Categories
SW group
(n=20)
BMI
20.3±2.5
TDD (U)
25.7±6.3
eGFR
56.8±41.6
%basal (%)
30.6±9.3
Diabetic retinopathy(Non/background/ 4/4/1/11
prePDR/PDR or more advanced)
NW group Significance
(n=28)
22.3±2.8
p<0.01
35.0±10.4 p<0.001
87.6±23.5 p<0.01
24.5±5.6
p<0.01
17/6/0/5 p<0.005
Supported by: Japan Diabetes Foundation
Supported by: Novo Nordisk, Inc.
937-P
935-P
Characterization of Insulin Glargine Protraction Mechanism and
Metabolism In Vivo
NORBERT TENNAGELS, HANS-PAUL JURETSCHKE, RONALD SCHMIDT, TANIA
ROMACHO-ROMERO, JUERGEN ECKEL, ULRICH WERNER, Frankfurt, Germany,
Düsseldorf, Germany
JITEN VORA, HELENA W. RODBARD, HENRIETTE MERSEBACH, RAHUL KAPUR,
STEWART B. HARRIS, Liverpool, United Kingdom, Rockville, MD, Søborg, Denmark,
London, ON, Canada
POSTERS
Clinical Diabetes/
Therapeutics
Lower Risk of Hypoglycemia With Insulin Degludec vs. Insulin
Glargine in Patients Diagnosed With Type 2 Diabetes for >10 Years:
Meta-Analysis of Five Randomized Trials
Insulin glargine (GLA) is a long-acting insulin analog with proven safe
and effective 24-hour glycemic control. GLA differs from human insulin by
substitution of Asp by Gly in position 21 of the A chain and by carboxyterminal extension of the B-chain by 2 Arg residues causing a pI-shift from
pH 5.4 to 6.7. Following s.c. administration as a clear solution of pH 4,
GLA forms a microprecipitate at the injection site, from which it is slowly
released but then rapidly metabolized to its major metabolite M1 that is
responsible for the pharmacodynamic effects in humans and animals.
In this study we characterize the mechanism of protraction and
metabolism of GLA in more detail. GLA injection into the subcutis of a rat
neck and subsequent inspection of the injection site indicated the formation
of a local amorphous depot. Protease activity as measured by near infrared
spectroscopy in these animals, and previous observation of efficient
degradation to M1 at the injection site in humans, suggests the contribution
of proteases to the dissolution process and metabolism in the s.c. depot. In
addition, i.v. studies in different species demonstrating a rapid formation of
M1 indicated that further metabolism can take place in the circulation.
Proteomic analysis of supernatants of human subcutaneous adipose
tissue revealed several proteases that are secreted into the medium and
might be involved in the rapid and efficient metabolism of GLA in the local
tissue. Among these, metallocarboxypeptidase E (CPE) could be validated
as effectively and rapidly degrading GLA to M1 in vitro. CPE is an adipokine
released by human adipocytes whose expression is upregulated during
adipogenesis.
In summary our data indicate that local depot formation by GLA is
followed by degradation already at the s.c. injection site and continues in
the circulation. Consequently, injection of GLA results in the rapid formation
of M1 as the principal circulating insulin that has a metabolic and mitogenic
activity comparable to that of human insulin.
Insulin degludec (IDeg), an ultra-long-acting basal insulin with a stable
and consistent glucose-lowering effect, is shown to be associated with
significantly lower rates of overall (17%) and nocturnal hypoglycemia
(32%) compared to insulin glargine (IGlar) in a pre-planned meta-analysis
of patients with type 2 diabetes (T2D). T2D is a progressive disease where
the incidence and rates of recurrent hypoglycemia increase with diabetes
duration and consequent intensification of insulin therapy. In this post-hoc
meta-analysis, hypoglycemia rates were compared between IDeg and IGlar
in a subset of T2D patients with a diabetes duration >10 years.
The meta-analysis included all five phase 3a, open-label, randomized,
treat-to-target (FPG < 90 mg/dL) clinical trials of 26 or 52 weeks’ duration in
which once-daily IDeg and IGlar were compared in T2D patients. Analysis
of A1C and FPG was based on an ANCOVA model; analysis of hypoglycemic
episodes was based on a negative binomial regression model.
In all, 1,651 (IDeg: n=1,143; IGlar: n=508) of 3,372 randomized patients had a
duration of T2D >10 years and were included in the meta-analysis. Treatment
groups were similar with respect to mean A1C at end-of-trial (treatment
difference (TD) IDeg−IGlar: 0.08% [-0.02; 0.17]95% CI; NS). IDeg was associated
with a significantly greater reduction from baseline in mean FPG (TD: -10.1 mg/
dL [-14.2; 5.8]; p<0.01). The rate of overall confirmed hypoglycemia (plasma
glucose < 56 mg/dL and severe episodes requiring assistance) was 21% lower
with IDeg vs IGlar (p<0.01); the rate of nocturnal confirmed hypoglycemia
(onset from 12.01AM to 5.59AM) was 29% lower with IDeg vs IGlar (p<0.01).
In conclusion, this meta-analysis demonstrates that treatment with
IDeg provides important clinical advantages in patients with a long-term
T2D. This includes significantly lower rates of both overall and nocturnal
hypoglycemia than IGlar at similar A1C levels.
Supported by: Sanofi
Supported by: Novo Nordisk, Inc.
936-P
938-P
The Characteristics of Type 1 Diabetic Patients Who Use Insulin
Pump With Square-Wave Bolus Insulin
Insulin Degludec Multi-Hexamers Retain the Native Protein Fold
of Human Insulin
AKIO KURODA, TAKESHI KONDO, KEN-ICHI AIHARA, ITSURO ENDO, TETSUYUKI
YASUDA, HIDEAKI KANETO, TAKA-AKI MATSUOKA, TOSHIO MATSUMOTO,
MUNEHIDE MATSUHISA, Tokushima, Japan, Suita, Japan
DORTE B. STEENSGAARD, MATHIAS NORRMAN, JADE BEARHAM, CHRISTIAN B. ANDERSEN, ANDERS V. FRIDERICHSEN, HOLGER M. STRAUSS, GERD
SCHLUCKEBIER, IB JONASSEN, Måløv, Denmark
Backgrounds: Square-wave bolus insulin of insulin pump might be a
beneficial option for patients with gastroparesis or with quick insulin
absorption. It has not been investigated the insulin pump setting in the
patients who use normal bolus insulin and square-wave bolus insulin.
Methods: Fifty-two type 1 diabetic patients (T1DM), who were using
insulin pump, were investigated during 2-3 weeks of hospitalization. Each
meal omission was done to confirm basal insulin rate. The amount and
duration time of each bolus insulin was adjusted to set blood glucose to
100 and 150mg/dL before and 2 hours after meal, respectively. Insulin pump
setting and clinical characteristics were investigated.
Results: The square-wave (30-120 minutes) bolus insulin was necessary
to achieve target glycaemia in 25 patients. Twenty patients used squarewave bolus insulin (SW group) and 28 patients used normal bolus insulin
(NW group) in all meals. The clinical characteristics were shown in the table.
BMI (t=-2.105, p<0.05) and %basal (t=2.027, p<0.05) were the independent
determinants for SW group according to the multiple regression analysis.
Conclusions: Low BMI and high %basal are the independent determinants
for the use of square-wave bolus insulin.
Insulin degludec (IDeg), an ultra-long-acting basal insulin, forms a soluble
and stable depot of multi-hexamers after subcutaneous injection with a
subsequent slow release of monomers into circulation, resulting in a duration
of action of greater than 42 hours. In a formulation that includes both zinc
and phenol, IDeg is organized as finite di-hexamers, but upon injection,
dissociation of phenol allows the soluble depot of IDeg multi-hexamers
to form. The depot is composed of long strands of multi-hexamers with a
width of 6.3 ± 0.9 nm as observed by transmission electron microscopy.
We have conducted various types of spectroscopy to provide insight into
the structure of the IDeg molecule and its organization and self-assembly in
the multi-hexamer. Circular dichroism, Infrared-, and Raman- spectroscopy
showed that the fold of the protein backbone in the multi-hexamer is very
similar to that of native insulin. The alpha-helical band is predominant and
no signs of increased beta-sheet structure relative to that of human insulin
were observed. Small angle x-ray scattering demonstrated the presence of
strongly elongated structures with a repeated structural unit distanced by
34.8 Å, as indicated by a Bragg peak. The repeated distance originates from
hexameric stacking and is close to the inter-hexameric distance also found
&
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
in classical crystals of human insulin. In contrast, amyloid fibril structures
are characterized by a Bragg peak of 4.7 Å and a predominant beta-sheet
structure.
In conclusion, the IDeg multi-hexamers are composed of micrometer
long linear arrays of hundreds of insulin hexamers. The ultra-long duration
of action for IDeg relies on the formation of soluble multi-hexamers in
subcutaneous tissue, and the protein fold adopted by insulin degludec in
these multi-hexamers is very similar to that of human insulin.
Supported by: Novo Nordisk, Inc.
939-P
Long- Acting Insulin Analogues for Type 1 Diabetes Mellitus: A Systematic Review and Meta-Analysis
Clinical Diabetes/
Therapeutics
There is uncertainty regarding the optimal use of long-acting insulin
analogues in type 1 diabetic patients (T1DM) because they are much more
expensive than human neutral protamine Hagedorn insulin (NPH), with
similar clinical outcomes. A systematic review and meta-analysis of clinical
outcomes associated with long-acting insulin analogues in T1DM was
done by searching all relevant electronic databases till April 2012.The main
search concepts were T1DM and long-acting insulin analogues compared to
NPH. The outcomes considered were the reduction of glycated hemoglobin
(HbA1c) concentration and cumulative rate of hypoglycemia events (total,
nocturnal and severe).Two reviewers independently extracted data from
the articles and disagreements were solved by consensus. Sequence
analysis of titles, abstracts and full texts resulted in the selection of 16
trials (8 detemir, 8 glargin). Most of the studies were of short to medium
duration and of low quality. There was a high degree of heterogeneity that
was not explained by patient characteristics of treatments. 15 studies had
a parallel design and 3 were crossover. The studies included 4192 T1DM in
total, with 2496 in the intervention groups and 1941 in the control group.
Differences between insulin analogues and NPH in terms of HbA1c were
marginal (SMD for insulin detemir: -0.15%, 95% CI -0.32% to 0.02%; for
insulin glargin: -1.17%, 95% CI -2.44% to 0.10). Detemir had a protective
effect for nocturnal hypoglycemias (SMD: 0.61, 95% CI 0.54 to 0.69), and
marginal effect on total hypoglycemias (SMD:0.79, 95% CI 0.77 to 0.99).
Glargin insulin did not demonstrated advantages for total, nocturnal or
severe hypoglycemias (SMD:1.01, 95% CI 0.88 to 1.16), SMD 0.76, 95% CI
0.47 to 1.23, SMD 1.04, 95% CI 0.79 to 1.23, respectively).The results of
this meta-analysis demonstrate that in type 1 diabetic patients, long-acting
insulin analogues offer little benefit relative to conventional insulins in
terms of glycemic control or hypoglycemia events.
Supported by: Sanofi
940-P
941-P
Asian Treat to Target Lantus Study (ATLAS): A 24-Week Randomized, Multinational Study
Once-Daily Lixisenatide as Add-On to Basal Insulin ± OADs in Patients With Type 2 Diabetes Selectively Reduces Postprandial Hyperglycemic Daytime Exposure
SATISH K. GARG, KARIM ADMANE, NICK FREEMANTLE, ATLAS STUDY GROUP,
Aurora, CO, Paris, France, London, United Kingdom
Self-adjustment of insulin dose and patient empowerment have been
effective in achieving better glucose control. The ATLAS study evaluated
titration of insulin glargine in uncontrolled insulin-naïve patients on 2 OADs
in Asia. A total of 552 patients were randomized into 2 titration arms: 275
patient-led (PA), 277 physician-led (PH). Insulin dose was adjusted using the
same algorithm to achieve a target FBG of 110 mg/dL in both arms. The
primary objective was non-inferiority of change in A1c at 24 weeks from
baseline. Baseline demographics and A1c were similar in both groups. A
significant decrease in A1c was observed at Week 12 (-1.2%) and Week 24
(-1.3%). LS mean change from baseline (PA versus PH) was -0.15 (95% CI:
-0.29 to -0.00; p=0.04), showing superiority. Proportions of patients with
A1c < 7.0% without severe hypoglycemia (HYPO) (32.0% versus 26.0%,
p=0.11) were similar in both groups. HYPO rate was low. Compared to PH,
severe HYPO was similar, but nocturnal (p=0.002) and symptomatic HYPO
(p=0.02) were higher in PA. Mean (±SD) insulin daily dose was 8.2 U (2.7) at
baseline and 24.4 U (16.5) at Week 24 with a greater increase in PA (p<0.001).
Few (2.6%) unrelated serious adverse events were reported. We conclude
that insulin glargine titration, patient or physician-led, is safe and effective
in achieving near target glucose control in Asian patients uncontrolled on
OADs. Contrary to common belief, Asian patients titrated insulin dose up
effectively when guided, similar to patients in the West.
ADA-Funded Research
&
MATTHEW C. RIDDLE, YUTAKA SEINO, BERTRAND CARIOU, RICARDO GÓMEZ
HUELGAS, CHRISTINE ROY-DUVAL, CAROLE HECQUET, ANDRES DIGENIO, JULIO ROSENSTOCK, Portland, OR, Osaka, Japan, Nantes, France, Málaga, Spain,
Chilly-Mazarin, France, Bridgewater, NJ, Dallas, TX
Basal insulin reduces basal hyperglycemia (BHG) but A1C may remain
high due to persisting postprandial hyperglycemia (PPHG). Lixisenatide
(LIXI), a GLP-1 receptor agonist in development for the treatment of T2DM,
can reduce PPHG and A1C with no weight gain, or with weight loss, and
thus has properties complementary to those of basal insulin. Patient-level
data were pooled from 3 randomized Phase III studies of either once-daily
LIXI + standard of care (SOC; basal insulin ± oral agents) vs placebo (PBO)
+ SOC to quantify the effects of LIXI on BHG and PPHG exposures. BHG
(24-hr area above 5.6 mmol/L and under the fasting level) and incremental
PPHG (area above fasting and under self-monitored 7-point plasma glucose
profiles [AUC24h]) exposures were calculated by a previously reported
method (Diabetes Care 2011;34:2508-14). The 753 eligible patients with
evaluable profile data had mean age 57 years, BMI 29.8 kg/m2, diabetes
duration 11.5 years, A1C 8.15% and fasting glucose 7.5 mmol/L. At baseline,
mean daytime BHG and PPHG exposures were 49.2 and 55.1 mmol/L*h,
respectively. Mean BHG and PPHG contributions to hyperglycemia were
42 and 58%, respectively. After 24 weeks of treatment, adjusted LS mean
A1C change was -0.77% with LIXI + SOC and -0.29% with PBO + SOC
(p<0.0001). The BHG exposure values for LIXI + SOC and PBO + SOC were
similar (adjusted LS mean change for AUC24h -13 mmol/L*h vs -11 mmol/L*h
[NS]), but PPHG exposure was reduced more with LIXI + SOC compared
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A239
POSTERS
LUCIANA R. BAHIA, HELENA CRAMER, MARCIO LASSANCE, BRAULIO SANTOS,
BERNARDO TURA, Rio de Janeiro, Brazil
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
with PBO + SOC (adjusted LS mean change -21 mmol/L*h vs -10 mmol/L*h,
p<0.0001). The mean BHG and PPHG contributions to hyperglycemia were
46% vs 54% with LIXI + SOC and 39% vs 61% with PBO + SOC. In conclusion,
this analysis suggests that once-daily LIXI complements the effects of basal
insulin on glycemic control in type 2 diabetes, decreasing A1C mainly by
reducing PPHG.
943-P
Encapsulated Islet Sheet for Transplantation in Diabetic Yucatan
Pigs
LOURDES ROBLES, TIANYI ZHOU, MORGAN LAMB, MICHAEL ALEXANDER,
EARL STEWARD, REMICK STAHL, RAHUL KRISHNAN, RICHARD STORRS, RANDY DORIAN, SCOTT KING, JONATHAN R. LAKEY, Orange, CA, San Francisco, CA
Supported by: sanofi-aventis
Encapsulating islets in a matrix, which would protect the cells from the
body’s immune system, would have immense value in the treatment of
diabetes. Our focus is the development of a biocompatible and retrievable
alginate encapsulation method for the transplantation of isolated islets.
The aim of this study was to use a large animal model of diabetes to test
the in vivo effect of implanted islets encapsulated in alginate sheets.
Yucatan pigs (20-50 kg) were rendered diabetic by an intravenous
injection of Streptozotocin (STZ, 150 mg/kg). Diabetes was confirmed by
two consecutive days of blood glucoses >350 mg/dL. Insulin was given
twice a day post diabetes confirmation. Subsequently, pigs received four
intra-abdominal sheets, roughly the size of a business card, made of purified
alginate. Sheets contained an average of 360,000-390,000 islet equivalents
per pig. No immunosuppression was given to the transplant recipients.
Within 24 hours of STZ injection, pigs developed hyperglycemia with blood
glucose levels >600 mg/dL. Prior to transplantation, insulin requirements
were on average 0.8 U/kg/day to maintain average glucose levels of 336
mg/dl. After Islet Sheet transplantation the pigs recovered well with no
signs of morbidity throughout the entire experimental period. The average
insulin U/kg/day did not change post transplantation, however, sheets were
removed after 48 days and remained both dithizone positive and viable
(Newport green/PI) (Pre txp: 80.5 +/-3%, Post Txp: 78.2 +/- 4%).
This study provides a reliable and reproducible method of inducing
diabetes in a large animal model and provides a safe method of implanting
encapsulated islets. Although the sheets were found to contain significant
adhesions, viable islets were observed in the alginate sheets after an
extended period. Future plans will focus on solidifying the sheet structure
for prolonged in vivo survival.
942-P
Hospital Management of Patients Prescribed U-500 Regular Insulin
POSTERS
Clinical Diabetes/
Therapeutics
PURNIMA TRIPATHY, CECILIA LANSANG, Cleveland, OH
Patients on U500 regular insulin (U500) as home regimen are often
switched to different insulins when hospitalized. This study aims to
determine the insulin regimen used and glucose levels of U500 users who
are hospitalized.
Retrospective chart review done on adult patients on U500 as their home
regimen, admitted to the Cleveland Clinic from 2001-2011. Patients were
divided into those switched to a different regimen (Group A) and those
continued on U500 (Group B). A subset of patients on U500 for >50% of
their stay was studied. Glucose levels were compared by Wilcoxon rank
sum test. Rates of hypo- and hyperglycemic days were compared by Poisson
regression models.
Total 61 patients, 59% males, BMI 41.4+10.8 (mean + SD), age 59+12
yr, A1C 9.1+1.9%, length of stay 6.6+4.7 days,60.6% had Endocrinology
consult. 32.7% of patients were switched to a combination of long-,
intermediate-, short- and fast-acting insulin. Mean glucose levels were
not significantly different between groups (Table 1). Group A was given
much less insulin compared to home regimen. Group B had more frequent
hypoglycemia (15.3+21.3 vs 2.8+6.4%). Group B had higher frequency of
severe hyperglycemia (16.8+ 21.9 % vs 6.3+9.8%).
One-third of patients were switched to a different insulin regimen. The
similar glucose levels between groups, lower admission insulin doses in
Group A, more frequent hypoglycemia and severe hyperglycemia in Group
B, suggest U500 may not be suitable to continue in some patients when
hospitalized.
Supported by: Hanuman Medical Foundation; University of California, Irvine
944-P
Table 1
Group A
Group B
(not continued (continued
on U500)
on U500)
N=20
N=41
Blood glucose during
207.9
237.6
admission (mg/dL)
(128.2-335.6) (115.5-392.1)
Median (range)
Insulin dose prior to
100
235
admission (units)
(10.0-500.0) (10.0-2450.0)
Median (range)
Insulin dose during
34.8
200
admission (units)
(5.0-99.5) (19.0-1156.9)
Median (range)
% hypoglycemia- days
2.8 (6.4)
15.3 (21.3)
(BG < 70 mg/dL)
Mean (SD)
% severe hypoglycemia1.3 (5.6)
0.1 (0.8)
days (BG < 40 mg/dL)
Mean (SD)
% hyperglycemia- days
80.6 (24.2) 78.9 (28.0)
(BG >200 mg/dL) Mean (SD)
% severe hyperglycemia6.3 (9.8)
16.8 (21.9)
ays (BG >400 mg/dL) Mean (SD)
*NA=too few patients to compare
p Value
0.48
Metabolism of Insulin Glargine in T2DM on Long-Term Glargine Use:
A Double Blind, Randomized, Cross-Over, Dose Response Study
Group B
Group B p Value
patients
patients
on U500 for on U500 for
>50% of
<50% of
hospital stay hospital stay
N=34
N=7
229.2
290.3
0.14
(115.5-392.1) (159.3-346.0)
0.068
235
207.5
(10.0-2450.0) (10.0-480.0)
0.79
<0.001
223.2
129.7
(19.0-1156.9) (32.5-387.5)
0.16
<0.001
12.8 (19.1)
15.8 (21.9)
0.26
NA*
0.0 (0.0)
0.2 (0.9)
NA*
0.55
81.9 (28.4)
78.2 (28.3)
0.90
<0.001
32.5 (30.2)
13.6 (18.7)
0.20
PAOLA LUCIDI, FRANCESCA PORCELLATI, PAOLA CANDELORO, PATRIZIA CIOLI,
ANNA MARINELLI ANDREOLI, STEFANIA MARZOTTI, RONALD SCHMIDT, GEREMIA B. BOLLI, CARMINE G. FANELLI, Perugia, Italy, Frankfurt, Germany
After subcutaneous (s.c.) injection in humans, insulin glargine (GLA)
undergoes cleavage of the di-arginine in 30-B position and subsequent loss
of threonine (30-B) with formation of metabolites M1 and M2, which do not
differ from human insulin for mitogenesis. Aim of the present cross-over
study was to establish metabolism of GLA after s.c. injection of therapeutic
and high doses of GLA in subjects with T2DM on long-term use of GLA.
Ten subjects were studied during 24 h of fasting after s.c. injection of 0.4
and 0.8 U/kg of GLA given in the morning, on two separate occasions during
euglycemic clamps. GLA, M1 and M2 over 24 h period were extracted using
immunoaffinity columns and quantified by a specific liquid chromatographytandem mass spectrometry assay.
Plasma M1 (AUC0-24 h) was detected in all subjects with both doses of
GLA and increased by increasing the dose from 0.4 U/Kg to 0.8 U/Kg by
54% (95% CI: 39 to 91, p=0.008). GLA was detectable in plasma in only six
and nine out of ten subjects after dosing 0.4 and 0.8 U/Kg, respectively. M2
was not detected. At the high dose of 0.8 U/Kg, plasma GLA concentration
(AUC0-24h) represented only 9.7% (4.6 and 15) of the total amount of insulin
measured in the blood.
After s.c. injection of GLA, even at high dose, this is nearly totally
metabolized to the active metabolite M1 and GLA parent is generally
scarcely detectable in blood. In vivo, GLA does not exert its metabolic
effects directly, but via its main metabolite M1.
Supported by: Sanofi
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945-P
947-P
Insulin Degludec (IDeg) and Insulin Aspart (IAsp) Can Be Co-Formulated such that the Formation of IDeg Multi-Hexamers and IAsp
Monomers Is Retained Upon S.C. Injection
IDegAsp Produces Dose-Proportional Glucose-Lowering Effect in
Subjects With Type 1 Diabetes
Insulin degludec/insulin aspart (IDegAsp) is a 70%/30% combination of
insulin degludec (IDeg) and insulin aspart (IAsp), providing both an ultralong-acting basal component and a rapid-acting bolus component in 1
injection. The pharmacodynamic (PD) properties of 3 doses of IDegAsp (0.4,
0.6, 0.8 U/kg body weight) were investigated in a double-blind, single-dose
incomplete block crossover trial in subjects with type 1 diabetes (T1DM).
Following each dose a 26-h euglycaemic clamp procedure was performed
(Biostator, glucose target: 100 mg/dL). A total of 33 C-peptide-negative
subjects with T1DM (mean age 39 y, BMI 25.1 kg/m2, HbA1c 8.0%) were
included. With increasing dose, the 24-hour area under the glucose infusion
rate (GIR) curve (area under the curve [AUC]GIR,0-24h,SD) and the maximum GIR
(GIRmax,SD) increased significantly and proportionally. Estimated log doselog AUCGIR,0-24h,SD (1.19, 95% CI: 0.99; 1.40) and log dose-log GIRmax,SD (0.89
[0.66,1.13]) both supported dose proportionality as 1.0 was included in the
95% CI. The 24-hour single-dose GIR profile of IDegAsp showed a distinct
peak action due to prandial IAsp, and separate and stable basal action from
IDeg (Fig 1). In conclusion, IDegAsp produces a proportional dose-response
across 3 clinically relevant dose levels and a PD profile with separate
prandial and basal components in T1DM.
Supported by: Novo Nordisk, Inc.
946-P
Development and Validation of a Clinical Score to Predict Insulin
Requirement for Optimum Control of Blood Glucose during Glucocorticoid Treatment in Patients With Autoimmune Diseases
HIROYUKI MORITA, ICHIRO MORI, KEI FUJIOKA, HIDEYUKI OKADA, TARO USUI,
MAYUMI TANIMOTO, KAZUO KAJITA, TATSUO ISHIZUKA, Gifu, Japan
Long-term glucocorticoid (GC) treatment may be necessary for patients
with various types of autoimmune diseases. It is important to predict insulin
requirement in advance for optimum control of GC-induced hyperglycemia
in autoimmune diseases. The aim of the present study is to develop and
validate a score to predict insulin requirement for optimum control of blood
glucose during GC treatment. We retrospectively evaluated 146 patients
with autoimmune diseases admitted between 2004 and 2011 to develop the
prediction score. Inclusion criteria indicated that the dosage of prednisolone
treatment should be more than 5 mg/day for 4 weeks at least.
Exclusion criteria included insulin therapy before GC administration or
use of a GLP-1 analog. Seventeen percent of GC-administered patients
required treatment with insulin. A logistic regression analysis revealed that
risk factors of insulin requirement during GC administration should be raised
for males, FPG, HbA1c, and maximum dose of prednisolone (PSL). A ROC
analysis showed that cutoff values of FPG, HbA1c, and PSL were 99 mg/dl,
6.7%, and 0.75 mg/kg, respectively. We scored patients profiles as follows;
male, 1 point; FPG (mg/dl), 90-98,1 point, 99-109, 2 points, more than 110
mg/dl, 3 points; HbA1c (%), 5.8-6.6, 1 point, 6.7-6.9, 2 points, more than
7.0, 3 points; PSL (mg/kg), 0.50-0.74, 1 point 0.75-0.99, 2 points, more than
1.00, 3 points. Sum of the scores was 6.5±1.4 for insulin-required patients
vs. 2.9±1.5 for others. When 5 points was defined as the cut-off value of
the sum of the scores, the sensitivity, specificity and accuracy were 96%,
90% and 91%, respectively. We validated the scoring to another 42 patients
admitted in 2012. The sensitivity, specificity and accuracy were 83%, 87%
and 86%, respectively. The clinical score is a valid and reliable tool to
predict insulin requirement for optimum control of blood glucose during GC
treatment.
ADA-Funded Research
&
Supported by: Novo Nordisk, Inc.
948-P
Glargine vs. Premixed Insulin for Management of Type 2 Diabetes
Patients Failing Oral Antidiabetic Drugs: The GALAPAGOS Study
PABLO ASCHNER, BIPIN SETHI, FERNANDO GOMEZ-PERALTA, WOLFGANG
LANDGRAF, MARIE-PAULE DAIN, VALERIE PILORGET, ABDURRAHMAN COMLEKCI, Bogotá, Colombia, Hyderabad, India, Segovia, Spain, Frankfurt, Germany,
Paris, France, Izmir, Turkey
GALAPAGOS was a 24-wk, open-label, multinational, superiority trial
of glargine (GLA) (± glulisine) vs premixed insulin (PRE) in insulin-naïve
T2DM patients (pts) uncontrolled on OADs. Pts were randomized to GLA
QD or PRE (QD or BID) while continuing OADs (at least metformin ± insulin
secretagogue [IS]). A 2nd PRE injection could be added any time; glulisine
could be added with main meal in GLA QD pts with A1C ≥7% and FPG <126
mg/dL at ≥ week 12. IS was stopped with 2nd injection. Insulin titration
targeted FPG ≤100 mg/dL. Primary endpoint was % of pts with A1C <7% and
no symptomatic confirmed (PG ≤56 mg/dL) hypoglycemia at 24 wks.
mITT population comprised 923 pts (GLA: 462; PRE: 461). Baseline
characteristics were similar in both groups (mean T2DM duration: 9 y; A1C:
8.7%; FPG: 161 mg/dL). Table shows key study endpoints. Similar percentages
of pts reached the primary endpoint in both groups, demonstrating noninferiority (prespecified margin: 25% of PRE rate), but not superiority, of
GLA. More GLA (57.5%) than PRE pts (36.5%) stayed on 1 injection/day over
24 wks. Symptomatic hypoglycemia was less with GLA than PRE. Efficacy
predictors in both arms were geographic region, diabetes duration, baseline
A1C and number of OADs at baseline.
For author disclosure information, see page 829.
Guided Audio Tour poster
A241
POSTERS
Insulin degludec is an ultra-long-acting insulin which is the first basal
insulin that can be co-formulated with a fast-acting insulin analogue
(insulin aspart). It has been previously demonstrated in vitro that the
prolonged absorption of IDeg and its resulting ultra-long duration of action
are due to the formation of soluble high molar mass complexes known
as multi-hexamers; whereas, the fast action of IAsp is achieved by rapid
dissociation of hexameric complexes after s.c. injection. The aim of this
study was to determine the mechanism underlying the ability of IDeg and
IAsp to be combined without altering their individual absorption profiles
after injection. Size exclusion chromatography (SEC) was used as an in vitro
model. The column was eluted with buffered saline including varying phenol
concentrations to simulate the disappearance of phenolic excipients from
the formulation upon s.c. injection. Two desB30 basal insulin analogues
acylated at LysB29Nɛ by hexadecandioyl-ɣ-Glu (IDeg) or lithocholyl-ɣ-Glu
and IAsp were compared with human insulin. The analogues were examined
by SEC, formulated alone and in different combinations of long acting and
fast acting insulin at a 70:30 ratio. Combinations of these long acting and
fast acting analogues were found to form mixed hexamers and di-hexamers,
but by adjusting the zinc concentration, it was possible to avoid mixed
hexamers and mixed di-hexamers of IDeg and IAsp and their individual SEC
elution profiles could be retained. It is concluded that the ability of IDeg to
form multi-hexamers in the presence of zinc is critical to avoid interactions
with IAsp such that the individual absorption profiles upon injection can be
retained.
Clinical Diabetes/
Therapeutics
TIM HEISE, LESZEK NOSEK, OLIVER KLEIN, HANS-VEIT COESTER, CARSTEN
ROEPSTORFF, ANNE LOUISE SVENDSEN, HANNE HAAHR, Neuss, Germany,
Søborg, Denmark
SVEND HAVELUND, ULLA RIBEL, FRANTA HUBÁLEK, THOMAS HOEG-JENSEN,
IB JONASSEN, Måløv, Denmark
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
A GLA- or PRE-based regimen resulted in similar % of well-controlled
pts without hypoglycemia; however, overall hypoglycemia was greater with
PRE and it should be considered in evaluating the treatment benefit/risk.
950-P
Pharmacological Benefi ts of Once Weekly Combination Treatment
using LAPS-Insulin and LAPS-Exendin-4 in Animal Models
Basal insulin and GLP-1 receptor agonist combination therapy offers the
most promising approach for DM patients based on its synergistic effects
on glycemic control and complementary effects on body weight. However,
the currently available combination regimens require frequent dosing
which give inconvenience to patients. We are developing both a once-aweek LAPS-Insulin (HM12460A) and a LAPS-Exendin-4 (INN: langlenatide,
once-a-week or once-a-month regimen) using the proprietary LAPSCOVERY
technology. The objective of this study was to investigate the beneficial
effects of a once-a-week combination of LAPS-Exendin-4 and LAPS-insulin
in animal models. From the oral glucose tolerance study in normal mice, we
confirmed that the combination regimen efficiently reduced both fasting and
post-prandial blood glucose. The same result was also observed in normal
dogs, where the synergistic pharmacological effects were sustained for
4 days post-injection. In db/db mice, once-a-week administration showed
several beneficial effects compared with the LAPS-Insulin monotherapy,
such as improved glycemic control, neutralizing body weight gain, and
reduction of insulin dose. Based on these observations, we concluded that
the once-a-week combination regimen of LAPS-Insulin and LAPS-Exendin-4
could be a therapeutic approach, which confers maximal convenience to
DM patients in addition to superior glycemic control.
POSTERS
Clinical Diabetes/
Therapeutics
CHANG KI LIM, YOUNG JIN PARK, IN YOUNG CHOI, GYU HWANG LEE, JA HOON
KANG, YOUNG HOON KIM, JEEWOONG SON, SE CHANG KWON, Hwaseong-si,
Republic of Korea, Seoul, Republic of Korea
Supported by: Sanofi
949-P
Association between TNF-Alpha (TNF) Promoter Allele and Effi cacy of Insulin Therapy in Chinese Type 2 Diabetic Patients
HAIXIA XU, WEN XU, FEN XU, HUA LIANG, JINHUA YAN, JIANPING WENG,
Guangzhou, China
Objectives: To investigate the genetic association between tumor
necrosis factor-α (TNF-α) polymorphisms [-1031T>C (rs1799964), -863C>A
(rs1800630), -857C>T (rs1799724)] and the clinical efficacy of insulin therapy
in treating Chinese type 2 diabetic patients.
Methods: Three hundred sixty-eight newly diagnosed type 2 diabetic
patients to 168 ethnically matched healthy individuals as controls were
involved. The three single nucleotide polymorphisms (SNPs) were analyzed
by PCR-direct sequencing and haplotype analysis were performed to
identify possible risk haplotypes for type 2 diabetes. Then patients carrying
the risk allele together with its controls received mixed protamine zinc
recombinant human insulin Lispro (25R) injection twice daily to attain
glycemia control. Fasting blood glucose (FBG), postprandial blood glucose
(PBG), glycohemoglobin A1C (GHAlc), fasting serum insulin (FSI) were
measured before and every three months after insulin therapy for a total
of one year.
Results: The frequency of the TNF allele designated -1031C, -863C, and
-857C was significantly increased in patients with type 2 diabetes (odds
ratio =2.665; P=0.015). Except for a lower level of HDL-c, carriers of -1031C/863C/-857C (CCC group) exhibited similar FBG, PBG, GHAlc, FSI and HOMAIR to those none CCC carriers (none CCC group) at baseline. After one year
of Lispro25R treatment, beta cell function was partially restored in most
patients as evidenced by dramatic increased FSI level in both groups.
Moreover, CCC group presented even higher FSI than none CCC ones
(p=0.033) while Homa-IR remained statistically comparable.
Conclusions: TNF allele of -1031C, -863C, and -857C might be both a risk
haplotype for developing type 2 diabetes and a predictive genetic factor for
clinical efficacy of insulin therapy.
951-P
Pharmacokinetics and Pharmacodynamics of Insulin Glargine,
Changes in Glucose and Lipid Metabolism after Either Evening or
Morning Injection in T2DM
FRANCESCA PORCELLATI, PAOLA LUCIDI, PAOLA CANDELORO, PATRIZIA CIOLI,
ANNA MARINELLI ANDREOLI, GEREMIA B. BOLLI, CARMINE G. FANELLI, Perugia, Italy
We have recently shown the differential pharmacokinetics and pharmacodynamics (PK/PD) of insulin glargine (GLA), when administered in T2DM at
different time of the day (Diabetes, 61 (Suppl.1): A249, 2012). Here we report
GLA effects on glucose (G) fluxes (deuterated G), lipid metabolism (plasma
FFA, β-OH-butyrate) in 9 persons with T2DM (mean±SD: age 62±3.5 yrs;
BMI 28±3.6 kg/m2; A1C 7.2±1.1%, known T2DM duration 19±9.9 yrs), during
a 24h euglycemic G clamp (cross-over study), with GLA given s.c. (0.4 U/kg),
either at 10 AM or at 10 PM. Total G metabolism (GIR_AUC0-24h) was similar
(1012±731, 1058±606 mg/kg, p=0.654), but AUC0-12h was greater in AM
vs PM (589±397 vs 358±259 mg/kg, p=0.010), whereas the opposite was
observed for AUC12-24h (424±357 vs 700±420 mg/kg, AM and PM, p=0.005).
PK of GLA and C-peptide did not differ in the two studies. The different GIR
in AM vs PM was explained by changes in endogenous G production (EGP)
with greater suppression in initial 12 h and lower in second 12 h, when GLA
was given at 10 AM; the opposite occurred whit GLA given at 10 PM (AUC012h 510±284 vs 744±384 mg/Kg, AM and PM, p=0.066). G utilization was not
stimulated neither in AM nor in PM studies. Lipolysis was more suppressed
in PM vs AM (FFA AUC0-24h 7.5±1.7 vs 9.2±1.7 mmol.h/L, p<0.001; β-OH AUC024h 6.8±5.0 vs 18±12 mmol.h/L, p<0.003). In conclusion: PD of insulin GLA in
T2DM is dependent on the time of daily injection. Evening administration
results in greater GIR requirements in the second 12 h of day (afternoon),
due to greater suppression of EGP and lipolysis, in contrast to morning
administration which displays a sensible reduction in metabolic activity
from 12 h to 24 h after GLA injection. Since PK and C-peptide were similar
in the 2 studies, the differential PD might reflect the contribution of diurnal
fluctuation in insulin sensitivity (higher in afternoon vs early morning).
&
For author disclosure information, see page 829.
A242
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
achieved on insulin may predict those patients who can later succeed in
controlling glucose levels with diet and physical exercise only.
952-P
Continuous Glucose Monitoring to Study the Effectiveness of
U-500 Regular Insulin as Basal Insulin in Severely Insulin Resistant Patients
954-P
SHUBHANGI G. SHIDHAM, VALERIE CHRISTENSEN, BEVERLY PINKSTON, Columbus, OH
Determinants of Reversibility of Beta-Cell Dysfunction in Response
to Short-Term Intensive Insulin Therapy in Patients With Early Type
2 Diabetes
Severe insulin resistance is defined as requiring more than 200 units of
insulin per day or more than 2 units of insulin per kg per day. This subset of
patients is more likely to have uncontrolled diabetes mellitus. Studies have
shown effectiveness of U500 regular insulin in this subset of patients and
is considered to have both prandial and basal activity. However, in clinical
practice we have found U-500 regular insulin to work best as a basal insulin.
To evaluate this observation we undertook following prospective study.
Fifteen severely insulin resistant patients (aged 59.9 ± 6.50, BMI 42.16
± 6.79 with baseline HgA1c of 9.33% ± 1.33) were administered preprandial BID or TID doses of U-500 regular insulin. No bedtime doses were
administered. Continuous Glucose Monitoring (CGM), HgA1c, and weight/
BMI measurements were performed before and 6 months after starting
U500 regular insulin.
HgA1C decreased from 9.33% to 7.98% (p=0.0004), BMI increased from
42.16 kg/m² to 44.4 kg/m² (p=0.004). The average glucose between 12 AM to
6 AM decreased from 210.2±59.2mg/dl to 180±41.5mg/dl (p=0.020) showing
effectiveness of U-500 as basal insulin. Average glucose in post prandial
periods also decreased, but these results were not statistically significant.
We therefore conclude that U-500 insulin works most effectively as basal
insulin supporting our clinical observation.
BMI kg/m²
HgA1c
Average glucose
12MN to 6am mg/dl
Average glucose post
breakfast mg/dl
Average glucose post
lunch mg/dl
Average glucose post
dinner mg/dl
6 months After U-500
(mean± SD)
44.45 ± 7.76
7.98% ± 0.82
180.2 ± 41.5
234.3 ± 55.1
210.5 ± 65.2
0.35
220.6 ± 35.1
196.3 ± 46.8
0.064
216.5 ± 41.1
200.5 ± 35.3
0.15
P value
0.004
0.0004
0.020
955-P
Metformin (M), Sulfonylurea (SU), or Both as Background OAD
Therapy for Insulin Glargine (IG): A Pooled Analysis of Treat-ToTarget Trials
Supported by: U.S. Dept. of Veterans Affairs
J. HANS DEVRIES, ANTHONY H. BARNETT, TIMOTHY REID, MARIE-PAULE DAIN,
WOLFGANG LANDGRAF, ALEKSANDRA VLAJNIC, LOUISE TRAYLOR, RICHARD
M. BERGENSTAL, Amsterdam, Netherlands, Birmingham, United Kingdom, Janesville, WI, Paris, France, Frankfurt, Germany, Bridgewater, NJ, Minneapolis, MN
953-P
This pooled, patient-level data analysis evaluated efficacy and safety of
adding IG to M, SU, or M+SU in uncontrolled T2DM.
Eligible studies were randomized, treat-to-target trials with FPG target
<100 mg/dL and ≥24 weeks duration. From 15 studies, 634 patients were
treated with IG+M, 906 with IG+SU, and 1297 with IG+M+SU (Table).
Hypoglycemia definitions included: overall (with plasma glucose [PG]
<70, <56 mg/dL or requiring assistance); nocturnal (0:01-5:59am); severe
(requiring assistance); and documented severe (requiring assistance and PG
<36 mg/dL). Event rates and incidence were modeled considering baseline
characteristics.
All treatments reduced A1C; fewer patients reached A1C <7.0% with
IG+SU vs IG+M or IG+M+SU. IG+SU and IG+M+SU treatment increased
overall hypoglycemia rates up to 3-fold compared with IG+M. Severe
hypoglycemia was rare in all groups. More IG+M patients achieved A1C
<7.0% without nocturnal hypoglycemia (PG <70 mg/dL), than IG+SU and
IG+M+SU patients. IG+M resulted in less weight gain than the other
combinations, despite a higher insulin dose. In an overall model including all
patients, baseline BMI, T2DM duration, age, and OAD group were significant
factors affecting hypoglycemia.
Thus, there may be a clinical advantage for IG+M therapy compared with
IG+M+SU or IG+SU in terms of body weight and minimizing hypoglycemia
risk while achieving glycemic goals, albeit with a higher insulin dose.
Transient Continuous Subcutaneous Insulin Infusion Therapy in
Newly Diagnosed Type 2 Diabetes With Obesity
YA DONG SUN, Changchun, China
The objective of this study was to investigate whether long-term optimal
glycemic control and recovery of β-cell function can be achieved without
medication by transient continuous subcutaneous insulin infusion (CSII) in
newly diagnosed type 2diabetes with obesity. A total of 179 subjects (52 ±
2 years old [range 35-64], BMI 30.8 ± 1.9 kg/m2) with newly diagnosed
type 2 diabetes were enrolled and had a 3 week treatment of CSII and then
discontinued. Intravenous glucose tolerance tests (IVGTTs) were performed,
and blood glucose, HbA1c, insulin, and C-peptide were measured before and
after CSII. Patients were followed longitudinally on diet and physical exercise
only after withdraw of insulin. All 179 subjects tolerated the intensive insulin
treatment well. 29 patients who failed to achieve excellent glycemic control
on CSII within 3 weeks were considered as early therapeutic failure and
excluded from further analysis. Before CSII, the glycemic control was poor
in the 150 diabetic patients, with average FPG of 15.27 ± 2.32 mmol/l, PPG
22.18 ± 3.43 mmol/l, and HbA1c 14.95 ± 2.42%. After treatment, FPG and PPG
levels were significantly reduced (5.52 ± 1.30 mmol/l and 7.18 ± 1.21 mmol/l,
respectively; P < 0.001). After 3 weeks CSII, there was a marked decrease
in HbA1c (from 14.95 ± 2.42 to 8.76 ± 1.33%, P < 0.05). The remission rates
(percentages maintaining near euglycemia) at the 3, 8, 16, and 24 weeks
were 83.8, 76.9, 70.1, and 67.1%, respectively. These results demonstrate
that in newly diagnosed type 2 diabetes patients with obesity and elevated
fasting glucose levels, a 3 week treatment of CSII can successfully lay a
foundation for prolonged good glycemic control. The improvement of β-cell
function, especially the restoration of first-phase insulin secretion, could
be responsible for the remission. The ease with which normoglycemia is
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A243
POSTERS
Short-term intensive insulin therapy (IIT) can improve beta-cell function
when administered early in the course of type 2 diabetes (T2DM). However,
the degree of reversibility of beta-cell dysfunction in response to this
therapy varies between patients. Thus, we sought to characterize the
determinants of reversibility of beta-cell dysfunction in response to shortterm IIT in early T2DM. In this study, 63 patients with mean 3.0 ±2.1 years
duration of T2DM and HbA1c 6.8 ±0.8% underwent 4 weeks of IIT, with oral
glucose tolerance test (OGTT) administered at baseline and one day postIIT. Beta-cell function before and after IIT was assessed on OGTT using
the Insulin Secretion-Sensitivity Index-2 (ISSI-2). Reversibility of beta-cell
dysfunction was defined as percentage change in ISSI-2 ≥25%. In the entire
cohort, there was an increase in ISSI-2 from baseline to post-IIT (median
183 vs 190, P=0.01), with 1/3 of participants achieving ≥25% improvement
in ISSI-2. Compared to their peers, those with increase in ISSI-2 ≥25% had
significantly greater decrements in fasting glucose (-1.6 ±1.0 vs 0.1 ±0.9
mmol/L, P<0.001), HbA1c (-0.8% ±0.5 vs -0.3% ±0.3, P=0.001), ALT [median -3
vs 1 IU/L, P=0.04), AST [ median -3 vs 1 IU/L, P=0.02], and HOMA-IR [median
-0.7 vs -0.1, P<0.001). On logistic regression analysis, baseline HbA1c (OR
2.83, 95%CI 1.16-6.88, P=0.02) and change in HOMA-IR (OR 0.008, 95%CI
0.0004-0.16, P=0.001) emerged as independent predictors of reversibility of
beta-cell dysfunction. Indeed, only those participants in whom IIT yielded
an improvement in HOMA-IR achieved reversibility of beta-cell dysfunction.
In conclusion, decline in HOMA-IR is a key determinant of improvement of
beta-cell function in response to short-term IIT, underscoring a fundamental
contribution of insulin resistance to the reversible component of beta-cell
dysfunction in early T2DM.
Clinical Diabetes/
Therapeutics
Before U-500
(mean± SD)
42.16 ± 6.79
9.33% ± 1.39
210.0 ± 59.2
CAROLINE K. KRAMER, HAYSOOK CHOI, BERNARD ZINMAN, RAVI RETNAKARAN, Toronto, ON, Canada
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
POSTERS
Clinical Diabetes/
Therapeutics
IG+M
(n=634)
54.7 (9.6)
47.9
31.5 (5.8)
88.0 (19.7)
7.3 (5.7)
8.7 (1.1)
188 (59)
7.0 (1.0)
−1.7 (1.2)
56.8
0.8 (4.0)
0.51 (0.27)
IG+SU
(n=906)
59.1 (10.4)
46.1
29.1 (5.2)
82.2 (18.0)
9.5 (6.6)
9.0 (1.1)
205 (58)
7.6 (1.2)
−1.4 (1.2)
31.5
2.8 (3.9)
0.43 (0.24)
IG+M+SU
(n=1297)
58.2 (9.3)
45.4
31.2 (5.0)
88.9 (17.4)
9.5 (6.3)
8.7 (1.0)
193 (52)
7.1 (0.9)
−1.6 (1.0)
49.3
2.0 (3.4)
0.42 (0.25)
957-P
Pooled
(N=2837)
57.7 (9.8)
46.2
30.6 (5.3)
86.6 (18.4)
9.0 (6.4)
8.8 (1.1)
196 (56)
7.2 (1.0)
−1.6 (1.2)
45.3
2.0 (3.8)
0.44 (0.26)
Interchangeability of Exhaled Gases for Plasma Insulin Prediction
in Obesity and Type 2 Diabetes
Age, y
Women, %
Baseline BMI, kg/m2
Baseline weight, kg
T2DM duration, y
Baseline A1C, %
Baseline FPG, mg/dL
Week 24 A1C, %
A1C change from baseline, %
Patients with A1C <7.0% at week 24, %
Weight change from baseline, kg
Week 24 insulin dose, U/kg
Overall hypoglycemia, event rate/PY (SE)a
<70 mg/dL
2.05 (0.24) 5.03 (0.84) 5.78 (0.55) 3.90 (0.21)
<56 mg/dL
0.64 (0.10) 1.60 (0.34) 2.16 (0.26) 1.30 (0.09)
a
Overall hypoglycemia, incidence, % (SE)
<70 mg/dL
37.0 (3.0)
52.0 (4.4)
50.7 (2.6)
46.5 (1.4)
<56 mg/dL
16.3 (2.3)
30.1 (4.5)
34.1 (2.7)
26.0 (1.3)
Nocturnal hypoglycemia, event rate/PY (SE)b
<70 mg/dL
0.37 (0.07) 0.75 (0.21) 0.79 (0.12) 0.60 (0.05)
<56 mg/dL
0.18 (0.04) 0.25 (0.10) 0.36 (0.07) 0.25 (0.03)
Nocturnal hypoglycemia, incidence, % (SE)b
<70 mg/dL
11.5 (1.8)
15.0 (3.5)
17.5 (2.1)
14.5 (1.0)
<56 mg/dL
4.8 (1.2)
5.4 (2.3)
11.3 (2.1)
6.7 (0.7)
Severe hypoglycemia, event rate/PY (SE)c
0.07 (0.03) 0.10 (0.03) 0.10 (0.03) 0.09 (0.02)
Severe hypoglycemia, incidence, % (SE)c
2.2 (0.6)
2.2 (0.5)
1.9 (0.4)
2.1 (0.3)
Documented severe hypoglycemia, event rate/PY (SE)d 0.01 (0.01) 0.007 (0.004) 0.002 (0.002) 0.005 (0.002)
Documented severe hypoglycemia, incidence, % (SE)c
0.4 (0.3)
0.3 (0.2)
0.1 (0.1)
0.2 (0.1)
A1C <7.0% at week 24 with no nocturnal hypoglycemia
48.0
27.0
35.8
35.7
(<70 mg/dL), %
Table. Baseline and week 24 data. Data represent mean (SD) unless otherwise specified. PY = patient year. Hypoglycemia incidence and event rates
estimated and analyzed using logistic and negative binomial regression: aadjusting for BMI, duration of diabetes, age, group, study, interaction of duration and group; badjusting for BMI, duration of diabetes, age, group, study;
cadjusting for BMI, duration of diabetes, age, group; dadjusting for duration
of diabetes, age, group.
STACY R. OLIVER, MATTHEW K. CARLSON, HEATHER SOPHER, SIMONE MEINARDI, DONALD R. BLAKE, PIETRO GALASSETTI, Irvine, CA
Exhaled volatile organic compounds (VOC) are ideal non invasive markers
of metabolism, whose practical application, though, remains challenging.
We previously estimated plasma glucose, insulin (INS) and lipids via VOC
analysis in healthy and type 1 diabetics, obtaining stronger predictions with
condition-specific gas patterns. Ideal predictive models, though, should
incorporate the same gas clusters for as many patient groups as possible.
INS testing is important in obesity (OW)/type 2 diabetes (T2D), where INS
changes far precede hyperglycemia. We hypothesize that interchangeable
exhaled gas clusters can yield similarly accurate INS predictions in OW and
T2D.
During 4 h of glycemic/INS fluctuations, we collected in 17 T2D and 12
OW subjects, 12 plasma, room air and breath samples; ~100 VOC were
quantified by gas chromatography, matched with plasma INS, and gas-based
INS predictions obtained by linear regression analysis. The gas clusters
yielding the strongest measured/predicted INS correlations were: acetone,
2-BuONO2, α-pinene in OW (r = 0.90); 2-methylpentane, CH3Cl, acetone,
n-heptane, 2-methylhexane in T2D (r = 0.93). Applying the T2D model to
OW, r = 0.91; applying the OW model to T2D, r = 0.85. More interchangeable
clusters were used between groups with r values > 0.8.
We show the feasibility of estimating plasma INS in OW and T2D with
interchangeable VOC clusters, a feature very relevant at the later stage of
practical development of actual testing devices.
Supported by: NIH (1UL1RR031985), (K24DK085223)
Supported by: Sanofi U.S., Inc.
956-P
958-P
Intensive Glucose Lowering Therapy Maintains Beta-Cell Function
for 6 Years in Newly Diagnosed Type 2 Diabetes
An Emergency Room Triggered Package of Measures in Hyperglycemic Patients Reduces Mortality and Hospital Stay—Results of
the GLUC-EMERGE Follow-Up Study
LINDSAY B. HARRISON, PHILIP RASKIN, BEVERLEY ADAMS-HUET, XILONG LI,
ILDIKO LINGVAY, Dallas, TX
THORSTEN SIEGMUND, EDIN ZELIHIC, BORIS PONELEIT, PETRA-MARIA
SCHUMM-DRAEGER, CHRISTOPH DODT, Munich, Germany
Diabetes is a progressive disease marked by a steady decline in beta-cell
function which leads to increased complications and treatment difficulty.
We assessed the efficacy of 6 years of early intensive therapy with either
insulin plus metformin (INS) or triple oral therapy (TOT) with metformin,
glyburide, and pioglitazone on glycemic control and beta-cell function.
We conducted a randomized trial of 58 patients with treatment-naïve newly
diagnosed type 2 diabetes. An initial 3-month lead-in period with insulin and
metformin was followed by randomization to INS or TOT. We evaluated
glycemic control, safety (hypoglycemia, weight gain), treatment satisfaction,
and beta-cell function (using mixed meal challenge testing). Analyses were
intention-to-treat and performed with repeated measures models.
Beta-cell function was preserved with no significant change from the
time of randomization (after 3 months of INS treatment) or difference
between the two groups as measured by area under the curve (AUC) of
c-peptide (p=0.14) or ratio of c-peptide to glucose AUC (p=0.7). Excellent
glycemic control was maintained in both groups (end-of-study HbA1c
7.3±1.9% INS versus 6.8±1.7% TOT) with 63.2% and 68.8% respectively
maintaining HbA1c <7% by the end of the study. BMI increased in both
groups but significantly more in the TOT group (35.6±6.6 to 35.4±8.4 kg/
m2 in INS and 36.5±8.0 to 38.8±10.1 kg/m2 in TOT) (p=0.04). Hypoglycemic
events decreased significantly over time but did not differ between groups.
There were 8 failures in INS and 6 in TOT (defined as HbA1c >8% on two
consecutive visits). Predictors of failure included randomization systolic
blood pressure, BMI, HbA1c, HOMA-IR, and c-peptide.
In conclusion, proactive intensive treatment at the time of type 2 diabetes
diagnosis - initial short-term insulin treatment followed by either an insulinbased or oral hypoglycemic-based therapy - can preserve beta-cell function
for at least 6 years.
Introduction: Hyperglycemia at hospital admission is associated with an
increased risk of complications and mortality. Only few trials investigated
hyperglycemic patients (P) during the whole hospital stay, starting from
the emergency room (ER) to the normal wards until discharge. This study
examines the effects of early identification followed by a structured
treatment of hyperglycemia.
Methods: We performed a prospective study of P (n=2832) admitted to
the ER of an academic teaching hospital over a time period of 3 months.
According to actual recommendations, P with a blood glucose (BG) of
≥ 140 mg/dl received active follow up (n=463). In P with severe BG
derailment (blood glucose ≥ 180 mg / dl, n=369), insulin was administered
by an individualized but prefabricated basal-bolus scheme followed by
diabetologists consultations. The effects were tested using a multivariate
regression analysis, correcting for BG-independent risk factors such as
age, creatinine and other laboratory parameters. Moreover, we performed
a comparison with the results of the GLUC-EMERGE (GES) study, an
observational study, when hyperglycemia was not treated actively with the
ER triggered package of medical measures.
Results: The GLUC-EMERGE follow-up study cohort showed a significant
decrease of BG-related hospital stay prolongation compared to the GES
cohort. It was possible to reduce the increased hospital stay by 50%
considering all blood-glucose-disturbed patients (-0.6 days) and by 60% in
patients with severe BZ-derailment (-1.4 days). Additionally we were able
to decrease the original 2-fold increased mortality risk for P with severe
BG derailment compared to normoglycemic P (GES, p <0.01) to the level of
normoglycemic P.
Supported by: Novo Nordisk, Inc.
&
For author disclosure information, see page 829.
A244
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULINS
Conclusions: An early and systematic BG intervention in patients with
a BG dysregulation leads to a significant reduction of hospital stay and
mortality and thus has significant implications for the patient and hospital.
959-P
Glycemic Variability as Predictor of Clinical Outcome in InsulinTreated Patients With Type 2 Diabetes
FARNOOSH FARROKHI, DAWN SMILEY, FRANCISCO PASQUEL, LIMIN PENG,
CHRISTOPHER NEWTON, DARIN E. OLSON, SOL JACOBS, GUILLERMO E. UMPIERREZ, Atlanta, GA
Glycemic variability (GV) has been shown to be an independent predictor
of mortality in critically ill patients; however, its impact in non-ICU patients
with T2D is not known. Accordingly, this post hoc analysis of a prospective,
randomized trial of insulin-treated medical and surgical subjects with T2D
determined the association of GV with hospital outcomes. A total of 279
patients were randomized to receive a Basal Bolus regimen (n=146, age:
59±11 yr, admission BG: 210±88 mg/dl, A1C: 8.7±2.5%, ±SD) starting at total
daily dose (TDD) of 0.5 U/kg, given half as glargine once daily and half as
glulisine before meals and to Basal Plus supplements (n=133, age: 59±13 yr,
admission BG: 207±83 mg/dl, A1C: 8.3±2.3%) with glargine once daily at a
TDD of 0.25 U/kg plus correction doses of glulisine before meals for BG>140
mg/dl. GV was calculated from all BG values using mean delta daily BG,
mean standard deviation (SD) and mean amplitude of glycemic excursions
(MAGE).
Basal plus regimen resulted in similar mean daily and fasting BG, number
of hypoglycemic events, hospital length of stay and complications compared
to basal bolus regimen (all, p=NS). There were no differences in GV between
treatment groups measured by delta change (72.5±36 vs. 69.3±34 mg/dl), SD
(38.5±18 vs. 37.1±16 mg/dl) and MAGE (67.5±33 vs. 66.1±38 mg/dl), all p=NS.
GV was higher in surgery patients treated with basal bolus (delta change
and SD: p=0.02, MAGE: p=0.009), but there were no differences in GV in
medical patients. Patients with high GV had higher number of hypoglycemic
events compared to those with low GV (p <0.001); however, no association
was found between GV and hospital complications (p=NS).
In summary, the basal plus regimen resulted in similar mean daily blood
glucose, glycemic variability and frequency of hypoglycemia compared to a
basal bolus regimen. This randomized controlled trial indicates that basal
plus is an alternative to basal bolus insulin regimen in general medicine and
surgery patients with T2D.
HANNAH SLABU, PETER A. SENIOR, Edmonton, AB, Canada
Hypoglycemia is a major barrier to tight glycemic control which reduces
microvascular and macrovascular complications in type 1 diabetes. Since
long acting insulin analogues reduce the risk of nocturnal hypoglycemia,
they may facilitate improved glycemic control. We sought to examine the
differences between target and achieved fasting plasma glucose (FPG)
levels, HbA1c and hypoglycemia rates for basal insulin analogs vs comparator
in clinical trials conducted in type 1 diabetes.
A systematic review of 14 trials comparing long acting insulin analogs
with a comparator was performed. Only trials reporting achieved FPG and
hypoglycemia rates were included. The trials of detemir (n=8) and glargine
(n=3) had NPH as comparator, while the trials of degludec (n=2) had glargine
as the comparator. One trial compared detemir to glargine. Hypoglycemia
rates were normalized to events per patient per year.
The target FPG in the trials ranged between 5-7.3 (mean 6.6) mmol/l
but was not achieved in any trial.The achieved FPG for analogs was 9.0
(range 7.6-10.7) mmol/l versus 9.8 (8.1-11.4) mmol/l for comparators. The
gap between target and achieved FPG was lower for analogs verses
comparators (2.3±0.9 v 3.2±1.1mmol/l, p=0.042). Nocturnal hypoglycemia
rates were lower for analogs (6.7±3.9 v 9.3±3.9 events/patient/year, p =
0.02) but overall hypoglycemia rates did not differ (44.6±22.0 v 52.5 ± 21.8
events/patient/year, p=0.08). In keeping with the treat to target design,
HbA1c levels did not differ (7.8±0.3 v 7.9±0.5%, p=0.3).
Long acting insulin analogs were associated with both a smaller gap
between target and achieved FPG and lower nocturnal hypoglycemia rates.
However, FPG targets were not achieved and few participants achieved
HbA1c levels <7% in these clinical trials. Achieving tight glycemic control
in type 1 diabetes while avoiding hypoglycemia in routine clinical practice
remains challenging despite the advantages of long acting insulin analogs.
960-P
Factors Associated With Achieving Improved Glycemic Control:
Findings From the Observational A1chieve Study
LEE-MING CHUANG, JIANWEN CHEN, LEÓN E. LITWAK, NABIL K. EL NAGGAR,
SERDAR GÜLER, Taipei, Taiwan, Zurich, Switzerland, Buenos Aires, Argentina, Jeddah, Saudi Arabia, Ankara, Turkey
A1chieve was a 24-week non-interventional study evaluating the safety
and clinical effectiveness of insulin analogs in people with type 2 diabetes
(n=66726) in routine practice in 28 countries across 4 continents. This
post-hoc analysis investigated factors predicting HbA1c change. 44,872
participants were insulin-naïve prior to the study (baseline mean[SD]
HbA1c 9.5[1.7] %, age 53.2[11.6] yrs, diabetes duration 6.6[5.4] yrs). 21854
participants were prior insulin users (baseline mean[SD] HbA1c 9.4[1.8] %,
age 55.6[12.5] yrs, diabetes duration 10.8[6.8] yrs). Factors significant in
the univariate analysis were diabetes duration; oral glucose-lowering drug
number; age; gender; hypoglycemia; baseline & pre-study treatment; region;
baseline HbA1c, FPG and PPG; dose titration. These factors were retained
in the multivariate analysis. The results showed that longer diabetes
duration, older age, female gender, prior insulin use, lower FPG, higher post
breakfast PPG and greater dose titration were associated with lesser HbA1c
reduction, while greater hypoglycemia frequency was associated with
greater HbA1c reduction (Table). In summary, this analysis identified and
confirmed metabolic factors that contribute to changes in glycemic control.
A more appropriate dose titration while avoiding hypoglycemia is strongly
recommended.
ADA-Funded Research
&
962-P
Comparison of Algorithms for Initiation of Basal Insulin in Different
Age Populations
GEORGE E. DAILEY, JASVINDER K. GILL, JOHN STEWART, RONG ZHOU, La Jolla,
CA, Bridgewater, NJ, Laval, QC, Canada, Cincinnati, OH
A range of titration algorithms are available for initiation/intensification
of basal insulin in patients with T2DM; however, safety and efficacy may
vary depending on age. This study compared 3 algorithms for insulin
initiation over a range of ages.
Data were pooled from 7 randomized controlled trials adding insulin
glargine to metformin and sulfonylurea at 10 IU starting dose. The algorithms
were 1) 1 IU daily when FPG was above target; 2) 2 IU/3 days; 3) treat-totarget, generally increasing 2-8 IU weekly based on 2-day mean FPG. Patients
were analyzed by age: < 55, ≥ 55 to < 65, and ≥ 65 yrs. Change from baseline
in endpoint variables was analyzed using a mixed model with algorithm as a
factor and corresponding baseline measurement as a covariate.
See Table for baseline characteristics and clinical outcomes. Despite
differing baseline values, all patients achieved similar endpoint A1C. In
those aged < 55 or ≥ 55 to < 65 yrs, there were fewer hypoglycemic events
in patients titrated by algorithm 2 than 1 or 3; and more patients using
algorithm 2 also achieved A1C < 7.0% with no hypoglycemic event < 56 mg/
dL in categories ≥ 55 to < 65 or ≥ 65 yrs.
For author disclosure information, see page 829.
Guided Audio Tour poster
A245
POSTERS
961-P
Fasting Glucose Targets are Not Achieved in (Treat to Target) Trials
of Basal Insulin Analogues: Systematic Review of Trials in Type 1
Diabetes
Clinical Diabetes/
Therapeutics
Supported by: Novo Nordisk A/S
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
POSTERS
Clinical Diabetes/
Therapeutics
This pooled analysis of data from 7 studies suggests that, regardless of
age, algorithm 2 leads to similar glycemic control with less hypoglycemia
than algorithm 3; the small number of patients ≥ 65 yrs make comparison
difficult. The variation in numbers for each subgroup, and the differences at
baseline, must be considered when interpreting these results.
Table. Baseline and outcomes for algorithms by age category. P<0.05: a: 2 vs
3, b: 1 vs 2, c: 1 vs 3
< 55 yrs
≥ 55 to < 65 yrs
≥ 65 yrs
Algorithm 1 Algorithm 2 Algorithm 3 Algorithm 1 Algorithm 2 Algorithm 3 Algorithm 1 Algorithm 2 Algorithm 3
(n=33) (n=31) (n=304) (n=35) (n=35) (n=280) (n=15) (n=16) (n=195)
Mean age, yrs
48
50
48
60
59
60
70
72
70
10a
10
12
12
Mean duration
7
6
7
10
8a
of diabetes, yrs
Mean baseline 8.83
8.60
8.78
8.45b 9.24a, b 8.75a
8.13c
8.44
8.73c
A1C, %
A1C change
–1.63 –1.44 –1.66 –1.29 –2.13 –1.75 –1.31 –1.90 –1.70
from baseline, %
Mean endpoint 7.20
7.16
7.11
7.16
7.11
7.00
6.81
6.54
7.03
A1C, %
Endpoint weight- 0.55
0.67a
0.48a
0.36b 0.60a, b 0.42a
0.29
0.29
0.33
adjusted insulin
dose, IU/kg
Confirmed hypo- 12/33 (36) 9/31 (29) 132/304 9/35 (26) 4/35 (11)a 115/280 4/15 (27) 5/16 (31) 71/195 (36)
glycemia < 56
(43)
(41)a
mg/dL, n/N (%)
Confirmed hypo- 19/33 (58)b 10/31 (32)a, 184/304 19/35 (54)b 7/35 (20)a, b 169/280 5/15 (33) 6/16 (38) 96/195 (49)
b
(61)a
(60)a
glycemia < 70
mg/dL, n/N (%)
Confirmed noc- 6/33 (18) 2/31 (6)a 89/304 (29)a 3/35 (9) 1/35 (3)a 64/280 (23)a 2/15 (13) 3/16 (19) 30/195 (15)
turnal hypoglycemia < 56 mg/
dL, n/N (%)
Endpoint A1C < 10/33 (30) 8/31 (26) 78/304 (26) 13/35 (37) 15/35 (43) 79/280 (28) 5/15 (33) 9/16 (56)a 54/195 (28)a
7.0% and no
hypoglycemic
events with glucose < 56 mg/dL,
n/N (%)
Supported by: Novo Nordisk A/S
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—
INSULIN DELIVERY SYSTEMS
Guided Audio Tour: Novel Insulin Delivery Methods (Posters: 964-P to
971-P), see page 15.
&
964-P
Randomised Controlled Study of 24h Closed-Loop Insulin Delivery
in Type 2 Diabetes
KAVITA KUMARESWARAN, HOOD THABIT, LALANTHA LEELARATHNA, KAREN
CALDWELL, DANIELA ELLERI, JANET M. ALLEN, MARIANNA NODALE, MALGORZATA E. WILINSKA, MARK L. EVANS, ROMAN HOVORKA, Cambridge, United
Kingdom
Conventional insulin treatment protocols for managing glucose on noncritical care wards often result in inadequate glycemic control. Our aim
was to evaluate feasibility and safety of a closed-loop system, linking
continuous glucose monitoring (CGM) and continuous subcutaneous insulin
infusion (CSII) using a model predictive control algorithm, in subjects with
type 2 diabetes, prior to larger inpatient studies over longer duration.
Twelve subjects (7M, age 57.2y, BMI 30.5kg/m2) with insulin-naïve type 2
diabetes (HbA1c 8.4%, diabetes duration 7.6y) were admitted to a clinical
research facility for two 24h visits (closed-loop and control) in a randomised
crossover design. During closed-loop, subjects’ routine diabetes therapy
was replaced with CSII. Basal infusion rates were adjusted manually every
15min based on CGM, using the algorithm. Meals were unannounced and
no additional insulin was administered for carbohydrates consumed. During
control visits, usual diabetes regimen was continued (Metformin 92%,
Sulfonylureas 58%, DPP-4 inhibitors 33%). On both visits, subjects consumed
matched 50-80g carbohydrate meals and optional 15g carbohydrate
snacks at regular intervals and remained largely sedentary, mimicking an
inpatient stay on a general ward. Plasma glucose measurements evaluated
closed-loop performance. Compared with conventional therapy, 24h of
closed-loop insulin delivery increased time spent in target plasma glucose
(3.9-8.0mmol/l) from 24% to 40% (p=0.016), and reduced time above
8.0mmol/l from 76% to 60% (p=0.016). The benefit of closed-loop was even
more striking overnight with 78% (vs. 35%; p=0.041) time in target glucose
range, and only 22% (vs. 65%; p=0.041) time in hyperglycemia. There were
no episodes of hypoglycemia and no time spent below 3.9mmol/l during
either intervention. Closed-loop insulin delivery in type 2 diabetes provides
safe and effective glucose control, and has the potential to provide a more
convenient mode of managing hyperglycemia in hospital.
Supported by: Sanofi U.S., Inc.
963-P
Impact of Insulin Detemir on Weight Change in Relation to Baseline
BMI: Observations from the A1chieve Study
PHILIP HOME, RACHID MALEK, VINAY PRUSTY, ZAFAR A. LATIF, JIHAD HADDAD,
Newcastle upon Tyne, United Kingdom, Sétif, Algeria, Zurich, Switzerland, Dhaka,
Bangladesh, Amman, Jordan
Weight gain associated with starting insulin therapy is a significant
perceived barrier for both people with type 2 diabetes and health-care
professionals. Such barriers result in extended exposure to poor glycemic
control. A1chieve was a global non-interventional study in non-Western
nations evaluating the safety and clinical effectiveness of insulin analogs
in people with type 2 diabetes (T2DM) in routine clinical care. The aim of
this subanalysis of 12,078 people starting insulin detemir is to examine
aspects of weight change after starting the insulin in insulin-naïve people
with T2DM, continuing or not continuing oral agents. Participants were
55% male, age 54.0 [11.3] (mean [SD]) yr, BMI 28.2 [5.3] kg/m2, and duration
of diabetes 7.6 [5.5] yr, with baseline HbA1c of 9.5 (1.6) % (80 [18] mmol/
mol). From a baseline weight of 76.5 [16.3] kg, change at 24 weeks was
-0.3 [4.0] kg. When stratified by quartiles of baseline BMI, greater weight
reduction was seen with increasing baseline BMI in the overweight/ obese
groups (Table), despite similar decreases in HbA1c and comparable final
insulin doses across BMI groups. At both baseline and 24 weeks a higher
proportion of people with a higher baseline BMI were on more than two
oral glucose-lowering agents (Table). Thus, in the A1chieve study, weight
reduction was greater at 24 weeks in people with type 2 diabetes with
higher BMI when beginning insulin detemir.
Supported by: NIHR; BRC
&
For author disclosure information, see page 829.
A246
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
&
965-P
To improve type 1 diabetes management, we have developed a model
predictive control (MPC) algorithm for closed-loop (C-L) glucose control. The
algorithm is based on a second order stochastic model specified by 3 patient
specific parameters: insulin sensitivity factor, insulin action time and basal
insulin infusion rate at C-L start.
We conducted 2 randomized cross-over studies. Study I compared C-L
with open-loop (O-L) control. Study II compared glucose control after C-L
initiation in the euglycemic (C-L-Eu) and hyperglycemic (C-L-Hyper) ranges,
respectively. Patients were studied from 22:00 to 07:00 on 2 separate
nights. The C-L system consisted of a continuous glucose monitor connected
via a USB cable to a laptop running the MPC algorithm. Insulin dosing was
computed every 15 min but manually administered via an insulin pump.
Rescue I.V. glucose was given if plasma glucose declined below 54 mg/dl.
Participants (N = 11): Female sex, 45%; Age 41 ± 9 years; BMI 24.9 ± 3.5 kg/
m2; HbA1c 7.2 ± 0.4%; all were insulin pump users. Table 1 shows overnight
glucose control. Of the 6 cases of I.V. glucose administration during C-L in
study I, 5 were given in 1 study night; however the same patient needed 6
administrations during O-L indicating that his usual basal insulin infusion
rate was too high.
This first clinical feasibility test of a novel MPC algorithm shows intriguing
results. However we learned that algorithm performance was sensitive to
sub-optimal empirical estimation of patient specific parameters.
The InsuPad device has been developed to enhance insulin absorption
by standardized warming of the insulin injection site. Primary objective
of this prospective study is the impact of InsuPad use on prandial insulin
dose and glycemic control when studied under real world conditions. This
interim analysis was performed with 78 patients (23 female, 55 male, 7 type
1 and 71 type 2 patients, age: 61.2±8.8 yrs., HbA1c: 7.2±0.47%, body weight:
104.0±17.8 kg). After a run-in treatment optimization and stabilization period
of up to 4 weeks, patients were randomized to continue therapy for three
months without (Control) or with InsuPad. During run-in, HbA1c decreased
from 7.2±0.5 % to 6.8±0.5 % (p<0.001), and further improved until study end
(Control group: 6.3±0.5 % InsuPad: 6.2±0.5 %; both p<0.001 vs. baseline).
Number of hypoglycemic events (blood glucose <63 mg/dL) during the
observation period was higher in the control group (6.7±8.3/patient) than
in the InsuPad group (3.4±4.4/patient, p<0.05). The similar improvements
in glycemic control in both groups required an increase in the daily prandial
insulin dose from baseline by 12 % (from 59.8±25.9U to 65.9±35.8U, n.s)
in the control group (basal insulin dose: 43.9±13.7U vs. 43.6±15.2U, n.s.),
but were achieved with significantly lower prandial insulin doses (from
66.2±44.9U to 52.9±35.3U; -20.1%, p<0.001) and a slight increase in the
basal insulin dose (from 52.5±35.1U to 55.6±40.2U. p<0.05) with InsuPad.
Total daily insulin dose increased in the control group (+5.2%) and decreased
with InsuPad (-8.3%, p<0.001). Use of InsuPad for three months resulted
in a lower frequency of hypoglycemic events and a reduction in insulin
requirements as compared to the Control group under real-world conditions.
InsuPad may be useful to achieve a safer and more efficient basal bolus
therapy in insulin-treated patients with diabetes.
Table 1. Data are mean [min; max]. Glucose values are CGM measurements
(mg/dl).
Study I
Study II
Open-Loop
Closed-Loop
Closed-Loop-EU Closed-Loop-Hyper
Glucose at 22:00 / 00:00
97 [45; 169] /
97 [59; 133] / 113 [86 ; 139] / 203 [140 ; 288] /
115 [47; 202]
103 [59; 137]
92 [56 ; 113]
167 [111 ; 254]
Mean glucose 22:00-07:00 110 [52; 207]
112 [94; 128]
124 [112 ; 133] 153 [103 ; 198]
% time spent within
43.7 [3.4; 86.7] 78.5 [48.5; 98.0] 64.0 [17.6 ; 94.5] 39.5 [0.0 ; 100.0]
70-144 mg/dl
% time spent within
52.7 [3.4; 100.0] 90.7 [77.9; 100.0] 82.1 [33.3 ; 100.0] 61.1[5.4 ; 100.0]
70-180 mg/dl
% time spent < 70 mg/dl 30.4 [0.0; 96.6] 9.1 [0.0; 22.1]
6.9[0.0 ; 32.7]
6.8[0 ; 12.9]
I.V. glucose administrations
9
6
1
0
Supported by: Insuline Medical
966-P
Absorption Kinetics of Insulin Following Subcutaneous Bolus Administration With Different Bolus Durations
WERNER REGITTNIG, MARTINA URSCHITZ, BARBARA LEHKI, JULIA MADER,
MARKUS EHRMANN, HARALD KOJZAR, MARTIN ELLMERER, THOMAS R. PIEBER, ON BEHALF OF THE AP@HOME CONSORTIUM, Graz, Austria
To cover meal-related insulin requirements, insulin pumps allow insulin to
be delivered at high rates over a short period of time (bolus delivery). The
length of this period (bolus duration) usually depends on the chosen bolus
size and on the used insulin pump model. This study assessed subcutaneous
absorption kinetics of rapid-acting insulin administered with bolus durations
commonly employed in commercially available insulin pumps (i.e., 2 and 40
seconds for delivering 1 U).
Twenty type 1 diabetic subjects were studied on 2 occasions, separated
by at least 7 days, using the euglycemic clamp procedure. Following an
overnight fast, subjects were given, in random order, a subcutaneous insulin
bolus (15 U of insulin lispro, Eli Lilly) either over 30 seconds using an Animas
IR2020 pump (short bolus) or over 10 minutes using a Medtronic Minimed
Paradigm 512 pump (long bolus). On each occasion, a new infusion set of the
same type was used.
Subcutaneous insulin administration with short bolus duration resulted in
an earlier onset of insulin action as compared to insulin administration with
long bolus duration (21.0 ± 2.5 vs. 34.3 ± 2.7 min; p<0.002). Furthermore,
time to reach maximum insulin effect was found to be 27 min earlier when
insulin was administered with short bolus duration as compared with
administrations using long bolus duration (98 ± 11 min vs. 125 ± 16 min;
p<0.005). In addition, the area under the plasma insulin curve from 0 to 60
min was higher for the bolus administration with short bolus duration than
the one with long bolus duration (10307 ± 1291 vs. 8192 ± 865 min·pmol/L;
p= 0.027).
In conclusion, our data suggest that insulin bolus administration with
short bolus duration may result in faster insulin absorption and, thus,
may provide a better control of meal-related glucose excursions than that
obtained with bolus administrations using long bolus durations. Moreover,
our findings may have important implications for the future design of the
bolus delivery unit of insulin pumps.
&
ANDREAS LIEBL, BERNHARD GEHR, CLAUS KIEHLING, COSIMA C. RIEGER,
CAROLINE PATTE, THOMAS FREI, Bad Heilbrunn, Germany, Bad Toelz, Germany,
Mannheim, Germany, Burgdorf, Switzerland
Introduction and aim: The new Accu-Chek® DiaPort system is a
percutaneous port system for continuous intraperitoneal insulin infusion
(CIPII). Compared to previous models, the new DiaPort has a substantially
improved design, material, and implantation tools.
The aim of this study was to investigate the clinical performance and
safety of the new device.
Method and Design: 12 adult patients with type 1 diabetes unsuccessfully
treated with continuous subcutaneous insulin infusion (CSII), defined as
frequent or severe hypoglycemia and/or HbA1c above 8.5%, got the new
Accu-Chek DiaPort system implanted and were followed for 12 months
(open und uncontrolled). This is the interim analysis after 6 months (1018
patient days). Mean duration of diabetes was 30 years ( ± 12 SD), mean
baseline HbA1c 9.0% (± 1.1% SD).
Results: Surgical procedure, ingrowth, local or intraperitoneal tolerability,
and function of the new Accu-Chek DiaPort system were without major
problems. One event of a superficial infection around the DiaPort could
be controlled with oral antibiotic and local therapy. One implantation was
revised due to non-compliance of the patient. Frequent catheter obstructions
occurred when using insulin lispro. After changing to buffered human
insulin, and successful exchange of 8 blocked intraperitoneal catheters, no
more catheter obstructions occurred. HbA1c improved significantly to 7.57%
(± 0.63% SD), p<0.001. Total daily insulin dose dropped from 49 to 45 U
Supported by: FP7-ICT-2009-4; 247138
ADA-Funded Research
&
968-P
Evaluation of the New ACCU-CHEK® DIAPORT, a Port System for
Continuous Intraperitoneal Insulin Infusion, in Patients With Type
1 Diabetes: First 6-Month Results
For author disclosure information, see page 829.
Guided Audio Tour poster
A247
POSTERS
SIGNE SCHMIDT, DIMITRI BOIROUX, ANNE KATRINE DUUN-HENRIKSEN, JOHN
BAGTERP JØRGENSEN, NIELS KJØLSTAD POULSEN, HENRIK MADSEN, OLE
SKYGGEBJERG, STEN MADSBAD, KIRSTEN NØRGAARD, Hvidovre, Denmark,
Lyngby, Denmark
ANDREAS PFÜTZNER, THOMAS FORST, KLAUS FUNKE, NORBERT HERMANNS,
MICHAEL DERWAHL, GABRIEL BITTON, RON NAGAR, THOMAS HAAK, Mainz,
Germany, Potsdam, Germany, Bad Mergentheim, Germany, Berlin, Germany, Petach
Tikva, Israel
&
967-P
Model-Based Closed-Loop Glucose Control in Type 1 Diabetes
Clinical Diabetes/
Therapeutics
&
Use of the InsuPad Device Results in Improvement of Glycemic
Control, Reduced Insulin Requirements and Reduced Hypoglycemia Frequency in a Real-World Setting—Interim Results from the
BARMER Study
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
(ns). CGM showed significant improvements in mean glucose and glucose
values in target range [%]. 2 severe hypoglycemias in the 12 patients during
6 months were observed (vs. 18 severe hypoglycemia in the previous 12
months).
Conclusion: First results indicate good performance of the new Accu-Chek
DiaPort system for CIPII. Significant improvements in metabolic control with
lower HbA1c and reduced risk of severe hypoglycemia could be observed in
patients failing on CSII.
insertion device. The Minimed Duo device was tested in 20 adult (9 male)
type 1 diabetes patients who were accustomed to using pumps and
sensors.
Each patient wore one MiniMed Duo and one Enlite sensor (control) for 3
days. The MiniMed Duo was used for glucose signal recording and insulin
delivery during 2 inpatient periods of 12 hours (7AM-7PM) on day 1 and day 3
during which subjects took 3 meals with insulin boluses and frequent blood
glucose (BG) tests. The remainder of the time was spent in the outpatient
setting. At the end of the study, a survey evaluating the experience with the
MiniMed Duo device was given.
Two-hour postprandial BG values were measured. On day 1 and 3 of
device wear (19 subjects, 114 meals), the mean 2-h postprandial BGs
were 138±58.5 mg/dL and 137.8±62.1 mg/dL, respectively; the inter-day
difference was not significant (P=0.9). Mean time needed for post-prandial
glucose values to return to pre-prandial levels was 128±65 min. Clarke Error
Grid analysis of all paired points over 3 days demonstrated comparable
accuracy of MiniMed Duo (A+B, 96.38%) and Enlite sensors (A+B, 97.07%,
P=0.41). Patients were generally satisfied with the overall experience (mean
of 6.6±0.74 on a 7-point Likert scale).
This feasibility study demonstrated that the new combination insulin
delivery-glucose sensing device can be effectively used for insulin
delivery and accurate measurement of glucose. Use of the MiniMed Duo
may enhance patient compliance and reduce the burden associated with
diabetes management.
Supported by: Roche Diabetes Care
&
969-P
Improved Postprandial Glucose after Mixed Meals With Preadministration of Hyaluronidase at Each Infusion Site Change During CSII
in T1DM
POSTERS
Clinical Diabetes/
Therapeutics
DOUGLAS B. MUCHMORE, LINDA MORROW, MARCUS HOMPESCH, DANIEL E.
VAUGHN, San Diego, CA, Chula Vista, CA
Recombinant human hyaluronidase (rHuPH20) is FDA-approved to increase
dispersion and absorption of other injected drugs. A 2-way crossover double
blind study evaluated its impact on post-breakfast glucose in 22 subjects
with T1DM using CSII. Hyaluronidase (1 mL of Hylenex® recombinant)
or sham was given by bolus via infusion cannula at each set change. Set
changes were every 3 days for 4 cycles for each treatment. After ~2hr of
IV insulin to bring FBS to 110 mg/dL, an insulin bolus was given by CSII just
prior to a standardized solid breakfast. Hyaluronidase was well tolerated
and reduced postprandial glucose excursions up to 29 mg/dL vs. sham. Early
hypoglycemia risk (AUC0-3h<70 mg/dL) was similar but late hypoglycemia risk
(AUC3-5h<70 mg/dL) was reduced ~42%. Hyaluronidase preadministration at
infusion set change reduces PPG and lowers late hypoglycemic risk in T1DM
using CSII.
&
971-P
Exercise-Induced Hypoglycemia in the ASPIRE Study: Lessons
Learned
SUIYING HUANG, JOHN B. WELSH, SCOTT W. LEE, JOHN SHIN, FRANCINE R.
KAUFMAN, ASPIRE STUDY GROUP, Northridge, CA
Hyaluronidase Effects on Post Prandial Glucose (PPG)
Sham Hylenex
Change
PPG-60 min (mg/dL)
179
150 -29 mg/dL (p=.003)
PPG-120 min (mg/dL)
162
139 -23 mg/dL (p=.022)
%Time0-4h 70-140 mg/dL
42%
53% +26% (p=.025)
%Time0-4h 60-180 mg/dL
64%
76% +19% (p=.002)
AUC0-4h >180 mg/dL (min*mg/dL))
3529 1922
-46% (p=.042)
Early Hypo Risk AUC0-3h<70 mg/dL (min*mg/dL) 110
122
+11% (p=.75)
64
-42% (p=.046)
Late Hypo Risk AUC3-5h<70 mg/dL (min*mg/dL) 110
The ASPIRE study showed that exercise-induced hypoglycemia is
mitigated by the Threshold Suspend (TS) feature, which automatically
suspends insulin delivery when hypoglycemia is detected. We studied
the association between the initial glucose response to exercise and the
development of hypoglycemia. Fifty subjects with type 1 diabetes were
studied on 133 occasions. They began exercise with plasma glucose (YSI)
values in the 100-140 mg/dL range, exercised to YSI ≤85 mg/dL, and rested
until hypoglycemia (50 ≤ YSI < 70 mg/dL) was reached. YSI rates of change
(ROC) were used to stratify the experiments: rising (ROC ≥0.3 mg/dL/min),
falling (ROC ≤-0.3 mg/dL/min), or stable. Groups were similar for age, A1C,
and BMI. Subjects with initially falling YSI values had fewer total exercise
sessions, required less exercise time to reach 85 mg/dL, and required less
time to reach 70 mg/dL than did subjects with initially rising or stable YSI
values. The ROC in the 30 min prior to exercise relates to the ROC during
exercise, and those in the rising group had the highest glucose value prior
to exercise. Groups were similar with respect to night-before SG values and
the ROC after exercise and before reaching 70 mg/dL (Table). Heterogeneity
in the initial glycemic response to exercise may be partially attributable
to glucose concentration and glucose ROC immediately before exercise.
Critical evaluation of glucose and its ROC prior to exercise might lead to
better glycemic control during and after physical activity.
Table
&
Rising
(n=20)
Falling
(n=90)
Stable
(n=23)
P value
970-P
Feasibility Assessment of the MiniMed Duo Device: Combined Insulin Delivery and Glucose Sensing
PRIOR TO EXERCISE
DURING AND AFTER EXERCISE
Total
Mean
ROC
Starting YSI
Total
ROC after
Time to
number of night-before 30 min
glucose
exercise exercise and reach target
exercise SG (mg/dL) prior to
(mg/dL) time (min) before reaching (min)
sessions
exercise
70 mg/dL
4.8±1.5 152.3±40.0 0.28±0.76 138.6±34.0 103.9±31.7 -0.24±0.47 190.3±77.5
3.1±1.4 147.3±46.2
-0.39±0.60 119.5±18.6
56.5±25.7 -0.24±0.32
131.1±70.7
4.8±1.7 132.3±36.4
-0.23±0.62 114.6±18.3
97.6±39.7 -0.19±0.10
214.7±74.6
<0.0001
0.14
0.016
0.0009
KIRSTEN NØRGAARD, GAYANE VOSKANYAN, SUMONA ADHYA, HENRIK EGESBORG, JULIE THEANDER, PRATIK AGRAWAL, RAJIV SHAH, Hvidovre, Denmark,
Northridge, CA
<0.0001
0.84
<0.0001
972-P
Insulin Requirement Profiles and Characteristics of Type 2 Diabetic
Patients With Continuous Subcutaneous Insulin Infusion Therapy
A rising number of insulin-requiring patients simultaneously use insulin
pumps and continuous glucose sensors, which currently are separately
inserted devices. Medtronic developed a new device (MiniMed Duo)
combining a sensor and an infusion catheter on the same platform. The
device improves on the Combo-set and features a steel needle for insulin
infusion and an Enlite sensor platform. It is inserted with a specialized
XIUZHEN ZHANG, JINHUA YAN, HAIXIA XU, WEN XU, BIN YAO, YANHUA ZHU,
GUOCHAO ZHANG, JIANPING WENG, Guangzhou, China
Optimal pump setting is indispensable for successful continuous
subcutaneous insulin infusion (CSII) therapy. Currently used protocol, which
&
For author disclosure information, see page 829.
A248
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
determines initial total daily dose (TDD) according to body weight and
allocates half of the TDD to total basal dose (TBD), derived from experience
in type 1 diabetes. Limited relevant studies were conducted in type 2
diabetes mellitus (T2D). This study aimed to investigate insulin requirement
profiles and analyze the related factors of insulin dose in T2D with CSII.
A total of 296 patients (male/femal:178/118; age: 52.9±12.7 years;
diabetes duration: 4.5±3.2 years; BMI, 24.4±3.1 kg/m2; HbA1c: 10.6±2.3%)
were enrolled. The patients were admitted to hospital for 1-2 weeks of CSII
therapy and provided with diets of 25-30 kcal/kg ideal body weight per day.
The insulin infusion was adjusted according to the fasting and postprandial
of three meals capillary blood glucose ([FBG] and [PBG]). After achieving
normoglycemia (defined as FBG≤7mmol/L and PPG≤10mmol/L), the insulin
requirement profiles were analyzed.
TDD was 51.8±17.0 units , TDD/kg was 0.80±0.27 units/kg, TBD was
20.6±7.8units, and the ratio of TBD to TDD(%TBD) was 40.2±9.2 % . When
stratified by BMI(normal: <23.9;overweight: 24-27.9;obesity: ≥28), it was
found that the obesity group needed more basal infusion than overweight
group(%TBD:43±8% versus 39±9.8%, p<0.05). Further multiple regression
showed that TDD was positively correlated with waist circumference
(r=0.309, p<0.001), and HbA1c(r=0.173, p<0.05). And %TBD was positively
associated with waist circumference (r=0.162, p<0.05), and negatively
correlated with 2-h postprandial C-peptide (r=-0.135, p<0.05). Neither TDD
nor %TBD was associated with weight, lipid profile or disease duration.
Basal insulin requirement was~40% of the TDD in Chinese T2D treated
with CSII. TDD was associated with parameters indicating glycemic control
and central obesity other than with body weight.
974-P
Effect of 2-Hr Suspensions of Basal Insulin on Elevating Nighttime
Sensor Glucose Concentrations
973-P
Pre-Clinical Safety and Efficacy Study of an Overnight Closed-Loop
System
ANIRBAN ROY, BENYAMIN GROSMAN, NEHA PARIKH, JINO HAN, MIKHAIL
LOUTSEIKO, NATALIE KURTZ, GAYANE VOSKANYAN, FRANCINE R. KAUFMAN,
JOHN MASTROTOTARO, BARRY KEENAN, Northridge, CA
An Overnight Closed Loop (OCL) insulin delivery system (comprising pump,
sensor, and control algorithm) should maintain normoglycemia under optimal
conditions, while assuring patient safety during sub-optimal circumstances,
such as erroneous sensor glucose readings. Medtronic’s Android-based OCL
system contains the ePID glucose control algorithm along with several failsafe algorithms that provide enhanced patient safety, particularly during
sensor failure modes. In this work, safety and efficacy of the mobile OCL
system were examined in 7 diabetic dogs.
Closed-loop (CL) mode was started between 10:00 and 11:00 PM and data
were collected until 6:00 AM the next day. Four dogs received a correction
bolus immediately before the start of CL-mode. Adjustments to insulin
delivery were based on sensor glucose values collected at 5-min intervals,
and blood glucose (BG) values collected at 30-min intervals were used for
retrospective sensor accuracy (MARD) calculations.
The average percentage time in-range (70-180 mg/dL) was 95.4%, mean
BG ranged from 99 to 153 mg/dL, and the BG concentration never fell below
80 mg/dL (Table).
Sensors in dogs fail more often than they do in humans. Despite poor
accuracy (high MARD values) of the sensors used in dogs 5 and 7, the
sensors were not replaced and the OCL system maintained near-euglycemia
at all times. Overall performance of the system in terms of maintaining
euglycemia was excellent. The next step is inpatient human testing of the
system.
975-P
High Sensitivity Occlusion Detection Using Fluid Pressure Monitoring During Basal Insulin Infusion
STEVEN KEITH, ELAINE MCVEY, RONALD J. PETTIS, Research Triangle Park, NC
We examined pressure-based occlusion detection during insulin lispro
basal infusion and correlated these to PK outcomes in a clinical study
comparing intradermal (ID) and subcutaneous (SC) infusion routes during
two 6h infusions (1 and 2U/h) separated by a 4h washout. The study
was an open label, randomized crossover in 20 T1 diabetic males [mean
age 38.5, BMI 26.1, HbA1c 7.56]. SC infusion utilized a 28 gauge, 6 mm
stainless steel infusion cannula and ID a developmental 34 gauge, 1.5
mm microneedle set. New freshly primed and seated sets were used for
each 6h infusion period. A programmable syringe pump delivered microboluses every 3min mimicking a pulsatile insulin pump basal profile. Fluid
pressure was continuously monitored using an in-line pressure transducer.
Serum insulin lispro concentrations were quantified by radioimmunoassay
at predetermined timepoints.
Previously reported PK endpoints (onset rate & AUC) were similar between
routes, with faster ID insulin offset. Using a proprietary algorithm to process
infusion fluid pressures, apparent occlusions were detectable in 5-25% of
all set/rate combinations. Occluded infusions exhibited physiologically
implausible insulin time-concentration profiles characterized by low initial
serum insulin levels at start-up or premature insulin declines before infusion
cessation. Occlusions paralleled periods of increasing or elevated fluid
pressures that were below typical insulin pump alarm thresholds (<10psi).
PK outcomes were subsequently modeled using flow input from the
OCL system performance based on YSI values (3 hours after start of CL-mode
until end of experiment)
Dog #
Time In-Range, Mean Blood Glu- Blood Glucose Mean Absolute Relative
70–180 mg/dL (%) cose (mg/dL)
Range (mg/dL)
Difference (MARD, %)
1
83.3
148
115 – 184
17.0
2
100.0
136
112 – 179
12.1
3
100.0
149
135 – 176
19.1
4
100.0
99
85 – 114
5.3
5
85.1
119
83 – 206
49.4
6
100.0
153
131 – 170
17.0
7
100.0
127
110 – 170
28.5
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A249
POSTERS
Low glucose suspend feature of the Medtronic Veo system automatically
interrupts basal insulin for 2-hrs if patients fail to respond to low glucose
alarms; a feature aimed at preventing prolonged hypoglycemia, especially at
night. We recently reported that such 2-hr suspensions of basal insulin are
safe, resulting in minimal increases in β-hydroxybuytrate levels (i.e., from
0.08 to 0.11 mmol/L) even when basal insulin is suspended on random nights
over a range of starting glucose values. To examine the efficacy of basal
suspensions in increasing nocturnal glucose levels, the 17 T1D subjects (age
24 ± 9 yr, A1c 7.3 ± 0.5) in the study wore a blinded sensor on 71 nights
when the basal insulin infusion was pre-programmed to include a 2-hr zero
basal rate at random times after 11:30p.m. At the start of the suspend, mean
sensor glucose (SG) was 134 ± 62mg/dL and ranged between 40-295 mg/
dL. As shown in the Figure, SG rose by 26 ± 47mg/dL by the end of the 2-hr
suspend and by 61 ± 60 mg/dL two hours later. This differed from 31 nonsuspend nights in which baseline SG was 124 ± 70mg/dL and change in SG
was not appreciated at 2 and 4hrs (p=ns). On the 11 nights with baseline
SG<70 mg/dL (mean 52 ± 10mg/dL), SG rose by 14 ± 35 mg/dL at 2 hrs and
SG was >60mg/dL on 91% of nights after 4 hrs. Automatic suspension of
basal insulin for 2-hrs is an effective and safe means of limiting the duration
of nocturnal hypoglycemia in patients with T1D.
Clinical Diabetes/
Therapeutics
JENNIFER SHERR, LORI R. CARRIA, KATE WEYMAN, MELINDA ZGORSKI, AMY
T. STEFFEN, EILEEN M. TICHY, MILADYS M. PALAU COLLAZO, EDA CENGIZ,
CAMILLE MICHAUD, WILLIAM V. TAMBORLANE, STUART WEINZIMER, New
Haven, CT
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
pressure algorithm, and were well correlated to experimentally determined
PK profiles.
This is the first study to correlate basal infusion flow mechanics to insulin
PK and demonstrates that transient occlusions may occur that are unlikely to
be accompanied by an infusion pressure alarm. Infusion pressure provides
highly sensitive occlusion detection and appears related to PK outcomes
using infusion model simulations.
This novel personalization scheme can maximize clinical benefits
of closed-loop BG control by ensuring safe delivery of insulin through
appropriate attenuation of control action based on readily available clinical
parameters. Clinical trials of this algorithm are underway at the Sansum
Diabetes Research Institute.
Supported by: JDRF
Supported by: JDRF
978-P
Cognitive Effects of Intranasal Insulin in Older T2DM Adults
976-P
SARA M. MONTI, ANDREW GALICA, PETER NOVAK, MEDHA MUNSHI, AMIR
ABDULJALIL, PAULA K. ROBERSON, BRAD MANOR, WILLIAM MILBERG, VERA
NOVAK, Boston, MA, Worcester, MA, Columbus, OH, Little Rock, AR
Home Overnight Closed-Loop Insulin Delivery Over Three Weeks:
WITHDRAWN
Randomised Controlled Trial in Adolescents with Type 1 Diabetes
Accelerated cognitive decline and altered cerebral vasoreactivity are
characteristic of Type 2 diabetes mellitus (T2DM). In non-diabetic adults
with mild cognitive impairment, intranasal insulin administration has shown
some therapeutic promise. This pilot safety and efficacy study investigates
the acute effects of intranasal insulin on regional perfusion and cognition in
older T2DM adults through a randomized, double-blind, cross-over, placebocontrol design.
14 T2DM (6 M, 8F, age 62.6+7.8 yrs) and 12 controls (9 M, 3 F, 59.8+9.9
yrs) completed baseline cognitive testing, single-dose administration of 40
IU of intranasal insulin (Novolin, Novo Nordisk) or saline placebo, and postadministration continuous arterial spin labeling (CASL) 3T MRI perfusion
studies and neuropsychological tests during a 2-night inpatient stay. The
protocol was well tolerated, with no serious adverse events or excess
expected mild adverse events. Plasma glucose and vital signs remained
stable during 1 hour post-insulin.
On insulin - relative to placebo, performance on visuospatial memory
tasks improved in both groups (MANOVA, p=0.03). Higher visuospatial
delayed recall scores correlated with perfusion increases during baseline
CASL in the left insular cortex (p=0.05)(LS model adjusted for group,
age, gender, and ΔCO2). Better visuospatial learning scores on insulin
correlated with increased vasoreactivity in the insular cortex (p=0.04) (LS
model adjusted for age, group, gender). Specific to the T2DM group, total
visuospatial memory recall was associated with increased vasodilatation
in the lepto MCA territory on insulin (p=0.035)(LS model adjusted for age,
group, gender), an effect not shown on placebo or in controls. This study
provides preliminary evidence that intranasal insulin may modify perfusion
and cognitive function in older T2DM patients.
POSTERS
Clinical Diabetes/
Therapeutics
ROMAN HOVORKA, DANIELA ELLERI, JANET M. ALLEN, MARIANNA NODALE,
HOOD THABIT, KAVITA KUMARESWARAN, LALANTHA LEELARATHNA, KAREN
CALDWELL, ESTHER O’SULLIVAN, HELEN R. MURPHY, ARTI GULATI, JASDIP
MANGAT, CRAIG KOLLMAN, PETER CALHOUN, MALGORZATA E. WILINSKA,
CARLO L. ACERINI, DAVID B. DUNGER, Cambridge, United Kingdom, Tampa, FL
Free-living studies are needed to assess benefits of closed-loop (CL)
insulin delivery to build on encouraging observations taken during controlled
clinical centre conditions. We evaluated home use of overnight CL, initially
in seven pump-treated adolescents with type 1 diabetes [M 4; age 15.5(2.1)
yrs; A1C 7.9%(0.8); BMI 23.3(2.2)kg/m2, duration of diabetes 6.1(3.8)yrs; total
daily dose 0.9(0.2)U/kg/day; mean(SD)] who, after training on study devices
and passing competency assessment, underwent two 3-week periods of
sensor augmented pump therapy (FreeStyle Navigator Transmitter and
Combined Controller, Abbott Diabetes Care; Dana R Diabecare pump, Sooil)
separated by 1 to 3 week washout. During one 3-week period, randomly
assigned, overnight insulin delivery was automatically modulated by
adaptive model predictive controller running on an ultraportable laptop.
Apart from overnight CL, diabetes management was identical during the
two study periods. Overall, CL was operational for at least 4 hrs on 112
(76%) nights; sensor data were available for at least 4 hrs on 107 (73%)
non-CL nights (night defined between 11pm and 7am). CL increased the time
glucose was in target range between 3.9 and 8.0mmol/L at night [58% (40,
77) vs. 42% (13, 69), CL vs. non-CL; P<0.001, median (IQR)]. Mean overnight
glucose was reduced during CL [7.9 (2.1) vs. 8.7 (3.1)mmol/L; P = 0.006,
mean(SD)] as was time > 8.0mmol/L [35.5% (17.7, 57.8) vs. 47.1% (17.7, 87.2),
P = 0.006]. Time < 3.9mmmol/L was comparable [1.4% (0.3, 4.4) vs. 0.5%
(0.0, 9.7), P = 0.24] but the percentage of nights with glucose < 3.5mmol/l
for at least 20 min was halved (7% vs. 19%, P = 0.01). No serious adverse
event or severe hypoglycaemia was observed. We conclude that overnight
closed-loop insulin delivery is feasible in home setting providing benefits
similar to those observed under controlled conditions in adolescents with
type 1 diabetes.
Supported by: NIH/NIDDK (5R21-DK084463-02); NIH/NIA (1R01AG028076-A2)
979-P
Insulin Therapy With a 4mm x 32G Pen Needle vs. Larger Needles
in Obese Subjects
Supported by: JDRF; BRC; NIHR
RICHARD M. BERGENSTAL, ELLIE STROCK, DIANA PEREMISLOV, VALENTIN PARVU, MICHAEL GIBNEY, LAURENCE HIRSCH, Minneapolis, MN, Franklin Lakes, NJ
977-P
We performed a prospective, randomized, multicenter, crossover noninferiority trial to compare glycemic control in obese subjects with a 4mm x
32G pen needle (PN) vs two larger PNs. Subjects (N=293) with BMI ≥ 30 kg/m2,
HbA1c 5.5-9.5% and who injected insulin ≥ 2 mos using only pens entered a
3-week wash-in period, using each PN one week. They were then randomized
to either 4mm vs 8mm x 31G (N=127) or 4mm vs 12.7mm x 29G PN (N=147)
study arms, with order of PN use controlled. The 1° outcome was HbA1c after
each 12-week study period; 2° outcomes included: pain by Visual Analog
Scale (VAS), preference, ease of use, ease of insertion, injection anxiety,
insulin leakage from skin, and safety. Of 274 subjects randomized, 52% were
male; 75% Caucasian, 18% Black; 92% T2DM. Mean age ± SD = 56.7 ± 11.0
yrs; BMI 37.0 ± 6.1, range 29.1-59.9 kg/m2; insulin use duration 6.9 ± 7.7 years;
total daily dose 78.4 ± 52.9, range 6-350 units; HbA1c 7.5 ± 0.9%; 226 subjects
are included in the 1° A1c analysis. HbA1c with 4mm PNs was 0.08% lower
(95% CI -0.21, 0.06) vs 8mm PNs, and 0.10% lower (-0.19, 0.00) vs 12.7mm
PNs, both within the ± 0.4% equivalence margin. Median insulin dose changes
were -2 to +5 units within study periods. Differences in perceived relative pain
by 150 mm VAS were 12.4mm (8.3%) and 30.1mm (20.1%) lower for the 4mm vs
the 8mm and 12.7mm PNs, respectively (both p < 0.05). Subjects preferred the
4mm vs the 12.7mm PN (p < 0.05), but NS vs the 8mm PN. The 4mm PN was
rated superior for ease of use, ease of injection, and anxiety vs both larger
PNs (p<0.05). Of ~ 131,000 injections, subjects reported skin leakage in 4.2%,
4.1%, and 4.3% of injections, respectively, with the 4mm, 8mm, and 12.7mm
PNs (NS). Hyperglycemic (BG > 400 mg/dL) and hypoglycemic (BG < 50 mg/
dL) event rates per 1000 patient days (1.9-3.0, and 8.0-9.9, respectively) did
not differ between PNs. In conclusion, for obese subjects a 4mm x 32G PN is
safe, provides equivalent glycemic control to larger PNs, is less painful, better
tolerated, and does not increase insulin leakage.
A Novel Model-Based Approach to Safe Personalized PID Controller Design for Artificial Pancreas
JOON BOK LEE, EYAL DASSAU, DALE SEBORG, HOWARD C. ZISSER, FRANCIS J.
DOYLE III, Santa Barbara, CA
Prevention of hypoglycemia caused by excess insulin delivery is paramount
in artificial pancreas (AP) design for blood glucose (BG) regulation. We present
a personalization scheme based on readily available clinical parameters that
is applied to a control-relevant model of insulin-glucose response. This model
is incorporated through an internal model control based approach into a
proportional-integral-derivative (PID) controller for an AP device.
Individual basal levels based on daily insulin profiles are used to optimize
closed-loop performance. The controller calculates relative deviation of the
subject’s basal profile compared to recommended basal levels calculated
from individual clinical parameters and adjusts insulin delivery accordingly.
An insulin feedback mechanism ensures safety of the design by preventing
excess insulin delivery when given previous deliveries.
The controller was evaluated using a 31 hour protocol and challenged
with three unannounced meal disturbances of 50g, 40g, and 50g CHO. Insilico simulations of this design on 100 subjects through the FDA accepted
Univ. of Virginia/Padova metabolic simulator provided excellent results.
93% of overall simulation time was spent within acceptable clinical range
of 70-180mg/dl and 65% in tight glycemic range of 80-140mg/dl. Nocturnal
glucose control (10:30PM – 7:00AM) was also exceptionally good, with only
one hypoglycemic event (BG <65mg/dl) over 100 subjects, and with 96%
of simulation time spent within acceptable clinical range and 78% spent
within tight glycemic range. Overall, 95% of all subjects were maintained
within the A-B zone of the control variability grid analysis system.
&
For author disclosure information, see page 829.
A250
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
Fig.1. Changes in individual C-peptide-genic index and Insulin sensitivity
index. Red dot indicate at baseline and blue dot indicate at 2 year-CSII.
980-P
Disposable Insulin Pump to Improve Diabetes Treatment
Clinical Diabetes/
Therapeutics
Intensive insulin therapy for type 2 diabetes requires the patient’s
persistent attention to adhere with injections. Several factors can
contribute to missed insulin injections including forgetfulness, a busy work
schedule, needle phobia, poor psycho-mental adaptation to the diabetes,
and the costs associated with the needles and syringes. We have employed
a new insulin delivery system for its ability to overcome these problems,
i.e. a relatively inexpensive, disposable insulin pump that administers only
short acting insulin. V-GoTM (Valeritas, Inc, Bridgewater, NJ) is a novel
insulin delivery system delivering up to 76 units/day. V-GoTM can deliver
basal insulin continuously (3 different settings allow basal delivery of
0.83, 1.25 or, 1.66 units/h) for 24 hours. In addition, by clicking a button
on the unit, it delivers bolus insulin in 2 unit increments up to 36 units/day.
Instead of multiple daily injections, patients deliver insulin by affixing the
device to the skin once a day. To date, we have initiated the disposable
pump insulin treatment for 7 patients with uncontrolled diabetes, six with
type 2, and one with type 1. Prior to V-GoTM -based treatment, despite total
daily insulin doses of 137 ± 37 units (mean± SD) injected 3 ± 1 times daily,
all had elevated glycohemoglobin (12.0 ±1.0 %, range 8.9% - 14.0%). We
reasoned that the V-GoTM insulin delivery system would be more convenient
and would promote insulin compliance. After less than 1 hour of education,
all 7 patients successfully implemented V-GoTM insulin therapy. All patients
have preferred the system’s convenience. For the three individuals for
whom follow up data is available at least 35 days (range 35-51 days) after
they initiated V-GoTM -based treatment, the average daily blood glucose
significantly decreased from 305 ± 60 mg/dL to 177 ± 21 mg/dL (p<0.02) and
total daily insulin use decreased from 139 ± 42 units to 59 ± 10 units (p=0.6).
Our observations suggest that the V-GoTM insulin delivery system is well
accepted by patients and can improve blood glucose control.
982-P
A Phase 1, Open-Label, Randomized Dose Proportionality Study of
Technosphere® Insulin Inhalation Powder (TI) Doses up to 80 U Administered With the Gen2 Inhaler in Healthy Subjects
ROBERT A. BAUGHMAN, NIKHIL AMIN, ELAINE WATKINS, PING-CHANG
CHUNG, JAMES P. NEZAMIS, ANDERS H. BOSS, Danbury, CT, Paramus, NJ, Chula
Vista, CA
981-P
Changes in Pancreatic Beta Cell Function and Insulin Sensitivity
in Type 2 Diabetes by Continuous Subcutaneous Insulin Infusion
Therapy for 2 Years
This study incorporated a 4-way crossover of TI doses (10, 30, 60
and 80 U) with a fifth treatment of sc insulin in subjects maintained via
hyperinsulinemic, euglycemic clamp. Clinical experience has that > 95% of
patient doses are 60 U TI or less. Thirty-two of the 35 randomized subjects
(57.1% male, 42.9% female; mean age 34.3 ± 9.7 years) completed all study
treatments and visits.
Primary PK parameters (area under the curve [AUC], maximum serum
concentration [Cmax]) were C-peptide corrected. Dose proportionality was
evaluated by comparing the proportionality slope and associated 90% CIs
for each PK parameter against predefined 90% CIs. Relative bioavailability
(Frel) was determined by dose-normalized AUC comparisons of the various
TI doses to sc insulin. The PD effect was assessed by the GIR required to
maintain euglycemia (90 ± 10 mg/dL) for 4 hours post-dosing.
The insulin exposure over three hours post-dosing (AUC0-180) of C-peptide
corrected data was the primary parameter, and was shown to be doseproportional (slope = 1.00 (90% CI: 0.939, 1.061) from 10 to 80 U. Evaluation
of exposure extrapolated to infinity (AUC0-inf) provided a slope = 0.949 (90%
CI: 0.880, 1.019). The median bioavailability of TI using the Gen2 inhaler
was approximately 24% relative to sc injection of 15 IU insulin. The glucose
infusion rate (GIR) during the clamp after TI dosing reached a maximum
within 30 - 50 minutes, whereas after sc insulin the GIR peaked at 170 - 234
minutes.
The most frequent adverse event was mild, asymptomatic hypoglycemia,
reported for 85% of subjects after TI dosing and 12.5% following sc insulin,
which was classified as related to study procedure (ie, inability of glucose
infusion to respond at a rate to maintain euglycemia post-dosing).
Insulin exposure following administration of TI doses from 10 to 80 U via
the Gen2 inhaler was shown to be dose-proportional.
SOO BONG CHOI, HYUN-JU AN, KYUNG-JIN KIM, EUN-KYOUNG JEON, YUNHEE NOH, Seoul, Republic of Korea
Type 2 diabetes is characterized with impaired beta cell function and
insulin sensitivity. To see if these abnormalities can be improved in type
2 diabetic patients through long-term continuous insulin infusion (CSII)
therapy, we examined changes in serum C-peptide-genic Index and modified
Matsuda Index during treatment for 2 years.
We discontinued oral antidiabetic drugs and applied CSII therapy to
subjects with type 2 diabetes who had failed to control hyperglycaemia
(number, 309 with 61 % of male; age, 57.5 ± 11.8 years; duration, 10.1 ± 7.8
years; HbA1c 8.5 ± 2.0 %).
After the 2 year-CSII treatment, the mean HbA1c significantly decreased
from 8.5 ± 2.0 % to 6.3 ± 0.45 % (p < 0.001)and the mean serum C-peptide
level increased from 4.7 ± 2.1 to 6.0 ± 2.24 ng/ml (p < 0.001) and the mean
serum C-peptide-gentic Index significantly increased from 0.025 ± 0.001
to 0.035 ± 0.002 (p < 0.0001) at 120 minutes after mixed meal ingestion
and modified Matsuda Index did not change after 2 years. The disposition
index increased from 0.077± 0.077 to 0.103 ± 0.723 (p < 0.05). The resolution
of glucotoxicity and maintenance of euglycaemia through long-term CSII
therapy may contribute to the restoration of β-cell function but may have no
effect on insulin sensitivity in type 2 diabetic patients.
ADA-Funded Research
&
For author disclosure information, see page 829.
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A251
POSTERS
ABDULKADIR OMER, ROBERTA POWELL, JOHN PAUL LOCK, SAMIR MALKANI,
DAVID M. HARLAN, Worcester, MA, Boston, MA
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
A prospective, observational, open-label, multicenter study is being
conducted in patients (pts) with type 2 diabetes previously treated with
any of the following: oral antidiabetic medications alone (OADs); OADs
+ incretins; QD or BID intermediate or long-acting insulin (LAI) ± OADs;
premixed insulin ± OADs; at least 3 insulin injections a day (MDI) ± OADs.
The pts are followed on previous therapy for 4-6 weeks before switching
to V-Go. Pts are treated by conventional practice by their physicians. A
planned interim analysis is presented.
To date, 47 pts had continuous V-Go use for 3 months. Average patient
age was 60 yrs with diabetes duration of 13 yrs. Most pts were previously
on LAI (34%) or MDI (55%) ± OADs. During the pre-randomization phase A1C
was reduced by 0.4% (9.0 to 8.6%) reflecting a clinical study effect. After
V-Go initiation A1C further improved and was significantly lower (P<0.05)
across the total population and MDI subgroup (table). Five pts reported
AE’s probably related to V-Go (primarily skin irritation). Six pts reported
hypoglycemia <70 mg/dl without severe events.
983-P
How Shall We Predict Patient’s Autonomy for CSII Utilization in
Type 2 Diabetes?
POSTERS
Clinical Diabetes/
Therapeutics
YVES REZNIK, AMEL ZENIA, REMY MORELLO, MICHAEL JOUBERT, Caen,
France
Insulin pump therapy is a valuable tool for insulin intensification in
type 2 diabetes patients uncontrolled by multiple daily injections (1,2).
Unrecognized cognitive disability may compromise the use of insulin
pump. In order to predict the patient’s ability to manage his pump, 39 type
2 on CSII were administered i) a 31 items CSII questionnaire for cognitive
and operative capacities, ii) the Montreal Cognitive Assessment (MOCA)
questionnaire to detect mild cognitive dysfunction. iii) the HADS and iv) the
DTSQ questionnaire. At discharge from 5 d training, patients had complete
(n=13) or partial autonomy (n=13) or were dependent from a nurse (n=13).
The 3 groups were matched for age (mean 61 ± 8 yr) .
Results: on pump, HbA1c dropped from 8.87 to 7.5% at1 yr. DTSQ score
showed a high level of satisfaction. HADS showed anxious (33%) and
depressive items (18%). At 1 yr, 30 patients had complete autonomy, 7
partial autonomy and 2 were still dependent. Autonomy score correlated
with MOCA score (r=0.771, p<0.001). By ROC analysis, MOCA identified
autonomous vs dependent patients at cut-off score 26 (AUC : 0.893,
sensitivity 72%, specificity 80%). On follow-up, all patients with partial
autonomy/dependency had a MOCA score <26, while 74% patients with
complete autonomy had a MOCA score >26.
Conclusion: type 2 diabetes patients with partial autonomy may progress
to complete autonomy, and MOCA score may predict patient’s ability to deal
with the pump device.
1- Reznik et al, Diabetes Technol Therap 2010;12:931
2- Berthe et al, Horm Metab Res 2007;39:224
Mean
*P<0.05
N
Month 0 A1C (%)
Month 3 A1C (%)
3 Month A1C change (%)
Change in Total Daily Insulin Dose
Change in Weight, Month 0 – 3 (lbs)
Total Population
47
8.6 (6.5 – 14.4)
7.8 (5.4 – 10.9)
-0.9(1.08)*
-11.7 U
+0.7
LAI +/- OAD
Subgroup
16
8.5 (7.1 – 10.9)
7.6 (5.4 – 10.9)
-0.9(0.91)
-1.6 U
-2.7
MDI +/- OAD
Subgroup
26
8.7 (6.5 – 14.4)
7.8 (6.1 – 10.9)
-0.9(1.2)*
-17.5 U
+2.7
The interim results suggest improved glycemic control across the population and major subgroups as well as reductions in total daily insulin dose in
pts switching to the V-Go.
984-P
986-P
Predictors of Nocturnal Hypoglycemia During the Run-In Period of
the ASPIRE-2 Study
Insulin Pump Therapy Optimization Using Run-to-Run Control With
Batch-Varying Gain
BRUCE W. BODE, SCOTT W. LEE, FRANCINE R. KAUFMAN, ASPIRE-2 STUDY
GROUP, Atlanta, GA, Northridge, CA
HUI WANG, YOUQING WANG, Beijing, China
Optimizing insulin pump therapy is a significant challenge for physicians,
and run-to-run (R2R) control has been recognized a promising candidate.
However, in the reported studies, the gain of R2R is always fixed and
designed based on experience, so an intelligent method is needed to adjust
the gain adaptively.
First, using least square method, an ARX glucose-insulin model was
identified, which can be used to predict the glucose level. Second, taking
square sum of glucose prediction error as a fitness function, particle swarm
optimization method was used to calculate the optimal gain for R2R in each
day. At last, R2R used the optimal gain to update the insulin pump therapy
from day to day.
The proposed method was evaluated on the UVa/Padova simulator. In
15 days, all ten virtual adult subjects followed a protocol of 3 meals at
7am, noon, and 6pm of 40g, 70g, and 60g of CHO, respectively. In terms
of blood glucose index (BGI), the proposed method was compared with the
conventional R2R with fixed gain in the following figure. For all subjects, the
proposed method can achieve less BGI values, which means better glycemic
control performance. In addition, all subjects’ blood glucose (BG) values can
be kept in the safe range (60-180mg/dL) without hyper- or hypo-glycemia
from 10 th day.
Through learning and optimization, the proposed method can adjust insulin
pump therapy automatically. Therefore, it can work as a capable assistant
for physicians and it will reduce physicians’ work load significantly.
ASPIRE-2 is a randomized controlled trial of the Medtronic Veo insulin
pump system with Threshold Suspend (TS) which stops insulin delivery
when a specified glucose threshold value is reached. Evaluation of nocturnal
hypoglycemia was performed during the run-in phase, prior to randomization.
Run-in period was conducted in hypoglycemia-prone subjects with type
1 diabetes, age 16-70, while using the sensor-augmented insulin pump
system without the TS feature. Nocturnal hypoglycemic events (defined
as SG <65 mg/dL for >20 min between 10pm and 8am without subject
intervention) during the last 2 wk of the run-in period were evaluated. As
of 12/03/2012, 314 subjects completed the run-in phase: 248 were eligible
for randomization, 66 were ineligible, and enrollment is now complete.
Hypoglycemic events (N=1313) occurred at a rate of 0.3 per patient-night.
Subjects with lower baseline A1C values had more hypoglycemic events than
those with higher values (p<0.001). More hypoglycemia was noted among
subjects with higher glycemic variability (GV) as measured by coefficient of
variation (p< 0.001). Older subjects (>50 yr) and those with longer diabetes
durations (>15 yr) had less hypoglycemia (p=0.002 for age, p=0.002 for
duration). The effects of age and diabetes duration, when adjusted for GV,
were not significant (p=0.96 for age, p=0.63 for duration). Those with higher
basal/bolus ratios experienced more hypoglycemic events than those with
lower basal/bolus ratios. When adjusted for GV, the basal/bolus ratio was
found to be significant as either a continuous variable (p=0.009) or as a
categorical variable (≤1 vs. >1, p=0.041). As expected, baseline A1C and
GV influenced nocturnal hypoglycemia rates. The finding of higher rates of
nocturnal hypoglycemia in younger subjects with shorter diabetes duration
appears to result from greater GV in these subjects. Assessing GV may be
useful to identify hypoglycemia-prone individuals in clinical practice as well
as during recruitment for hypoglycemia studies.
985-P
Effectiveness of V-Go® for Patients With Diabetes in a Real-World
Setting (SIMPLE)
GEORGE GRUNBERGER, BRUCE W. BODE, KENNETH HERSHON, CHERYL
ROSENFELD, POUL STRANGE, Bloomfield Hills, MI, Atlanta, GA, New Hyde Park,
NY, Denville, NJ, Princeton Junction, NJ
The V-Go is a disposable 24-hour device that delivers a continuous basal
rate of insulin and on-demand bolus dosing. The purpose of this study is
to observe changes in glycemic control, insulin requirements and safety
related to its use.
Supported by: EFSD; CDS/Eli Lilly and Company; NSFC (61074081)
&
For author disclosure information, see page 829.
A252
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989-P
Effect of the InsuPad Device on Post Meal Glucose Levels With Delayed Insulin Bolus Injection
XIU-HONG LIN, MINGTONG XU, FENG LI, XIAOYUN WANG, LIFANG MAI, YAN LI,
LI YAN, Guangzhou, China
GABRIEL BITTON, DMITRY FELDMAN, TAL ALON, RON NAGAR, ANDREAS
PFÜTZNER, ITAMAR RAZ, Petach Tikvah, Israel, Holon, Israel, Mainz, Germany,
Jerusalem, Israel
Recent studies show that lipoprotein-associated phospholipase A2
(LP-PLA2) and secretory phospholipase A2 (sPLA2) are closely related to
chronic inflammation and atherosclerosis. In this study, we evaluate plasma
level of LP-PLA2 and sPLA2 in patients with newly diagnosed T2DM, and
investigate the effect of short-term intensive insulin treatment on it. We
enrolled 90 patients with newly diagnosed T2DM and 58 People with normal
glucose, 30~60 years old, from Oct.2010 to Mar. 2012. Plasma LP-PLA2 and
sPLA2 were determined in all subjects with an empty stomach. All patients
received continuous subcutaneous insulin infusion with an insulin pump for
10~14 days. IVGTT and OGTT were carried out before and after treatment.
As to gender, age, BMI, waist-hip ratio, blood pressure and lipid profile,
there were no statistically differences between these two groups (P>0.05).
Plasma levels of LP-PLA2 and sPLA2 were significantly higher in diabetics,
especially in those with macroangiopathy (P<0.05). After treatment, level of
sPLA2 was significantly reduced (P<0.05), while there was no statistically
difference of LP-PLA2 (P>0.05). Regarding to β cell function, AUCIns of
IVGTT and OGTT, AIR, ΔIns30/ΔG30, MBCI and HOMA-βwere all increased
after treatment even when corrected by the influence of insulin resistance
(P <0.001). With respect to insulin resistance, HOMA-IR was lower after
treatment, and SIM, IAI and QUICKI were higher (P <0.05). Correlation
analysis showed that LP-PLA2 and sPLA2 were positively correlated
with HOMA-IR in all the subjects (P <0.05). In a multiple linear regression
analysis, LP-PLA2 and sPLA2 were independent correlative factors of
HOMA-IR (P<0.05). Thus we conclude that plasma levels of LP-PLA2 and
sPLA2 are closely related to T2DM, insulin resistance and macroangiopathy
of diabetics. And we inferred that intensive insulin therapy might be helpful
for the improvement of insulin resistance as well as the protection of
diabetic macroangiopathy.
The InsuPad device is intended for use by diabetic subjects using rapid
acting insulin analogs for meal time bolus injections. The device applies
local controlled heat to the skin in the vicinity of the injection site which
promotes local blood perfusion and enables faster absorption of the insulin
from the injection site. This increased speed of absorption may enable
flexibility with the timing of meal time insulin bolus injections. Previous
studies have shown improved insulin absorption and better post prandial
control when the InsuPad device is used. In this study we tested the effect
of the InsuPad on post meal glucose levels when the meal time insulin bolus
was injected 30 minutes post meal compared to bolus injection before meal
when the InsuPad device was not used.
Type 2 diabetic patients on basal bolus insulin therapy were admitted after
overnight fast for a meal tolerance test. Subjects consumed standardized
liquid meals. The study was conducted twice: with the InsuPad device
(0.2U/kg insulin bolus injected 30 min post meal; Test) and without the
InsuPad device (0.2U/kg injected before meal; Control). Blood samples for
glucose measurements were taken from a venous line during the study. The
aim of the study was to show non-inferiority of post meal glucose levels
under Test compared to the Control.
15 type 2 diabetic subjects participated in the study (4 females), aged
58.4 ± 6.8 years, with HbA1c of 8.6 ± 1.1 and BMI of 28.2 ± 4.7 kg/m^2.
Mean maximum glucose excursion was lower when the InsuPad device
was used (129±15 mg/dl vs. 142±15 mg/dl p=0.013). Area under the curve
of the glucose excursion during five hours post meal was lower, when the
InsuPad device was used (54 ±9 mg/dl/Hr vs. 70±9 mg/dl/Hr p=0.017).
Similar results were obtained for glucose excursions at 3 and 4 hours post
meal.
Using the InsuPad device enabled 30 minutes post meal injection with
better post meal glucose control. This added flexibility when using the
InsuPad device may have benefit in subjects with unpredictable eating
patterns.
988-P
Effects of Glargine Insulin Delivery Method (Pen-Device vs. VialSyringes) on Glycemic Control and Patient Preferences
STACEY SEGGELKE, MATTHEW HAWKINS, JOANNA GIBBS, ELIZABETH
COHLMIA, ELIZABETH COHLMIA, NEDA RASOULI, CECILIA WANG, BORIS
DRAZNIN, Aurora, CO
990-P
A Feasibility Assessment of PaQ®, a Simple 3-Day Basal/Bolus Insulin Delivery Device, in Patients With Type 2 Diabetes
We evaluated the effects of 2 glargine insulin delivery methods (pen vs.
vial-syringes) on glycemic control and patient preferences in a randomized,
open-label, crossover study. Thirty-one patients discharged from the
University of Colorado Hospital were recruited for this study. In the hospital,
all patients were treated with basal/bolus regimen. Upon discharge, 21
patients received glargine by pen for 3 months and were then switched
to vial-syringes for the next 3 months (Group 1). Group 2 consisted of 10
patients discharged on vial-syringes and converted to pens after 3 months.
Hemoglobin A1c (HbA1c) was measured at enrollment, and at 3 and 6
months. A questionnaire assessing patient preference was administered
at 3 and 6 months. The groups had similar baseline HbA1c (10.7±2.2% and
11.2±2.5%, Groups 1 and 2, respectively) and similar reduction in HbA1c at
3 months (7.8±1.7% and 7.3±1.4%, Groups 1 and 2, respectively, p< 0.001
vs. baseline). However after crossover, the changes in HbA1c from 3 to 6
months were significantly different between groups. The HbA1c increased
to 8.5±2.0% at 6 months in Group 1 after switching to vial-syringes, but
remained unchanged (7.1±1.6%) in Group 2 after switching to pens (p<0.01,
Group 1 vs. 2). Patient questionnaires after each phase of the trial revealed
that when asked “How satisfied would you be to continue with your present
form of therapy?”, patients were more satisfied with the pen-device than
with vial-syringe (5.8+0.4 vs. 2.7+0.7, pen vs. syringe, p<0.0001, on the scale
from 0 to 6, with 6 being “very satisfied” and 0 being “very dissatisfied”).
Furthermore, patients found the pen-device more convenient and were
more likely to recommend this insulin delivery method to someone else.
In conclusion, patients switching to glargine pen achieved lower HbA1c at
6 months of follow-up. Patients in both groups overwhelmingly preferred
glargine pens over vial-syringes.
JULIA K. MADER, LESLIE C. LILLY, FELIX ABERER, JÖRG PACHATZ, STEFAN KORSATKO, ELLIE STROCK, ROGER MAZZE, PETER DAMSBO, THOMAS R. PIEBER,
Graz, Austria, Marlborough, MA, Minneapolis, MN
PaQ (CeQur, SA) is a simple patch-on device that provides set basal
rates and bolus insulin on demand. This 6-week open-label single-arm
study assessed; feasibility of use, method of transition from multiple
daily injections (MDI), ability to maintain glycemic control and safety in
patients with type 2 diabetes (T2D) treated with PaQ. Twenty patients (age
59 ±5 y, T2D duration 15±7 y, A1C 7.7 ±0.7 %), on a stable MDI regimen
were enrolled. The study was comprised of three 2-week periods; baseline
(MDI), transition to PaQ, and PaQ therapy. The first PaQ basal rate (dose/
day) selected was ≤ the patient’s basal MDI dose. There was no attempt
to treat to target. Eighteen patients completed the study. All were able to
assemble and use PaQ. Mean total daily dose (TDD) for all patients at the
end of PaQ therapy (57±15 U) was not different from baseline (60.4 ± 19 U).
Changes in self-monitored blood glucose values (mean ± SD mg/dL) during
PaQ therapy showed a trend toward better glycemic control compared
to baseline; pre- and post-breakfast -10.7±28 (P=0.12), -13.0±34 (P =0.13),
pre-and post-lunch 8.6±41 (P =0.39), -2.6±36 (P =0.76), pre- and post-dinner
-2.7±27 (P =0.67), 10.6±61 (P =0.48) and bedtime -17.9±45 (P =0.12). Blinded
continuous glucose monitoring (CGM) data during PaQ therapy revealed a
trend towards improved glycemic control, with a mean change in average
24 hour glucose exposure of -190.3 mg/dL (P = 0.18) compared to baseline.
The reduction in glucose exposure occurred overnight and during the day.
CGM revealed no episodes of severe hypoglycemia. The improved glucose
exposure was consistent with a mean change in A1C of -0.3±0.4%. No
cannula site infections occurred and PaQ was well tolerated. MDI treated
patients with T2D were easily and safely transitioned from MDI to PaQ.
Despite similar TDD during MDI and PaQ study periods, there was a trend
toward improved glycemic control with PaQ therapy. Future studies will
assess longer-term PaQ efficacy and safety.
Supported by: Sanofi
Supported by: CeQUr Corporation
ADA-Funded Research
&
For author disclosure information, see page 829.
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A253
POSTERS
987-P
The Effect of Intensive Insulin Treatment on Plasma Level of LPPLA2 and sPLA2 in Patients With Newly Diagnosed T2DM
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
991-P
Dynamic Bayesian Network (DBN) Model for Blood Glucose Prediction
JUSTIN LEE, ROBERT KIRCHER, DON MATHESON, RICHARD MAUSETH, Redmond, WA
The goal of this project is to develop an algorithm that produces a DBN
statistical model that accurately predicts future BG values, given glucose
and insulin on board (IOB) information up to and including the current time.
The current goal is 2 hours. At each time T the algorithm selects the BG
value B that maximizes the conditional probability:
POSTERS
Clinical Diabetes/
Therapeutics
p(Bt>=T |B t<T, I t<T ) where B is blood glucose and I is IOB.
The preceptron learning algorithm uses a set of patterns or curves that
are designed to match medically important aspects in the respective BG
and IOB histories. Each pattern is a sequence of integers representing
15-minute sample times. The algorithm also uses a features metric h(t) for
each such pattern, which indicates how well, at time t the current BG and AI
histories matched the patterns. The output from the training algorithm is a
real-valued [1 x J+K] vector lambda L, where each Li (1<=i<=J+K) expresses
how important the ith feature is at predicting BG. J and K are the number of
BG and IOB feature patterns respectively. The above conditional probability
at time t is calculated as edot(L,h(t)).
The BG and IOB training datasets come from our 2011 JDRF-funded clinical
study. A 5-minute sample time was used. The IOB sequence is calculated
from the dosing values using a 3.5-hour insulin action curve. Currently there
are 21,000 BG and IOB 1-hour integer-valued feature patterns.
Initial results show that during fasting periods the DBN model predicts
BG values 75 minutes in the future within 8.8 % of the actual clinical values.
Using the same interval, post meal accuracy is within 6.6-15.8%. The
training algorithm is independent of subject and will be validated on each of
the 2011 clinical subjects.
In addition to shutting off insulin when low blood sugars are predicted,
the model will be used postprandially to adjust dosing based on the
predicted BG values. Refinements and testing are ongoing for the planned
incorporation into the version 3.0 controller planned for use in our 2013 NIHfunded clinical studies.
Supported by: RG56692
993-P
Efficacy of Outpatient Closed-Loop Control (CLC)
BORIS P. KOVATCHEV, CLAUDIO COBELLI, ERIC RENARD, HOWARD ZISSER,
Charlottesville, VA, Padova, Italy, Montpellier, France, Santa Barbara, CA
Following early feasibility tests of a portable artificial pancreas - the
Diabetes Assistant (DiAs) based on Android smart phone - we now report
first randomized cross-over trials (RCT) of outpatient CLC.
Twenty type 1 diabetes patients enrolled at 4 sites in the U.S. and Europe,
N=5/site for two 38-hour outpatient sessions: CGM-augmented insulin
pump therapy vs. CLC. Each session includes meals at local restaurants and
45-minute light exercise (walk in town). During both sessions the patient
operates DiAs via graphical user interface; DiAs receives CGM data from a
Dexcom Gen 4 sensor, runs the CLC algorithm, and controls a Tandem t:slim
insulin pump. Study personnel monitor the trials remotely via 3G or WiFi and
are available on site for assistance.
Preliminary results: at this time, one 24-hour pilot and 7 (out of 40)
sessions have been completed. Figure 1 illustrates the system action during
the pilot: DiAs manipulates basal rate to maintain normoglycemia overnight,
administers corrections during the day, suggests pre-meal insulin upon entry
of estimated meal carbohydrates, and predicts/ mitigates hypoglycemia.
On open- vs. closed-loop control, the average glucose was 120 vs. 130mg/
dl; the time within target (70-180mg/dl) was 85% vs. 84% (90% vs. 96%
overnight); there were 3 vs. 2 hypoglycemic episodes. Complete results are
expected in April, 2013.
First RCT of outpatient CLC show control performance similar to previous
inpatient studies and comparable to state-of-the-art sensor-augmented
insulin treatment.
Supported by: NIH; JDRF
992-P
Usability of FlorenceD Closed-Loop System during Overnight Home
Use in Adolescents With Type 1 Diabetes
JANET M. ALLEN, DANIELA ELLERI, MARIANNA NODALE, ARTI GULATI, HOOD
THABIT, LALANTHA LEELARATHNA, KAREN CALDWELL, MALGORZATA E. WILINSKA, ESTHER O’SULLIVAN, HELEN R. MURPHY, CARLO L. ACERINI, DAVID B.
DUNGER, TIMOTHY T. WYSOCKI, ROMAN HOVORKA, Cambridge, United Kingdom, Jacksonville, FL
Assessing user-friendliness of new technology is important to identify
system strengths and limitations. We are undertaking overnight closedloop studies at home in adolescents with type 1 diabetes using a purpose
built FlorenceD system consisting of an insulin pump, CGM device and
ultra-portable computer running model predictive algorithm. We used an
eight point questionnaire to evaluate the usability of the system. Data
relate to 8 adolescents (age 15.2±2.1years, HbA1c 8.0±0.7%, duration of
diabetes 6.5±3.7years) following 3 weeks of overnight closed-loop at home.
Response options for each question ranged from 1=Terrible, 2=Poor, 3=Fair,
4=Good, to 5=Excellent. Results are summarised in Table. Items relating
to accuracy and reliability of closed-loop performance scored highest,
with fashion issues, battery life and flexibility of functions scoring lowest.
Ease of start-up, instructions and technical support were rated as Good or
Excellent by majority of subjects (range 62.5-71.4%). Over 87% of subjects
rated screen information and alarms as Fair, Good or Excellent. Battery life
and ease of replacement was rated poorly by 50% of subjects. Responses to
items 2 and 3 show two groups of adolescents (62.5% Excellent/Good, 25%
Poor). Further qualitative assessments are warranted to understand these
differences. Next generation FlorenceD system will focus on miniaturisation
of the system, improving battery life and increasing flexibility of functions.
Supported by: JDRF (22-2011-649); NIH (RO1DK085623)
&
For author disclosure information, see page 829.
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Table 1.
Parameter
Group A
Group B
Group C
P value
n=29
n=15
n=6
(ANOVA)
Mean Glucose (mg/dl)
161.73 (147 - 176) 179.83 (146 - 214) 186.91 (135 - 239) P 0.34
(95% CI)
(ON CSII)
(ON CSII)
(OFF CSII)
292.81 (37 - 548) 194.51 (166 - 223) 187.49 (156 - 219) P 0.78
(ON & OFF CSII) (ON & OFF CSII) (ON & OFF CSII)
Mean Frequency (%) of Hyperglycemic 26.57 (17 - 36)
34.79 (23 - 47)
42.45 (12 - 73) P 0.27
(>200 mg/dl) events
(ON CSII)
(ON CSII)
(OFF CSII)
(95% CI)
28.75 (20 - 37)
40.77 (31 - 51)
41.08 (22 - 60) P 0.12
(ON & OFF CSII) (ON & OFF CSII) (ON & OFF CSII)
Mean Frequency (%) of Hypoglycemic 6.87 (4 - 10)
9.71 (0 - 19)
7.7(0 - 15)
P 0.73
(<70 mg/dl) events
(ON CSII)
(ON CSII)
(OFF CSII)
(95% CI)
6.99 (4 - 10)
5.13 (2 - 8)
7.12 (1 - 13)
P 0.66
(ON & OFF CSII) (ON & OFF CSII) (ON & OFF CSII)
“ON CSII” = glucose readings only while the patients were on the insulin
pump
“ON & OFF CSII” = glucose readings while on pump and off the pump (such
as for surgical procedures, on insulin infusion)
“OFF CSII” = glucose readings off insulin pump
LUTZ HEINEMANN, DIETMAR WEBER, MATTHIAS KALTHEUNER, NIKOLAUS
SCHEPER, GABRIELE FABER-HEINEMANN, DOROTHEA REICHERT, Düsseldorf,
Germany
Aim: Surprisingly little data are available about the success of insulin
pump therapy under daily life conditions and which problems show up.
Methods: 1142 patients treated in 40 practices specialized on diabetes
therapy (DSP) answered a two-page patient questionnaire in the period
from 01.04.2012 to 30.06.2012. Results: 59% (668) of the patients were
female / 41% (471) men, their mean (SD) age was 42±15 years, duration
of diabetes 21±13 years, HbA1c 7.2±1.1% and the duration of CSII therapy
7.9±6.1 years. 69% of the patients got the pump in a DSP, 21% in a diabetes
clinic, 9% and 4% in a clinic by their GP. 55% used a pump from Medtronic,
41% of one of Roche Diagnostics. 97% of the patients are satisfied with
their therapy. 76% of patients use a temporary basal rate, 63% a bolus
calculator, and 49% one of the bolus options. More Teflon catheters are
used then steel catheters (58% vs. 39%). The wear time of steel catheters
was shorter in comparison to that of Teflon catheters (p<0.001). Most
catheters are inserted vertically and not with an angle (82% vs. 12%). 91%
of the catheters are placed in the abdomen. 39% of the patients use a
needle length of 8 mm (6 mm 22%). 45% use a tube length of 60 cm (80 cm
21%). 52% change their catheter every 2 day (3 days 39%). 35% of patients
reported differences in blood glucose curve during the wearing time of the
catheter. More patients observed increases in glycemia with steel catheters
(yes 210 (52%) vs. no 195 (48%)) in comparison to Teflon catheters (313 (59%)
vs. 222 (41%); p<0.05). 39% of patients reported catheter problems: bending
19%, leakage 12%, air bubbles 12%, others 33%. Conclusion: This evaluation
shows that the reality of pump therapy usage differ in some aspects from
the usual recommendations. The type of catheter used has an impact on the
metabolic control. Such evaluations also provide hints for improvement of
insulin pump therapy.
996-P
Poor Numeracy as a Limiting Factor for Successful Treatment of
Type 1 Diabetes Mellitus (T1DM) Patients on Continuous Subcutaneous Insulin Infusion (CSII)
EVGENYA M. PATRAKEEVA, NATALIA N. ROMANOVA, ALSU G. ZALEVSKAYA,
EVGENYA V. SHLYAKHTO, Saint Petersburg, Russian Federation
Background: poor numeracy is one of the main factors with great influence
on quality of glycemic control in T1DM patients (D. Kerr, 2010 (1)).
Aim: to evaluate possibilities to calculate simple mathematical task and
it´s relation to quality of glycemic control in T1DM patients on CSII.
Subjects and methods: 43 T1DM patients were switched to CSII therapy
after traditional structural educational course. After 3 months of CSII
patients were divided into 2 groups: group 1-28 patients with frequent (more
than 1 square (S) and/or dual wave (DW) boluses per day) and group 2-15
patients with less frequent usage of different types of boluses. HbA1c level
investigation and continuous glucose monitoring with standard deviation
(SD) measurement and amount of hypoglycemia episodes were calculated.
According to idea of importance of numeracy for all patients simple
mathematical task was given (ranged as a 3d-class task for elementary
school) to all patients. Due to results of task completion the decision about
re-education of different boluses lessons was obtained.
Results: HbA1c level after 3 months was comparable in both groups
(7,4±1,1 vs 7,6±1,2), but difference in SD and amount of non-severe
hypoglycemia episodes were statistically significant (p< 0,001). Right
answer for mathematical task was given by 86% of group 1 patients and
33% of group 2 patients and there were no any differences in educational
level, age or diabetes duration in both groups. In a month, after additional
education of group 2 patients (for 4 hours) the amount of S/DW boluses
was increased.
Conclusion: numeracy assessment is an essential tool for successful
education of patients on CSII.
1 - D.Kerr. Poor Numeracy: The Elephant in the Diabetes Technology
Room. Journal of Diabetes Science and Technology. 2010; Volume 4, Issue
6:1284-1287
995-P
Patient Characteristics and Glycemic Control in Patients on Insulin
Pump
SUBRAMANIAN KANNAN, ELLEN CALOGERAS, PATRICIA LOCK, MARIA CECILIA LANSANG, ANKITA SATRA, Cleveland, OH
When hospitalized patients are allowed to use their insulin pump (CSII),
multiple factors affect glycemic control.
This study aimed to determine glycemic control and characteristics of
CSII-using patients which can affect their glycemic control in the hospital.
Starting Jan 2012, our certified diabetes educators standardized their
assessment of hospitalized patients on pumps. Data on diabetes history,
CSII knowledge assessment and glycemic control, were collected by chart
review on adults hospitalized between January to July 2012. Patients were
categorized into 3 groups: those who continued on CSII and did not need
any education (Group A), those who continued on CSII but needed education
(Group B) and those who were considered unsuitable for CSII (Group C) and
were treated with insulin injections.
There were 50 patients, 57% males, mean age 48 + 13 years, 86% T1DM.
Mean DM duration was 26 + 14 years, mean duration of CSII was 8.7 + 6
years, mean A1c was 7.6 + 1.4 %. Mean duration of hospital stay was 5 + 4
days. Mean blood glucose levels (MBG), frequency of hyper/hypoglycemic
events among the three groups is shown in Table 1. On univariate analysis,
DM duration, knowledge of pump settings, and knowledge of hypoglycemia
correction significantly correlated with glucose control, but only the latter
was significant on multivariate analysis. (P < 0.001).
MBG was not different among the three groups. Knowledge of hypoglycemia correction significantly correlated with MBG during hospitalization.
997-P
Glycemic Control, Pain and Leakage With 4mm vs. Larger Pen Needles in Obese Patients Treated With Lantus® or High Insulin Doses:
Pre-Specified Subgroup Analyses
ELLIE STROCK, RICHARD M. BERGENSTAL, VALENTIN PARVU, LAURENCE
HIRSCH, MICHAEL GIBNEY, Minneapolis, MN, Franklin Lakes, NJ
Despite controlled studies that show 4mm x 32G pen needles (PNs) provide
equivalent glycemic control with less injection pain, without increased
skin leakage vs larger PNs (CMRO 2010;26:1531-41; DTT 2012;14:1084-90),
there is clinician reluctance to recommend or to use 4mm PNs in patients
taking high insulin doses and/or Lantus (glargine, IG). From a study of obese
insulin-requiring subjects, we report on pre-defined subgroups taking high
insulin doses (≥ one daily injection ≥ 40 units) or IG. This was a multi-center,
prospective, open-label, randomized cross-over non-inferiority study with
two arms - either 4 vs 8mm x 31G or 4 vs 12.7mm x 29G PNs, with order
of PN use controlled. HbA1c was measured after each 12-week period;
relative pain by 150 mm Visual Analog Scale and insulin backflow from skin
was also evaluated. In 274 subjects randomized, baseline mean ±SD BMI =
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A255
POSTERS
994-P
Reality of Insulin Pump Treatment in Germany: Results from a Survey With 1142 Patients Treated in 40 Specialized Practices
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—INSULIN DELIVERY SYSTEMS
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
37±6.1 kg/m2, HbA1c 7.5±0.9%, total daily dose (TDD) 78.4±52.9, range 6 to
350 units, 92% were T2DM.There were 118 subjects (43%) who took high
dose injections (TDD 113.5±54.9, range 40 to 350 units), 174 (64%) used IG
(TDD 77.5±53.3, range 7 to 350 units); 107 and 154 subjects, respectively,
completed. HbA1c levels with the 4mm PN were -0.09% (95% CL -0.23,
0.05) compared to pooled 8mm and 12.7mm PNs in the high-dose subjects,
and -0.08% (-0.16, 0.01) vs the longer PNs in the IG group, both within preset
HbA1c equivalence criteria (±0.4%). The 4mm PN was rated significantly less
painful than 8mm PNs in high-dose subjects, and vs 12.7mm PNs in the IG
subjects, both p < 0.05. Pain ratings trended similarly in the other subgroups
but were NS. Reports of leakage for the three PN lengths were infrequent
and NS, ranging from 3.4 to 5.1% in high-dose subjects, and 3.7 to 4.7% in
IG users. In conclusion, in obese subjects taking high insulin doses and/
or using insulin glargine, the 4mm x 32G PN provides equivalent glycemic
control vs longer PNs and does not increase insulin leakage or pain.
999-P
Artificial Pancreas With Diurnal Control Law for Safe Overnight
Glucose Control at Home: Interim Clinical Results
RAVI GONDHALEKAR, EYAL DASSAU, HOWARD C. ZISSER, REBECCA A. HARVEY, FRANCIS J. DOYLE III, Santa Barbara, CA
Effective nighttime glucose control is crucial for people with type 1
diabetes mellitus (T1DM). An artificial pancreas that automatically delivers
insulin based on continuous glucose monitoring must strive to prevent
over-delivery of insulin, especially during sleep, and thus avoid nocturnal
hypoglycemia, with minimal user interaction. A novel “diurnal” control
strategy for insulin dosing was proposed for this purpose. The proposed
strategy is based on periodic zone model predictive control, and was
evaluated in clinic and subsequently compared to a time-invariant model
predictive control strategy.
The diurnal strategy is fully automatic at all times, modulates its
action based on the time of day, and is designed to deliver insulin more
conservatively at night. It thus strategically alleviates the risk of nocturnal
hypoglycemia.
A preliminary study of 4 subjects with T1DM for 7-43 years, ages 2856, underwent a 24h study with 2 unannounced meals and 30min exercise.
Subjects served as their own control group, based on an identical protocol
and the invariant strategy. Here we focus on the overnight (10pm-7am)
results. The proposed strategy strategically performed up to 2.5h pump
suspensions to circumnavigate impending hypoglycemia, possibly induced
by an over-delivery in response to dinner. Specifically, the amount of insulin
delivered was 5.2+-1.9 [U], compared with 6.76+-1.8 [U] in the invariant
case. Furthermore, the proposed strategy resulted in a 1.26+-0.8 [U] underdelivery from basal, as opposed to a 0.31+-0.3 [U] over-delivery in the
invariant case. However, the resulting average (diurnal 129+-19 [mg/dL],
invariant 137+-10 [mg/dL]) and breakfast time (7am, diurnal 121+-22 [mg/
dL], invariant 117+-21 [mg/dL]) glucose values demonstrated no clinically
significant differences.
The proposed diurnal control strategy is a significant step towards
safe and continuous operation of artificial pancreases in outpatient
environments.
Supported by: Becton Dickinson
CHAOFENG YAN, YOUQING WANG, Beijing, China
POSTERS
Clinical Diabetes/
Therapeutics
998-P
A Novel Physician-Friendly Closed-Loop Control Algorithm for Artificial Pancreas (AP)
The existing AP control algorithms are generally too complicated for
physician to understand and also those algorithms do not use clinical
parameters sufficiently. By using standard clinical parameters, a model-free
algorithm was proposed in this study, which is very easy to understand for
physicians.
Proportional controller was used to design the current insulin infusion
rate; i.e., the infusion rate is proportional to the difference between the
glucose prediction and setpoint, where the proportional gain is related
with subject-specific correction factor (CF). Then, linear insulin-on-board
(IOB) curve was employed to eliminate the influence of insulin cumulation.
Because CF and IOB are involved, the proposed method is termed as Clinical
Parameter based Proportional Controller (CPPC).
CPPC was evaluated in silico using the UVa/Padova simulator. Ten virtual
adult subjects followed a 24-h protocol of 3 meals at 7am, noon, and 6pm
of 40g, 70g, and 60g of carbohydrates, respectively. As a reference, CPPC
was compared with the standard model predictive control (MPC). As shown
in the following table, CPPC can evidently increase the percentage of time
when BG within the safe range and decrease the mean value and standard
derivation of BG.
CPPC is effective in achieving normoglycaemia and has excellent
robustness to unannounced meals. The simplicity of the proposed method
makes it physician-friendly, so it has great potential for extensive use.
Supported by: NIH
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—
NON-INSULIN INJECTABLES
Guided Audio Tour: Clinical Use of GLP-1 Agonists (Posters: 1000-P to
1007-P), see page 17.
&
1000-P
Effects of the GLP-1 Receptor Agonist on Fatty Liver in Patients
With Type 2 Diabetes
JUN OGINO, CHIHIRO YONEDA, KANAKO TAJIMA, YASUHIKO ICHIMURA, SAYAKA FUKUSHIMA, TAKENORI HARUKI, YUKIE SAKUMA, RIE IWAI, TAKAYOSHI
NISHINO, YOSHIFUMI SUZUKI, NAOTAKE HASHIMOTO, Yachiyo, Chiba, Japan,
Asahi, Japan
Glucagon-like peptide-1 (GLP-1) has extra-pancreatic effects on a variety
of tissues in addition to the pancreatic actions. We evaluated the effects
of the GLP-1 receptor agonist on fatty liver in patients with type 2 diabetes
(T2D).
Twenty two T2D patients (11 males, 11 females; mean age 56.9±9.4 years)
with fatty liver who had no custom of alcohol abuse, viral and autoimmune
hepatitis were examined in clinical characteristics, metabolic parameters,
insulin secretion, biochemical markers for hepatic inflammation and fibrosis.
Hepatic fat content was measured by 1H-magnetic resonance spectroscopy
(1H-MRS) before and after GLP-1 receptor agonist liraglutide treatment.
Baseline mean body mass index (BMI) was 31.5±4.8, duration of T2D;
9.9±6.4 years, HbA1c; 8.6±1.4%, postprandial plasma glucose; 197±77mg/dl,
postprandial C-peptide; 3.2±2.5ng/ml. BMI, HbA1c, CPI (CPR index), AST and
ALT levels were significantly improved (p<0.05) at 3 months after liraglutide
treatment. Serum ferritin and cytokeratin-18 levels had a tendency to
decrease. Hepatic fat concentration measured by 1H-MRS decreased from
34.1% to 18.2% (p<0.05) at 6 months after liraglutide treatment. Patients
who improved intrahepatic fat accumulation had a tendency to have shorter
T2D duration, more improvement of BMI, ALT, and YKL-40 than those who
didn’t. Patients who improved HbA1c after liraglutide had a tendency to
have shorter T2D duration, higher baseline CPR, lower baseline YKL-40,
more improvement of BMI, ΔALT, and hepatic fat concentration.
Supported by: EFSD; CDS/Eli Lilly and Company; NSFC (61074081)
&
For author disclosure information, see page 829.
A256
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
In conclusion, metabolic parameters, liver function, biomarkers for hepatic
inflammation and fibrosis, and intrahepatic fat accumulation improved after
liraglutide treatment. Although it is unclear whether these results were
caused by the direct effect on hepatocytes or indirect effect through weight
reduction by liraglutide, GLP-1 receptor agonist may potentially ameliorate
fatty liver.
&
1001-P
Effect of a Dual Agonist of Glucagon-Like Peptide-1/Glucose-Dependent Insulinotropic Peptide (MAR701) on Insulin Secretion Rate
and Gastric Emptying in Healthy Volunteers
&
Clinical Diabetes/
Therapeutics
MAR701 is a novel peptide analog with activity on both glucagon-like
peptide-1 and glucose-dependent insulinotropic peptide receptors. The
effects of MAR701 on insulin secretion rate (ISR) and gastric emptying
(GE) were assessed in this phase I, two part, placebo- and active-control,
sequential, single blind study in healthy volunteers.
Part 1: After a >10 h overnight fast subjects (Cohort 1; n=6, all male, mean
age 35.0 years, mean BMI 26.9 kg/m2) received 2 SC injections of placebo
(-120 and 0 min) in the abdomen on Day 1 followed by 2 SC injections of
Byetta® 5 µg (10 µg total at -120 and 0 min) in the abdomen on Day 2.
Part 2: Subjects (n=18, 15 male, mean age 35.9 years, mean BMI 26.9 kg/
m2) received placebo on Day 1 followed by MAR701 8 mg on Day 2 (Cohort 2,
n=6), placebo on Day 1 followed by MAR701 4 mg on Day 2 (Cohort 3, n=6),
and placebo on Day 1 followed by MAR701 16 mg on Day 2 (Cohort 4, n=6).
ISR was assessed using a 2.5 hr graded glucose infusion (GGI) at 2, 4, 6,
8, and 12 mg/kg/min (30 min per step of 20% dextrose, IV) with sampling for
glucose, insulin and C-peptide. GE was assessed by measuring absorption
of 1000 mg oral acetaminophen elixir over 240 min..
A dose-dependent increase in ISR was observed in response to Byetta
at each GGI rate compared with placebo (p<0.001). MAR701 at all doses
significantly increased ISR in a dose-dependent manner during each GGI
step (p<0.0001). In contrast to Byetta, treatment with MAR701 did not
significantly delay GE at any dose.
Treatment with MAR701 was generally safe and well tolerated. The most
common adverse events associated with treatment with MAR701 were
hypoglycemia (occurring after discontinuation of the GGI) and mild nausea
that was not dose-dependent.
In conclusion, MAR701 significantly increased ISR at doses that had
either no or minimal effects on GE.
Supported by: Sanofi
Effect of GLP1R/GCGR Dual Agonist in Monkeys
Peptide-based analogs of the gut-derived incretin hormone glucagon-like
peptide 1 (GLP-1) stimulate insulin secretion in a glucose-dependent manner.
Such therapy improves the management of T2D and is often accompanied by
modest weight loss. This has promoted the search for a safe and effective
approach to enhance such efficacy. We have previously reported that
balanced co-agonism at the GLP-1 receptor (GLP1R) and glucagon receptor
(GCGR) can improve glucose metabolism and exhibit superior weight loss
when compared to selective GLP1R agonism in diabetic-obese rodents. We
now report the translation of these observations to obese, non-diabetic
rhesus monkeys, which were treated with a protease-resistant GLP1R/
GCGR dual agonist. Daily administration of the dual agonist at a nearly
sevenfold lower dose (3µg/kg s.c.) to commercially-sourced GLP1R selective
agonist (Victoza®) (20µg/kg s.c.) caused superior weight loss. The impact on
glycemic control and the potential diabetogenic risk of GCGR activation was
assessed in diabetic rhesus monkeys. Victoza® (10 µg/kg s.c.) was again
used as a comparative benchmark for selective GLP1R agonism. All monkeys
after appropriate wash-out were also treated with the dual agonist at a
tenfold lower dose (1 µg/kg s.c.). Sizable reductions in fasting glucose were
achieved through one week of treatment. At end of study improved glucose
tolerance was observed in the absence of changes in body weight and food
intake. These results demonstrate successful translation of the superior
pharmacology of GLP1R/GCGR dual agonists from rodents to non-human
primates, deepening our belief that this approach constitutes a promising
new mechanism in the treatment of T2DM.
1002-P
THOMAS KISSNER, MARTINA DORAU, AUREL PERREN, ANNIKA BLANK, MARTIN HEINRICHS, GABRIELE DIETERT, Frankfurt, Germany, Bern, Switzerland
In C cells isolated from human thyroid gland tissue, only marginal GLP-1R
expression has been observed. This study assessed the expression of GLP1R in human thyroid tissue with proliferative C-cell findings compared to
tissue without C-cell pathology. 49 tissue samples were examined from 3
studies; human thyroid tissue without C-cell pathology (n=19; Group A), C-cell
carcinoma (sporadic; n=10; Group B), C-cell carcinoma (multiple endocrine
neoplasia; n=10; Group C), & non-neoplastic & neoplastic C-cell hyperplasia
(Groups D1 [n=5] & D2 [n=5]). C- & follicular cells were examined separately
for GLP-1R expression, with calcitonin expression levels determined to
ensure proper separation of cell fractions. Calcitonin expression levels in
the follicular cells were low or undetected in Groups A (cycle time [CT]=32.1)
& D (CT=28.4) & higher in Groups B (CT=20.1) & C (CT=23.9). In the C-cell
fractions the levels were consistently higher with CTs of 21.5-26.6, 23.7,
25.0, 29.2 & 27.0 in Groups A, B, C, D1 & D2, respectively. In both C- &
follicular cell samples GLP-1R expression levels were low or undetected
in all groups. Calcitonin RNA was expressed in the C cell & to a much
lower extent the follicular cell samples demonstrating that they had been
successfully separated. In conclusion, no difference in GLP-1R expression
was observed between thyroid tissue samples with or without proliferative
C-cell findings, neither in follicular nor C-cell fractions.
&
1003-P
JULIE LAO, BARBARA C. HANSEN, RICHARD DIMARCHI, ALESSANDRO POCAI,
Rahway, NJ, Tampa, FL, Bloomington, IN
Comparison of GLP-1R Expression in Human C-Cell Thyroid Tumor
Tissue and Human Thyroid Tissue Without C-Cell Pathology
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A257
POSTERS
MARCUS HOMPESCH, LINDA MORROW, KHIN WIN, LOUIS VIGNATI, JONATHAN HAUPTMAN, Chula Vista, CA, Carmel, IN, Nutley, NJ
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
&
Liraglutide 0.6 Estimated Liraglutide Estimated Liraglutide Estimated treatmg/ treatment dif- 1.2 mg/ treatment dif- 1.8 mg/ ment difference
placebo ference (ETD) placebo ference (ETD) placebo (ETD) or Ratio
or Ratio (R)
or Ratio (R)
(R) [95% CI]
[95% CI]
[95% CI]
p-value
p-value
p-value
R = 0.91 28.8/37.2 R = 0.77 28.4/37.5
R = 0.76
Glucagon (pg/mL) at 34.7/38.1
[0.66 ; 1.25]
[0.56 ; 1.08]
[0.55 ; 1.05]
nadira
(primary endpoint)
P = 0.555
p = 0.126
p = 0.092
Change in mean glu- 3.9/4.1
ETD = -0.2 3.6/2.5
ETD = 1.1
4.3/6.0
ETD = -1.7
cagon (pg/mL) from
[-4.0 ; 3.6]
[-2.8 ; 5.1]
[-5.7 ; 2.2]
PG 5.5 mmol/L to
p = 0.910
p = 0.569
p = 0.379
nadir (post-hoc)
Adrenaline (pg/mL) 133.8/139.9 ETD = 0.96 100.2/61.4 ETD = 1.63 127.1/122.1 ETD = 1.04
[0.54 ; 1.70]
[0.90 ; 2.96]
[0.58 ; 1.87]
at nadira
p = 0.875
p = 0.104
p = 0.891
Noradrenaline (pg/ 151.3/141.9 ETD = 1.07 148.9/100.5 ETD = 1.48 133.3/136.7 ETD = 0.97
[0.67 ; 1.71]
[0.91 ; 2.42]
[0.60 ; 1.58]
mL) at nadira
p = 0.784
p = 0.112
p = 0.916
AUCGIR (mg/kg) at
42.6/58.5
R = 0.73 57.8/69.4 R = 0.83 44.0/68.3
R = 0.64
nadira
[0.55 ; 0.97]
[0.62 ; 1.12]
[0.48 ; 0.86]
p = 0.029
p = 0.213
p = 0.004
AUCGIR, (mg/kg) dur- 93.1/103.8 R = 0.90 108.3/153.8 R = 0.70 75.4/98.2
R = 0.77
ing recoveryb
[0.67 ; 1.19]
[0.52 ; 0.95]
[0.57 ; 1.04]
p = 0.442
p = 0.022
p = 0.087
Note: Data are presented as estimated means.
a Nadir: PG = 2.5 mmol/L. b Recovery = from nadir to PG 4.0 mmol/L
Abbreviations: AUC = area under the curve; GIR = glucose infusion rate;
PG = plasma glucose
1004-P
Safety and Efficacy of Dulaglutide vs. Sitagliptin after 104 Weeks in
Type 2 Diabetes (AWARD-5)
POSTERS
Clinical Diabetes/
Therapeutics
RUTH S. WEINSTOCK, GUILLERMO E. UMPIERREZ, BRUNO GUERCI, MICHAEL A.
NAUCK, KAREN L. BOLEYN, ZACHARY SKRIVANEK, ZVONKO MILICEVIC, Syracuse, NY, Atlanta, GA, Nancy, France, Bad Lauterberg, Germany, Indianapolis, IN,
Vienna, Austria
This Phase 3, adaptive, double-blind, parallel arm trial compared dulaglutide (DU), a once-weekly, long-acting GLP-1 receptor agonist, with
sitagliptin (sita) and placebo (PL) in metformin-treated type 2 diabetes.
Primary endpoint was 52 weeks (wks); final endpoint was 104 wks. Patients
(N=1098; mean baseline age 54; A1C 8.1%; weight 86.4 kg; diabetes duration
7 years) were randomized to DU 1.5 mg or 0.75 mg, sita 100 mg, or PL (to
26 wks).
Similar proportions of DU and sita patients completed 104 wks. Adverse
events (AE) were the most common reason for discontinuation. Both DU
doses reported higher incidence of treatment-emergent AEs vs sita due to
gastrointestinal (GI) events (Table 1). Incidence of GI AEs peaked during the
first 12 wks, with no difference after 26 wks. Both DU doses were superior
vs sita for change in A1C (Table 2).
The AE profile and superior A1C vs sita after 104 wks indicate an
acceptable benefit/risk profile of DU over a longer time.
Table 1. Summary of Select Gastrointestinal TEAEs Over 104 Weeks
TEAE
DU 1.5 mg DU 0.75 mg Sita 100 mg
(N=304)
(N=302)
(N=315)
Nausea, n (%)
53 (17.4)
44 (14.6)
21 (6.7)
Vomiting, n (%)
41 (13.5)
25 (8.3)
11 (3.5)
Diarrhea, n (%)
49 (16.1)
36 (11.9)
18 (5.7)
Constipation, n (%)
14 (4.6)
16 (5.3)
4 (1.3)
Abdominal distension, n (%)
13 (4.3)
15 (5.0)
3 (1.0)
Supported by: Novo Nordisk A/S
&
Table 2. Summary of Efficacy Measures Over 104 Weeks
Final Endpoint
DU 1.5 mg DU 0.75 mg Sita 100 mg
(104 Weeks, ITT, LOCF)
(N=304)
(N=302)
(N=315)
A1C change (%), LS Mean (SE)
-1.00±0.06†† -0.71±0.07†† -0.32±0.06
% of patients with A1C <7%
54.3#
44.8#
31.1
#
Weight change (kg), LS Mean (SE) -2.88±0.25 -2.39±0.26## -1.75±0.25
††multiplicity adjusted (based on tree gatekeeping) 1-sided p<0.001 for superiority vs sita for A1C change only.
#2-sided p<0.001 vs sita.
##2-sided p=0.054 vs sita.
PARESH DANDONA, HUSAM GHANIM, KELLY GREEN, SANAA ABUAYSHEH,
SANDEEP DHINDSA, AJAY CHAUDHURI, ANTOINE MAKDISSI, MANAV BATRA,
REEMA PATEL, Buffalo, NY
We have recently demonstrated that exenatide exerts a rapid and a potent
anti-inflammatory effect including the suppression of IL-1β expression in
peripheral blood mononuclear cells (MNC). Suppression of IL-1β secretion
or activity has significant implications for insulin sensitivity and secretion
and on glycemic control since it modulates the synthesis of SOCS-3 which
interferes with insulin signaling and it mediates the inflammatory damage
of the β-cell. We have now hypothesized that exenatide induces an increase
in plasma concentrations of IL-1RA which is known to improve glycemia and
β-cell function in type 2 diabetics. Twenty four obese type 2 diabetics were
prospectively randomized to be injected subcutaneously with either exenatide
10 µg twice daily (n=12, mean age: 56 ±3 years; mean HbA1c:8.6±0.4%) or
placebo twice daily (n=12, mean age: 54±4 years; mean HbA1c:8.5±0.3%) for
12 weeks. HbA1c fell by 0.5% while there was no change in body weight. IL1β expression was suppressed by 22±10% in MNC, plasma concentration of
IL-18 fell by 19% (from 546±58 to 436±46 pg/ml) while IL-1 RA concentrations
increased significantly by 61±18% (from 318±53 to 456±88 pg/ml; p<0.05 for
all). Exenatide also suppressed the mRNA expression in MNC of SOCS-3 and
PTP-1B, two proteins that interfere with insulin signaling, by 31±10% and
18±5%, respectively. These modulators of inflammation and insulin signaling
did not change in the placebo group. We conclude that exenatide induces an
increase in IL-1RA concentrations in addition to suppressing IL-1β expression
and plasma concentrations of IL-18. The combination of these effects would
potentially be of benefit to both the integrity and function of the β-cell and
insulin resistance.
Supported by: Eli Lilly and Company
&
1006-P
Exenatide Increases Interleukin-1 Receptor Antagonist (IL1-RA)
Concentration
1005-P
Effects of Liraglutide as Adjunct to Insulin on Counter-Regulatory
Hormone Responses to Hypoglycemia in Type 1 Diabetes: A Randomized, Double-Blind, Crossover Trial
THOMAS PIEBER, SIGRID DELLER, MARTINA BRUNNER, LENE JENSEN, ERIK
CHRISTIANSEN, FUMIAKI KIYOMI, SIMON HELLER, Graz, Austria, Søborg, Denmark, Tokyo, Japan, Sheffield, United Kingdom
This trial investigated the counter-regulatory hormone (CRH) response to
hypoglycemia, an important protective mechanism in type 1 diabetes (T1D),
with liraglutide as adjunct to insulin.
Adults with T1D (n=45) were allocated to 1 of 3 dose groups of liraglutide/
placebo for 4 weeks in a crossover design. At the end of each treatment
period, a stepwise hyperinsulinemic, hypoglycemic clamp assessed
glucagon, other CRHs, and vital signs at PG levels 5.5, 3.5, 2.5 mmol/L (nadir)
and 4.0 mmol/L (recovery). Glucose infusion rate (GIR) was also measured.
Baseline characteristics: age 34.5±11.2 yrs, BMI 23.9±2.4 kg/m2, A1C
7.6±0.8%, T1D duration 16.6±9.4 yrs [mean±SD]. At nadir, no significant
differences in glucagon and no systematic differences in catecholamines
(Table) or other CRHs were seen between treatments (not shown). However,
a trend toward lower glucagon at increasing liraglutide dose was seen. No
counter-regulatory differences were seen in change in glucagon or other
CRH from PG 5.5 mmol/L to nadir. Pulse was higher for liraglutide at nadir,
but with similar change from 5.5 mmol/L to nadir across groups (not shown).
GIR for liraglutide indicated a tendency for less glucose needed at recovery
and other PG levels.
To conclude, no safety concerns related to CRH responses, including
recovery from hypoglycemia, were raised with liraglutide as adjunct to
insulin in T1D.
&
1007-P
Liraglutide as Adjunct to Insulin in Type 1 Diabetes: Effects on Glycemic Control and Safety in a Randomized, Double-Blind, Crossover Trial
SIMON R. HELLER, STEFAN KORSATKO, JAMALA GURBAN, LENE JENSEN, ERIK
CHRISTIANSEN, FUMIAKI KIYOMI, THOMAS R. PIEBER, Sheffield, United Kingdom, Graz, Austria, Søborg, Denmark, Tokyo, Japan
Treatment with a GLP-1 analog as adjunct to insulin may improve glycemic
control in type 1 diabetes (T1D). In a trial investigating effects of liraglutide
as adjunct to insulin on counter-regulatory responses to hypoglycemia, we
also assessed glycemic control and safety.
&
For author disclosure information, see page 829.
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
Adults with T1D (n=45) were allocated to 1 of 3 dose groups of liraglutide/
placebo for 4 weeks in a crossover design. Liraglutide was started at 0.6
mg/day with weekly 0.6 mg increases until target dose for each arm was
reached.
Baseline characteristics: age 34.5±11.2 years, BMI 23.9±2.4 kg/m2, A1C
7.6±0.8%, T1D duration 16.6±9.4 years [mean±SD]. A significant decrease
in insulin dose was seen with 1.2 and 1.8 mg vs. placebo. No change in A1C
was seen. Frequency of hypoglycemic events (none severe) was unaffected.
As expected, gastrointestinal (GI) adverse events (AEs) were more frequent
with liraglutide; none were severe. 1 of 3 AE withdrawals was treatmentrelated. Liraglutide induced up to 3.3 kg weight loss, not considered a safety
issue.
To conclude, the decrease in insulin dose indicates that liraglutide has a
pharmacologic effect in T1D that may contribute to glycemic control. Besides
the known GI side effects, no liraglutide-related safety or tolerability issues
were identified in this short-term trial in T1D. The observed weight loss is of
potential clinical benefit and worth investigating in larger and longer term
trials.
these functional data, relative GLP-1R mRNA expression levels were ~150fold higher in the rat C-cell line 6-23 than in human TT cells.
In summary, signaling through the GLP-1R by all 4 specific agonists was
strong only in the rat C-cell line and weak in the human C-cell line, while
there was strong GIPR signaling by native GIP in both species. Activity at
the GLP-1R correlated with mRNA expression levels in both species. In
conclusion, there are significant species differences in GLP-1R expression
and responsiveness between rats and humans. This suggests that GLP1R-mediated C-cell proliferation seen in rodents, after long-term exposure
to high concentrations of GLP-1R agonists, might be a rodent-specific
phenomenon and does not seem to be relevant to humans.
Supported by: Sanofi
&
1009-P
Liraglutide Estimated treat- Liraglutide Estimated treat- Liraglutide Estimated treat0.6 mg/ ment difference 1.2 mg / ment difference 1.8 mg / ment difference
placebo
(ETD)
placebo
(ETD)
placebo
(ETD)
[95% CI]
[95% CI]
[95% CI]
p-value
p-value
p-value
Changea in daily insulin -2.0 / 2.7
ETD = -4.7
-10.4 / 0.2 ETD = -10.6 -11.7 / -2.2 ETD = -9.5
dose (U)
[-10.5 ; 1.0]
[-16.5 ; -4.6]
[-15.3 ; -3.6]
p = 0.104
p < 0.001
p = 0.002
-0.10 / -0.01 ETD = -0.09 -0.12 / -0.12 ETD = 0.01 -0.04 / -0.02 ETD = -0.02
Changea in A1C (%)
[-0.36 ; 0.18]
[-0.27 ; 0.28]
[-0.29 ; 0.25]
p = 0.504
p = 0.971
p = 0.891
Hypoglycemicb events 14 (93.3) 289 /
N/A
13 (92.9) 263 /
N/A
14 (100) 316 /
N/A
N (%) E
14 (100) 313
13 (100) 326
15 (100) 295
Changea in pulse (beats/ 5.7 / 4.8
ETD = 0.9
9.1/ 4.7
ETD = 4.3
4.9 / -0.4
ETD = 5.3
min)
[-5.9 ; 7.6]
[-2.7 ; 11.3]
[-1.6 ; 12.1]
p = 0.794
p = 0.218
p = 0.128
GI AEs
10 (66.7) 12 /
N/A
12 (85.7) 24 /
N/A
13 (92.9) 31 /
N/A
N (%) E
2 (14.3) 2
1 (7.7) 2
3 (20.0) 5
Changea in BW (kg)
-1.2 / 0.8
ETD = -2.0
-3.3 / 0.4
ETD = -3.7
-2.9 / 0.4
ETD = -3.3
[-3.1 ; -0.9]
[-4.9 ; -2.6]
[-4.4 ; -2.2]
p < 0.001
p < 0.001
p < 0.001
Note: Unless otherwise stated, data are presented as estimated means.
a = change from baseline to end of treatment. b = assessed according to ADA
standard.
Abbreviations: AE = adverse event; BW = body weight; CI = confidence interval; E = events; GI = gastrointestinal; N = number; N/A = not applicable; U =
units.
Critical illness-induced hyperglycemia is associated with poor outcomes
and most patients do not have diabetes. Exogenous glucagon-like peptide-1
(GLP-1) attenuates, but does not normalize, the glycemic response to enteral
nutrition in the critically ill. In health, co-administration of glucose-dependent
insulinotropic polypeptide (GIP) and GLP-1 has an additive insulinotropic
effect.
We aimed to evaluate whether GIP, when administered with GLP-1,
confers additional glucose-lowering effects in the critically ill.
Twenty critically ill patients without diabetes participated in a prospective,
randomised, double-blinded, crossover study. Patients were fasted and
insulin withheld. Between T0 and T420 minutes GLP-1 (1.2 pmol/kg/min),
together with GIP (2 pmol/kg/min) or saline control, were administered
intravenously on consecutive days. From T60 liquid nutrient was infused into
the small intestine. Blood was sampled frequently.
Baseline blood glucose, insulin and glucagon concentrations were no
different. The addition of exogenous GIP doubled plasma GIP concentrations,
but was not associated with any reduction in peak blood glucose (P=0.43) or
overall glycemic response to nutrient (Figure 1).
This study indicates that the addition of exogenous GIP to GLP-1 does
not have additional glucose-lowering or insulinotropic effects in critically
ill patients, and that further evaluation of incretin-based therapies should
focus on GLP-1 and its agonists.
Supported by: Novo Nordisk A/S
Guided Audio Tour: New Insights in GLP-1 Therapy (Posters: 1008-P to
1013-P), see page 17.
&
1008-P
Functional Activity of Lixisenatide and GLP-1 Receptor Expression
in In-Vitro Thyroid C-Cells of Rat and Human Origin
U. SCHWAHN, S. STENGELIN, ULRICH WERNER, Frankfurt, Germany
GLP-1 receptor (GLP-1R) agonists are a new class of antidiabetic drugs.
However, some GLP-1R agonists have been shown to induce proliferation of
rodent thyroid C-cells in preclinical safety studies. Whether this is a class
effect in rodents or a ligand-specific phenomenon is still under debate.
Therefore, we studied the effect of the GLP-1R agonist lixisenatide (LIXI) in
two thyroid C-cell lines derived from rats or humans.
LIXI, exendin-4 (EXE), GLP-1(7-36) amide (GLP-1) and liraglutide (LIRA) were
tested in a functional cAMP assay for effects on the rat (6-23) and human
(TT) thyroid C-cell carcinoma cell lines. GIP, the natural ligand of the GIP
receptor (GIPR), which also uses cAMP as 2nd messenger, was tested for
comparison.
There was a strong response to all 4 GLP-1R agonists in the rat cell line
6-23 (Emax% ~100%) compared to a weak response in human TT cells (Emax%
~20%). In rat-derived cells EC50 for LIXI, EXE, GLP-1 and LIRA was 8, 4, 7
and 715 pM, resp. while it was 56 and 38,600 pM for GLP-1 and LIRA, resp.
in human TT cells. Due to marginal signals no numerical values could be
determined for LIXI and EXE. In contrast, GIP induced strong responses in
both cell lines (Emax% = 76% and 102%; EC50 = 1320 and 181 pM). In line with
ADA-Funded Research
&
Supported by: NHMRC (Australia)
&
1010-P
Treatment Satisfaction With Albiglutide and Liraglutide in Patients
With Type 2 Diabetes Uncontrolled With Oral Therapy
ALAN A. MARTIN, SUSAN L. JOHNSON, JUNE YE, RICHARD E. PRATLEY, Uxbridge, United Kingdom, Research Triangle Park, NC, Orlando, FL
We assessed treatment satisfaction with albiglutide (ALB) a QW GLP1 agonist and QD liraglutide (LIR) in patients with Type 2 diabetes (T2D)
inadequately controlled by oral antidiabetics.
In a 32-week, open-label trial (HARMONY 7), T2D patients treated with
oral antidiabetics with A1C 7%-10% were randomized to ALB QW 30mg
titrated to 50mg (n = 404) or LIR 0.6mg titrated to 1.8 mg QD (n = 408).
Primary endpoint was change from baseline in A1C. Treatment satisfaction
was measured In US patients (728 out of 812 subjects randomized) using a
For author disclosure information, see page 829.
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A259
POSTERS
MICHAEL LEE, MAHESH UMAPATHYSIVAM, ADAM M. DEANE, MARIANNE
CHAPMAN, KRISHNASWAMY SUNDARARAJAN, JONATHAN FRASER, CAROLINE COUSINS, CHRISTOPHER ANNINK, MICHAEL HOROWITZ, JURIS J. MEIER,
CHRISTOPHER K. RAYNER, Adelaide, Australia, Bochum, Denmark
Clinical Diabetes/
Therapeutics
The Effect of Exogenous GIP in Combination With GLP-1 on Glycaemia in Critically Ill Patients
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
for 14 weeks. All subjects met with a dietician once a week and were
advised to decrease calorie intake by 500 kcal/day. To quantify changes
in insulin resistance, steady-state plasma glucose (SSPG) concentration
was measured during the insulin suppression test. We also measured
blood pressure, pulse, fasting glucose, and lipoprotein concentrations
to assess changes in CVD risk factors. Eleven out of 35 individuals (31%)
assigned to liraglutide dropped from the study compared with 6 out 33
(18%) on placebo (p=0.26). Subjects who remained on liraglutide (n=24) lost
twice as much weight as those on placebo (n=27): 6.8 vs. 3.3 kg, p<0.001.
In addition, liraglutide-treated subjects had a significant improvement in
SSPG concentration (-58 vs. 3 mg/dL, p <0.001), as well as significantly
greater lowering of systolic blood pressure (-8.1 vs. -2.6 mmHg, p=0.04),
fasting glucose (-9.5 vs. 0.3 mg/dL, p<0.001) and triglyceride (-37 vs -13
mg/dL, p=0.04) concentration. However, pulse increased after liraglutide
treatment (6.4 vs. -0.9 beats/min, p=0.001). In summary, individuals with
prediabetes who were able to tolerate liraglutide treatment experienced
twice as much weight loss as those on placebo. Weight loss associated with
liraglutide treatment led to improvement in insulin resistance and several
CVD risk factors but was accompanied by increase in pulse. Liraglutide can
significantly augment weight loss and improve many CVD risk factors in this
population at high risk to develop T2DM and CVD.
POSTERS
Clinical Diabetes/
Therapeutics
validated instrument, the Diabetes Medication Satisfaction questionnaire
(DMS), which measures satisfaction in three domains, treatment burden,
efficacy and unwanted side effects (symptoms), and overall satisfaction. All
scores range from 0 (worst) to 100 (best).
At baseline, demographics were well matched and mean DMS scores
were similar. At 32 weeks, change from baseline in A1C was −0.78% with
ALB and −0.99% with LIR, which did not meet prespecified non-inferiority
criteria (0.3) vs. LIR (95% CI 0.08-0.34%). Weight loss was greater and
nausea and vomiting more frequent with LIR (abstract 945-P ADA 2012).
DMS overall score improved in both groups, and the greatest improvements
were in the efficacy domain (Table). No between group differences reached
significance.
Treatment satisfaction improved with both albiglutide and liraglutide
mainly due to satisfaction with perceived efficacy.
&
1013-P
Direct Effect of Exenatide on Endothelial Function in Humans
JURAJ KOSKA, KALYANI RARAVIKAR, DAWN C. SCHWENKE, DAVID A.
D’ALESSIO, PETER D. REAVEN, Phoenix, AZ, Cincinnati, OH
&
Exenatide (Ex) improves postprandial endothelial function (EF), an effect
that is partially, but not entirely explained by reduced postprandial glucose
or lipid levels. Since endothelium express active GLP-1 receptors, we
hypothesized that Ex may also improve EF under fasting conditions directly
via GLP-1 receptor mediated mechanisms.
Following an overnight fast, 32 participants (31 males, age 60 [mean] ±
6 [SD] years, BMI 33 ± 12 kg/m2) with impaired glucose tolerance (IGT) or
diet controlled type 2 diabetes received intravenous a) Ex (50ng [12 pmol]/
min), b) Ex with GLP-1 receptor antagonist exendin-9 (Ex9, 600 pmol/kg·min),
or c) placebo (Pl) in a randomized three-period crossover fashion. EF was
measured as reactive-hyperemia index (RHI) by peripheral arterial tonometry
before and during the last 15 minutes of the infusions (Figure).
1011-P
Albiglutide Does Not Impact the Counter Regulatory Hormone Response or Recovery Time from Hypoglycemia in Patients With Type
2 Diabetes (T2DM): A Randomized, Double-Blind, Placebo Controlled, Stepped Automated Glucose Clamp Study
MARCUS HOMPESCH, ANGELA LEONE-JONES, MOLLY C. CARR, JESSICA MATTHEWS, HUI ZHI, MALCOLM A. YOUNG, LINDA MORROW, RICKEY REINHARDT,
Chula Vista, CA, King of Prussia, PA
The impact of Albiglutide (Albi) a selective GLP-1 receptor agonist on
counter regulatory hormones and recovery time from hypoglycemia was
assessed in a glucose clamp study in T2DM patients. Participants received
either a single SC dose of Albi (50mg, N=22) or P (N=22) 3 days before
the clamp procedure (glycemic targets: 9.0, 5.0, 4.0, 3.3, and 2.8 mmol/L).
Assessments included safety, hormonal responses (glucagon , c-peptide
(CP), de-convoluted insulin secretion rate (ISR), cortisol, epinephrine,
norepinephrine, growth hormone) at all glycemic targets (30 min duration
each) and recovery time (RT) to 3.9 mmol/L after release of IV insulin infusion
at the end of the 2.8 mmol/L period.
Demographics were similar between groups (mean age 49 yrs, BMI 33.4
kg/m2, 46% male). In patients on oral anti-hyperglycemic drugs, therapy was
discontinued 2 weeks before study drug dosing; except metformin which
was discontinued only on the clamp day. Hormonal responses for all counter
regulatory hormones at all glycemic targets were similar between treatment
groups. ISR (de-convoluted from CP) was significantly higher at the end of the
hyper- and euglycemic plateaus for Albi (0.32 vs 0.22 and 0.15 vs 0.08 mU/h,
p< .05) with no differences between Albi and P at any of the hypoglycemic
plateaus. RT to 3.9 mmol/L was similar between Albi and P, median (95% CI;
35 (CI 30-45) vs 30 (CI 25-40) min).
There were no clinically relevant differences in safety data between Albi
and P. Treatment emergent adverse events were similar between Albi (9) and
P (10). Two mild TEAEs in the Albi group were related to study drug.
In conclusion, a single dose of Albi in T2DM patients did not impair the
counter regulatory hormone response to hypoglycemia and had no impact
on the RT from hypoglycemia. It was confirmed that Albi stimulates ISR in a
glucose dependent manner.
&
The increment in RHI was greater with Ex than Pl and this was completely
abolished with Ex9 (Figure). The differences in RHI between Ex alone versus
Pl or versus Ex+Ex9 remained significant after adjustment for changes in
glucose (p=0.02), insulin (p=0.007), and both glucose and insulin (p=0.02)
concentrations. There were no differences in responses to treatments
between those with IGT and type 2 diabetes (p=0.95).
These findings are consistent with improvement of EF by Ex via a direct
action on endothelial GLP-1 receptors. Combined with our previous data, Ex
appears to improve EF by both direct and indirect (improved postprandial
glucose and lipid values) mechanisms.
1012-P
Liraglutide for Overweight, Older Individuals With Prediabetes
SUN KIM, FAHIM ABBASI, CINDY LAMENDOLA, ALICE LIU, DANIT ARIEL, PATRICIA SCHAAF, KAYLENE GROVE, GERALD REAVEN, Stanford, CA
Older, overweight/obese individuals with prediabetes are at high risk to
develop type 2 diabetes (T2DM) and cardiovascular disease (CVD). The aim
of the present study was to evaluate the efficacy of liraglutide, a glucagonlike peptide 1 (GLP-1) analogue, to augment weight loss and improve CVD risk
factors in this population. We randomized 68 older individuals (40-70 years
of age) with overweight/obesity (BMI 25-40 kg/m2) and prediabetes to this
double-blind study of liraglutide 1.8 mg versus matching placebo injections
Supported by: Amylin Pharmaceuticals, LLC.; Eli Lilly and Company
&
For author disclosure information, see page 829.
A260
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
1014-P
1016-P
Relationship between Postprandial Glucagon-Like Peptide 1, Glucagon Levels and Short and Long-Acting Insulin Requirement in CPeptide Negative Type 1 Diabetic Patients
GLP-1 (32-36) Amide, a Novel Pentapeptide Cleavage Product of
GLP-1, Modulates Whole Body Glucose Metabolism in Dogs
We have previously demonstrated that under euglycemic clamp
conditions in human subjects GLP-1(9-36) amide infusions inhibited
endogenous glucose production without substantial insulinotropic effects.
Earlier reports indicate that GLP-1(9-36)amide is cleaved in vivo to a
nonapeptide, GLP-1(28-36)amide and a pentapeptide GLP-1(32-36)amide
(LVKGRamide). Here we study the effects of the pentapeptide on whole body
glucose disposal during hyperglycemic clamp studies. Five dogs underwent
indwelling catheterizations. Following recovery, dogs underwent a 180 min
hyperglycemic clamp (basal glucose+98 mg/dl) in cross-over studies. Saline
or pentapeptide (30 pg·kg-1·min-1) was infused during the last 120 min after
commencement of hyperglycemic clamp in a primed continuous manner.
During the last 20 min of the pentapeptide infusion, glucose utilization (M)
significantly increased to 21.3 ± 3.00 mg·kg1·min 1compared to M of 15.4 ±
1.6 mg/kg/min during the saline infusion (P=0.04). No significant differences
in insulin (27 ± 3.4 vs. 24 ± 2.6 µU/ml, P=NS) or glucagon secretion (35 ± 2.7 vs.
33 ± 1.1 pg/ml, P=NS) were observed. These findings demonstrate that under
hyperglycemic clamp studies, the GLP-1-derived pentapeptide, GLP-1(32-36)
amide has biological actions in the modulation of glucose metabolism by
stimulation of whole-body glucose disposal. Further, the findings suggest
that the metabolic benefits previously observed during GLP-1(9-36) amide
infusions in humans might be due, at least in part, to the metabolic effects
of the pentapeptide that is cleaved from the pro-peptide, GLP-1(9-36) amide
in the circulation.
1017-P
Optimizing Glycemic Control in T2DM Patients Previously Treated
With Intensive Insulin Therapy and Switched to Exenatide-Insulin
Glargine Combination
IAKOVOS AVRAMIDIS, CHRISTINA SPYRIDONIDOU, DIMITRIS STOIMENIS, ANTIGONI LALIA, Thessaloniki, Greece
1015-P
Pharmacokinetics and Pharmacodynamics of a Chemically Stable
Micro-Dosed Glucagon in a Diabetic Swine Model of Type 1 Diabetes
The introduction of insulin in T2DM patients is frequently complicated
with weight gain and high occurrence of hypoglycemia. Moreover, in many
trials exenatide has been associated with improved glycemic control with
less hypoglycemic events and weight reduction. The present study evaluated
the glycemic control in patients who were previously treated with intensive
insulin therapy and were switched to exenatide-insulin glargine.
56 patients (aged 68.50 years (8), BMI 35.42 kg/m2 (5.71), HbA1c 8.10%
(1), diabetes duration 17.46 years (6.50), insulin therapy duration 6.25 years
(4.11), hypoglycemic episodes/month 5 (5); means (SD)) were included in the
study. All patients received basal insulin and 3 doses of prandial insulin
(basal insulin dose 44 IU (21), total insulin dose 74 IU (34)). Subjects continued
taking their metformin dose and insulin glargine. Pioglitazone was added in
17 patients. Subjects served as their own controls.
The average follow-up was 12.5 months (7, range 3-27). Mean HbA1c
reduction was 1% (1.22) and weight loss was 8 kg (6.33). The basal and total
insulin dose reduction from baseline was 4 IU (15) and 34 IU (25) respectively
(p=0.020 and p<0.001). Diabetes and insulin therapy duration were not
associated with response to treatment (p=0.620 and p=0.712 respectively).
Mean HbA1c reduction was 0.80% (1) during the first 6 months and the
additional reduction was 0.40% (0.90) from 6 months to the end of followup. Weight reduction was 4.60 kg (4.20) and the further reduction was 3.50
kg (4.50).
Based on the target of HbA1c of <7% the percentage of patients achieving
goal glycemic status differed at follow-up (53.57%) compared with baseline
(5.36%, p<0.001). Hypoglycemic episodes were reported only by one
patient.
Our study indicated that in a group of patients the exenatide-basal insulin
combination achieved sustained glucose control with weight improvement
and significant lower incidence of hypoglycemia.
JOHN JIANG, KATHERINE M. MCKEON, FIRAS H. EL-KHATIB, STEVEN J. PRESTRELSKI, NANCY L. SCOTT, BRETT J. NEWSWANGER, PATRICK SLUSS, STEVEN
J. RUSSELL, EDWARD R. DAMIANO, Boston, MA, Austin, TX
In order to market a bihormonal bionic endocrine pancreas that provides
both insulin and glucagon replacement therapy for people with type I
diabetes, a pumpable glucagon formulation is needed that is bioactive
on the liver and chemically stable for up to up to three days at near body
temperatures.
We analyzed the pharmacokinetics (PK) and pharmacodynamics (PD) of
a stable, non-aqueous, concentrated (5 mg/ml), pumpable, liquid glucagon
formulation (XeriSol™, Xeris Pharmaceuticals) in a porcine model of type 1
diabetes. Doses of XeriSol that were fresh or aged 7-8 days with agitation
were administered subcutaneously using an insulin pump. Experiments
began ~5 hours postprandially with blood glucose regulated to 60-140
mg/dl. Two consecutive glucagon doses (separated by > 60 minutes) were
administered for each experiment. Venous blood glucose concentration was
measured every 10 minutes. Plasma samples were drawn every 10 minutes
for offline analysis of plasma glucagon concentration. Identical experiments
were conducted using a freshly reconstituted commercially available
glucagon formulation (Eli Lilly), which is chemically stable in solution for only
a few hours.
The second dose response for each experiment (n = 3 experiments) was
considered when calculating the increase in blood glucose in response to
glucagon dosing. Every dose was considered in the calculation of glucagon
tmax. The mean tmax for fresh and aged XeriSol were 9 + 2 and 12 + 5
minutes, respectively and 10 + 5 minutes for fresh Lilly glucagon. The
average increase in blood glucose response for fresh and aged XeriSol was
14 + 6 and 18 + 2 mg/dL/10µg, respectively (n = 3 experiments), compared
with 19 + 4 mg/dl/10µg for fresh Lilly glucagon (n = 2 experiments).
These results suggest that both aged and fresh XeriSol shows comparable
efficacy to freshly reconstituted Lilly glucagon in STZ-treated diabetic pigs.
This paves the way for an upcoming first-in-human study.
1018-P
Add-On Treatment With Exenatide Once Weekly vs. Daily Basal Insulin in Patients With A1C ≥8.5%
ERICH BLASE, STEVEN C. BRUNELL, YAN LI, MICHAEL GRIMM, San Diego, CA
Typically, basal insulin (b-INS) is the add-on treatment of choice for
patients with severe hyperglycemia, but it can be questioned whether b-INS
is the best option. The current post hoc analyses compared the efficacy and
tolerability of exenatide once weekly (EQW) with those of b-INS in patients
Supported by: Frederick Banting Foundation
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A261
POSTERS
It has been suggested that glucagon-like peptide 1 (GLP-1) in C-peptide
negative type 1 diabetic (T1DM) patients decreases glucose concentration
through reducing glucagon secretion. Although mechanisms by which GLP-1
affects glucagon secretion has not been well understood, in patients with
preserved GLP-1 secretion decreased glucagon secretion and improved
glucose control were documented.
We assessed the difference in postprandial total GLP-1 level in relation
to glucagon secretion and both, short and long-acting insulin requirement in
79 C-peptide negative T1DM patients (median age 46 years, T1DM duration
of median 21 years, hemoglobin A1c median level 7.3%, short-acting insulin
requirement mean 0.1 and long-acting insulin requirement median 0.3
unit/kg/day). Plasma total GLP-1 and glucagon levels were measured by
ELISA assay (DRG Diagnostic, Germany). The group of patients with higher
postprandial total GLP-1 concentration (≥2.6 pmol/L, n=40) required lower
dose of long-acting insulin (0.28 vs 0.31, p=0.043), had higher fasting total
GLP-1 concentration (1.25 vs 0.82, p=0.007), fasting glucagon (118.1 vs
95.3 pg/mL, p=0.048) and postprandial glucagon (126.6 vs 99.1, p=0.007)
concentration. There was no difference in short-acting insulin requirement
(p=0.053).
Inappropriate elevation of glucagon could be explained by lack of inhibition
of glucagon secretion due to low total GLP-1 concentration documented in our
patients. Lower total GLP-1 concentration in our patients might be explained
by insulin therapy causing an increase in serum dipeptidyl peptidase IV
activity, which was recently reported in T1DM patients.
Endogenously secreted GLP-1 plays an important role in glucoregulation
in T1DM by modulating glucagon levels. The complex interplay between
GLP-1, glucagon secretion and exogenously administered insulin should be
investigated in future clinical trials of T1DM patients.
Clinical Diabetes/
Therapeutics
AMIN VAKILIPOUR, FRANCA S. ANGELI, OLGA D. CARLSON, LI CHEN, YOU-TANG
SHEN, EVA TOMAS-FALCO, JOEL F. HABENER, RICHARD P. SHANNON, JOSEPHINE M. EGAN, DARIUSH ELAHI, Philadelphia, PA, Baltimore, MD, Boston, MA
KARIN ZIBAR, TOMISLAV BULUM, KRISTINA BLASLOV, LEA DUVNJAK, Zagreb,
Croatia
POSTERS
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
with T2DM on metformin ± SFU with baseline A1C ≥8.5%. Data were pooled
from two 26-week, randomized, controlled studies (EQW vs insulin glargine
and EQW vs insulin detemir; N = 137 [EQW], 126 [b-INS]). Patients treated
with EQW had a significantly greater decrease in A1C from baseline than
those treated with b-INS (LS mean ± SE change: -2.0% ± 0.08 vs -1.6% ±
0.08; P=0.0008) and were significantly more likely to reach an A1C goal of
<7.0% (39.4% vs 23.0%; P=0.002). Decreases in FPG were smaller in the
EQW group (-52.2 ± 3.70 vs -61.9 ± 3.74 mg/dL; P=0.062]). Mean ± SE weight
loss with EQW was -2.4 ± 0.23 kg, whereas weight gain with b-INS was 2.0 ±
0.24 kg (LS mean difference between groups, -4.4 kg; P<0.0001). Patients in
the EQW group were significantly more likely to achieve a composite goal
(A1C <7.0%, no weight gain, and no hypoglycemia [requiring assistance
or self-treated with blood glucose <54 mg/dL]) than were patients in the
b-INS group (33.6% vs 3.2%; P<0.0001). Hypoglycemia occurred at a rate
of 0.08 exposure-adjusted events per patient year in the EQW group and
0.37 events in the b-INS group. The most common adverse events were
nausea (28.5%), nasopharyngitis (16.8%), and hypoglycemia (14.6%) in the
EQW group and hypoglycemia (38.9%) and nasopharyngitis (19.0%) in the
b-INS group. Results of these analyses show that treatment with EQW was
associated with significantly greater reductions in A1C and body weight,
and a lower rate of hypoglycemia than treatment with b-INS. Results
from this post hoc analysis suggest that EQW is a treatment alternative to
b-INS in patients with A1C ≥8.5% who are receiving treatment with oral
antihyperglycemic medications and are concerned about weight gain and
the risk of hypoglycemia.
weeks (5 ug bid×4 weeks followed by 10 ug bid×8 weeks). Eighteen healthy
subjects (age 49.6±9.2 yrs, BMI 25.2±1.9 kg/m2, Male/Female 8/10) were
recruited as normal control. The effects of exenatide on the expression of
cytokines, toll-like receptor (TLR)-2, c-Jun N-terminal kinase (JNK)-1 and IκB
kinase (IKK) β were investigated.The plasma levels of tumor necrosis factor
(TNF)-α, interleukin (IL)-1β and IL-6 were significantly higher in T2D subjects
than those of normal control (18.2±2.4 vs 12.5±3.6 pg/ml, 7.3±1.5 pg/ml vs
4.3±0.8 pg/ml, 49.4±30.4 vs 6.2±2.9 pg/ml, respectively (P < 0.001 for all).
After treatment with exenatide for 12 weeks, fasting blood glucose fell
from 9.6±1.8 to 7.1±1.2 mmol/L, postprandial blood glucose from 16.2±3.8 to
10.8±2.8 mmol/L, HbA1c from 8.5±0.9 to 6.5±0.9 % with BMI from 27.1±3.7
to 25.7±3.9 kg/m2 (P < 0.05). There was a significant reduction in plasma
levels of TNF-α, IL-1β and IL-6 by 37.6±14.9, 35.8±21.0 and 61.7±16.1% ,
respectively, and the mRNA expression of TNF-α, IL-1β and IL-6 in PBMCs by
54.4±14.2, 75.6±18.4 and 51.2±12.5 %, respectively (P < 0.05 for all) after 12
weeks of exenatide. The expression of TLR-2, JNK-1 and IKKβ in PBMCs was
suppressed by 72.1±19.4, 60.1±33.6 and 59.3±31.2%, respectively (P <0.05
for all). The study suggested that exenatide exerts an antiinflammation
effect in PBMCs of newly diagnosed and drug-naïve T2D patients.
1019-P
JULIO ROSENSTOCK, MAEVA GERME, EDWARD WANG, JAY LIN, RICCARDO C.
BONADONNA, PEDRO DE PABLOS-VELASCO, RONAN ROUSSEL, DENIS RACCAH,
Dallas, TX, Paris, France, Bridgewater, NJ, Verona, Italy, Las Palmas, Spain, Poitiers,
France, Marseille, France
Supported by: NSFC (81025005), (81100556)
1021-P
Expanding the Basal-Plus Regimen: Basal Insulin + Lixisenatide Is
More Likely to Achieve the Composite Outcome Of Hba1c <7%, No
Documented Symptomatic Hypoglycemia and No Weight Gain Compared With Basal + Prandial Insulin
Biological Profile of LY2405319, a Human FGF21 Variant and a Clinical Candidate
ALEXEI KHARITONENKOV, JOHN M. BEALS, TAMER COSKUN, JAMES D. DUNBAR, BARBARA C. HANSEN, THOMAS F. BUMOL, DAVID E. MOLLER, Indianapolis,
IN, Tampa, FL
Lixisenatide (LIXI), a novel once-daily prandial GLP-1 receptor agonist,
is in development for T2DM management as add-on to oral antidiabetic
drugs ± basal insulin. An analysis of patient-level data from 5 randomized
trials (GetGoal-Duo1, GetGoal-L, OPAL, ELEONOR, 1-2-3) was conducted to
evaluate basal insulin + LIXI 20 µg QD vs a basal-plus regimen (basal + 1
dose of prandial insulin). Composite efficacy endpoints were evaluated using
linear or logistic multivariate regression analyses in 1184 overall patients
(519 basal + LIXI; 665 basal-plus). A slightly higher proportion of patients
in the basal + LIXI group achieved HbA1C <7% vs basal-plus (OR: 1.62 [95%
CI: 1.06-2.48] p=0.025), while basal-plus was more likely to result in weight
gain (estimated difference: 1.38 kg [95% CI: 0.83−1.93] p<0.0001) and more
documented symptomatic hypoglycemia (OR: 1.51 [1.01−2.25] p=0.045). Basal
+ LIXI was 2.5x more likely to result in HbA1C <7% and no weight gain, and
nearly 3x more likely to result in HbA1C <7%, no documented symptomatic
hypoglycemia and no weight gain (Table). In conclusion, both basal + LIXI
and basal-plus regimens are effective in reducing HbA1C but basal + LIXI
is significantly more likely to result in HbA1C <7% with no documented
hypoglycemia and no weight gain vs basal-plus in T2DM patients not
reaching HbA1C goals on basal insulin.
Fibroblast growth factor 21 (FGF21) is a novel hormone-like metabolic
regulator which has been implicated as a therapeutic target for type 2
diabetes, obesity, hepatic steatosis, and cardiovascular disease. However,
development of human recombinant wild type FGF21 as a therapeutic agent
is challenging due its poor biopharmaceutical properties. In order to improve
protein stability and facilitate homogenous protein production, we designed
a novel FGF21 variant, LY2405319 that contained four engineered changes:
L118C, A134C, S167A substitutions and deletion of the four N-terminal amino
acids, HPIP. LY2405319 was profiled for bioactivity in a panel of in vitro and
in vivo assays which confirmed that biological properties of LY2405319
were essentially identical to FGF21. In mouse and human cells, LY2405319
and FGF21 have comparable potency while the critical features of FGF21
mechanism, KLB-dependence together with the non-mitogenic character of
action, remained intact in LY2405319. Administration of LY2405319 in mice
over 14 days resulted in a 25-50 % lowering of plasma glucose coupled with
a 10-30 % reduction in body weight. The FGF21 variant also induced a variety
of metabolic effects in diabetic rhesus monkeys. Treatment consisted of
three subcutaneous LY2405319 dose levels, 1.5, 9 and 50mg/kg (daily), for
seven weeks. All 6 monkeys at the end of LY2405319 administration showed
12-25% body weight loss, 90% mean reduction in serum triglycerides,
lowering of total and LDL-cholesterol (50 % and 30%, respectively), and a ≈3
fold elevation in HDL-cholesterol; hyperglycemia was completely normalized
in 5 out of 6 animals. In summary, LY2405319 exhibited biological properties
that were indistinguishable from native FGF21. Thus, the profile of LY2405319
had features required for initiation of a clinical program designed to test
the hypothesis that administration of exogenous FGF21-based molecule
could result in efficacy with respect to important disease-related metabolic
parameters in humans.
Basal + LIXI vs basal-plus: composite endpoints
Endpoints
Basal + Basal- Odds 95% CI p value
LIXI*
plus† ratio
n=519
n=665
% patients
Regression analysis
28.3
29.8
1.89 1.20−2.97 p=0.0057
HbA1C <7% and no documented
symptomatic hypoglycemia
27.9
22.5
2.56 1.63−4.01 p<0.0001
HbA1C <7% and no weight gain
HbA1C <7%, no documented symptom19.6
15.8
2.76 1.64−4.64 p=0.0001
atic hypoglycemia and no weight gain
*Includes GetGoal-Duo 1 (NCT00975286) and GetGoal-L (NCT00715624);
†Includes OPAL (NCT00272012), ELEONOR (NCT00272064), 1-2-3
(NCT00135083).
CI=confidence interval; HbA1C=glycated hemoglobin; Basal + LIXI=basal insulin + lixisenatide; Basal-plus=basal insulin + one dose of prandial insulin;
documented symptomatic hypoglycemia=blood glucose <3.33 mmol/L.
1020-P
Antiinflammation Effect of Exenatide in Chinese Newly Diagnosed
and Drug-Naïve Type 2 Diabetic Patients
XIAOHUAN XING, JINHUA YAN, WEN XU, HAIXIA XU, HUA LIANG, FEN XU, JIANPING WENG, Guangzhou, China
Type 2 diabetes has been considered as a chronic inflammatory disease.
Previous studies indicated that exenatide, a glucagon-like peptide-1 (GLP-1)
receptor agonist, might have the effect of attenuating the inflammation of type
2 diabetic (T2D) patients. The study aims to investigate the antiinflammation
effect of exenatide in peripheral blood mononuclear cells (PBMCs) of newly
diagnosed and drug-naïve T2D patients. Nine newly diagnosed and drugnaïve T2D patients [age 45.1±6.1 yrs, body mass index (BMI) 27.1±3.7 kg/m2,
Male/Female 3/6] were enrolled and received exenatide treatment for 12
Supported by: sanofi-aventis
&
For author disclosure information, see page 829.
A262
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
1022-P
1024-P
Targeting Insulin Resistance in Type 2 Diabetes via Immune Modulation of Cord Blood-Derived Multipotent Stem Cells (CB-SCs) in
Stem Cell Educator Therapy
A Novel Long-Acting GLP-1R Agonist, SKL-18287, Has Unique Properties Compared to Liraglutide
Supported by: Chinese Government Funding
1023-P
1025-P
Reductions in A1C and Fasting Glucose With Exenatide Are Not Affected by Relative β-Cell Function in T2DM Patients
Chronic Continuous Exenatide Infusion Does Not Cause Pancreatitis or Ductal Hyperplasia in Baboons: A 14 Weeks Longitudinal
Controlled Study
MICHAEL GRIMM, YAN LI, JENNY HAN, RICHARD PENCEK, San Diego, CA
A1C reduction associated with the GLP-1 receptor agonist exenatide has
been attributed in part to improvement in β-cell function and sensitivity, but
it is unclear if it is dependent upon baseline β-cell function. This analysis
of pooled data from 11 randomized, controlled, 24-30 week, clinical trials
of exenatide twice daily (EBID, 7 trials) and once weekly (EQW, 4 trials)
assessed glycemic control in relation to baseline β-cell function. Baseline
HOMA-B, an estimate of steady-state β-cell function, was calculated from
the homeostatic model assessment using fasting glucose (FG) and C-peptide.
Patients treated with both EBID and EQW were divided into tertiles according
to baseline HOMA-B with the lowest values in tertile 1 (table). Baseline A1C
and FG were highest in the 1st HOMA-B tertiles and decreased in higher
HOMA-B tertiles, implying a manifest association in baseline characteristics
between glycemic control and β-cell function. Changes in A1C and FG were
evaluated by ANCOVA models adjusted for baseline values of A1C or FG. All
tertiles exhibited statistically significant reductions in A1C and FG (P<0.05).
There were no statistically significant differences in changes in A1C or FG
among tertiles within EBID or EQW groups. Adverse events were consistent
with the known exenatide safety profile. In summary, both exenatide
formulations resulted in meaningful improvements in A1C and FG regardless
of underlying β-cell function.
TERESA VANESSA FIORENTINO, MICHAEL OWSTON, GREGORY ABRAHAMIAN, STEFANO LAROSA, ALESSANDRO MARANDO, GIOVANNA FINZI, FAUSTO
SESSA, SUBHASH KAMATH, FRANCESCA CASIRAGHI, GIUSEPPE DANIELE,
FRANCESCO ANDREOZZI, ANTHONY COMUZZIE, MARK SHARP, PRISCILLA WILLIAMS, RALPH A. DEFRONZO, GLENN HALFF, EDWARD DICK, FRANCO FOLLI, San
Antonio, TX, Varese, Italy
The effects of GLP-1-analogues and DPP-IV inhibitors on exocrine pancreas
are subject to intense investigations. Here, we evaluated the effects of
chronic exenatide (EXE) treatment on exocrine pancreas structure and cell
replication of non-human primates (baboons). 52 animals underwent 10-30%
resection of pancreatic tail followed by continuous infusion of EXE (0.014
ug/kg-hour) or Saline (SAL) for 14 weeks. EXE plasma levels (753±244 pg/
mL) were 3-4 fold higher than those achieved in treated diabetic patients.
Morphometry and immunocytochemistry for exocrine cell proliferation (Ki67)
and apoptosis (M-30) were performed on baseline (tail) and after treatment
samples (body/head). Pancreatitis and PanIN (pancreatic intraepithelial
neoplasia) were never observed in EXE and SAL group. Ductal hyperplasia
was increased by ~ 4 fold at the end of the study in both groups (EXE: 17 vs
4, p=0.003; SAL: 12 vs 3, p=0.006) suggesting a strong surgery effect. At the
end of study, Ki67 positive acinar cells number did not significantly change,
as compared to baseline, in SAL and EXE group. Ki67 positive ductal cells
were significantly increased after EXE treatment (1.83±0.34 vs 0.71±0.22,
p=0.04), however the delta of Ki67 positive ductal cells in EXE group was not
significantly different from SAL (1.17±0.32 vs 0.17±0.55, p=0.13). The number
of M-30 positive acinar and ductal cells did not change after SAL and EXE
treatment in comparison to baseline. In conclusion, continuous infusion of
EXE for 14 weeks did not produce any negative effects on exocrine pancreas,
neither promoting pancreatic inflammation nor hyperplasia in non-human
primates.
Supported by: NIH (R01DK080148); Amylin/Lilly
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A263
POSTERS
SKL-18287 is a novel long-acting GLP-1R agonist designed to exhibit
DPP4 resistance and multimer formation for improving in vivo stability
with several natural amino acid modifications of native GLP-1 that is
currently being developed as QD and QW GLP-1R agonist product. To clarify
further characteristic of SKL-18287, we investigated and compared it with
liraglutide.
SKL-18287 showed agonistic activity to mouse and human GLP-1R in
vitro with ED50 values of 1.2 and 274 nmol/L, respectively. The competitive
binding curve of SKL-18287 to human GLP-1R was not affected by increment
of albumin concentration in the system while that of liraglutide was shifted
toward the right side. It is noteworthy that radioactivity was distributed to
the pancreas at nearly the same level as that to the plasma which was much
more than to the other tissues after subcutaneous injection of 3H-[Tyr]SKL18287 to Sprague Dawley (SD) rats. As a consequent of this unique tissue
distribution of SKL-18287 in vivo, 4 weeks repeated injection of SKL-18287
(6-12 nmol/kg) significantly and dose-dependently lowered HbA1c in GotoKakizaki T2DM rats. The reduction in HbA1c during 4 weeks of SKL-18287
administration (-0.26%) was more potent than that with liraglutide (-0.10%)
when the same dosage was used. Interestingly, the inhibitory effect on gastric
empty of SKL-18287 (12 nmol/kg) was nearly the same as that of liraglutide
(8 nmol/kg) in SD rats. It is also known that GLP-1R agonists increase plasma
calcitonin via GLP-1R in the thyroid C-cell in rodents. Because of its unique
tissue distribution, the increment effect of SKL-18287 on plasma calcitonin
in alloxan-induced diabetic mice was weaker than that of liraglutide and
exenatide when SKL-18287 exhibited potent blood glucose lowering effect.
These results suggest that SKL-18287 is a novel long-acting GLP-1R agonist
which keeps a balance between efficacy and adverse effects. Considering
these properties, we believe that SKL-18287 has potential as a new class of
GLP-1R agonist.
Mounting evidence points to the involvement of immune dysfunction
in insulin resistance in T2D, suggesting that immune modulation may
be a useful tool in treating the disease. We have developed a Stem Cell
Educator therapy in which a patient’s blood is circulated through a closedloop system that separates mononuclear cells by aphaeresis, briefly cocultures them with adherent CB-SCs, and returns the educated cells to the
patient’s circulation. In an open-label, phase1/phase 2 study, patients (N =
36) with long-standing T2D were divided into three groups (Group A, oral
medications, n = 18; Group B, oral medications + insulin, n = 11; and Group C
with impaired β-cell function, oral medications + insulin, n = 7). Median age
was 51 years, and median diabetic duration was 9 years. All subjects received
one Stem Cell Educator therapy. Clinical findings indicate that T2D patients
achieve improved metabolic control and reduced inflammation markers after
receiving Stem Cell Educator therapy. Median glycated hemoglobin (HbA1C)
in Group A and B was significantly reduced from 8.61% ± 1.12 at baseline to
7.9% ± 1.22 at 4 weeks (p = 0.026), 7.25% ± 0.58 at 12 weeks (p = 2.62E-06),
and 7.33% ± 1.02 at one year post treatment (p = 0.0002). Homeostasis model
assessment (HOMA) of insulin resistance (HOMA-IR) demonstrated that
insulin sensitivity was improved post treatment. Notably, the β-cell function
in Group C subjects was markedly recovered, as indicated by the restoration
of C-peptide levels (0.36 ± 0.19 ng/ml at baseline vs 1.12 ± 0.33 ng/ml at
one year post treatment, p = 0.00045). Mechanistic studies revealed that
Stem Cell Educator therapy reverses immune dysfunctions through immune
modulation on monocytes and balancing Th1/Th2/Th3 cytokine production.
Stem Cell Educator therapy is a safe and innovative approach that produces
lasting improvement in metabolic control for individuals with moderate or
severe T2D who receive a single treatment.
Clinical Diabetes/
Therapeutics
YU YAMAGUCHI, MIYUKI TAMURA, HIROSHI KINOSHITA, MASAYUKI OKAMOTO, RYUJI OKAMOTO, MITSUAKI TAKEUCHI, YUKIE MIZUNO, SHINJI FURUTA,
KATSURA TSUKAMOTO, SANWA KAGAKU KENKYUSHO, Inabe, Japan
YONG ZHAO, ZHAOSHUN JIANG, ZHAOHUI YIN, YE ZHANG, JIE SHEN, TINGBAO
ZHAO, MINGLIANG YE, YALIN DIAO, YUNXIANG LI, HATIM THAKER, SUMMIT
JAIN, HENG LI, Lisle, IL, Jinan, China, Chicago, IL
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
1026-P
1028-P
Early Liraglutide Treatment Improves β-Cell Function in Patients
With Type 2 Diabetes
Acute Metabolic Effects of GLP-1 Analogue in Type 1 Diabetes
POSTERS
Clinical Diabetes/
Therapeutics
TARA GHAZI, LINDA RINK, JENNIFER L. SHERR, KEVAN C. HEROLD, New Haven,
CT
YOSHINOBU KONDO, SHINOBU SATOH, YUICHIRO INOUE, MASAYO KIMURA,
MASAYUKI HIRAMA, URU NEZU, YASUO TERAUCHI, Kanagawa, Japan, Okinawa,
Japan
Some studies have suggested that GLP-1 receptor agonists may be
beneficial to patients with Type 1 diabetes (T1D); however, the mechanisms
of action are not clear.
We studied the acute effects of exenatide (Byetta 5 µg) on insulin
secretion, glucagon, GLP-1and GIP levels, and gastric emptying to oral
mixed meal tolerance tests (MMTT) or an intravenous glucose tolerance
test (IVGTT) in subjects with T1D, with (n=7) or without (n=5) residual insulin
secretion (age: 30.4±9.5 years, HbA1c: 7.3±0.9 %, BMI: 27.9±5.2 kg/ m2,
insulin usage: 0.62±0.2 U/kg/d, diabetes duration: 17.5±10.2 years). We
calculated the area under the curve (AUC) for each metabolite.
MMTT and IVGTT were performed while patients took basal but not bolus
insulin, with and without pretreatment with exenatide. The glucose levels
during the MMTT were reduced when exenatide was given (71957.7±26043.8
vs. 42921.9±13917.4 mg/dL, P=0.0005) but were unaffected during the IVGTT
(3555.7±469.9 vs. 3612.1±489 mg/dL, P=0.687). The improved oral meal
tolerance was accompanied by reduced glucagon levels (16106.9±3430.1 vs.
12835.9±5685.7 pg/mL, P=0.027) and delayed gastric emptying of acetaminophen
(2034.6±517.1 vs. 606.4±365.6 µg/mL, P= 0.022) when exenatide was given. In
subjects with residual insulin production there was a trend for reduced insulin
secretion with exenatide (14321.9±17606.7 vs. 9272.5±8395.7 pmol/min,
P=0.438). The fasting levels of GIP were lower when exenatide was given.
In conclusion, our results show that exenatide suppresses glycemic
excursion during MMTT regardless of β- cell function. The effect seemed
to be mediated by decreased glucagon levels and delayed gastric emptying.
Insulin secretion tended to be lower which may be the result of the latter.
Preclinical studies with liraglutide have suggested improvements in
β-cell function. Therefore, we investigated these effects using the glucagon
stimulation test (GST). Sixty-six insulin-treated patients with type 2 diabetes
were switched to liraglutide monotherapy and their β-cell function was
measured with 1 mg intravenous GST at weeks 0 and 24. Liraglutide was
initiated at 0.3 mg/day and titrated up to 0.9 mg/day. Its effect on β-cell
function was assessed by the change in the area under the curve (AUC) of
serum C-peptide immunoreactivity (CPR) during GST (AUC-CPR = (sum of CPR
levels before and 6 min after GST) x 6 min/2). In full-set analysis, AUC-CPR
increased after 24 weeks of liraglutide treatment (10.25 ± 5.04 to 11.90 ± 4.86
ng/ml·min, p = 0.005). In univariate regression model analysis, a negative
correlation was seen between change in AUC-CPR (ΔAUC-CPR = (AUC-CPR
at week 24) − (AUC-CPR at week 0)) and duration of diabetes (duration: β =
−0.28, 95% confidence interval (CI), −0.43 to −0.14, p < 0.001, R2 = 0.19).
In multivariate regression model analysis, the effect of treatment duration
on ΔAUC-CPR was confirmed even after adjustments for age, gender,
change in body weight, change in glycated hemoglobin, and insulin dose
before liraglutide initiation (duration: β = −0.24, 95% CI, −0.42 to −0.06, p =
0.009, R2 = 0.28). In tertile analysis by duration of diabetes, early liraglutide
treatment (duration ≤ 3 years) significantly improved AUC-CPR (10.00 ± 6.03
to 13.44 ± 5.78 ng/ml·min, p < 0.001), whereas late liraglutide treatment
(duration ≥ 11 years) did not (10.68 ± 5.29 to 10.07 ± 4.37 ng/ml·min, p =
0.59). In receiver operating characteristic (ROC) analysis, the cut-off value
for treatment duration for positive liraglutide effect on ΔAUC-CPR was 12
years (area under the ROC curve 0.73, sensitivity 86% and specificity 59%).
These findings suggest that early liraglutide treatment potentially improves
β-cell function in patients with type 2 diabetes.
1027-P
Patient-Reported Outcomes With Dulaglutide vs. Metformin
(AWARD-3)
MATTHEW REANEY, BETH D. MITCHELL, PING WANG, VALERIA PECHTNER,
BRAD CURTIS, KATE VAN BRUNT, Indianapolis, IN
1029-P
This 52-week (wk) Phase 3, randomized, double-blind, parallel-arm,
monotherapy study compared safety and efficacy of dulaglutide (DU), a longacting GLP-1 receptor agonist, to metformin (MET) in patients (pts) with early
type 2 diabetes (A1C 6.5-9.5%). Pts received once-weekly DU 1.5 mg or 0.75
mg or MET 1000 mg twice daily. Both DU doses at 26 wks and DU 1.5 mg at
52 wks demonstrated superior glycemic control compared to MET (p<0.025).
Weight reductions were observed in all groups. Patient-reported outcome
measures of treatment satisfaction (DTSQ), weight-related self-perception
(IW-SP), diabetes symptoms (DSC-R), and ability to perform activities of
daily living (APPADL) were administered at baseline (BL), 26 and 52 wks. Pts
in all groups achieved significant (p<0.05) LS mean changes from BL in total
DTSQ and IW-SP scores at 26 and 52 wks. There were no significant LS mean
changes from BL for any treatment group in total DSC-R and APPADL scores
at 26 and 52 wks. LS mean improvements (decreases in score) from BL in
frequency of perceived hyperglycemia (DTSQ) were observed in all groups
at 26 and 52 wks, and improvement of hyperglycemia symptoms (DSC-R)
was observed in both DU doses at 26 and 52 wks (Table). In conclusion,
both once-weekly DU doses and MET demonstrated improvements from BL
in DTSQ and IW-SP at 26 and 52 wks. Improvement of patient-perceived
hyperglycemia was observed in both DU doses at 26 and 52 wks.
Change from
BL Score
ITT, LOCF
DTSQ, total
DU 1.5 mg DU 0.75 mg MET DU 1.5 mg DU 0.75 mg
(N=269) (N=270) (N=268) (N=269) (N=270)
26 wks
26 wks 26 wks 52 wks 52 wks
1.93
1.81
2.04
1.82
1.29
(0.39)‡
(0.38)‡
(0.39)‡ (0.44)‡
(0.43)‡
IW-SP, total
0.72
0.63
0.79
0.45
0.61
(0.19)‡
(0.18)‡
(0.18)‡ (0.19)‡
(0.19)‡
DSC-R, total
0.61
-0.40
1.02
1.23
1.05
(0.89)
(0.88)
(0.88) (0.99)
(0.97)
APPADL, total
0.09
0.19
0.02
0.39
-0.05
(0.33)
(0.32)
(0.32) (0.33)
(0.33)
-1.09
-0.86
-1.09
-1.10
DTSQ (Hyperglycemia)
-1.25
(0.14)‡
(0.14)‡ (0.14)‡# (0.14)‡#
(0.14)‡#
DSC-R (Hyperglycemia) -0.20
-0.20
-0.02
-0.21
-0.16
(0.07)‡#
(0.06)‡# (0.06) (0.07)‡# (0.07)‡
Data presented are LS mean (SE).
‡, # 2-sided p<0.05 vs. BL, and MET, respectively.
Comparing Effectiveness of Prandial Insulin and Glucagon-Like
Peptide-1 Treatment Regimens in Patients With Type 2 Diabetes
on Background Basal Insulin in a Real-World Setting in the United
States
ANDRES DIGENIO, SUDEEP KARVE, SEAN CANDRILLI, MEHUL DALAL, Bridgewater, NJ, Research Triangle Park, NC
This study documented demographic characteristics and outcomes among
patients with type 2 diabetes mellitus (T2DM) initiating prandial insulin
(INS) or glucagon-like peptide-1 (GLP-1) analog while on basal INS therapy.
Electronic medical records (EMR) of patients with T2DM aged ≥18 years
who had an EMR activity of ≥6 mo prior to, and ≥12 mo after their prandial
INS or GLP-1 analog initiation date, were analyzed. Primary study endpoints
included glycated hemoglobin (HbA1c), body weight, and health care
resource utilization. The unmatched cohort comprised 1,962 GLP-1 analog
users and 31,848 prandial INS users. Differences in patient characteristics
were controlled by matching the groups on baseline variables including age,
HbA1c, and body mass index. The resulting matched cohort comprised 1,143
GLP-1 analog users and 5,557 prandial insulin users, with the following
mean baseline characteristics: age of 56.0 and 56.6 years; HbA1c of 8.5%
and 8.6%; and weight of 111.1 and 108.9 kg, respectively. The outcomes of
the matched analysis are presented in the Table.
This study showed that, in a real-world setting, the addition of a GLP1 analog to basal INS in patients with T2DM was associated with similar
glycemic control, but significantly higher reduction in body weight, lower
incidence of hypoglycemia, and lower health care resource utilization
compared with prandial INS.
MET
(N=268)
52 wks
1.94
(0.44)‡
0.75
(0.19)‡
1.48
(0.97)
0.28
(0.33)
-0.66
(0.14)‡
-0.03
(0.07)
&
For author disclosure information, see page 829.
A264
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
TRAcP5b
(U/L)
Baseline
Week24
Change
P value
Lumbar BMD Baseline
(g/m2)
Week24
Change
P value
2.879±1.243
3.181±1.322
0.302±0.149
0.461
0.980±0.040
1.003±0.039
0.024±0.016
0.679
3.415±1.86
3.539±1.076
-0.124±0.395
0.786
0.895±0.053
0.886±0.058
-0.006±0.017
0.892
2.529±1.216
3.115±1.170
0.586±0.183
0.126
0.926±0.029
0.929±0.029
-0.001±0.016
0.943
0.195
0.551
0.5580.303
0.129
0.382-
1031-P
Patient-Reported Outcomes With Dulaglutide, Exenatide, or Placebo (AWARD-1)
1030-P
Effect of Exenatide, Insulin and Pioglitazone on Bone Metabolism in
Newly Diagnosed T2DM
RENYUAN LI, HAIXIA XU, WEN XU, JINHUA YAN, BIN YAO, GUOCHAO ZHANG,
JIANPING WENG, Guangzhou, China
Preclinical studies suggested that insulin, incretin and thiazolidinediones
had effect on regulation of bone metabolism. But clinical data is limited. We
assessed the effects of these antihyperglycemic agents on bone metabolism
in newly diagnosed T2DM.
Sixty-two newly diagnosed and drug naïve T2DM were randomized to
exenatide (20), mixed Protamine Zinc Recombinant Human Insulin Lispro
Injection (25R) (21) or pioglitazone (21) group for 24-week treatment. HbA1c,
bone turnover markers, including osteoclasin (OC), C-telopeptide of type I
collagen (CTX) and tartrate-resistant alkaline phosphatase 5b (TRAcP5b),
body mineral density (BMD) and fat mass index (FMI) were assessed at
baseline and week 24.
Baseline characteristics were similar among groups (Table 1). At week 24,
HbA1c improved in all patients. Patients treated with exenatide lost body
weight remarkably. Meanwhile, there was no significant change of body
weight in insulin or pioglitazone group, maybe for lifestyle improvement.
Greater reduction of FMI was found in exenatide group compared with that
in insulin and pioglitazone group. But no significant improvement of OC, CTX,
TRAcP5b or BMD was observed at week 24.
24-week treatment of exenatide, insulin and pioglitazone had improved
glucose control in newly diagnosed T2DM. But with 24-week treatment, no
significant change of OC, CTX, TRAcP5b or BMD was demonstrated. Among
the three agents, exenatide showed beneficial effects on body weight and
FMI.
Table1
Change from BL Score DU 1.5 mg
ITT, LOCF, LS Mean (SE) (N=279)
26 wks
DTSQ, total
2.40
(0.34)‡*#
IW-SP, total
0.56
(0.15)‡
APPADL, total
0.18
(0.27)
EQ-5D Index
0.01
(0.01)
EQ-5D VAS
4.50
(0.85)‡*
DTSQ (Hyperglycemia) -1.93
(0.13)‡*#
DTSQ (Hypoglycemia) 0.11
(0.11)#
Comparison of treatment groups at baseline, after treatments and change
from baseline
Variable
Exenatide
Insulin
Pioglitazone Pvalue
Age (years)
45.7±2.3
53.0±2.4
51.3±1.8
0.147
Gender,M/F
13/7
10/11
9/12
0.230
HbA1c
Baseline
8.4±0.2
8.7±0.2
8.6±0.2
0.759
(%)
Week24
6.0±0.1
6.4±0.1
6.6±0.2
0.265
Change
-2.4±0.3
-2.4±0.3
-2.0±0.2
0.200P value
<0.001
<0.001
<0.001
Body
Baseline
72.6±2.3
67.6±2.3
67.1±2.7
0.893
weight
Week24
67.8±2.2
66.9±2.4
66.1±2.8
0.177
(Kg)
Change
-4.7±0.8
-0.7±0.8
-1.1±0.9
0.021
P value
0.013
0.774
0.682
FMI
Baseline
8.0±0.6
7.6±0.5
8.1±0.4
0.684
(Kg/m2)
Week24
7.1±0.7
7.5±0.5
8.3±0.5
0.227
Change
-0.9±0.3
-0.1±0.2
0.2±0.2
0.009P value
0.025
0.930
0.778
OC
Baseline 11.658±4.169 11.535±6.745 11.226±4.977 0.639
(ng/ml)
Week24 11.040±5.465 12.172±6.058 11.077±5.273 0.825
Change
-0.619±0.728 0.637±0.787 -0.150±0.691 0.289P value
0.690
0.731
0.926
CTX
Baseline 0.634±0.332 0.825±0.415 0.673±0.346 0.227
(ng/ml)
Week24
0.781±0.416 0.813±0.380 0.746±0.452 0.631
Change
0.147±0.046 -0.012±0.074 0.073±0.094 0.361P value
0.225
0.926
0.551
ADA-Funded Research
&
‡, *, #2-sided
DU 0.75 mg
(N=280)
26 wks
2.56
(0.33)‡*#
0.47
(0.15)‡
0.12
(0.27)
0.01
(0.01)
2.41
(0.85)‡
-1.77
(0.13)‡*#
0.16
(0.11)#
EX
PL
(N=276) (N=141)
26 wks 26 wks
0.85 0.49
(0.33)‡ (0.45)
0.46 0.45
(0.15)‡ (0.20)‡
0.47 0.03
(0.27) (0.36)
0.00 0.00
(0.01) (0.02)
3.94 0.71
(0.85)‡* (1.15)
-1.10 -0.47
(0.13)‡* (0.18)‡
0.48 0.27
(0.11)‡ (0.15)
DU 1.5 mg
(N=279)
52 wks
2.05
(0.36)‡#
0.50
(0.15)‡
0.18
(0.29)
0.02
(0.01)
5.15
(0.89)‡
-1.89
(0.14)‡#
-0.05
(0.11)#
DU 0.75 mg
(N=280)
52 wks
2.11
(0.36)‡#
0.47
(0.15)‡
-0.18
(0.29)
0.01
(0.01)
3.52
(0.89)‡
-1.63
(0.14)‡#
0.03
(0.11)#
EX
(N=276)
52 wks
0.69
(0.36)
0.64
(0.15)‡
0.35
(0.29)
0.00
(0.01)
3.51
(0.89)‡
-1.13
(0.14)‡
0.34
(0.11)‡
p<0.05 vs BL, PL and EX, respectively
1032-P
The Effect of Prolonged Glucagon-Like Peptide-1 Receptor Stimulation on Gastric Emptying and Glycemia
MAHESH M. UMAPATHYSIVAM, MICHAEL Y. LEE, KAREN L. JONES, CHRISTOPHER ANNINK, CAROLINE E. COUSINS, RAJ SARDANA, LAURENCE TRAHAIR,
MARIANNE CHAPMAN, CHRISTOPHER K. RAYNER, MICHAEL A. NAUCK, MICHAEL HOROWITZ, ADAM M. DEANE, Adelaide, Australia, Bad Lauterberg, Germany
Exogenous glucagon-like peptide-1 (GLP-1) and GLP-1 agonists, when
given acutely slow gastric emptying (GE), which is the major mechanism for
reducing postprandial glycemia. There is evidence that this slowing of GE is
attenuated with prolonged stimulation of the GLP-1 receptor.
We aimed to determine whether such attenuation occurs with prolonged
GLP-1 infusion, and if it can be avoided with intermittent GLP-1 dosing.
Subjects were randomised to receive 3 regimens of IV GLP-1 (0.8 pmol.
kg-1.min-1); (i) ‘Prolonged’ - a continuous 24 hour infusion, (ii) ‘Intermittent’ two 4.5 hour infusions separated by 19.5 hours of 0.9% NaCl, (iii) ‘Acute’ For author disclosure information, see page 829.
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This 52-week (wk), Phase 3, randomized study compared once weekly,
long acting GLP-1 receptor agonist dulaglutide (DU) 1.5 mg and 0.75 mg to
twice daily exenatide (EX) and placebo (PL, 26 wks only) in patients (pts)
with type 2 diabetes. Both DU doses were superior to PL (26 wks) and EX (26
and 52 wks) in A1C change from baseline (BL; p<0.001). Weight reductions
were observed in DU 1.5 mg and EX. Patient reported outcome measures
for treatment satisfaction (DTSQ), weight related self-perception (IW-SP),
ability to perform activities of daily living (APPADL), and health status
(EQ-5D) were administered at BL, 26, and 52 wks. Significant (p<0.05)
improvements from BL were observed in IW-SP (26 and 52 wks, all groups)
and total DTSQ scores (26 wks, both DU doses and EX; 52 wks, both DU
doses). A decrease in frequency of perceived hyperglycemia (all groups) was
observed at 26 and 52 wks, but an increase in perceived hypoglycemia was
observed with EX at 26 and 52 wks. EQ-5D visual analog scale (VAS) score
showed significant improvements for both DU doses and EX at 26 and 52
wks. No significant changes were observed in APPADL and EQ-5D index
scores for any group. Some significant between group differences were
observed (Table). In conclusion, both once weekly DU doses and EX showed
improvements from BL for IW-SP, total DTSQ, perceived hyperglycemia, and
EQ-5D VAS scores. Improvement in total DTSQ and perceived hyperglycemia
scores were greater in both DU doses vs EX.
Clinical Diabetes/
Therapeutics
MATTHEW REANEY, PING WANG, MARK LAKSHMANAN, KATE VAN BRUNT,
BRAD CURTIS, BETH MITCHELL, Indianapolis, IN
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
POSTERS
Clinical Diabetes/
Therapeutics
a 4.5 hour infusion and Placebo (0.9% NaCl). GE of a mashed potato meal
(643kcal), labeled with 20MBq 99mTc-calcium phytate, was measured by
scintigraphy in 10 fasted healthy men (24±3yr).
GLP-1 acutely slowed GE compared to placebo (P<0.01). Slowing of GE
was attenuated with prolonged infusion (P=0.02), whereas slowing was
maintained with intermittent dosing. The magnitude of the reduction
in postprandial glycemia was diminished with prolonged infusion, but
maintained with intermittent infusion, of GLP-1 (P=0.01).
Sustained receptor activation attenuates, but does not abolish slowing of
GE induced by GLP-1. This is consistent with the concept that short acting
GLP-1 agonists are superior to long acting GLP-1 agonists in minimizing
postprandial glycemic excursions.
Supported by: Novo Nordisk A/S
1034-P
Quantification of the Benefi t-Risk Relationship Between Glycemic
Control and Hypoglycemia: A Comparison of Exenatide Once Weekly With Titrated Insulin Glargine
JENNY HAN, MING ZHOU, JARET MALLOY, LARRY SHEN, San Diego, CA
The DURATION-3 trial reported significantly greater A1C reduction and
lower risk of hypoglycemia (hypo) with the GLP-1 receptor agonist exenatide
once weekly (EQW) compared with insulin glargine (IG) over 3 years. As the
risk of hypo typically increases when better glucose control is achieved,
these analyses further quantify the benefit-risk relationship between
A1C and hypo by baseline characteristics in 233 EQW and 223 IG patients
(mean baseline A1C 8.3%). Exposure-adjusted event rates (EAER) of hypo
in relation to the lowest or the weighted average A1C over 26 weeks, 1
year, and 3 years were evaluated by the Poisson regression model. Time to
first hypo episode with EQW compared with IG, adjusted for endpoint A1C,
was evaluated by the Cox proportional hazard model. Treatment (EQW or
IG), concomitant antidiabetes therapy (with or without SFU), BMI, duration
of diabetes, and A1C (lowest, endpoint, or weighted average A1C) were
statistically significant (P<0.05) factors that impacted the risk of hypo. The
EAER of hypo by week 26 with EQW, adjusted for lowest A1C, was 0.37 of
that observed with IG (figure). The estimated survival function (probability
of no hypo) at week 26, adjusted for endpoint A1C (figure) provided a hazard
ratio of hypo between EQW and IG of 0.33. In conclusion, although risk of
hypo increased with the benefit of decreased A1C, such risk was significantly
reduced with EQW compared with IG.
1033-P
The Effect of Liraglutide on A1c and Body Weight Is Largely Dependent on Diabetes Duration
JOCHEN SEUFERT, TIMOTHY S. BAILEY, CLAUS B. SVENDSEN, MORTEN DONSMARK, MICHAEL A. NAUCK, Freiburg, Germany, Escondido, CA, Søborg, Denmark,
Bad Lauterberg, Germany
The LEAD phase 3 clinical program demonstrated liraglutide’s (lira)
effectiveness across the continuum of type 2 diabetes (T2D). Using 26-28week data from 7 phase 3 trials, this pooled analysis evaluated the effect
of baseline diabetes duration (DD) on changes in A1C and body weight (BW)
from baseline with lira 1.8 mg (n=1581), lira 1.2 mg (n=1117) and placebo
(n=524). DD ranged from <1 to >40 years (y), with a mean of ~8y for pooled
groups. The slope for change in A1C or BW vs DD was determined by linear
regression. There was a clinically nonrelevant trend for a greater A1C
reduction with shorter DD with lira (Figure 1); statistical significance was
achieved for pooled lira 1.2 mg (p<0.05) but the difference only equated to
-0.2% A1C/10y shorter DD. The effect of lira on BW was independent of DD
(Figure 2). In conclusion, the proven effectiveness of lira to reduce A1C and
BW is largely independent of DD. Therefore, lira can be successfully used
across the continuum of T2D.
1035-P
Efficacy and Tolerability of Exenatide Twice Daily in Asian vs. White
Patients With T2DM
WAYNE H.H. SHEU, WENYING HUANG, STEVEN C. BRUNELL, ERICH BLASE,
MARK HORNG, STEVE CHEN, Taichung, Taiwan, San Diego, CA, Taipei, Taiwan
The 2012 ADA/EASD position statement on hyperglycemia management
highlights the need for individualized treatment. Previous studies have
shown that postprandial glucose concentrations in response to identical
meals are greater in Asian than in White patients (pts). Exenatide twice daily
&
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1038-P
Meta-Analysis of GLP-1 Agonist Lixisenatide Use in Patients Insufficiently Controlled With Oral Antidiabetic Drugs Suggests Improved Results in Efficacy, Hypoglycemia & Weight Gain
1036-P
DENIS RACCAH, ANTONIO CERIELLO, PIERRE GOURDY, LUC SAGNARD, JAY LIN,
JULIO ROSENSTOCK, Marseille, France, Barcelona, Spain, Toulouse, France, Paris,
France, Flemington, NJ, Dallas, TX
Effects of Pramlintide on A1C, Weight, and Hypoglycemia in Patients With Type 1 or Type 2 Diabetes: Subgroup Analysis by Duration of Diabetes
The safety & efficacy of lixisenatide (LIXI) has been evaluated as addon to oral antidiabetic drugs (OADs) in patients with T2DM in 5 GetGoal
Phase 3 studies (GetGoal-M, -P, -S, -M-Asia, and -F1). We report on a metaanalysis on composite efficacy and safety outcomes vs placebo. Baseline
characteristics (no significant differences between LIXI & placebo (PBO)
groups): mean age 55.5 yrs, mean BMI 31.5 kg/m2, duration of diabetes
7.4 yrs, duration of OAD use 4.5 yrs, metformin use 92.3%, SU use 35.6%,
TZD use 16.5%. The total patients studied were 1828 LIXI & 932 PBO. A
significantly greater proportion of LIXI patients achieved HbA1C <7% (odds
ratio [OR] 2.66, [2.09, 3.38], p<0.0001). LIXI was also significantly better
than PBO for the composite endpoints of HbA1C <7% & no weight gain (OR
2.64 [2.00, 3.48], p<0.0001), HbA1C <7% & no documented symptomatic
hypoglycemia (OR 2.56 [2.04, 3.20], p<0.0001) & HbA1C <7%, no weight gain
& no documented symptomatic hypoglycemia (OR 2.53 [1.94, 3.28], p<0.0001)
(Table). Only 1 patient suffered documented severe hypoglycemia (0.05%) (in
the LIXI group, add-on to SU). In summary, treatment with LIXI in patients
with T2DM inadequately controlled on OADs significantly reduces HbA1C
(-0.87% vs -0.33%; p<0.0001) & is 2.5 times more likely to result in HbA1C
<7% with no documented symptomatic hypoglycemia and/or no weight gain
than PBO.
KATHRIN HERRMANN, STEVEN C. BRUNELL, KEVIN SHAN, STEVE CHEN, San
Diego, CA
Duration of disease affects various factors including insulin resistance and
hypoglycemia awareness in patients with either type 1 (T1D) or type 2 (T2D)
diabetes. This retrospective analysis evaluated the relationship between
duration of diabetes and response to pramlintide treatment in T1D or T2D.
Patients who received pre-meal pramlintide (30 or 60 mcg for T1D [n=714];
120 mcg for T2D [n=292]); or placebo (n=537 vs T1D; 284 vs T2D) as an adjunct
to insulin in 5 randomized trials were stratified by duration of diabetes tertile
(Tert) within each diabetes type. Across all groups, baseline mean age
ranged from 37 to 61 years, A1C from 8.6% to 9.5%, and duration of diabetes
from 6 to 30 years. Across all Terts (in both T1D and T2D), pramlintide
reduced A1C more than placebo. Pramlintide was associated with weight
loss across all Terts and diabetes type, whereas placebo was associated
with weight gain (except for Tert 3 in T2D). Generally, the incidence (but
not the event rate) of severe hypoglycemia was higher among pramlintidetreated patients than among placebo-treated patients. The incidence and
event rate of severe hypoglycemia rose with increasing duration of T1D, but
not T2D, in both pramlintide- and placebo-treated patients. These results
indicate that, compared with placebo treatment, pramlintide treatment was
associated with improved A1C and decreased body weight regardless of
baseline duration of diabetes or diabetes type.
Meta-analysis* results: composite endpoints
LIXI (% PBO Odds Ratio 95% p value
(OR) CI of
of Pts) (% of
Pts) Lixi vs PBO OR
HbA1C <7%, no weight gain†
35.83 18.88
2.64
2.00, <0.0001
3.48
HbA1C <7%, no documented symp- 40.86 22.96
2.56
2.04, <0.0001
tomatic hypoglycemia‡
3.20
2.53
1.94, <0.0001
HbA1C <7%, no weight gain, no doc- 33.53 18.24
umented symptomatic hypoglyce3.28
mia†,‡
*Meta-analysis includes GetGoal-M (NCT00712673), GetGoal-P
(NCT00763815), GetGoal-S (NCT00713830), GetGoal-M-Asia (NCT01169779)
and GetGoal-F1 (NCT00763451); †Δ Weight: Endpoint -Baseline≤0; ‡symptomatic hypoglycemia with BG <60 mg/dL
OR=odds ratio; CI=confidence interval; HbA1C=glycated hemoglobin;
PBO=placebo; LIXI=lixisenatide. Lixisenatide is currently in development for
the treatment of type 2 diabetes mellitus
1037-P
Does Liraglutide Therapy Affect the Metabolic Response in Patients
With Elevated Alanine Aminotransferase and Type 2 Diabetes Mellitus?: The ABCD Nationwide Liraglutide Audit
PIYA SEN GUPTA, KEN Y. THONG, MATTHEW ARMSTRONG, PHILIP N. NEWSOME, PETER WINOCOUR, REJ RYDER, Birmingham, United Kingdom, Welwyn
Garden City, United Kingdom
The aims were to evaluate the effect of 1) liraglutide on metabolic
response in patients with elevated ALT; 2) baseline ALT on metabolic
response to liraglutide.
Data was obtained from the UK ABCD audit of liraglutide in realclinical use (2009-2012, n=5650). Inclusion criteria: patients with baseline
ADA-Funded Research
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and follow-up ALT (>6 weeks). Exclusion criteria: liraglutide cessation.
Descriptive statistics were performed (expressed as %frequency, mean±SD,
median(IQR)). Patients were categorised into normal or abnormal baseline
ALT groups according to gender-based levels (normal ALT males ≤30.0,
females ALT≤19.0U/l). Changes in ALT, weight and HbA1c over time were
calculated within and between ALT groups (ANCOVA, Wilcoxon tests).
Spearman’s correlation was used to assess the relationship between
baseline variables including ALT and metabolic response.
Of 1309 patients (aged 55.5±11.3years, 54.8% male, 66.6% Caucasian,
diabetes duration 9.0(6.0-13.0 years)), baseline ALT was 28(21-42U/l),
weight 110.1±22.3kg, BMI 38.7±7.3kg/m2 and HbA1c 9.1±1.70%. Over 8.5
months(5.1-13.0), median ALT reduction was 1.0U/l(-8.0 to 4.0), BMI 0.8kg/
m2(-1.7-0.0) and HbA1c 0.7%(-1.7-0.1) (all P<0.0001). Comparing the normal
baseline ALT group (n=524, 40.0%) to high ALT group (n=784, 59.9%), ALT
changed from 19.0(16.0-24.0) to 20.0(15.0-26.0) (slight rise; P<0.001) and
38.0(29.0-50.0) to 33.0U/l(25.0-47.0) (P<0.0001), respectively. Baseline ALT
did not correlate with weight or HbA1c response but correlated with ALT
change (correlation coefficient -0.40, P<0.0001). Baseline HbA1c and weight
did not correlate with ALT response.
This analysis of serum ALT may have implications regarding non-alcoholic
fatty liver disease, associated with T2DM. We conclude that liraglutide in
real clinical use has a clinically significant impact on ALT reduction in T2DM
patients with a high baseline ALT.
(EBID; administered before the 2 main meals of the day) has been shown to
potently reduce postprandial glucose in pts with T2DM. The current post hoc
analysis explored the effects of EBID in Asian (N=787) and White (N=2223)
pts using data pooled from 21 randomized, controlled studies (duration, 1230 weeks). At baseline, Asian pts had a lower body weight (71 vs 95 kg),
higher A1C (8.4% vs 8.1%), lower FPG (166 vs 175 mg/dL), and more SFU use
(75% vs 42%) than White pts. Self-monitored blood glucose data showed
that, at baseline, Asian pts had higher postprandial glucose concentrations.
At endpoint, EBID decreased preprandial glucose in both groups and had
a greater effect on postprandial glucose in Asian pts. Changes in A1C
differed at endpoint in Asian and White pts (-1.1% and -0.9%). Nausea was
reported in 27% of Asian and 36% of White pts. In both Asian and White pts,
hypoglycemia was more common in pts treated with an SFU (31% and 19%)
than in those not treated with an SFU (3% and 10%). EBID was effective and
tolerated in pts of both races; the reduction in postprandial glucose levels
with EBID is of particular relevance to Asian patients considering their higher
postprandial glucose excursions.
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
significant difference in weight loss, A1C, lipid profile or blood pressure
when GLP-1 analogs were used in the management of patients with type 2
diabetes who participated in intensive weight management program.
1039-P
Perioperative Liraglutide Therapy for Japanese Subjects With
T2DM
POSTERS
Clinical Diabetes/
Therapeutics
NAOKO KATAGIRI, SHIZUKA KANEKO, YUMIKO TAHARA, YUICHI SATO, KUMIKO
HAMANO, Takatsuki, Japan, Kawasaki, Japan
1041-P
Diabetic patients with limited exercise during perioperative period tend
to gain weight, and their glycemic control frequently deteriorates. However,
temporary insulin therapy has a risk of hypoglycemia. To investigate the
efficacy and safety of perioperative liraglutide therapy, we performed a
retrospective case analysis.
61 Japanese subjects with T2DM (male/female;39/22, Age;67.7±12.8,
HbA1c;8.2±2.0, BMI;25.6±3.9) were initiated with liraglutide therapy
before elective operations, e.g. orthopedic operations (23 cases), cardiac
catheterizations for ischemic heart disease (21), cataract (12), prostate
cancer (2), and breast cancer (1). In case of hyperglycemia induced by
stress hormones during operation, regular insulin was added. As liraglutide
decreases gastrointestinal motility, surgical cases with gastrointestinal
tracts were excluded. BMI change, glucose profile and perioperative
complications were analyzed.
The BMI decreased (-1.7±0.7) before operation. Liraglutide therapy
achieved good glycemic control throughout the perioperative period (Fig.).
Additional regular insulin was not needed except 5 patients. HbA1c stayed in
good range (6.8±0.8 after 6 months). Hypoglycemic episodes, wound healing
retardations, or other complications were not observed.
Liraglutide provides an effective and optional way to safely achieve good
glycemic control in perioperative subjects with T2DM, especially those with
limited exercise ability and at risks of hypoglycemia.
The Novel Long Acting GLP-1/Glucagon Dual Agonist HM12525A
Reduces Body Weight and Improves Glycermic Control in Rodent
Models
SUNG YEOB JUNG, JIN SUN KIM, IN YOUNG CHOI, KYU HANG LEE, YOUNGMI LEE, YOUNG HOON KIM, JAHOON KANG, SE CHANG KWON, Hwaseong-si,
Republic of Korea, Seoul, Republic of Korea
Oxyntomodulin is believed to exert its biological effects by activating
both the GLP-1 and the glucagon receptor. The combined mechanism of food
intake inhibition and increased energy expenditure is expected to enhance
body weight loss. In addition, lipid metabolism is also expected to improve
via the hypolipidemic effects of glucagon. HM12525A was developed by
conjugating a novel GLP-1/Glucagon dual agonist with the constant region of
the human IgG via a non peptidyl linker. HM12525A (LAPS-GLP-1/Glucagon
dual agonist) is a potent dual agonist with well balanced affinities for the
individual receptors. It has a pK profile compatible with once weekly or less
frequent dosing regimens. The pharmacological effects of HM12525A were
studied in HF DIO mice and in db/db mice. The HF DIO mice were treated
once weekly sc with HM12525A (1, 3, and 5 nmol/kg) for 2 wks, and 100
nmol/kg of liraglutide was treated daily as an acitive comparator. HM12525A
induced dose dependent body weight loss (-3, -10, -31%) compared to that of
liraglutide (-17%). Also, the glucose lowering efficacy was evaluated in db/db
mice by once-a-week administration of 6 nmol/kg HM12525A for 4 wks, and
60 and 100 nmol/kg of liraglutide was administered daily. The result showed
that 6 nmol/kg of weekly HM12525A had comparable HbA1c reduction to the
100 nmol/kg of daily liraglutide. In conclusion, HM12525A showed potent
body weight loss as well as glucose lowering efficacy in rodent models.
1040-P
The Role of GLP-1 Analogs in Long-Term Weight Management Within a Multidisciplinary Intensive Lifestyle Intervention for Patients
With Type 2 Diabetes
OSAMA HAMDY, NUHA ELSAYED, AMR MORSI, ADHAM MOTTALIB, MARTIN J.
ABRAHAMSON, Boston, MA
1042-P
GLP-1 analogs use is associated with reductions in A1C and body
weight. To investigate the impact of their use within a multidisciplinary
weight management program, we evaluated body weight, A1C and other
cardiometabolic outcomes in 104 obese patients with type 2 diabetes who
enrolled in the Weight Achievement and Intensive Treatment (Why WAIT)
program, a 12-week weight management program, focused on intensive
lifestyle modifications. At entry, mean weight was 111.3±18.6 kg; BMI 38.7±5
kg/m², age 54.5±10.1 yrs and A1C 7.4±1.2%. Fifty five patients were started
on GLP-1 analogs at the beginning of the program. Only 35 remained on GLP1 analogs for the 4 years of follow up (group A) and 49 patients never used
GLP-1 analogs (group B). At baseline no difference in BMI (39±5.7 vs. 38.2±4.7
kg/m²), A1C (7.2±1.2 vs. 7.4±1.3%), diabetes duration, blood pressure or lipid
parameters were noted between the 2 groups. At 12 weeks, weight loss
was higher in group A but not significantly different from group B (-12.1±5.3
vs. 10.5±3.9 kg). A1C followed the same trend (6.2±0.7 vs. 6.5±0.9%). Weight
loss in group A over 4 years of follow up tends to be higher (-10.1, -7.8, -8.0,
-8.4 kg respectively) but was not significantly different from group B (-7.9,
-6.2, -6.2, -6.7 kg respectively). Similar observation was seen in A1C. At 4
year, A1C in group A was 6.9±1.3 vs. 7.5±1.3% in group B (p=0.07). LDL was
significantly lower in group A vs. group B at 3 and 4 yrs (86.4 vs.100 mg/dL,
p<0.05) but other lipid parameters and blood pressure were not significantly
different over the 4 years. In conclusion, except for LDL there was no
WITHDRAWN
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A268
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
ΔQTcI and ΔQTcF. The resulting mean placebo-corrected ΔQTcI (ΔΔQTcI) was
small with the largest ΔΔQTcI of 1.1 msec (upper bound of 90% CI: 3.8 msec)
on Day 4 (Albi 30 mg) and -0.6 msec (upper bound of CI: 1.8 msec) on Day 39
(Albi 50 mg). Results from the analysis of QTcF were consistent with QTcI.
Moxifloxacin caused a peak effect on ΔΔQTcI of 10.9 msec and the lower
bound of the CI was above 5 msec at all preselected time points, which
demonstrated assay sensitivity. The slope of the relationship between Albi
plasma levels and ΔΔQTcI was negative, demonstrating that increasing
exposures of Albi were not associated with QT prolongation.
Albiglutide was well-tolerated and there were no clinically relevant
differences in treatment safety data between Albi and P.
In conclusion, Albi at doses up to 50mg in healthy subjects did not prolong
the QTc interval in a clinically relevant way.
Basal+LIXI vs basal-bolus: composite endpoints
Endpoints
Basal+LIXI
BB
Odds Wald 95% CI p value
n=519* n=1165† ratio
% patients
Regression analysis
(unadjusted)
HbA1C <7% and no documented
28.32 18.63
3.71 2.52−5.48 p<0.0001
symptomatic hypoglycemia
HbA1C <7% and no weight gain
27.94 14.55
3.63 2.47−5.32 p<0.0001
HbA1C <7%, no documented symptom19.65
5.34
8.95 5.26−15.25 p<0.0001
atic hypoglycemia and no weight gain
*Includes GetGoal-Duo1 (NCT00975286) and GetGoal-L (NCT00715624);
†Includes HMR1964A/3002, HMR1964A/3005, HMR1964A/3502
(NCT00135057) and HMR1964A/3511 (NCT00135083); BB=basal-bolus;
CI=confidence interval; HbA1C=glycated hemoglobin; documented symptomatic hypoglycemia=blood glucose <3.33 mmol/L.
1045-P
An adaptive, double-blind, placebo (PL)- and sitagliptin (sita)-controlled
Phase 3 trial with dose-finding, efficacy and safety objectives to assess
dulaglutide (DU), a long-acting GLP-1 receptor agonist, in type 2 diabetes
mellitus (T2DM). We present the dose-finding results that selected doses for
the DU clinical development plan.
Patients with T2DM (A1c ≥7.0% to ≤9.5%), treated with diet and exercise
only, oral antihyperglycemic medication (OAM) monotherapy, or metformin
(MET) combined with OAM were randomized 1:1:3 to PL, sita 100 mg QD,
or 1 of 7 once-weekly DU doses (0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 3.0 mg), after
stabilization on MET monotherapy. Of 1202 randomized patients, the initial
230 participated in dose-finding. Allocation to DU occurred with adaptive
randomization, updated bi-weekly with accumulating data for a prespecified
efficacy and safety composite endpoint based on model predicted A1c,
weight, pulse rate, diastolic blood pressure (Table). The algorithm continued
adaptive randomization until 2 doses were selected that demonstrated
clinically meaningful benefit based on prespecified selection criteria
including ≥ two-fold concentration difference. A Data Monitoring Committee
discontinued DU 3.0 mg before dose selection. The adaptive algorithm
selected DU 0.75 and 1.5 mg; randomization continued to DU 0.75 and 1.5 mg
and comparators to assess long-term efficacy and safety.
1043-P
The Novel Anti-Glucagon Spiegelmer NOX-G16 Ameliorates Hyperglycemia in a Murine Type 1 Diabetes Model
AXEL VATER, PRZEMYSLAW KACZMAREK, EWA PRUSZYNSKA-OSZMALEK,
SIMONE SELL, CHRISTIAN MAASCH, KLAUS BUCHNER, PAWEL KOLODZIEJSKI,
WERNER G. PURSCHKE, KRZYSZTOF W. NOWAK, MATHIAS Z. STROWSKI, SVEN
KLUSSMANN, Berlin, Germany, Poznan, Poland
In the absence of postprandial insulin increases in type 1 diabetes mellitus
(T1DM), excessive secretion of glucagon leads to abnormally high glucose
production in the liver thus contributing to postprandial hyperglycemia. We
have identified NOX-G16, a PEGylated mirror-image (L-)oligonucleotide (a
so-called Spiegelmer ®) that binds glucagon with an affinity of 1.7 nM and
blocks glucagon-induced cAMP generation in vitro with IC50 of 2.4 nM. Due
to its mirror-image configuration NOX-G16 is not cleaved by plasma DNases
or RNases and exhibits a plasma half-life of approx. 6 h in mice.
NOX-G16 was administered ip once daily to mice with streptozotocin
(STZ)-induced insulinopenic diabetes as a model for T1DM. In intraperitoneal
glucose tolerance tests (ipGTT) performed 2 h after dosing on days 1, 3
and 7 glucose excursions were dose-dependently diminished as seen by
reduced peak glucose levels and a significantly lower area under the curve
for glucose, compared to vehicle treatment. Endogenous gluconeogenesis
was significantly diminished. Free fatty acids were slightly and ketone
bodies were clearly reduced, while plasma triglycerides were comparable
to vehicle-treated animals. Importantly, neither healthy controls nor T1DM
mice experienced hypoglycemia.
In summary, having accomplished anti-diabetic proof of concept in this
model of T1DM, NOX-G16 may be a drug candidate for insulin sparing in
T1DM patients. Additional pre-clinical work in T2DM is warranted.
Model Adjusted Mean (95% CI) Changes from Baseline
Treatment
A1c
Weight
Pulse Rate
(%)
(kg)
(beats/min)
52-week sitagliptin- 26-week placebo- 26-week placeboadjusted
adjusted
adjusted
0.25 mg
-0.12 (-0.38; 0.20) -0.49 (-1.36; 0.44) -1.16 (-4.40; 1.90)
dulaglutide
n=13
n=16
n=16
0.50 mg
-0.24 (-0.44; 0.02) -0.97 (-1.80; -0.12) -1.32 (-4.30; 1.80)
dulaglutide
n=16
n=22
n=22
0.75 mg
-0.23 (-0.44; 0.08) -0.44 (-1.16; 0.44) -1.80 (-5.50; 2.10)
dulaglutide
n=20
n=20
n=20
1.00 mg
-0.30 (-0.58; 0.08) -1.53 (-2.44; -0.60) -0.71 (-4.00; 2.50)
dulaglutide
n=7
n=9
n=9
1.50 mg
-0.63 (-0.98; -0.20) -1.67 (-2.48; -0.92) -0.07 (-3.20; 2.70)
dulaglutide
n=18
n=22
n=22
2.00 mg
-0.58 (-0.76; -0.32) -1.99 (-2.88; -1.20) 0.78 (-2.10; 3.80)
dulaglutide
n=23
n=29
n=29
3.00 mg
-0.29 (-0.62; -0.02) -3.93 (-4.84; -2.88) 2.98 (-0.60; 8.70)
dulaglutide
n=9
n=13
n=13
1044-P
Albiglutide Does Not Prolong the QTc Interval in Healthy Subjects:
A Thorough QT/QTc Study
BORJE DARPO, MEIJIAN ZHOU, JESSICA MATTHEWS, HUI ZHI, CAROLINE R.
PERRY, RICKEY REINHARDT, Solna, Sweden, Rochester, NY, Research Triangle Park,
NC, Upper Merion, PA
Supported by: Eli Lilly and Company
The effect of albiglutide (Albi), a selective once-weekly GLP-1 receptor
agonist being developed for the treatment of T2DM, on cardiac repolarization
(QTc interval), was assessed in a randomized, double blind, placebo (P)
controlled, parallel group study in healthy subjects with a nested cross-over
comparison for moxifloxacin (MX). Subjects were randomized to Albi (n= 78)
or placebo (n= 79) and received injections of 30 mg Albi/P on Days 1 and 8
and injections of 50 mg Albi/P on Days 15, 22, 29, and 36. In the placebo
group, moxifloxacin (MX) was administered on Day -1 in half of the subject
and on Day 40 in the other half. Albi PK was drawn on Days 4 and 39 and
serial ECG were extracted from continuous recordings on Day -2 (baseline),
-1, Days 4, 39, and 40.
Demographics were generally similar between Albi and P: mean age 2930 yrs; BMI 25 kg/m2. Mean change from Baseline (BL) in QTcI and QTcF on
Albi 30mg (~ Cmax after 30mg SD, Day 4) and Albi 50mg (~ Cmax after 50mg
RD, Day 39) was similar to the P response. MX caused a clear prolongation of
ADA-Funded Research
&
Diastolic Blood
Pressure (mm Hg)
26-week placeboadjusted
0.35 (-2.60; 3.60)
n=16
0.11 (-2.40; 3.20)
n=22
-0.27 (-3.00; 2.50)
n=20
-0.55 (-3.90; 2.20)
n=9
-0.62 (-3.40; 2.30)
n=22
-0.41 (-2.60; 3.20)
n=29
-0.19 (-2.70; 2.80)
n=13
1046-P
Injection Force (IF) of Rusable Insulin Pens in India: NovoPen® 4
(NP4), NovoPen® 3 (NP3), HumaPen® Ergo (HPE), Glaritus® Pen Royale (WR), INSUPen® (IP) and AllStar ® (AS)
ARND FRIEDRICHS, VOLKER KORGER, STEFFEN ADLER, Brannenburg, Germany,
Frankfurt, Germany
The IF of an insulin pen is an important practical aspect of therapy for
patients with diabetes mellitus, especially those with limited dexterity,
and is a key element in the design and characteristics of insulin pens. We
compared the IF of 6 reusable insulin pens available in India: NP4, NP3 (Novo
Nordisk), HPE (Eli Lilly), WR (Wockhardt), IP (Biocon) and AS (Sanofi). There
were 20 measurements per pen type per test series. Mean IF was measured
by dispensing 60 U of insulin. IF was tested with dispense rates of 6 and
For author disclosure information, see page 829.
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POSTERS
ZACHARY SKRIVANEK, JENNY Y. CHIEN, BRENDA GAYDOS, MICHAEL HEATHMAN, MARY JANE GEIGER, ZVONKO MILICEVIC, Indianapolis, IN, Santa Clara,
CA, Vienna, Austria
Clinical Diabetes/
Therapeutics
Dose-Finding Results in an Adaptive Trial of Dulaglutide Combined
With Metformin in Type 2 Diabetes (AWARD-5)
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—NON-INSULIN INJECTABLES
Meta-analysis results: composite endpoints*
LIXI + basal PBO + basal Odds ratio (OR) 95% CI p
insulin
insulin
LIXI + basal of OR value
(n=665; %
(n=533; % insulin vs PBO +
of patients) of patients) basal insulin
26.32
17.26
2.65
1.30, 0.007
HbA1C <7%, no documented
symptomatic hypoglycemia†
5.38
27.37
12.38
3.35
1.66, 0.0008
HbA1C <7%, no weight gain
6.77
HbA1C <7%, no weight gain,
18.50
9.76
2.64
1.48, 0.0009
no documented symptomatic
4.70
hypoglycemia
*Includes GetGoal-Duo1 (NCT00975286), GetGoal-L (NCT00715624) and GetGoal-L Asia (NCT00866658); †symptomatic hypoglycemia with blood glucose
<60 mg/dL; LIXI is currently in development for the treatment of type 2 diabetes mellitus
LIXI=lixisenatide; PBO=placebo; CI=confidence interval; HbA1C=glycated
hemoglobin
Supported by: sanofi-aventis
POSTERS
Clinical Diabetes/
Therapeutics
10 U/s (constant volume flow rate). Pens were fitted with different needles
as recommended by the manufacturers’ instructions (Becton Dickinson
Micro-Fine® 31G x 5mm for HPE, WR, IP, AS and NovoFine® 31G 6mm for
NP4 and NP3) and tested with different insulins: Lantus® for AS, Glaritus®
for WR, Humulin® 30/70 for HPE, Basalog® for IP, NovoMix® 30 for NP3 and
NovoRapid® for NP4.
AS required a significantly lower mean IF vs NP3, HPE and IP (Table). Mean
IF for NP4 and WR was similar to AS. Mean IF was 56, 49, 21 and 7% higher
with NP3, HPE, IP, WR vs AS, respectively (p<0.05) at 6 U/s. Mean IF in all
pens increased at 10 U/s, but IF remained lower for AS, NP4 and WR vs other
pens (p<0.05).
AS, NP4 and WR require a lower IF at different dispense rates vs
other reusable insulin pens. This may enable patients, especially those
with dexterity problems, to administer insulin more easily and improve
management of their diabetes.
1048-P
Efficacy and Safety of Lixisenatide in Japanese Patients With Type
2 Diabetes Mellitus: A Meta-Analysis of 2 Randomized Controlled
Trials
YUTAKA SEINO, NOBUYA INAGAKI, YUKIKO ONISHI, YUKIO IKEDA, KARIM ADMANE, JAY LIN, LUC VAN GAAL, Osaka, Japan, Kyoto, Japan, Tokyo, Japan, Paris,
France, Flemington, NJ, Antwerp, Belgium
The incidence of diabetes is increasing in Japan, with approximately
13.5% of the population now diagnosed with T2DM or impaired glucose
tolerance. We conducted a meta-analysis of data from 2 randomized,
double-blind trials to evaluate the efficacy & safety of adding lixisenatide
(LIXI) to SU ± MET (GetGoal-S) or basal insulin therapy ± SU (GetGoal-L
Asia) vs placebo (PBO) in Japanese patients with T2DM (LIXI, n=143; PBO,
n=136). LIXI significantly reduced HbA1C (-1.08% vs PBO; p<0.0001), as well
as FBG & PPG (-12.93 mg/dL [p=0.0072] & -149.82 mg/dL [p<0.0001] vs PBO,
respectively). A significantly higher proportion of patients achieved HbA1c
<7% with LIXI (31.47 vs 2.21% with PBO, p<0.0001). There was a trend
towards weight reduction with LIXI (-0.3 kg vs PBO, p=0.22). The incidence
of symptomatic hypoglycemia was 20.98% with LIXI vs 9.56% with PBO (all
patients were treated with SU &/or basal insulin). There were no cases of
severe hypoglycemia in either group. A significantly higher proportion of
patients achieved a composite endpoint comprising HbA1C <7%, no weight
gain & no documented symptomatic hypoglycemia in the LIXI group vs PBO
group (Table). In Japanese patients with T2DM inadequately controlled
on SU ± MET or basal insulin therapy, LIXI may improve glycemic control
without weight gain and with no severe hypoglycaemia. LIXI may also enable
a higher proportion of patients to achieve composite endpoints.
Supported by: Sanofi
1047-P
Meta-Analysis of Randomized Controlled Trials of Lixisenatide as
Add-On to Basal Insulin in Patients With Type 2 Diabetes Mellitus
BERNARD CHARBONNEL, EDWARD WANG, JAY LIN, MELANIE DAVIES, VIVIAN
FONSECA, Nantes, France, Bridgewater, NJ, Leicester, United Kingdom, New Orleans, LA
The safety and efficacy of lixisenatide (LIXI), a new once-daily glucagon-like
peptide-1 receptor agonist, has been evaluated as add-on to basal insulin ±
oral antidiabetic drugs (OADs) in 3 Phase III, randomized, placebo (PBO)controlled trials (GetGoal-L, -Duo1 and -L Asia) in T2DM. Endpoints included
HbA1C, weight, insulin dose, fasting blood glucose, postprandial glucose and
hypoglycemia. A meta-analysis was performed on the safety and efficacy
outcomes in 1198 patients (mean age: 57.2 yrs; diabetes duration: 11.7 yrs;
BMI: 30.3 kg/m2) enrolled to these trials, using a random effects model
(RevMan). A significantly higher proportion of LIXI-treated patients achieved
HbA1C <7% vs PBO (odds ratio [OR] 3.67 [1.64, 8.19] p=0.002). Furthermore,
LIXI was more than 3× as likely to result in HbA1C <7% and no weight gain (OR
3.35 [1.66, 6.77] p=0.0008), and more than 2.5× as likely to result in either i)
HbA1C <7% + no documented symptomatic hypoglycemia (OR 2.65 [1.30, 5.38]
p=0.007), or ii) HbA1C <7% + no weight gain + no documented symptomatic
hypoglycemia (OR 2.64 [1.48, 4.70] p=0.0009) (Table). In patients with T2DM,
LIXI as add-on to basal insulin ± OADs is significantly more effective than
PBO in achieving HbA1C <7%, and is more than 2.5 times as likely to result
in HbA1C <7% with no documented hypoglycemia and no weight gain; it is,
therefore, an attractive potential option as add-on to treatment with basal
insulin.
Analysis of composite endpoints*
LIXI†
PBO
p value
N
%
N
%
HbA1C
32
22.38
2
1.47 <0.0001
45
31.47
3
2.21 <0.0001
HbA1C
HbA1C
36
25.17
3
2.21 <0.0001
25
17.48
2
1.47 <0.0001
HbA1C
HbA1C
36
25.17
3
2.21 <0.0001
*Japanese subanalysis of GetGoal-S (NCT00713830) and GetGoal-L Asia
(NCT00866658) trials; †Lixisenatide is currently in development for the treatment of type 2 diabetes mellitus; LIXI=lixisenatide; PBO=placebo;
HbA1C=glycated hemoglobin; documented symptomatic hypoglycemia=blood
glucose
Supported by: Sanofi
&
For author disclosure information, see page 829.
A270
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1049-P
&
Evaluation of Effect of Exenatide Treatment in Serum Calcitonin in
Levels in Morbidly Obese Type 2 Diabetic Patient
MUSTAFA DEMIRPENCE, ALIYE PELIN TÜTÜNCÜOGLU, DEVRIM DOLEK, FUSUN
SALGUR, GONCA ORUK, MITAT BAHCECI, Izmir, Turkey
DAVID J. KAZIERAD, JEFFREY A. PFEFFERKORN, ARTHUR BERGMAN, XIN WANG,
TIMOTHY P. ROLPH, JAMES M. RUSNAK, Cambridge, MA, Groton, CT
Background and aim: Exenatide provides a reduction in glycated
hemoglobin with no weight gain. It was shown that exenatide might cause
an increased incidence in thyroid C-cell tumors in rats. We aimed was to
determine serum calcitonine levels during 6 monthly exenatide treatment
period in type 2 diabetic patients.
Subjects and methods: Obese (BMI≥35 kg/m2) newly diagnosed 33 type 2
diabetic patients aged with 48.4±12.9 yr were included to study. Exenatide
therapy was started with 5µg b.i.d in addition to metformin (2 gr/day). At the
1st month of treatment an additional visit was scheduled for all subjects to
verify the compliance to drug prescription and the occurrence of possible
side effects.
Exenatide dosage was increased to 10 µg b.i.d (20 µg/day) in appropriate
patients at the 1st month of treatment. Serum calcitonin, fasting and
postprandial glucose, amylase, A1c, lipid levels; and body weight and body
mass index (BMI) were measured in three visits (baseline, 3rd and 6th month
of treatment).
Results: Serum calcitonin levels did not show any significant difference
during with exenatide treatment (baseline: 2.44±4.17, 3rd month: 2.35 ±4.13,
6th month: 2.52±4.04 ).
During the treatment period serum calcitonin levels remained in normal
range. Whereas A1c levels (baseline: 8.17±1.83, 3rd month: 7.45 ±1.20, 6th
month: 6.80±1.10), fasting (baseline: 186±59.7, 3rd month: 141 ±27.8, 6th
month: 120±17.07) and postprandial glucose levels (baseline: 254±86.6,
3rd month: 183 ±43.8, 6th month: 143±20.4), body weight (kg) (baseline:
126.2±28.9, 3rd month: 120.7 ±27.7, 6th month: 116.2±28.2) and BMI (kg/m2)
(baseline: 48.1±9.88, 3rd month: 45.9 ±9.58, 6th month: 44.1±9.48) showed
significant improvements (p<0.05).
Conclusion: Exenatide treatment could not give rise to increment in
calcitonine levels at least 6 monthly period, whereas this treatment may
ameliorate fasting and postprandial glucose, A1c levels and body weight in
morbidly obese type-2 diabetic patients.
PF-04991532 (PF) is a liver selective GKA in development for T2DM.
Two 12-week, Phase 2, randomized, blinded studies investigated the
efficacy and safety of PF in T2DM patients receiving stable background
metformin therapy. In 1 study, patients were randomized to once daily oral
administration of 1 of 3 doses of PF, placebo, or sitagliptin. The mean ranges
for baseline demographics were similar across the dose groups: age 55-58
yrs; HbA1c 8.0-8.6%; duration of T2DM 7.1-8.4 yrs. The second study, of the
same design and with similar baseline demographics, was conducted using
a BID regimen at total daily doses of 50-600 mg. Results of both studies will
be discussed, with the representative QD study data summarized below.
Supported by: Pfizer, Inc.
&
1052-P
SLC47A1 Gene rs2289669 G>A Variant Influences the Hypoglycemic
Effect of Metformin in T2DM Patients
FANG LIU, DAN DAN ZHANG, TAI SHAN ZHENG, JUN LING TANG, HUI JUAN LU,
WEIPING JIA, Shanghai, China
1050-P
Background and aims: The SLC47A1 gene encodes for multidrug and
toxin extrusion 1(MATE1) which plays a pivotal role in the metabolism and
excretion of metformin. The present study is to investigate whether the
SLC47A1 gene polymorphism influence the therapeutic effect of metformin in
Chinese Hans who suffered from type 2 diabetes mellitus (T2DM). Methods:
The SLC47A1 single nucleotide polymorphism (SNP) rs2289669 G/A was
genotyped in 497 T2DM patients, including a metformin treated group (n =
224) and a non-metformin-treated group (n = 288) with PCR-restriction
fragment length polymorphism method. HbA1c was followed up for 6 months
after metformin treatment. Results: Three SLC47A1 genotypes, GA, GG and
AA were found and the frequency of the SLC47A1 rs2289669 G/A and A
allele was 46.99% in T2DM patients with the similar frequency in metformin
group(47.1%) and non-metformin group(46.9%). The plasma lactate levels
was significantly higher in AA carrier patients(1.18±0.47mmol/L ) than that
in patients who carried GA(1.04±0.39mmol/L) and GG(1.04±0.34mmol/L,
P=0.008), and the incidence of hyperlactatemia increased significantly
in patients with SLC47A1 rs2289669 AA genotype(5.9%) compared to
GA(3.4%) and GG genotype(1.5%, P<0.01). The 6-month follow-up of 250
patients revealed that there was greatest reduction of HbA1c in patients
with SLC47A1 rs2289669 AA genotype than that of GA and GG genotype
(ΔHbA1c -2.3% in AA genotype vs. -1.3% in GA, and -1.1% in GG genotype,
P<0.01).Conclusions: The SLC47A1 gene rs2289669 G>A variant influences
the hypoglycemic effect of metfotmin in Chinese T2DM patients, and the
patients with AA genotype got better HbA1c reduction.
SIVARAM PILLARISETTI, ISH KHANNA, La Chaux-de-Fonds, Switzerland
Insulin resistance is the underlying defect in >90% of patients with type
2 diabetes mellitus and is the key pathologic mechanism for associated
susceptibility to premature cardiovascular complications. Currently there
is no safe insulin sensitizer in market that targets skeletal muscle insulin
resistance. AMP-activated protein kinase (AMPK) is an energy-sensing
enzyme that is expressed in many insulin-responsive tissues including
liver and skeletal muscle. Activation of AMPK promotes glucose uptake in
skeletal muscle and inhibits gluconeogenesis and lipogenesis in liver. We
have developed a series of non-AMP mimetic, small molecule activators of
AMPK. In cell based assays, a lead molecule KU-5039 activated AMPK with
sub-micromolar potency compared to AICAR at 500 uM. KU-5039 exhibited
excellent oral availability including distribution and AMPK modulation across
targeted tissues (liver and skeletal muscle). In dbdb model of diabetes and
insulin resistance, KU-5039 stabilized plasma glucose to near normal levels
within 7 days of treatment. The plasma insulin levels were undetectable
and insulin resistance, as measured by HOMA, was normalized by day 7.
Unlike pioglitazone whose insulin sensitization was associated with weight
gain, KU-5039 treatment of dbdb mice resulted in no weight gain. Similarly
KU-5039 showed markedly improved insulin sensitization with no effect on
plasma lactic acid levels versus metformin. The lead KU-5039 represents a
promising approach for the treatment of insulin resistance in type 2 diabetes
without the side effects associated with marketed insulin sensitizers. A
detailed profile of the lead KU-5039 will be presented
Supported by: NSFC (81070650)
For author disclosure information, see page 829.
Guided Audio Tour poster
A271
POSTERS
Sitagliptin 100 mg QD
(N=54)
After 12-weeks of dosing, 60.5% of patients receiving PF 750 mg QD doses
achieved target HbA1c values <7%, compared to 16.3% and 39.6% in the
placebo and sitagliptin groups, respectively. Overall, PF was safe and well
tolerated across a range of QD and BID doses. There appeared to be doserelated trends for increases in LFTs and serum triglyceride values in the PF
groups; and 3 subjects discontinued from the BID study due to increased TG
values. Administration of PF-04991532, either QD or BID, resulted in clinically
meaningful decreases in HbA1c and minimal episodes of hypoglycemia.
Discovery of an Orally Efficacious, Novel AMPK Activator as Potent
Insulin Sensitizer
&
PF-04991532 QD
150 mg
450 mg
750 mg
(N=52)
(N=54)
(N=53)
HbA1c (%)*
0.08 (-0.13, 0.29) -0.49 (-0.71, -0.28) -0.58 (-0.80, -0.36) -0.71 (-0.92, -0.50)
Triglycerides (%)#
0.96 (0.83, 1.11) 1.12 (0.96, 1.30) 1.16 (1.00, 1.34) 0.92 (0.80, 1.07)
Hypoglycemia** 1 (1.9) 1 (1.9)
2 (3.7)
0 (0.0)
2 (3.7)
* Mean (80% CI) placebo-corrected change from baseline for the mixed
model repeated measures analysis at 12 weeks
# Geometric mean ratio to placebo (95% CI) change from baseline
** Episodes (% of total N) occurring over 12 weeks
Guided Audio Tour: Innovative Oral Agents—Innovative Discoveries (Posters: 1050-P to 1057-P), see page 19.
ADA-Funded Research
Placebo
(N=53)
Clinical Diabetes/
Therapeutics
Parameter
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—
ORAL AGENTS
&
1051-P
The Hepatoselective Glucokinase Activator (GKA) PF-04991532,
Lowers HbA1c after 12-Weeks of Dosing in Patients With Type 2
Diabetes (T2DM)
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
&
1053-P
The Mechanism of the Anti-Diabetic Effect of Ranolazine: Inhibition of Glucagon Secretion in Rat Pancreatic Islets via Na+ Channel
Blockade
POSTERS
Clinical Diabetes/
Therapeutics
KRIS KAHLIG, MING YANG, CHENG XIE, SRIDHARAN RAJAMANI, ARVINDER K.
DHALLA, LUIZ BELARDINELLI, Fremont, CA
The anti-anginal drug Ranolazine (RAN) is a Na+ channel blocker that has
been shown to reduce HbA1c levels in subjects with diabetes mellitus in
clinical trials. However the mechanism of action of its anti-diabetic effects
is unclear. Pancreatic α-cells express Na+ channels, which participate in
generating the electrical activity necessary for glucagon secretion. We
hypothesize that RAN inhibits Na+ current (INa) in pancreatic α-cells thus
reducing glucagon secretion. The effect of RAN on INa and electrical activity
in rat pancreatic α-cells was tested using perforated patch-clamp technique.
RAN (10µM) reduced INa by 25±4% (-98.0±18pA to -74.1±15pA, n=7, p<0.01)
and spontaneous electrical activity by 70±14% (99 ± 22 mV*s to 32 ± 6
mV*s, n=3, p<0.05). The reduced activity translated to a 36±6% reduction in
glucagon secretion measured from intact islets in the presence of RAN. The
role of INa was confirmed using selective (GS-458967) and broad spectrum
(tetrodotoxin, TTX) Na+ channel inhibitors, which both significantly reduced
α-cell INa and spontaneous electrical activity. Glucagon release from intact
islets was inhibited by 3µM GS-458967 (53±8%) or 100nM TTX (47±6%). The
INa activator veratridine (15µM) increased spontaneous electrical activity
by 6-fold) and glucagon release from islets by 3.5-fold. Veratridine-evoked
hyperexcitability was reduced by either 10µM RAN (290 ± 17 mV*s to 81 ±
35 mV*s, n=4, p<0.05) or 300nM GS-458967 (392 ± 42 mV*s to 55 ± 9 mV*s,
n=3, p<0.05). Likewise, veratridine-evoked glucagon release was reduced
by 10µM RAN (69±11%), 3µM GS-458967 (100%) or 100nM TTX (100%).
In summary, Na+ channel blockers reduce electrical activity of α-cells and
inhibit glucagon release. These data suggest the anti-diabetic effect of RAN
is mediated by the inhibition of islet glucagon secretion secondary to the
inhibition of α-cell INa. This mechanism of action reflects a novel target for
the development of anti-diabetic therapeutics.
&
&
1056-P
Combination Naltrexone/Bupropion Therapy Resulted in Clinically
Meaningful Improvements in Weight and Quality of Life (QoL): Integrated Analysis of Four Phase 3 Trials
RONETTE L. KOLOTKIN, COLLEEN BURNS, BRANDON WALSH, PRESTON KLASSEN, Durham, NC, La Jolla, CA
Comprehensive treatment for obesity ideally will improve physical,
psychological, and social aspects of health in addition to facilitating
weight loss. This integrated analysis of the four Phase 3, 56-week trials
of combination naltrexone sustained-release (SR) / bupropion SR (NB) vs
placebo (PBO) investigated changes in body weight and weight-related
QOL using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) scale
at baseline and at 8, 16, 28, and 56 weeks of treatment. All patients (NB
[n=2043], PBO [n=1319]) were overweight/obese (BMI: ≥27 and ≤45 kg/
m2). Treatment group differences (LS mean±SE) in the modified ITT-LOCF
population (≥1 post-baseline weight while on study drug) were evaluated
by ANCOVA with treatment, study, and baseline values as covariates.
Baseline characteristics (mean±SD) were similar between treatment arms:
81% female, 79% Caucasian, 46±11 y, 36±4 kg/m2, type 2 diabetes: 12.6%,
IWQOL-Lite total score: 71±18. Completion rate was 66% (NB) and 59%
(PBO). Weight loss with NB was significantly greater than PBO at all time
points (Week 56: -7.0±0.2% NB vs -2.3±0.2% PBO; p<0.001). At Week 56,
NB resulted in significantly greater improvement in IWQOL-Lite total score
(+11.9±0.3 vs +8.2±0.3; p<0.001) and all subscores (Physical function, Selfesteem, Sexual life, Public distress, Work; all p<0.05 vs PBO). At Week 56,
significantly more patients reduced body weight by ≥5% with NB (53% vs
21%; p<0.001), and greater mean improvement in IWQOL-Lite total score
was observed in these patients. The safety/tolerability profile of NB was
consistent with its individual components; the most common adverse events
were nausea (32%), constipation (19%), headache (18%), and vomiting (11%).
Thus, NB improved both weight and psychosocial outcomes, with 36% of NB
patients (vs 12% PBO; p<0.0001) achieving clinically meaningful improvement
in both IWQOL-Lite and body weight (≥5% reduction) after 1 year.
1054-P
Dose Response to Oral Insulin Capsules in Fasting, Healthy Subjects
ROY ELDOR, EHUD ARBIT, DANIEL SCHURR, MIRIAM KIDRON, AVRAM HERSKO,
Jerusalem, Israel, Haifa, Israel
Oral alternatives to injectable insulins are expected to better mimic
physiological portal vein insulin gradients, while inducing far fewer side
effects than systemically delivered insulins. After establishing safety and
efficacy of an insulin capsule (ORMD-0801), the presented research efforts
set out to explore the ideal dose and active ingredient:adjuvant ratios by
evaluating dose-responses of healthy, fasting individuals treated with orally
administered insulin (ORMD-0801). One capsule containing 8 mg insulin,
two capsules of 8 mg insulin each (8+8mg) or one capsule of 16 mg insulin
were administered to subjects, followed by a 300-min monitoring period.
Interim analyses demonstrated responses in 7/10 subjects, with maximal
blood glucose responses for all treatments observed following a lag of ≥60
min from administration, as expected of an enteric-coated capsule. Dose
response was manifested by significantly lower mean blood glucose Cmin
following the 8+8mg (47.9 ± 11.3 mg/dL, p=0.006) and 16mg (57.3 ± 8.4 mg/
dL, p=0.001) treatments, when compared to that which followed 8mg dosing
(64.6 ± 6.2 mg/dL). Significant reductions in glucose area under the curve
(AUC) values were observed following both 8+8mg and 16mg treatments
(13.2% and 8.1%, respectively), when compared to 8mg (p=0.003 and 0.008,
respectively). No adverse events were reported or observed following any
of the treatments. In conclusion, increasing doses of ORMD-0801 were well
tolerated by healthy individuals and response intensity positively correlated
with the administered dose.
&
1057-P
A Dose-Ranging Study of Diacerein in Patients With Type 2 Diabetes
CARL O. BROWN, WEISHU LU, EMILY LIN, CALVIN CHEN, Taipei, Taiwan
The cytokine interleukin (IL)-1Beta, a regulator of inflammatory response,
is implicated in the progression of type 2 diabetes mellitus (T2DM) through
both insulin resistance and beta-cell function mechanisms. We assessed
the safety and efficacy of diacerein, an orally available small molecule that
modulates IL-1Beta signaling, in patients with T2DM uncontrolled on a stable
regimen of 1 to 3 oral antidiabetic medications (OADs).
In Study AC-201-DM-001, a randomized, double-blind, placebo-controlled,
dose-ranging, 24-week Phase 2 study, 259 patients were randomized 1:1:1:1
to receive twice daily (BID) 25 mg, 50 mg, or 75 mg diacerein, or placebo. At
baseline, patients with mean (SD) glycosylated hemoglobin (A1C) of 8.4 (0.7)
% and fasting plasma glucose of 172 (43) mg/dL were enrolled and treated
at 21 sites in the US (N=150) and Taiwan (N=109).
In the Full Analysis Set (N=249), diacerein showed placebo-corrected
least squares mean (SE) A1C reductions of 0.20 (0.17) %, 0.29 (0.18) %, and
1055-P
WITHDRAWN
&
For author disclosure information, see page 829.
A272
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
0.35 (0.18) %* (*p<0.05) after 24 weeks of treatment in the 25 mg, 50 mg, and
75 mg groups, respectively. In the per-protocol (PP) population (N=184), the
placebo-corrected A1C reduction was 0.37 (0.19) %, 0.42 (0.18) %*, and 0.49
(0.19) %*, for 25 mg, 50 mg, and 75 mg groups, respectively. Further, the US
cohort had placebo-corrected A1C reductions in the PP population (N=104) of
0.61 (0.27) %*, 0.72 (0.25) %*, and 0.93 (0.26) %*, for 25 mg, 50 mg, and 75
mg groups, respectively. Differences in patient profiles such as background
therapy (54% in Taiwan vs. 9% in US on 3 OADs) are possible reasons for the
differences in efficacy results.
The most frequent adverse event with diacerein was diarrhea (9%, 19%,
16%, and 32% in placebo, 25 mg, 50 mg, and 75 mg groups, respectively),
which was mostly mild.
Diacerein showed good dose response and was well tolerated up to 75 mg
BID, demonstrating potential as a treatment for T2DM with a unique mode
of action targeting the inflammation pathway associated with both impaired
beta-cell function and insulin resistance.
ΔI30/ ΔG30) improved 7 and 10 fold in the K and G gps. When adjusted for
insulin sensitivity (EIR/HOMA-IR) the improvement was 2 fold greater in the
K vs. G gp. Hypoglycemia (BG 50-69 mg/dL) occurred less in the K gp (7.4%
vs. 21.2%).
Combination of saxagliptin and metformin is an effective initial therapy
for glycemic and beta cell function improvement in T2DM pts with severe
hyperglycemia.
1058-P
A Comparative Study of the Effects of a Dipeptidyl Peptidase-IV Inhibitor and Sulfonylurea on Glucose Variability in Type 2 Diabetic
Patients With Inadequate Glycemic Control on Metformin
HUN-SUNG KIM, HAE KYUNG YANG, JEONG AH SHIN, SEUNG-HWAN LEE, JAEHYOUNG CHO, HO-YOUNG SON, KUN-HO YOON, Seoul, Republic of Korea
Objective: This study aimed to compare the effects of sitagliptin on
glycemic change and 24-hour blood glucose variability to those of the
sulfonylurea glimepiride.
Methods: A 4-week randomized double blind-labeled prospective design
was used. We recruited 33 patients who had been treated with metformin
for at least 2 months (≥1000 mg). Each participant prescribed with metformin
was randomly assigned to either the sitagliptin (100mg) or the glimepiride
(2mg) group. A continuous glucose monitoring (CGM) was used to monitor
glycemic changes for 3 successive days in both group at baseline and at the
4-week follow-up. Glycemic changes and glucose variability were obtained
using CGM and these data were averaged over all subjects.
Results: The comparison of HbA1c between baseline and the 4-week
follow-up showed that HbA1c was significantly reduced in the sitagliptin
group (7.0 ± 0.5 to 6.6 ± 0.4 %, p<0.001) and glimepiride group (7.3 ± 0.4 to 6.9 ±
0.4, p<0.001). The sitagliptin and glimepiride groups had similar HbA1c and
fasting glucose levels after 4 weeks, and there were no significant differences
between the 2 groups. The mean amplitude of glycemic excursions (MAGE)
decreased significantly in the sitagliptin group (88.8 ± 18.5 to 67.3 ± 16.6 mg/
dL, p<0.001), but no significant difference was observed in the glimepiride
group (103.0±27.2 to 89.3±26.1 mg/dL, p=0.175). The SD and oxidative stress
markers did not differ significantly between the 2 groups.
Conclusions: When sitagliptin was combined with metformin, the patients
showed much more efficient blood glucose controlling effects not only the
3 indexes fasting blood glucose, postprandial blood glucose, and HbA1c but
also MAGE.
Supported by: Bristol-Myers Squibb
&
DANIEL M. FORD, MERAV BAZ-HECHT, NABIL A. SAID, BEN TAO, KENNETH E.
TRUITT, HUBERT S. CHOU, Edison, NJ
Previous studies evaluated the effects of COL combined with metformin-,
sulfonylurea-, or insulin-based therapy, but it had not previously been
extensively studied in combination with thiazolidinediones. A study was
recently conducted to evaluate COL as an add-on to PIO-based therapy in
adults with T2DM who had inadequate glycemic control (hemoglobin A1C
≥7.5% to ≤9.5%) on a stable dose of PIO (30 or 45 mg/day), with or without
1-2 other oral antidiabetes agents (metformin, a sulfonylurea, or a dipeptidyl
peptidase [DPP]-4 inhibitor). Eligible subjects were randomized to receive
COL 3.75 g/day (n=280) or matching placebo (PBO; n=282) in addition to
existing PIO-based therapy for 24 weeks. Subjects’ mean age was 56.0
years, 56.9% were male, and the mean duration of T2DM diagnosis was
8.4 years. Concomitant antidiabetes medications also included metformin
(83.3%), a sulfonylurea (32.6%), and a DPP-4 inhibitor (3.2%). At Week 24,
with last observation carried forward, COL treatment showed reductions
from baseline in A1C (least squares mean treatment difference -0.32%;
P<0.001) and fasting plasma glucose (-14.7 mg/dL; P<0.0001) vs PBO. COL
also decreased LDL cholesterol (-16.4%), total cholesterol (-6.5%), non-HDL
cholesterol (-9.8%), and apolipoprotein (apo) B (-8.8%; all P<0.0001), and
increased apoA1 (+3.4%) and triglycerides (median treatment difference
+11.3%; both P<0.001) vs PBO. The most frequently reported adverse events
in the COL group were hypoglycemia (COL, 4.0%; PBO, 6.1%), constipation
(COL, 4.0%; PBO, 2.9%), increased blood creatinine phosphokinase (COL,
3.7%; PBO, 1.1%), urinary tract infection (COL, 3.3%; PBO, 4.3%), upper
respiratory tract infection (COL, 2.9%; PBO, 3.2%), nausea (COL, 2.9%; PBO,
1.1%), and peripheral edema (2.9% for both). In conclusion, and similar to
prior add-on studies, adding COL to PIO-based therapy significantly improved
glycemic and most lipid parameters (triglycerides excepted) in patients with
T2DM.
Supported by: Merck & Co., Inc.
&
1059-P
Combination of Saxagliptin and Metformin Is Effective as Initial
Therapy in Type 2 Diabetes Mellitus (T2DM) With Severe Hyperglycemia
AMBIKA BABU, SAMIH BARCHAM, LOUIS DANIEL, LEON FOGELFELD, Chicago, IL
Performance of two oral hypoglycemic regimens was tested in newly
diagnosed T2DM patients (pts) with severe hyperglycemia presenting to
different acute care sites.
In a 12-week open label, RCT of 100 T2DM pts with blood glucose (BG) of
300-450 mg/dL were randomized to Glipizide XL 10 mg daily (G group [gp])
versus combination of Saxagliptin with Metformin extended release 5/2000
mg daily (Kombiglyze XR: K gp). The primary outcome was maintenance of a
fasting and random BG of <300 and <400 mg/dL upto 6 weeks and <250 and
<300 mg/dL thereafter, and no return ED visits.
Interim data are presented for 60 pts (27 in K gp, 33 in G gp). Baseline
characteristics were similar between both gps except for age (47, 41 in K, G).
Two pts in K gp did not achieve the primary outcome. The enrollment BG of
340 (K gp) and 339 mg/dL (G gp) declined significantly by week 1 to 245 and
239 mg/dL and by week 12 to 131 and 126 mg/dL, respectively (figure). A1c
improved significantly; 10.9 to 6.9% (K gp) and 11.1 to 7.2% (G gp). HOMA
β-cell improved significantly 6 and 4 fold and early insulin response (EIR:
ADA-Funded Research
&
1060-P
Efficacy and Safety of Colesevelam HCl (COL) as an Add-On to Pioglitazone (PIO) for Type 2 Diabetes Mellitus (T2DM)
For author disclosure information, see page 829.
Guided Audio Tour poster
A273
POSTERS
&
Clinical Diabetes/
Therapeutics
Guided Audio Tour: Clinical Pearls (Posters: 1058-P to 1065-P), see page 19.
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
&
&
1061-P
Durability of the Efficacy and Safety of Alogliptin Compared to Glipizide When Used in Combination With Metformin: 1 Year Interim
Analysis
OLIVIA J. PHUNG, DIANA M. SOBIERAJ, SAMUEL S. ENGEL, SWAPNIL N. RAJPATHAK, Pomona, CA, Storrs, CT, North Wales, PA, Whitehouse Station, NJ
POSTERS
STEFANO DEL PRATO, RICCARDO CAMISASCA, CRAIG WILSON, PENNY FLECK,
Pisa, Italy, Deerfield, IL
Clinical Diabetes/
Therapeutics
1063-P
Early Dual Therapy Is Associated With Improved Glycemia in Type 2
Diabetes: A Meta-Analysis
Treatment guidelines for type 2 diabetes recommend add-on agents when
metformin alone fails to provide adequate glycemic control. However, early
dual therapy may benefit patient outcomes. A systematic literature search
in MEDLINE and CENTRAL through 07/2012 sought RCTs on the initiation of
dual therapy with metformin vs metformin monotherapy. A random effects
model yielded weighted mean differences (WMDs) and RRs. The metaanalysis included 15 RCTs (6693 pts; mean age range: 48.4-62.7 yrs; mean
baseline A1c 7.2-9.9%, and mean diabetes duration: 1.6-4.1 yrs.) with median
follow-up of 6 mos, with 10 reporting A1c change, 11 reporting A1c goal
attainment of <7% and 10 reporting change in fasting plasma glucose (FPG).
Add-on drugs were TZDs in 5, insulin secretagogues in 4, DPP-4 inhibitors
in 4 and SGLT-2 inhibitors in 2 RCTs. Compared to metformin alone, dual
therapy provided statistically significant reductions in A1c (WMD -0.43%,
95%CI -0.56,-0.30), increases in attainment of A1c goal of less than 7% (RR
1.40, 95%CI 1.33-1.48), and reductions in FPG (WMD -14.30 mg/dL, 95%CI
-16.09,-12.51) (Figure). Heterogeneity was seen in all outcomes (I2 52-76%)
except A1c goal (I2=0%). These results suggest a potential benefit of initial
dual therapy on glycemic outcomes in diabetes compared to metformin
monotherapy across a wide range of baseline A1c levels. Further research
should explore if early dual treatment may also affect longer term health
outcomes in diabetes.
The durability of the efficacy and safety of alogliptin (ALO) compared to
glipizide when used in combination with metformin (MET) in subjects with
type 2 diabetes was evaluated using a 3-arm multicenter, randomized,
double-blind, active-controlled study. The total duration of the study will be
104 weeks; however, these data are from the prospective 1 year interim
analysis. The 3 treatment arms included ALO 12.5 mg QD + MET (ALO 12.5)
(n=880), ALO 25 mg QD + MET (ALO 25) (n=885), and glipizide 5 mg titrated
up to a max of 20 mg + MET (GLIP) (n=873), with the primary endpoint being
change from A1c at 52 weeks. The majority of subjects were white (62%),
women (50.3%), mean age of 55 years, body mass index of 31, diabetes
duration of 5.5 years, and baseline A1c of 7.6%. Reductions in A1c at week
52 (primary endpoint) were -0.62%, -0.61%, and -0.52% for ALO 12, ALO 25,
and GLIP, respectively. Significantly more subjects achieved an A1c <7% with
ALO 25 (55.3%) vs GLIP (47.4%) (P<0.001). Reductions in FPG were -5.0 mgl/
dL for ALO 12.5, -7.2 mg/dL for ALO 25, and 0.9 mg/dL for GLIP; reductions for
ALO were significantly greater for both doses compared to GLIP (P<0.001).
Change in weight from baseline at 52 weeks was -0.64, -0.91, and 0.89
for ALO 12.5, ALO 25, and GLIP, respectively; both doses of ALO were
significantly different from GLIP (P<0.001). A higher percentage of subjects
in the GLIP group (23.8%) experienced ≥ 1 hypoglycemic event compared to
ALO 12.5 (2.5%) and ALO 25 (1.4%). A similar number of subjects experienced
≥ 1 adverse event (AE) in all 3 groups; in addition, a comparable number of
subjects experienced an AE leading to treatment discontinuation. A total of
8 deaths occurred in the study with 2 in the ALO 12.5 group, 3 in the ALO 25
group, and 3 in the GLIP group. In summary, a significantly higher number
of subjects achieved the A1c goal of <7%. The safety profile was similar
between all treatment arms; however, significantly less hypoglycemia was
observed in the ALO dose groups.
Supported by: Takeda Global Research & Development Center, Inc.
&
1062-P
Vitamin B12 Deficiency and Hyperhomocysteinemia in Patients
With Type 2 Diabetes Receiving Metformin
YUKA SATO, KEISHI YAMAUCHI, YOSHIKO FUNASE, TORU AIZAWA, Matsumoto,
Japan
Metformin (Mf) therapy is often associated with B12 deficiency which
is a cause hyperhomocysteinemia, a risk factor for vascular complications.
However, status of plasma homocysteine (Hcy) in relation to vascular
complication in Mf -treated patients with T2DM has not been studied. We
determined plasma concentration of B12 and Hcy and status of vascular
complications in T2DM patients with and without Mf therapy. Those with
vitamin supplementation, renal dysfunction (Scr >115 µmol/L) or a history
of gastrectomy were excluded. In 62 consecutive Mf-treated patients (M/F
49/13, the mean age 62 yrs, HbA1C 7.5%, Mf dosing 1.1 g/day and duration
of Mf therapy 2.9 yrs), B12 deficiency (<150 pmol/L) was found in 8 (13%) and
borderline deficiency (150-220 pmol/L) in 18 (29%). The larger the Mf dosing,
the lower the B12 (r = -0.30, P = 0.02). B12 was lower in smokers than in
non-smokers (222±85 vs 300±83 pmol/L, P <0.01). However, Mf dosing was
correlated with B12 even after adjustment for smoking. B12 in Mf-treated
patients was lower than the age- and sex-matched non-Mf-treated T2DM
patients (n = 44 each, 256 ± 99 vs 309 ± 120 µmol/L, P = 0.03). In the Mf-treated
patients, there was no significant relation between B12 concentration and
RBC, eGFR, and macrovascular complications and no anemia in those with
B12 deficiency. Plasma Hcy was inversely correlated with B12 (Spearman’s
ρ = -0.42, P <0.01) and Hcy concentration was >10 µmol/L in 20 (45%).
Importantly, prevalence of diabetic retinopathy was 8, 14 and 27% in those
belonging to homocyteine Tertile 1 (T1, < 9.0 µmol/L), T2 (9.0-11.0 µmol/L)
and T3 (> 11.0 µmol/L), respectively (P = 0.13). Oral B12 administration
(1.5 mg/day), without cessation of Mf, normalized B12 concentration. In
conclusion, Mf therapy was dose-dependently associated with lowering of
B12, which was in turn correlated with elevation of Hcy. Deleterious effect of
hyperhomocysteinemia on diabetic retinopathy was suggested. Mf-induced
B12 deficiency was responsive to B12 supplementation.
Supported by: Merck & Co., Inc.
&
1064-P
Differential Regulation of Metabolic Parameters between SuperResponders and Non-Responders Treated With Sitagliptin
EIJI KUTOH, YASUHIRO UKAI, Tokyo, Japan
The aim of this work is to investigate the clinical characterization of
responders vs. non-responders treated with sitagliptin. Treatment naïve
subjects with T2DM received 50 mg/day sitagliptin monotherapy (n=41).
At 3 months, levels of metabolic parameters were compared with those at
baseline. Since it is known that the response to sitagliptin is proportional to
the baseline HbA1c levels, the novel index called A1c index (ΔHbA1c/baseline
HbA1c) was used to assess the glycemic efficacy of sitagliptin. The subjects
were divided into three groups according to this index; super-responders
(A1c index <-0.2, n=20, average ΔHbA1c: -3.84 %), responders (A1c index
between -0.2~-0.1, n=10, average ΔHbA1c -0.96%) and non-responders (A1c
index >-0.1, n=11, average ΔHbA1c -0.11%). At baseline, TG (140.35 vs. 438.71
mg/dl, p<0.005), non-HDL-C (156.45 vs. 188.14 mg/dl, p<0.01), atherogenic
index (AI: log10 [TG/HDL-C], 0.381 vs. 0.782, p<0.02), HOMA-R (2.75 vs. 5.42,
p<0.05) and BMI (23.66 vs. 27.26, p<0.05) were significantly lower in superresponders than non-responders. At 3 months, significant increases of
HOMA-B (from 17.57 to 48.57, p<0.003) and BMI (23.66 to 24.10, p<0.05)
were observed in super- responders, while these and other parameters
did not change in non-responders or responders. In super-responders,
Supported by: Chiiki Igaku Kenkyu Kikin Foundation
&
For author disclosure information, see page 829.
A274
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
normal bladder cells and J82 cells (from 24h to 72h, 10M PGZ) were showed
no changes at all. However, the expressions of CyclinD1 and P53 from J82
cells under 10M PGZ (for 8 to 10d) were decreased in spite of cells’ normal
growth. Finally, PGZ addition may not elevate the risk of bladder cancer in
normal urothelial cells nor promote J82 cell proliferation. But prolonged
usage may weaken the carcinogenicity of bladder cancer. PGZ can cause
normal bladder cell apoptosis in a tissue-specific way, which needs further
investigations to clarify its significance.
significant correlations were observed between ΔHbA1c and ΔHOMA-B
(R=0.50951, p<0.03) or ΔBMI (R=-0.4589, p<0.05). These results suggest
that 1) sitagliptin is more effective with those with lower levels of insulin
resistance, TG, non-HDL-C, AI or BMI. 2) significant body weight gain was
observed in super-responders and the improvement of glycemic control was
associated with body weight gain. Potential involvement of GIP pathway in
super-responders will be presented.
Supported by: SHPJ1408400
&
1067-P
TYLER DRAKE, DON HIRE, ELIZABETH SEAQUIST, Minneapolis, MN, WinstonSalem, NC
Does Sulfonylureas Increase the Incidence of Cancers in Type 2
Diabetes? A Systematic Review and Meta-Analysis
Achieving target glycemia in older patients with type 2 diabetes is a
challenge in clinical practice. In clinical trials, patients are managed by
protocols to achieve glycemic goals, but information from these protocols
has not been readily transferred to the clinic. Here, we sought to indentify
factors in the standard therapy arm of ACCORD (goal A1C 7.1-7.9%)
that were associated with failure to achieve an A1C similar to guideline
recommendations.
ACCORD patients reached target glycemia by 12 mo and then maintained
that level. Standard patients whose A1C was ≥8.0% at 12 mo were
compared to those whose 12 mo A1C was 7.1-7.9%. Patients were analyzed
based on baseline characteristics, medication classes used, weight gain,
and hypoglycemic events. Of the 5123 patients randomized to the standard
group, complete data were available for 4693 (1988 with A1C 7.1-7.9%, 1493
with A1C ≥8.0% at 12 mo). At baseline, patients with an A1C ≥8.0% at 12 mo
were younger (61.3 vs 62.8 yrs, p<0.0001), had a higher BMI (32.5 vs 32.0 kg/
m2, p=0.0148), longer duration of diabetes (12.0 vs 10.8 yrs, p<0.0001), and
had a higher baseline A1C (8.7 vs 8.2%, p<0.0001). They were more likely
to be female (39.7 vs 36.4%, p=0.0458) and to be Hispanic or Black (8.8 vs
5.8%, p=0.0007 and 22.2 vs 15.6%, p<0.0001, respectively). There was no
difference in the use of metformin, secretagogues, glucosidase inhibitors,
or incretins at 12 mo, but patients above goal were more likely to be on
thiazolidinediones (40.1 vs 36.4%, p=0.0294). Patients above goal had more
hypoglycemic events (1 event: 2.8 vs 1.2%, p=0.0023; >1 event: 0.5 vs 0.4%,
p=0.0023) and more weight gain (1.0 vs 0.1 kg, p<0.0001) at 12 mo.
Patients in the standard therapy group of the ACCORD trial who failed to
reach their A1C goal 12 mo after randomization had significant differences
in both baseline characteristics and clinical features when compared to
patients who reached goal A1C. These characteristics may prove useful in
identifying patients who may or may not reach the desired A1C in clinical
practice.
HUI GAO, YUNFENG SHEN, XIAOYANG LAI, JIANPING WENG, HUA LIANG, Nanchang, China, Guangzhou, China
Sulfonylurea is one of main drugs for treating type 2 diabetes. A wide
variety of sulfonylureas are currently available in practice. But these agents
were concerned to increase the potential risk of cancers. In this study, we
assessed whether sulfonylureas increased the incidence of cancers with
a meta-analysis of randomized controlled trials and cohort studies. Also,
the risks of various cancers were evaluated. The following sources were
used: the Cochrane library; EMBASE, MEDLINE, Web of Science, CBM, VIP,
CNKI. Search terms including diabetes mellitus, type 2 diabetes mellitus,
sulfonylurea, tolbutamide, chlorpropamide, glibenclamide, gliclazide,
glipizide, gliquidone, glimepiride, malignancy, tumor, cancer, neoplasm,
carcinoma, tumorigenesis in meta-analysis, randomized controlled trials
and cohort studies. New cancer data were available for 308,972 patients
in one randomized clinical trial and four cohort studies. Data on common
types of solid organ tumors were available for 6,649 patients from these
studies. Patients receiving sulfonylureas had no significant increased risks
in new cancer occurrence compared with patients in controls, with an RR
of 1.24 (95%CI 0.91~1.69) for metformin, 1.04 (95%CI 0.88~1.23) for insulin
and 1.17 (95%CI 0.93~1.47) for other anti-diabetics. Among specific solid
organ tumors examined, colorectal (RR 0.95, 95%CI 0.76~1.17), liver (RR
1.17, 95%CI 0.60~2.29) and pancreatic (RR 1.34, 95%CI 0.87~2.06) cancers
were no significantly higher risks in patients receiving sulfonylureas.
Interestingly, sulfonylureas treatment significantly reduced risk of bladder
cancer (RR 0.64, 95%CI 0.46 to 0.90). In conclusion, our results suggested
that sulfonylureas were not associated with increased risk of new cancer.
Surprisingly, sulfonylureas reduced the bladder cancer risk. These findings
warrant further investigation.
&
Guided Audio Tour: Off-Target Effects of Glucose Lowering Drugs (Posters:
1066-P to 1071-P), see page 15.
&
MATTIJS OUT, ADRIAAN KOOY, PHILIPPE LEHERT, CASPER G. SCHALKWIJK,
COEN D.A. STEHOUWER, Hoogeveen, Netherlands, Louvain, Belgium, Maastricht,
Netherlands
1066-P
Effect of Pioglitazone on the Normal Bladder Cell and Bladder Cancer Cell
Metformin is a key treatment option in type 2 diabetes (T2D), but is
associated with lowering of vitamin B12 (B12) levels. Although it is commonly
assumed that lower B12 levels reflect biological B12 deficiency, this is in
fact not certain. Accumulation of methylmalonic acid (MMA) may reflect
a biologically important B12 deficit. Therefore, we investigated whether
treatment with metformin during 52 months affects serum levels of MMA.
In this placebo-controlled trial, 390 patients with T2D were randomized
to metformin or placebo added to insulin therapy. Baseline characteristics
have been described previously (BMJ 2010). MMA levels were measured
by ultra performance liquid chromatography tandem mass spectrometry
(UPLCMSMS).
Multivariate regression showed that metformin treatment significantly
raised MMA serum concentrations. Compared to placebo, metformin
increased MMA by 0.03 nmol/l (95% 0.003 to 0.063; p=0.03; after adjustment
for MMA at baseline). Renal function and age did not affect this increase. In
addition, this effect appeared to be dose-related (P<0.001).
This long-term placebo controlled trial is the first study to show that in
patients with T2D metformin not only reduces serum levels of B12, but also
increases serum MMA, thus supporting the view that metformin-associated
lowering of B12 levels reflects biological B12 deficiency.
JIJIAO WANG, HONG LI, BENLI SU, XIAOLAN YUAN, JIAOJIAO ZHOU, CHUNYAN
LI, BHAVNA TOHOOLOO, NAVINA PRIYA JHUMMON, HUI SHENG, SHEN QU,
Shanghai, China, Dalian, China
Recently, pioglitazone (PGZ) has become the focus for the possible
relation with bladder cancer. Though many large-scale clinical studies
have been terminated, more observational studies are needed for further
interpretation.Our study aims to investigate the effect of PGZ on the normal
bladder cells and bladder cancer cell line (J82). Normal urothelial transitional
epithelium cells (from bladder of SD-rats) and J82 cells were treated with
different concentration of PGZ (from 5 to 40M) respectively. We observed
the surviving status of cells and detected the expressions of key mRNA and
protein including P53 and CyclinD1 as well as apoptosis associated gene
Bcl-2 and Bax at from 0h to 10d, after treatment with PGZ. We observed
that morphology of normal bladder cells was shown significant decrease of
cell viability after 48h in the 10M PGZ group. The inhibitory effects were
time and dose dependent. But PGZ used, visibly did not inhibit the growth
of J82 cells. The results of flow cytometry technology (FCT) further showed
the apoptosis ratio of normal bladder cells (for 72h, 10M PGZ, vs. control
group) was 11.3% vs. 49.7%. Liver cells, kidney cells and vascular endothelial
cells of SD-rats treated with PGZ were shown no cell deaths in any of them.
Accordingly, we hypothesized that PGZ exerts ‘toxicity’ which is highly tissue
selective for bladder cells.Meanwhile, tested by western blot and Rt-PCR,
the expressions of Bax and Bcl-2, as well as of CyclinD1 and P53 from both
ADA-Funded Research
&
1068-P
Metformin Treatment Is Associated With Increased Serum Levels of
Methylmalonic Acid in Patients With Type 2 Diabetes Treated With
Insulin: A Placebo-Controlled 4-Year Trial
For author disclosure information, see page 829.
Guided Audio Tour poster
A275
POSTERS
1065-P
Clinical Diabetes/
Therapeutics
&
Achieving Goal Hemoglobin A1C in the Standard Therapy Group of
the ACCORD Trial
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
&
1070-P
Sulfonylureas Associated With Higher Emergency Room use in Elderly With Diabetes
SWAPNIL RAJPATHAK, CHUNMAY FU, KIMBERLY BRODOVICZ, SAMUEL S. ENGEL, North Wales, PA
Emergency room (ER) use due to drug adverse events pose significant
economic burden on US healthcare system. Recent evidence among elderly
suggests that drugs for type 2 diabetes account for 25% of ER hospitalizations,
often linked with hypoglycemia. However, it is yet unknown whether
sulfonylureas (SU) are associated with ER use. We conducted a retrospective
study using MarketScan® (2009-10) to evaluate this association. The study
included 112,607 patients aged ≥65 years on oral monotherapy for diabetes
at baseline (34.3% on SU, 52.0% on metformin, 10.8% on TZDs and 2.9% on
other oral agents; insulin users excluded). Mean emergency room (ER) visits
was 0.67 among SU users compared to 0.47 among non-users in the one
year period (p<0.0001). Further, SU use was reported in 31.6% with no ER
visit, 37.0% with 1 and 44.0% with ≥2 ER visits. Hypoglycemia, which was
more common among SU users, was associated with more frequent ER use
(Table). In a multivariable logistic regression simultaneously accounting for
propensity to use SU and for potential confounders, the adjusted ORs were
1.16 (95% CI: 1.12-1.19) for 1 ER visit and 1.27 (95% CI: 1.22-1.32) for ≥2 ER
visits. For specific comparison of SU vs. metformin monotherapy, these ORs
were 1.21 (95% CI: 1.16-1.23) for 1 and 1.36 (95% CI: 1.30-1.42) ≥2 ER visits.
Results suggest that elderly SU users are more likely to use ER compared to
non-users. Further research should confirm this and consider evaluation of
factors associated with ER use among SU users.
&
POSTERS
Clinical Diabetes/
Therapeutics
Supported by: Altana AG; Lifescan, Inc.; E. Merck/Santé; Merck Sharpe & Dohme;
Novo Nordisk, Inc.
1069-P
Genital Mycotic Infections With Canagliflozin (CANA) in Subjects
With Type 2 Diabetes Mellitus (T2DM)
PAUL NYIRJESY, JACK SOBEL, ALBERT FUNG, CRISTIANA GASSMANN-MAYER,
KIRK WAYS, KEITH USISKIN, Philadelphia, PA, Detroit, MI, Raritan, NJ, Titusville,
NJ
CANA, an SGLT2 inhibitor, lowers plasma glucose by increasing urinary
glucose excretion. Genital mycotic infections (GMIs) with CANA were
assessed in subjects with T2DM (N = 2,313; mean age, 56 y; A1C, 8%; BMI,
32 kg/m2) from 4 randomized, double-blind, 26-wk, placebo (PBO)-controlled
studies. Rates of GMIs were 11% vs 3% (women) and 4% vs 1% (men) with
CANA relative to PBO (Table). GMIs were generally considered mild or
moderate in severity by investigators and few led to discontinuation; most
events with CANA were treated with antifungal agents (women, 82%; men,
83%).
CANA-treated women with GMIs were more likely to have a history of
vulvovaginitis (29% vs 12%), be pre-menopausal (35% vs 27%), and reside in
North America (60% vs 42%) than those without GMIs. CANA-treated men
with GMIs were more likely to have a history of balanitis/balanoposthitis
(25% vs 2%), have a slightly longer mean T2DM duration (9 vs 7 y), and
to reside in Europe (44% vs 26%) than men without GMIs. With CANA
treatment, 2% and 1% of females and males, respectively, had >1 GMI. In a
larger dataset (N = 9,439) from 8 studies with longer mean exposure (CANA,
68 wks; control, 64 wks), a higher rate of male GMIs was seen (n = 5,493;
8% and 2% for CANA and control), more commonly in uncircumcised than
circumcised men (11% vs 3%) and infrequently associated with phimosis or
the need for circumcision. In summary, CANA was associated with modestly
higher rates of GMIs that were generally manageable with standard
treatments.
No ER visits
1 ER visit
≥2 ER visits
SU users (n=38,282)
Total N (%)
25,245(65.9) 7,262(19.0)
5,775(15.1)
Hypoglycemia, N (%)
235(0.9)
222(3.1)
398(6.9)
Non-users (n=74,325)
Total N(%)
54,632(73.5) 12,327(16.6)
7,366(9.9)
Hypoglycemia, N (%)
251(0.5)
190(1.5)
220(3.0)
OR (95% CI) Hip Fracture comparing SU users vs. non-users
Unadjusted
1
1.43 (1.40-1.47) 1.70 (1.63-1.76)
Adjusted*
1
1.16 (1.12-1.19) 1.27 (1.22-1.32)
*Age, gender, health insurance, geographic region, history of CVD, stroke,
hypertension and dyslipidemia, and use of benzodiazepines and anti-convulsant therapy, and propensity to use SU
&
1071-P
The Effect of DPP-4 Inhibitor, Alogliptin, on Bone Metabolism in Patients With Type 2 Diabetes Mellitus
YUICHIRO YAMAUCHI, SHIN TUNEKAWA, YUSUKE SEINO, EITA UENISHI, TETUJI
OKAWA, ATUSHI FUJIYA, KOUTA ISHIKAWA, HIDETADA OGATA, ATUSHI IIDA,
RYOICHI BANNO, HIROSHI ARIMA, YOJI HAMADA, YUTAKA OISO, Nagoya, Japan
Type 2 diabetes (T2D) has been associated with a high risk of bone
fractures. Recent studies showed that treatment with DPP-4 inhibitors could
be associated with a reduced risk of bone fractures in the meta-analysis
and incretin hormones increased bone density in experimental models.
However, the clinical effects of DPP-4 inhibitors on bone metabolism
remain to be clarified. Therefore, we examined the effect of DPP-4 inhibitor,
Alogliptin (Alo), on bone metabolism in Japanese patients with T2D. This
prospective observation study was performed in 20 patients including 8 men
and 12 postmenopausal women. The patients were treated with 25mg Alo
once a day for 16 weeks, and GIP, calcitonin, biochemical markers of bone
metabolism and bone mineral density were evaluated in a fasting state at
baseline and post-treatment. Wilcoxon signed-rank test revealed that Alo
significantly decreased HbA1c from 7.1±0.5% to 6.6±0.5% and serum bone
alkaline phosphatase (BAP) from 18.3±11.9µg/L to 15.3±7.6µg/L, respectively.
In contrast, Alo did not affect GIP and other bone metabolic markers such
as osteocalcin(OC), serum NTX and OC/BAP ratio. Bone mineral density
in lumbar vertebra and proximal femur did not change significantly during
16 weeks, but ΔBAP was associated with the elevation of bone density in
proximal femur. It is noteworthy that Alo significantly elevated the level of
calcitonin that was known to be increased by GLP-1 and to reduce fracture
risk. (baseline: 22.7±5.7 pg/ml, post-treatment: 26.5±5.1 pg/ml). However, the
elevation was not associated with the change of bone density. Multivariate
regression analysis revealed that ΔBAP and Δcalcitonin were independent
of ΔHbA1c, respectively. These data suggest that the long-term use of DPP-4
&
For author disclosure information, see page 829.
A276
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ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
Conclusion: Reduced β-cell function (IS/IR index) and impaired rise in
plasma adiponectin characterize non-responsiveness to PIO.
inhibitor may exert beneficial effects on bone quality by suppressing the
unsuitable bone metabolism in T2D. The role of elevated calcitonin by the
DPP-4 inhibitor on bone metabolism remains obscured at this study and
further investigation is necessary.
1074-P
The Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitor Empagliflozin Improves Glycemic Control in Patients With Type 1 Diabetes:
A Single-Arm Clinical Trial
1072-P
Ranolazine Inhibits Glucagon Secretion from Human Pancreatic Islets via Blockade of Nav 1.3 Channels in α-Cells
Adjunctive therapy to basal-bolus insulin regimens may provide an added
strategy to improve glycemic control in patients with type 1 diabetes. In an
8-week single-arm open-label pilot study of the SGLT2 inhibitor empagliflozin
25 mg po QD in subjects receiving optimized standard of type 1 diabetes
care, we evaluated the efficacy on glycemia and rates of hypoglycemia
compared to a 2-week placebo run-in period (NCT01392560). Other outcome
measures were urinary glucose excretion (UGE), insulin requirement, and
anthropometrics. We recruited 42 normoalbuminuric patients (28 insulin
pump, 14 multiple daily injection) with mean±SD age 24±5 years, A1c 8.0±0.9
%, and fasting plasma glucose (FPG) 10.0±4.8 mmol/L. 40 patients completed
8 weeks of treatment with empagliflozin and the mean A1c decreased by
0.4% to 7.6±0.9% (p<0.0001). FPG decreased non-significantly to 8.6±3.1
mmol/L (p=0.06). Symptomatic hypoglycemia (<3.0 mmol/L) declined from
0.12 to 0.04 events per day (p=0.005) and mean daily insulin dose declined
from 55±20 to 46±19 U/day from the placebo run in period (p<0.0001). The
mean UGE increased from 19±19 at baseline to 134±61 g/day at 8 weeks
(p<0.0001). Weight decreased by 2.7 kg from 72.6±12.7 (p<0.0001) and
waist circumference decreased by 3.8 cm from 82.9±8.7 (p<0.0001). Apart
from hypoglycemia, polyuria (79%) and thirst (74%) were the most frequent
adverse events. 2 subjects were withdrawn after the early occurrence
of diabetic ketoacidosis (one in the setting of gastroenteritis, the other
in the setting of insulin pump failure). In patients with type 1 diabetes,
empagliflozin as adjunctive to insulin therapy was generally well-tolerated
and associated with short-term improvement in glycemic control, a reduction
in rates of hypoglycemia and reduced insulin requirement and body weight.
A randomized clinical trial of the efficacy of adjunctive empagliflozin in type
1 diabetes is warranted.
1073-P
Reduced Beta Cell Function and Inadequate Rise in Plasma Adiponectin Characterizes Non-Responsiveness to Pioglitazone in Individuals With Impaired Glucose Tolerance in ACT NOW
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1075-P
DEVJIT TRIPATHY, DAWN C. SCHWENKE, MARY ANN BANERJI, GEORGE A.
BRAY, THOMAS A. BUCHANAN, STEPHEN CLEMENT, ROBERT R. HENRY, ABBAS
E. KITABCHI, SUNDER MUDALIAR, ROBERT E. RATNER, FRANKIE B. STENTZ, PETER D. REAVEN, NICOLAS MUSI, RALPH A. DEFRONZO, San Antonio, TX, Phoenix,
AZ, Brooklyn, NY, Baton Rouge, LA, La Canada, CA, San Diego, CA, Memphis, TN,
Alexandria, VA
Efficacy and Safety of Canagliflozin (CANA) in Subjects With Type
2 Diabetes Mellitus (T2DM) and Chronic Kidney Disease (CKD) Over
52 Weeks
JEAN-FRANCOIS YALE, GEORGE BAKRIS, BERTRAND CARIOU, JAVIER NIETO IGLESIAS, EWA WAJS, KATHERINE FIGUEROA, JOEL JIANG, KEITH USISKIN, GARY
MEININGER, Montreal, QC, Canada, Chicago, IL, Nantes, France, Ciudad Real, Spain,
Beerse, Belgium, Raritan, NJ
Multiple studies have shown thiazolidinediones (TZDs) delay/prevent
onset of type 2 diabetes mellitus (T2DM). However, a significant number
of individuals with IGT fail to respond to TZDs. We examined factors that
predict lack of response to pioglitazone in ACT NOW, a randomized doubleblind, placebo-controlled study to test whether pioglitazone (45 mg/day) can
prevent/delay development of T2DM in IGT (n= 602). Insulin secretion and
insulin sensitivity indices (derived from plasma glucose, insulin, C peptide
during OGTT and frequently sampled intravenous glucose tolerance test)
and plasma adiponectin were measured at baseline and study end (median
2.4 yrs). Diabetes developed in 50 PLAC-treated subjects vs. 15 PIO-treated
subjects (HR=0.28: 95% CI= 0.16,-0.49; p<0.001). Of 213 PIO-treated subjects
who completed the study, 101 (47%) reverted to NGT (responders) and 112
(53%) either remained IGT or developed T2DM (non-responders) At baseline
there were no differences in FPG, 2-h PG, Matsuda Index of insulin sensitivity
(MI) and plasma adiponectin between responders and non-responders. At
study end all indices of beta cell function were lower in non-responders
versus responders: insulin secretion/insulin resistance index (ΔI0-120/
ΔG0-120 x MI) (2.90 ± 0.2 vs. 3.57 ± 0.2, p=0.002); acute insulin response
(312±27vs 415± 39, p=0.03); disposition index from FSIVGTT (684±72 vs 908±
69, p=0.02). Plasma adiponectin increased 2.6 fold (12± 0.7 to 32±2.0 µg/ml)
in non-responders versus 4.2 fold (11± 0.5 to 46± 4.0 µg/ml) in responders
(p<0.001). The increase in adiponectin correlated with the improvement in
FPG (r=0.322, p<0.001), 2-h PG (r=0.281, p<0.001), Matsuda Index (r=0.526,
p<0.005) and ΔI0-120/ΔG0-120 x MI (r=0.306, p<0.005).
ADA-Funded Research
&
CANA is an SGLT2 inhibitor in development for the treatment of T2DM.
This randomized, double-blind study enrolled subjects with T2DM and Stage
3 CKD (eGFR ≥30 and <50 mL/min/1.73 m2). Subjects (N = 269; mean age,
68.5 y; A1C, 8.0%; fasting plasma glucose [FPG], 164.0 mg/dL; BMI, 33.0
kg/m2; eGFR, 39 mL/min/1.73 m2; median albumin/creatinine ratio [ACR], 30
µg/mg) received CANA 100 or 300 mg or placebo [PBO] added to current
therapy (74% on insulin) during a 26-week core period followed by a 26-week
extension (n = 207). Over 52 weeks, CANA 100 and 300 mg reduced A1C,
FPG, body weight, and systolic BP, with small increases in HDL-C and small
decreases in LDL-C relative to PBO.
Overall AE rates were 86%, 81%, and 87% and serious AE rates were
20%, 24%, and 27% with CANA 100 and 300 mg and PBO; AE-related
discontinuation rates were low across groups. Proportion of subjects with
hypoglycemia (64%, 59%, 46%) and rates of osmotic diuresis-related AEs
(eg, pollakiuria; <5% per group) were higher with CANA 100 and 300 mg
than PBO; rates of UTIs and AEs related to reduced intravascular volume
(eg, postural dizziness) were higher with CANA 300 mg than PBO. Increases
in BUN (12%, 16%, 5%) and decreases in eGFR (-4%, -8%, -3%) and median
ACR (-1, -7, 2 µg/mg) were seen with CANA 100 and 300 mg relative to
PBO. In summary, CANA improved glycemic control and was generally well
tolerated in subjects with T2DM and Stage 3 CKD over 52 weeks, similar to
findings at Week 26.
For author disclosure information, see page 829.
Guided Audio Tour poster
A277
POSTERS
Ranolazine (RAN) inhibits sodium current and electrical activity of rat
pancreatic α-cells by blocking Na+ channels (NaCh), which play an important
role in generating action potentials for glucagon secretion. We determined
the effects of RAN and other NaCh blockers (GS-458967 and tetrodotoxin,
TTX) on glucagon secretion in human pancreatic islets and identified the
NaCh isoform responsible for these effects.
RAN and GS-458967 significantly reduced glucagon secretion in human
islets in a concentration-dependent manner, with 25±3 and 51±9% reduction
for RAN (10 µM) and GS-458967 (3 µM), respectively. Veratridine, a NaCh
activator, increased glucagon secretion in human islets in a concentrationdependent manner, with a 10-fold increase at 30 µM and an EC50 of 33±6 µM.
RAN, GS-458967 and TTX, in a concentration-dependent manner, reduced
the increase in glucagon secretion caused by 30 µM veratridine. Glucagon
secretion was reduced by 36±11, 71±10 and 86±8% for RAN (10 µM), GS458967 (3 µM) and TTX (30 nM), respectively. Based on qPCR analysis of
whole pancreatic islets, the major isoforms of NaCh expressed are Nav1.3
and 1.7, followed by 1.2 and 1.6. In dispersed human islet cells, transfection
with siRNAs for the Nav1.3 or 1.7 isoform resulted in specific knockdown
of their gene expression by 65±6 or 55±3%, respectively, compared to the
control (n=6). Both veratridine- and L-arginine-induced glucagon secretion
was significantly reduced (≥60%) by Nav1.3 but not by Nav1.7 knockdown
(n=4), compared to the control. In summary, RAN and other NaCh blockers
inhibit glucagon secretion from human islets by blocking Nav1.3 channels.
Data suggest that NaCh play an important role in the regulation of glucagon
secretion in human islets. We propose that the anti-diabetic effects of RAN
in humans are due to a reduction of glucagon secretion by blockade of Nav1.3
channels in pancreatic α-cells.
Clinical Diabetes/
Therapeutics
BRUCE A. PERKINS, DAVID Z. CHERNEY, HELEN PARTRIDGE, NIMA SOLEYMANLOU, HOLLY TSCHIRHART, BERNARD ZINMAN, NORA FAGAN, STEFAN
KASPERS, HANS-JUERGEN WOERLE, ULI C. BROEDL, ODD ERIK JOHANSEN,
Toronto, ON, Canada, Mississauga, ON, Canada, Ridgefield, CT, Ingelheim, Germany,
Rud, Norway
ARVINDER DHALLA, MING YANG, RUTH CHU, LUIZ BELARDINELLI, Fremont, CA
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
CANA in Phase 3 studies. In summary, CANA reduced BP compared with PBO
in subjects with a range of baseline BP; absolute reductions were greater in
subjects with higher BP, but PBO-subtracted decreases were similar across
groups.
1076-P
SARA T. HJULER, MICHAEL FEIGH, KIM V. ANDREASSEN, MORTEN A. KARSDAL,
KIM HENRIKSEN, Herlev, Denmark
POSTERS
Clinical Diabetes/
Therapeutics
Oral sCT Intervention Improves Glucose Homeostasis and Insulin
Sensitivity in an Animal Model of Type 2 Diabetes
Oral salmon calcitonin (sCT) has previously been reported to have positive
effects on glucose homeostasis and it has been suggested that this effect
could mediated through increased insulin sensitivity. In this study the effect
of chronic administration of oral sCT was evaluated in regards to fasting and
non-fasting blood glucose, glycated hemoglobin (HbA1c), insulin sensitivity,
and glucose tolerance in a rat-model of type 2 diabetes.
Diet-induced obese (DIO) rats was given a low dose (25 mg/kg) of streptozotocin (STZ) resulting in diabetic hyperglycemia without hypoinsulinemia.
The DIO-STZ rats were orally dosed with either 0.5 mg/kg salmon calcitonin
(sCT) or its oral vehicle 5-CNAC once daily for 21 days. Postprandial blood
glucose (PPG) was measured on day 1, 3, 5, 14, and 21. Oral sCT improved
hyperglycemia during the intervention period resulting in 5 mM reduction
of PPG at study end when compared to vehicle (p<0.01). During oral glucose
tolerance test, oral sCT improved glucose intolerance by reducing the area
under the curve with ~35 % when compared to vehicle (p<0.001). Furthermore,
oral sCT reduced fasting blood glucose and HbA1c at study end by ~7 mM
and 1 % respectively (p<0.05). Oral sCT did not exert an insulinotropic action.
In contrast, compared to vehicle group, oral sCT caused a 2-fold increased in
glucose disappearance rate (KITT) during intravenous insulin tolerance test
(p<0.01) indicating increased insulin sensitivity. Both the vehicle and sCT
groups lost weight after injections with STZ with no significant difference
between groups. Finally oral sCT improved hyperleptinemia by 11 %
compared to vehicle (p<0.05).
In conclusion oral sCT improved the glucose homeostasis and insulin
sensitivity independent of body weight in DIO-STZ rats. This study
demonstrates oral sCT as a therapeutic agent against of type 2 diabetes in
an intervention model of diabetes.
1078-P
Inhibition of Phosphodiesterase as a Mechanism of Action for Silymarin-Induced Insulin Secretion in HIT-T15 Cells
GINA MENG, JANA MAHADEVAN, SARA VALLERIE, ELIZABETH OSEID, JOSEPH
BEAVO, R. PAUL ROBERTSON, Seattle, WA
Silymarin (SIL) is an oral antioxidant that has been shown in several placebocontrolled human trials to significantly improve fasting glycemia and HbA1c
levels in type 2 diabetic subjects. These beneficial effects were attributed
to nullification of oxidative stress; however, no measurements were made
of markers of oxidative stress or of insulin secretion. To define mechanisms
of action for SIL, we examined insulin responses to 11.1 mM glucose (GSIS)
using the glucose-responsive β-cell line HIT-T15. In a drug concentrationdependent fashion, SIL had a bimodal effect; initial enhancement of GSIS at
drug concentrations of 25-100 µM (EC50 = 38 µM), but with concentrations
>200 µM diminishment of GSIS was observed. The SIL concentrations that
augmented GSIS were shown also to decrease phosphodiesterase activity in
the presence of Ca2+/calmodulin (IC50=26 µM). The higher SIL concentrations
that had diminished GSIS were shown by florescent microscopy to have
undergone apoptosis. Only the higher concentrations of SIL demonstrated
anti-oxidant effects on the accumulation of peroxides in cell culture media
(100-500 µM). We conclude that the beneficial effects of SIL on GSIS may
be primarily due to decreased phosphodiesterase activity and consequently
greater endogenous c-AMP levels with resultant enhancement of glucoseinduced insulin secretion rather than via its antioxidant effects.
1079-P
Supported by: The Danish Ministry of Science
INdividualized Treatment Targets for EldeRly Patients Using VildaWITHDRAWN
gliptin Add-On or Lone therapy
(INTERVAL) Study
W. DAVID STRAIN, VALENTINA LUKASHEVICH, WOLFGANG KOTHNY, MARIEJOSE HOELLINGER, PÄIVI M. PALDÁNIUS, Exeter, United Kingdom, East Hanover,
NJ, Basel, Switzerland
1077-P
Lower Blood Pressure (BP) With Canagliflozin (CANA) in Subjects
With Type 2 Diabetes Mellitus (T2DM)
Management of type 2 diabetes mellitus (T2DM) in elderly patients is
challenging and complicated by multiple comorbidities, polypharmacy and
increased risk of hypoglycemia. Current guidelines suggest individualizing
treatment targets for these patients, despite no evidence-base for such an
approach. We evaluated the feasibility of such an approach in parallel with
conventional HbA1c reduction using vildagliptin vs. placebo.
We enrolled 278 drug-naïve or inadequately controlled (HbA1c ≥7.0% to
≤10.0%) T2DM patients aged ≥70 years in a multinational, double-blind, 24-week
study. Investigators set individualized treatment targets based on age, baseline
HbA1c, comorbidities and frailty status before 1:1 randomization to vildagliptin
(50 mg qd or bid as per label) or placebo. Vildagliptin had a higher likelihood
of achieving the individualized treatment targets (OR=3.16), accompanied by
clinically relevant reductions in overall HbA1c (Table). Vildagliptin was well
tolerated in this elderly cohort, with no new safety signals emerging.
INTERVAL is the first study to introduce investigator-defined individualized
HbA1c targets as an endpoint in any T2DM population. It demonstrates the
feasibility of evaluating individualized targets when exploring diabetes
management in the growing elderly population. It also confirmed that
individualized glycemic target levels are achievable using vildagliptin
without any tolerability issues.
MATTHEW R. WEIR, ANDRZEJ JANUSZEWICZ, RICHARD GILBERT, FERNANDO
LAVALLE GONZÁLEZ, GARY MEININGER, Baltimore, MD, Warsaw, Poland, Toronto,
ON, Canada, Monterrey, Mexico, Raritan, NJ
Hypertension is a common comorbidity of T2DM. The BP-lowering
response of CANA, an SGLT2 inhibitor, was evaluated using pooled data
from 6 randomized, double-blind, placebo (PBO)-controlled Phase 3 studies
in subjects with T2DM (N = 4,158, mean age, 59 y; A1C, 8%; BMI, 33 kg/
m2). Relative to PBO, CANA 100 and 300 mg provided modest reductions in
systolic BP (SBP; -3.3 and -4.5 mmHg) and diastolic BP (DBP; -1.5 and -1.9
mmHg) in the overall population (Table). In subjects with SBP ≥140 mmHg
(n = 1,267), reductions in SBP were seen with both CANA doses versus PBO
(P <0.001); the PBO-subtracted decrease was slightly larger with CANA 300
mg than was seen in the overall population, and similar with CANA 100 mg.
In subjects with DBP ≥90 mmHg (n = 355), a reduction in DBP was seen with
CANA 300 mg versus PBO (P = 0.028); the PBO-subtracted decrease was
modestly larger with CANA 300 mg than was seen in the overall population,
and smaller with CANA 100 mg. PBO-subtracted BP decreases with both
CANA doses were similar among subjects on antihypertensives and those
not on these agents. Changes in heart rate were -0.6, -0.4, and -0.1 beats/min
with CANA 100 and 300 mg and PBO, respectively. With CANA’s glucoretic
effect, a low incidence of osmotic diuresis adverse events was seen with
&
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Supported by: Novartis Pharma AG
1080-P
Canagliflozin (CANA) Added on to Dipeptidyl Peptidase-4 Inhibitors (DPP-4i) or Glucagon-Like Peptide-1 (GLP-1) Agonists With or
Without Other Antihyperglycemic Agents (AHAs) in Type 2 Diabetes
Mellitus (T2DM)
CAROL H. WYSHAM, VINCENT C. WOO, CHANTAL MATHIEU, MEHUL DESAI,
MARIA ALBA, GEORGE CAPUANO, GARY MEININGER, Spokane, WA, Winnipeg,
MB, Canada, Leuven, Belgium, Raritan, NJ
1082-P
Empagliflozin as Add-On to Metformin Plus Sulfonylurea (SU) for 24
Weeks Improves Glycemic Control in Patients With Type 2 Diabetes
(T2DM)
CANA is an SGLT2 inhibitor in development for the treatment of T2DM.
This post hoc analysis of data from the CANagliflozin cardioVascular
Assessment Study (CANVAS; subjects with T2DM and a history/high risk
of cardiovascular disease) evaluated CANA 100 and 300 mg compared with
placebo (PBO) in subsets of subjects who were on DPP-4i (N = 316; mean age,
63 y; A1C, 8.1%; BMI, 32.3 kg/m2) or GLP-1 agonists (N = 95; mean age, 61
y; A1C, 8.1%; BMI, 37.4 kg/m2) as monotherapy or in combination with other
AHAs. At Week 18, CANA 100 and 300 mg reduced A1C and body weight
relative to PBO in both subsets.
Overall adverse event (AE) rates were higher with CANA than with PBO
in the DPP-4i subset, and comparable or lower with CANA relative to PBO in
the GLP-1 agonist subset; serious AE rates were generally higher with CANA
than with PBO in both subsets. Documented hypoglycemia rates were higher
with CANA 100 and 300 mg than PBO in subjects on insulin, sulfonylurea,
or meglitinide in the DPP-4i subset (17/70, 29/87, and 12/74) and the GLP-1
agonist subset (11/29, 11/22, and 4/26); only 2 and 1 CANA-treated subjects
who were not on these concomitant agents reported hypoglycemia in the
DPP-4i and GLP-1 agonist subsets, respectively. In summary, CANA added
on to DPP-4i or GLP-1 agonists (+/- other AHAs) lowered A1C, reduced
body weight, and was generally well tolerated in subjects with T2DM at
18 weeks.
HANS-ULRICH HÄRING, LUDWIG MERKER, ELKE SEEWALDT-BECKER, MARC
WEIMER, THOMAS MEINICKE, HANS J. WOERLE, ULI C. BROEDL, Tübingen, Germany, Dormagen, Germany, Biberach, Germany, Ingelheim, Germany
A Phase III trial investigated the efficacy and safety of empagliflozin
(EMPA) in patients with T2DM on metformin plus SU. Patients (mean age
57.1 [SD 9.2] years; mean BMI 28.2 [SD 5.3] kg/m2) were randomized doubleblind and treated with EMPA 10 mg (n=225), 25 mg qd (n=216) or placebo
(PBO; n=225) for 24 weeks. The primary endpoint was change from baseline
in HbA1c at week 24. Key secondary endpoints were change from baseline in
weight and mean daily glucose (MDG) at week 24.
EMPA significantly reduced HbA1c, weight and MDG vs PBO. Further
analyses showed significant reductions in systolic blood pressure (SBP), FPG
and 2h PPG vs PBO. Weight loss >5% was achieved by 27.6% of patients
on EMPA 10 mg, 23.6% on EMPA 25 mg and 5.8% on PBO. Adverse events
(AEs) were reported by 67.9%, 64.1% and 62.7% of patients on EMPA 10
mg, 25 mg and PBO, respectively. Hypoglycemia (plasma glucose ≤70 mg/dL
and/or requiring assistance) was reported in 16.1% of patients on EMPA 10
mg, 11.5% on EMPA 25 mg and 8.4% on PBO; none required assistance. AEs
consistent with urinary tract infection were reported in 10.3% of patients on
EMPA 10 mg, 8.3% on EMPA 25 mg and 8.0% on PBO. AEs consistent with
genital infection were reported in 2.7% of patients on EMPA 10 mg, 2.3% on
EMPA 25 mg and 0.9% on PBO.
To conclude, EMPA 10 mg and 25 mg for 24 weeks as add-on to metformin
plus SU improved glycemic control, and reduced weight and SBP versus PBO,
and were well tolerated in patients with T2DM.
1081-P
A Novel Oral Peptide-Mimetic (UGP302) Enhance Insulin Action and
Improves Glucose Homeostasis in Type 2 Diabetic Rats
MICHAEL FEIGH, SARA T. HJULER, KIM V. ANDREASSEN, NOZER METHA, WILLIAM STERN, CLAUS CHRISTIANSEN, MORTEN A. KARSDAL, KIM HENRIKSEN,
Herlev, Denmark, Boonton, NJ
Controversy exists whether the peptide hormone salmon Calcitonin (sCT)
exerts a diabetogenic action. We demonstrated that oral administration of
sCT improved diabetic hyperglycemia in animal models of type 2 diabetes.
UGP302 is a novel oral dual-action amylin and calcitonin receptor agonist
with an enhanced pharmacological profile to native sCT. In here, we investiADA-Funded Research
&
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
For author disclosure information, see page 829.
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A279
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gate the anti-diabetic efficacy of oral UGP302 vs oral sCT in a proof of
concept study using Zucker diabetic fatty (ZDF) rats.
Male ZDF rats were treated with oral sCT or UGP302 (0.5, 1 or 2 mg/kg) or
oral vehicle twice daily for 7 weeks. Fasting and non-fasted plasma glucose
and HbA1c were determined to evaluate glucose homeostasis. Additionally,
OGTT and ITT were performed to investigate treatment effects on glucose
intolerance and insulin resistance.
Oral UGP302 attenuated diabetic hyperglycemia during the intervention
period. At study end, oral UGP302 at doses of 1 mg/kg and 2 mg/kg reduced
fasting and non-fasted plasma glucose by approx 8 mmol/l and HbA1c by
1.6% when compared to vehicle (p < 0.001). Furthermore, oral UGP302
improved glucose intolerance during OGTT by reducing incremental area
under the curve by approx 50% at doses of 1 mg/kg and 2 mg/kg (p < 0.001).
In contrast, only at highest dosing regimen (2 mg/kg) did oral sCT induce a
comparable glucoregulatory effect. Finally, oral UGP302, at doses of 1 mg/
kg and 2 mg/kg, exerts comparable insulin sensitizing effects and enhanced
plasma glucose disposal during ITT by approx 23% compared to vehicle (p <
0.001). In contrast, a comparable alleviation of insulin resistance for oral sCT
was only observed at 2 mg/kg dose.
Oral UGP302 is a superior dual-action amylin and calcitonin receptor
agonist to native salmon Calcitonin. Oral UGP302 attenuates diabetic
hyperglycemia in ZDF rats by improving fasting and postprandial glycemic
control and alleviating insulin resistance. These data indicate the clinical
usefulness of oral UGP302 as anti-diabetic treatment.
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1083-P
Favorable Gastrointestinal and Genitourinary Safety Profile of
LX4211 Added-On to Metformin in a Phase 2b Study
IKE OGBAA, GUI-LAN YE, PABLO LAPUERTA, BRIAN ZAMBROWICZ, PHILLIP
BANKS, KENNY FRAZIER, ARTHUR SANDS, The Woodlands, TX
LX4211 is a dual inhibitor of SGLT1 and SGLT2, the major glucose
transporters in the gastrointestinal (GI) tract and kidney. It has shown a
favorable GI and genitourinary (GU) safety profile in healthy subjects and
small studies of patients with type 2 diabetes. In a 12-week dose ranging
study, 299 patients with inadequately controlled T2DM on metformin were
randomly assigned to LX4211 (75 mg qd, 200 mg qd, 200 mg bid, or 400 mg
qd) or placebo (PBO). The GI and GU tolerability and overall safety of LX4211
were evaluated.
POSTERS
Clinical Diabetes/
Therapeutics
1085-P
Empagliflozin Monotherapy Improves Glucose Control in DrugNaïve Patients With Type 2 Diabetes (T2DM)
MICHAEL RODEN, JIANPING WENG, JENS EILBRACHT, BRUNO DELAFONT, GABRIEL KIM, HANS J. WOERLE, ULI C. BROEDL, Düsseldorf, Germany, Canton, China,
Biberach, Germany, Reims, France, Ingelheim, Germany
A Phase III trial investigated the efficacy and safety of empagliflozin
(EMPA) in drug-naïve patients with T2DM. Patients (mean age 55.0 years;
mean BMI 28.4 kg/m2) were randomized double-blind and treated with EMPA
10 or 25 mg qd (n=224 each), sitagliptin 100 mg qd (SITA; n=223), or placebo
(PBO; n=228) for 24 weeks. Patients with HbA1c >10% (n=87) received openlabel EMPA 25 mg qd for 24 weeks. Primary endpoint was change from
baseline in HbA1c at week 24. Key secondary endpoints were change from
baseline in weight, systolic blood pressure (SBP) and diastolic BP (DBP) at
week 24.
EMPA significantly reduced HbA1c, weight, and SBP versus PBO. DBP
changes were not significant versus PBO. Weight loss of >5% was achieved
by 22.8% of patients on EMPA 10 mg, 29.0% on EMPA 25 mg, 6.3% on SITA
and 4.4% on PBO. Proportion of randomized patients with adverse events
(AEs) was similar with PBO (61.1%), EMPA (54.9-60.5%), and SITA (53.4%).
Hypoglycemia (plasma glucose ≤70 mg/dL and/or requiring assistance)
was reported by 1 (0.4%) patient per randomized group; none required
assistance. AEs consistent with urinary tract infection were reported in 5.46.7% of randomized patients on EMPA, 5.2% on PBO and 4.9% on SITA. AEs
consistent with genital infection were reported in 3.1-4.0% of randomized
patients on EMPA, 0 on PBO and 0.9% on SITA.
To conclude, EMPA 10 mg and 25 mg for 24 weeks reduced HbA1c, weight,
and SBP versus PBO, and were well tolerated in drug-naïve patients with
T2DM.
In the safety population, the incidences of diarrhea and nausea were
comparable between all LX4211-treated patients and PBO. Diarrhea was
7.2 vs 6.7% and nausea was 6.8 vs 5.0% in all LX4211-treated patients vs
PBO, respectively. Diarrhea was not dose-dependent or related to initiation
of dosing. Nausea and diarrhea were generally mild and resolved without
treatment. Constipation and vomiting were less common with LX4211
vs PBO; constipation 3.4 vs 6.7%, and vomiting 0.4 vs 5.0%. Urinary tract
infections occurred evenly among treatment groups. Vaginal yeast or
bacterial infections were seen only with LX4211; they were mostly mild,
their incidence was low, and none led to therapy discontinuation. There
were no deaths, treatment related serious AEs, or episodes of hypoglycemia
reported. LX4211 combined with metformin was safe and well-tolerated in
this study. Studies of greater exposure duration are needed to characterize
long term safety of LX4211.
1084-P
Effects of Canagliflozin Added on to Basal Insulin +/- Other Antihyperglycemic Agents in Type 2 Diabetes
JULIO ROSENSTOCK, MELANIE DAVIES, RICHARD DUMAS, MEHUL DESAI, MARIA ALBA, GEORGE CAPUANO, GARY MEININGER, Dallas, TX, Leicester, United
Kingdom, Montreal, QC, Canada, Raritan, NJ
Canagliflozin (CANA) is an SGLT2 inhibitor in development for the
treatment of type 2 diabetes mellitus (T2DM). This exploratory analysis from
the CANagliflozin cardioVascular Assessment Study (CANVAS; in T2DM with
a history or high risk of cardiovascular disease) evaluated CANA 100 and
300 mg versus placebo (PBO) in a subset of subjects in the insulin substudy
on stable, non-titrated basal (but not prandial) insulin (≥30 IU/d basal insulin
at study entry) +/- other antihyperglycemic agents (N = 278; baseline mean
age, 63 y; A1C, 8.3%; fasting plasma glucose [FPG], 159 mg/dL; BMI, 34.4 kg/
m2; insulin dose, 59 IU/d). At Week 18, CANA 100 and 300 mg reduced A1C
relative to PBO (-0.86% and -0.89%); both CANA doses reduced FPG (by 2531 mg/dL) and body weight (by 1.8%-2.7%) versus PBO (Table). Post-baseline
daily insulin dose (prior to glycemic rescue) was unchanged for 93% of PBOtreated subjects versus 85% and 86% of subjects with CANA 100 and 300 mg
(mostly dose reductions with CANA). Overall AE, AE-related discontinuation,
and serious AE rates were higher with CANA than PBO. The proportion of
subjects with documented hypoglycemia (≤70 mg/dL or severe events) was
higher with CANA 100 and 300 mg than PBO (42%, 43%, 25%), with severe
hypoglycemia rates of 0%, 1%, and 2%, respectively. In summary, CANA
added on to basal insulin improved glycemic control, reduced body weight,
and was generally well tolerated, with some increase in hypoglycemia risk,
in subjects with T2DM at 18 weeks.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1086-P
Na Channel Blockers Exert Anti-Diabetic Effects via Lowering Glucagon Levels in ZDF Diabetic Rats
YUN NING, MICHAEL VAN PETTEN, JENNY JIANG, LUIZ BELARDINELLI, ARVINDER K. DHALLA, Fremont, CA
Ranolazine (RAN), an anti-anginal drug, is a Na channel blocker (NCB) that
also has shown anti-diabetic effects in clinical and non-clinical studies. RAN
appears to exert its anti-hyperglycemic effects via a novel glucagon-related
mechanism. We tested the hypothesis that blockade of Na channels in
&
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Glucago (pg/mL)
Baseline Week 10
Vehicle (n=7)
130 ± 14 313 ± 15
GS-458967(n=8) 100 ± 4 254 ± 17 *
RAN (n=8)
135 ± 10 243 ± 3 *
Sitagliptin (n=8) 106 ± 10 221 ± 7 *
FPG (mg/dL)
Baseline Week 10
105 ± 5 315 ± 18
106 ± 3 166 ± 33 **
103 ± 4 177 ± 25 **
108 ± 4 223 ± 26 **
HbA1c (%)
Baseline Week 10
1.7 ± 0.03 8.3 ± 0.2
1.7 ± 0.04 4.2 ± 0.5 **
1.7 ± 0.04 4.3 ± 0.4 **
1.7 ± 0.06 5.5 ± 0.8 **
1089-P
Glucagon-Like Peptide (GLP-1) Response to an Oral Glucose Tolerance Test in Impaired Glucose Tolerance: Does GLP-1 Play a Significant Role?
1087-P
MEHMET SARGIN, HATICE DEGISMEZ, SAKIN TEKIN, ASUMAN ORCUN, BUKET
TEKIN, NIHAL YUCEL, TULAY KARABAYRAKTAR, MEHMET ALIUSTAOGLU, Istanbul, Turkey
Dissociation Between Metformin Plasma Exposure and its GlucoseLowering Effect: A Novel Gut-Mediated Mechanism of Action
Glucagon-like peptide 1 (GLP-1) is an insulinotropic hormone that regulates
glucose levels by potentiating glucose- induced insulin secretion and
inhibiting glucagon release. There has been much speculation about the role
of GLP-1 in the pathogenesis of type 2 diabetes, especially the progression
from normal to impaired glucose tolerance. Our aim is to determine the
effect of fasting and postchallange concentrations of total GLP-1 on
postchallange glucose and insulin in impaired glucose tolerance (IGT). A total
of 64 subjects (female/male: 47/17) participated in the cross-sectional study.
Mean age was 46.8±7.2 years and body mass index (BMI) was 33.9±5.0 kg/
m2. Subjects were divided into two groups who had normal (n: 32) and IGT
(n: 32). The two groups were matched according to gender, BMI and body fat
percentage. We performed a 75 g oral glucose tolerance test (OGTT) with
insulin, glucagon, c-peptide and GLP-1 measurements. Postchallange GLP-1
levels positively correlated with glucose (r: 0.59, p<0.001) and insulin (r: 0.39,
p<0.005) concentrations, but this correlation was not significantly associated
with glucose tolerance status. Area under curve (AUC) and time to reach
maximum concentrations of total GLP-1 indicated no significant association
with glucose tolerance status. Peak GLP-1 and insulin concentrations were
achieved at 30. and 60. min in both groups, respectively.
GLP-1 secretion does not seem to contribute significantly to the pathogenesis of IGT because of the lack of association of GLP-1 concentrations
with glucose tolerance status. However, studies with large numbers
of subjects are necessary in order to determine the role of GLP-1 in the
pathogenesis of IGT.
RALPH A. DEFRONZO, JOHN B. BUSE, TERRI KIM, SHARON SKARE, ALAIN BARON, MARK FINEMAN, San Antonio, TX, Chapel Hill, NC, San Diego, CA
We designed a delayed release (DR) metformin (Met) tablet that targets
the lower bowel to reduce Met bioavailability and test whether Met plasma
exposure is required for its glucose-lowering effects. Met DR was compared
to commercially available immediate release (IR) Met in a randomized,
double-blind, crossover study. Subjects with type 2 diabetes (N=24, age
51 y, BMI 33 kg/m2) were withdrawn from oral diabetes therapy for 2 wks,
then received each treatment orally twice daily (BID) for 5 days, separated
by a 9—12 day washout: 1000mg IR, 1000mg DR, 500mg DR. Plasma Met,
glucose, insulin, GLP-1 and PYY were measured from 7am—5pm (7am
breakfast; 12pm lunch) at baseline (BL) and day 5. Compared to 1000mg
IR, Met exposure was reduced by 45 and 57% with 1000mg and 500mg
DR (N=19, both p<0.0001). The reduction in fasting plasma glucose from
BL (197—200 mg/dl) was similar for all treatments (LSmean±SE: 22.5±6.8
mg/dl, 1000mg IR; -19.9±5.0 mg/dl, 1000mg DR; 16.4±3.8 mg/dl, 500mg
DR; all p<0.01 vs. BL). The 10h glucose AUC was similarly reduced in all
treatments by 8—14% (all p<0.0001 vs. BL). Insulin AUC was unchanged
from BL. All treatments increased fasting and postprandial PYY and GLP-1
(all p<0.05 vs. BL). The GLP-1 AUC increased by 87, 62 and 69% and PYY
AUC increased by 55, 38, and 46% for 1000mg IR, 1000mg DR and 500mg
DR (all p<0.0001 vs. BL). Nausea (9%) and vomiting (9%) occurred with Met
IR but not Met DR. Diarrhea (10—15%) occurred in all treatments. Despite
substantial reductions in exposure, a Met DR formulation that targets the
lower bowel was as effective as Met IR with better tolerability. Met IR and
DR similarly increased plasma gut peptide levels. This evidence indicates
that the glucose-lowering effects of Met are in a large part due to Met
actions on gut enteroendocrine cells. By directly targeting the lower bowel,
Met DR may provide maximum efficacy with improved tolerability at lower
doses (≤1000mg total daily) than typically used with currently available
formulations.
1090-P
Linagliptin vs. Placebo Followed by Glimepiride in Type 2 Diabetes
Patients With Moderate to Severe Renal Impairment
MARKKU LAAKSO, JULIO ROSENSTOCK, PER-HENRIK GROOP, UWE HEHNKE,
ILKKA TAMMINEN, SANJAY PATEL, MAXIMILIAN VON EYNATTEN, HANS-JUERGEN WOERLE, Kuopio, Finland, Dallas, TX, Helsinki, Finland, Ingelheim, Germany,
Bracknell, United Kingdom
1088-P
Renal impairment (RI) is a serious T2DM complication that restricts options
for managing hyperglycemia and associated increased cardiovascular risk.
This randomized double blind trial evaluated the efficacy and tolerability of
the dipeptidyl peptidase 4 inhibitor linagliptin (LINA) in T2DM pts (HbA1c
7-10%) with moderate to severe RI (estimated glomerular filtration rate
[eGFR] <60 mL/min/1.73m2; not on dialysis). Pts received LINA 5 mg qd
(n=113) or placebo (PBO) (n=122) for 12 wks, then PBO pts were switched
to glimepiride 1-4 mg qd (GLIM) and treatment continued to wk 52. Primary
endpoint was HbA1c change from baseline at wk 12. At baseline, 63.4% were
male, mean age 67±9 y, HbA1c 8.1±0.9% and eGFR 37±13 mL/min/1.73 m2.
Most had T2DM for >10 y (76.4%) and were on insulin (85.8%). At wk 12,
adjusted mean±SE HbA1c change with LINA was -0.50±0.06% (change with
Features in Subjects With Increased Fasting Glucagon Concentration after Administration of a DPP-4 Inhibitor
TOMOKO MORITA, CHIOKO MORISAWA, NATSUKO OSHITANI, YOSHIMI ABE,
YOSHITAKA AKIYAMA, MASAKO YAZAWA, AKIFUMI KUSHIYAMA, SHOJI
KAWAZU, MASAFUMI MATSUDA, Kawagoe, Japan, Tokyo, Japan, Kawagoe-shi,
Japan
Abnormal regulation of glucagon secretion is a feature of type 2 diabetes
mellitus. Dipeptidyl peptidase 4 inhibitors (DPP4-Is) may ameliorate the
glucagon regulation. After administration of a DPP4-I, however, an increased
fasting glucagon conc. paradoxically has been observed in some patients.
To identify the features in those subjects, we conducted oral glucose
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tolerance tests (OGTTs) in 10 such subjects (GlunH) and compared with 10
subjects without increased fasting glucagon conc (C). Total 20 patients
(M/F:11/9, age=66±7 y.o., duration of diabetes=12±9 y., HbA1c=6.5±0.5%,
BMI = 25±4kg/m2) received OGTTs. 16 patients received sitagliptin, and four
received vildagliptin. Insulin secretion and insulin sensitivity indices obtained
from OGTT were compared with the fasting glucose, glucagon, insulin,
C-peptide, and proinsulin conc. Basal glucagon conc. before administration
of a DPP4-I was slightly lower in the GlunH group (72±17 vs 82±21pg/ml,
NS), while glucagon levels were significantly increased at least two weeks
after DPP4-I administration (by +16±9 vs -7±12 pg/ml). FPG was decreased
in both groups (104±20 to 102±17 vs 131±29 to 116±23 mg/dl in C). Fasting
insulin conc. was significant lower in the GlunH group (3.1±2.2 vs 4.7±2.5
microU/ml in C, p<0.05) before DPP4-I and slightly increased by 1.8±2.0 vs
-0.1±1.0 microU/ml in C, p=NS. Matsuda index was significantly higher in the
GlunH group (15.6±6.8 vs 7.7±2.9 in C, p<0.01), while insulinogenic index and
HOMA-IR were not statistically different between the two groups (0.11±0.13
vs 0.10±0.09, and 0.9±.0.8 vs 1.6±0.6, respectively). Increment of glucagon
conc. 30 min after an oral glucose intake was similar (4.0±13.0 vs 4.4 ±25.0
pg/ml in C, p=NS). In conclusion, paradoxical increase of fasting plasma
glucagon conc. after DPP4-I administration coincides with increased whole
body insulin sensitivity, suggesting the counteracting mechanism to avoid
hypoglycemia by GLP-1 activation even during fasting state.
α-cells leads to glucagon suppression resulting in a glucose lowering effect.
We determined the effects of another Na channel blocker, GS-458967
along with RAN and sitagliptin (positive control) in ZDF rats on glucagon,
fasting plasma glucose (FPG), HbA1c levels and pancreatic morphology.
Male ZDF rats (6 weeks old) were treated for 10 weeks with GS-458967
(0.6 mg/kg/d), RAN (150-180 mg/kg/d), or sitagliptin (30 mg/kg/d) added
to chow. Vehicle-treated rats had hyperglucagonemia and hyperglycemia
at week 10 (table). Chronic treatment with NCBs (GS-458967 and RAN)
led to significant lowering in glucagon levels, which was associated with
significant decreases in FPG and HbA1c. The anti-diabetic effect of NCBs
was comparable to those of sitagliptin. Morphology data showed that
pancreatic islets from vehicle-treated animals had less insulin-positive cells
and more glucagon-positive cells. In contrast, all three compounds reversed
the abnormal insulin:glucagon ratio by decreasing glucagon-positive and
increasing insulin-positive cells. In conclusion, the anti-hyperglycemic effect
of RAN is due to glucagon suppression mediated by blockade of Na channels
in α-cells.
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1092-P
Empagliflozin as Add-On to Metformin for 24 Weeks Improves Glycemic Control in Patients With Type 2 Diabetes (T2DM)
HANS-ULRICH HÄRING, LUDWIG MERKER, ELKE SEEWALDT-BECKER, MARC
WEIMER, THOMAS MEINICKE, ULI C. BROEDL, HANS J. WOERLE, Tübingen, Germany, Dormagen, Germany, Biberach, Germany, Ingelheim, Germany
A Phase III trial investigated the efficacy and safety of empagliflozin
(EMPA) in patients with T2DM on background metformin. Patients (mean
age 55.7 [SD 9.9] years; mean BMI 29.2 [SD 5.5] kg/m2) were randomized
double-blind and treated with EMPA 10 mg (n=217) or 25 mg qd (n=213) or
placebo (PBO; n=207) for 24 weeks. The primary endpoint was change from
baseline in HbA1c at week 24. Key secondary endpoints were change from
baseline in weight and mean daily glucose (MDG) at week 24.
EMPA significantly reduced HbA1c, weight and MDG vs PBO (table). Further
analyses showed significant reductions in systolic blood pressure (SBP), FPG
and 2h PPG vs PBO. Weight loss of >5% was achieved by 21.2% of patients
on EMPA 10 mg, 23.0% on EMPA 25 mg and 4.8% on PBO. Adverse events
(AEs) were reported by 57.1%, 49.5% and 58.7% of patients on EMPA 10
mg, 25 mg and PBO, respectively. Hypoglycemia (plasma glucose ≤70 mg/dL
and/or requiring assistance) was reported in 1.8% of patients on EMPA 10
mg, 1.4% on EMPA 25 mg and 0.5% on PBO; none required assistance. AEs
consistent with urinary tract infection were reported in 5.1% of patients on
EMPA 10 mg, 5.6% on EMPA 25 mg and 4.9% on PBO. AEs consistent with
genital infection were reported in 3.7% of patients on EMPA 10 mg, 4.7% on
EMPA 25 mg and none on PBO.
To conclude, EMPA 10 mg and 25 mg for 24 weeks as add-on to metformin
improved glycemic control, and reduced weight and SBP versus PBO, and
were well tolerated in patients with T2DM.
POSTERS
Clinical Diabetes/
Therapeutics
PBO -0.08±0.07%: difference -0.42%, 95% CI -0.60 to -0.24; p<0.0001). In the
40 wk extension, HbA1c was lower with LINA than GLIM (Figure). Incidence
of drug-related adverse events was similar in the first 12 wks (LINA 23.9%,
PBO 24.6%), and lower with LINA in the extension (LINA 38.3%, GLIM
46.5%). Hypoglycemia was less frequent with LINA (LINA 57.9%, GLIM
69.3%). Mean adjusted weight increase after 52 wks was 0.06 kg (LINA) and
1.74 kg (PBO/GLIM). In conclusion, LINA was efficacious and well tolerated in
T2DM pts with moderate to severe RI, with less hypoglycemia and relative
weight loss vs GLIM. NCT01087502.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1091-P
The Effect of Combination Linagliptin and Voglibose on Glucose
Control and Body Weight
KATIE HEADLAND, STEVEN VICKERS, SHARON CHEETHAM, ROBERT JONES, MICHAEL MARK, THOMAS KLEIN, Nottingham, United Kingdom, Biberach, Germany
We investigated whether combination therapy with the dipeptidyl
peptidase-4 inhibitor linagliptin and the α-glucosidase inhibitor (AGI)
voglibose can improve glycemic and body weight control. Male ZDF-Leprfa/
Crl (diabetic fa/fa) rats fed standard chow were allocated (n=10/group) based
on body weight and fasting plasma glucose (FPG). Rats were dosed (po) daily
for 4 days in 2 studies - S1: vehicle, linagliptin (1 mg/kg), high-dose voglibose
(10 mg/kg), or linagliptin + voglibose; S2: as S1 except low-dose voglibose
(1 mg/kg). An oral sucrose tolerance test (4 g/kg po) was performed on Day
4 and body weight was recorded daily. Mean vehicle FPG levels on Day 4
were 7.39 and 8.18 mM in S1 and S2, respectively, and mean insulin levels
were 2.01 and 3.76 ng/mL. Improved glucose control AUC (0-30 min) was
observed with linagliptin (S1: -10%, S2: -17%; both p<0.05), voglibose (S1:
-33%, p<0.001; S2: -18%, p<0.01), linagliptin + voglibose (S1: -33%, S2: -33%;
both p<0.001) compared with vehicle. Improvements in glucose control were
potentiated with linagliptin + low-dose voglibose compared with either drug
alone (p<0.01). Plasma active GLP-1 was increased 5 min after the sucrose
load with linagliptin (S1: 160%, p<0.01; S2: 144%, p<0.001) and linagliptin +
voglibose (S1: 834%, S2: 639%; both p<0.001) compared with vehicle, and
was larger than linagliptin or voglibose alone (p<0.001 for all). Compared
with vehicle, linagliptin-induced improvements in glucose control were
body-weight independent (S1: +0.7%, S2: -0.2%; both p=ns). In contrast,
voglibose (S1: -3.0%; S2: -1.7%) and linagliptin + voglibose (S1: -3.4%; S2:
-2.0%) reduced overall weight compared with vehicle (p<0.001 for all).
Therapy with linagliptin + voglibose potentiates improvements in glucose
control. This combination may minimize the side effects of AGIs because
lower doses of voglibose may be required to maintain glycemic control. In
addition, beneficial effects due to the supra-additive increase in active GLP1 levels may be evident.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
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1093-P
1095-P
Linagliptin Improved Glycemic Control Without Weight Gain or
Hypoglycemia in Patients With Type 2 Diabetes Inadequately Controlled by a Combination of Metformin and Pioglitazone
Metformin Use in Octogenarians
With the increasing life expectancy more and more subjects with Type
2 diabetes are aged over 80. According to DECODE study, over 40% of
octogenarians suffer from diabetes. There are no specific guidelines for
the treatment of this group of elderly patients, and metformin use in this
population is controversial. We have assessed cross-sectionally modes
of type 2 diabetes therapy used in randomly selected subjects aged 8090 (n=158) and retrospectively analyzed 3-year safety of thereof. The
comparative group comprised Type 2 diabetes subjects aged 60-70 years
(n=112). The treatment modes and cardiovascular risk factors distribution is
presented in the Table 1 (mean±SD or %). Symptomatic hypoglycemia was
recorded in 21% of octogenarians and 45% of the controls (p<0.01) in the
3-year period preceding the cross-sectional analysis. No case of ketoacidosis
or lactic acidosis was noted in the studied subjects. In conclusion, almost
two thirds of octogenarians are treated safely with metformin. Moreover,
glucose control and cardiovascular risk profile is more favorable in the
octogenarians than in younger subjects, suggesting the effective use of
available therapies. Therefore, very elderly subjects with Type 2 diabetes,
despite differing at many instances from younger patients, can be effectively
and safely treated with traditional therapies, including metformin.
This multicenter, Phase IIIb, randomized, double-blind, placebo (PBO)controlled study examined the efficacy and safety of the DPP-4 inhibitor
linagliptin (LINA) in type 2 diabetes patients inadequately controlled by
a combination of metformin (MET) and pioglitazone (PIOG). All patients
entered a 2-wk PBO run-in period before being randomized to receive either
LINA 5 mg qd (n = 183) or PBO (n = 89) in addition to MET and PIOG for 24 wks.
The primary endpoint was the change from baseline in HbA1c after 24 wks
of treatment. Baseline demographics were similar between LINA and PBO
groups. The majority of patients were Asian (68.8%), 51.5% were female, the
mean ± SD age was 53.8 ± 9.3 years and mean BMI was 28.2 ± 5.3 kg/m2.
The mean ± SD baseline HbA1c was 8.39 ± 0.84% in the LINA group and 8.47
± 0.78% in the PBO group. After 24 wks of treatment with LINA, the PBOadjusted mean ± SE change from baseline in HbA1c was -0.58 ± 0.13% (p <
0.0001), which was largely driven by the Asian population (-0.90 ± 0.16%).
In patients with baseline HbA1c ≥7.0%, 32.4% of patients in the LINA group
and 13.8% in the PBO group achieved HbA1c <7.0% (odds ratio [OR] 2.94; p
= 0.0033). Patients in the LINA group were more likely to achieve an HbA1c
reduction of ≥0.5% (65.4% LINA, 49.4% PBO, OR 2.06; p = 0.0071). The PBOadjusted mean ± SE change from baseline in FPG at wk 24 was -10.4 ± 4.7
mg/dL (p = 0.0280). The % of patients who reported ≥1 adverse event (AE)
was 62.3% with LINA and 48.3% with PBO. The % of serious AEs was 2.2%
with LINA and 3.4% with PBO. Investigator-defined hypoglycemia occurred in
5.5% of the LINA group and 5.6% of the PBO group. No meaningful changes
in mean body weight were noted for either group. In summary, LINA as addon therapy to MET and PIOG produced significant and clinically meaningful
improvements in glycemic control, largely attributed to the results in the
Asian population. There was no additional risk of hypoglycemia and no
weight gain. NCT00996658
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1094-P
Pioglitazone Improves Indices of Skeletal Muscle Insulin Sensitivity Without Change in Energy Balance or Mitochondrial Metabolism
in Patients With Type 2 Diabetes
KEVIN E. CONLEY, SUDIP BAJPEYI, LAUREN M. SPARKS, STEVEN R. SMITH, Seattle, WA, Baton Rouge, LA, Orlando, FL
Thiazolidinediones (TZDs) are oral anti·diabetic drugs that improve
metabolic control in patients with type 2 diabetes (T2D) through the
improvement of insulin sensitivity, energy balance and mitochondrial
function.
Here we evaluated the impact of pioglitazone in T2D patients on skeletal
muscle indices of insulin sensitivity and metabolism after 8 weeks of
either drug (n= 14) vs. placebo (n=8) treated T2D patients with low insulin
sensitivity (GDR < 5). Paired non-invasive phosphorus magnetic resonance
(31P MRS) and optical spectroscopic measurements were made on vastus
lateralis muscle. Pioglitazone treatment resulted in significant improvements
in cell indices of insulin sensitivity (lowering phosphodiesters, PDE, by 15
.7%, P<0.009) and glucose balance (lower cell pH, P<0.002). In contrast,
stable cell and mitochondrial metabolism was evident from unchanged
values in an index of cell energy balance (PCr/Pi), ATP and O2 fluxes, as
well as mitochondrial ATP synthesis capacity. The finding of reduced PDE is
consistent with the effect of TZDs on lipoprotein lipase, while lower cell pH
indicates improved carbohydrate metabolism leading to greater cell lactic
acid accumulation. Thus non-invasive tools applied in vivo indicate that
pioglitazone treatment in T2D patients improves muscle insulin sensitivity
and carbohydrate metabolism without impact on cell energy balance or
mitochondrial metabolism.
Supported by: Medical University of Lodz
1096-P
A Promising Combination for Future Treatment of Type 2 Diabetes:
Coadministration of Empagliflozin (SGLT-2 Inhibitor) With Linagliptin (DPP-4 Inhibitor)
MATTHIAS KERN, NORA KLÖTING, ROLF GREMPLER, ERIC MAYOUX, MICHAEL
MARK, THOMAS KLEIN, MATTHIAS BLÜHER, Leipzig, Germany, Biberach, Germany
Combining different drug classes to improve glycemic control is one
treatment strategy for type 2 diabetes. Here we investigated the effects
of long-term treatment with empagliflozin (EMPA), a sodium glucose
cotransporter-2 (SGLT-2) inhibitor in clinical development, alone and
in combination with the DPP-4 inhibitor linagliptin (LINA; an approved
antidiabetes drug) on whole body and organ-specific insulin sensitivity
in db/db mice using euglycemic-hyperinsulinemic clamps. In 8-week old
female db/db mice (n=15/group) treated for 8 weeks, the glucose disposal
rate was improved in the 10 mg/kg/d EMPA group (5.9 mg/kg/min; p<0.001),
the 3 mg/kg/d LINA group (3.4 mg/kg/min; p<0.01) and the EMPA+LINA
group (combination 10 mg/kg/d EMPA plus 3 mg/kg/d LINA: 7.8 mg/kg/
min; p<0.001) compared with vehicle (1.9 mg/kg/min). Insulin-mediated
suppression of hepatic glucose production (HGP) was significantly (p<0.05)
higher in the EMPA (13.1 mg/kg/min) and EMPA+LINA groups (11.8 mg/kg/
min) compared with vehicle (26.3 mg/kg/min). LINA monotherapy decreased
HGP (21.8 mg/kg/min), although statistical significance was not achieved.
Tissue-specific labeled glucose uptake was higher in liver and kidney with
EMPA (liver: 822 dpm/g/mL; kidney: 1580 dpm/g/mL; p<0.05 for both),
LINA (liver: 935 dpm/g/mL; kidney: 1660 dpm/g/mL; p<0.05 for both) and
Supported by: NIH
ADA-Funded Research
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POSTERS
MANDEEP BAJAJ, RONALD GILMAN, SANJAY PATEL, JOAN KEMPTHORNERAWSON, HANS-JUERGEN WOERLE, Houston, TX, East Providence, RI, Bracknell,
United Kingdom, Ridgefield, NJ, Ingelheim, Germany
Clinical Diabetes/
Therapeutics
LESZEK CZUPRYNIAK, NATALIA SZYLLO, ELEKTRA SZYMANSKA-GARBACZ,
MACIEJ PAWLOWSKI, MALGORZATA SARYUSZ-WOLSKA, JERZY LOBA, Lodz,
Poland
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
EMPA+LINA (liver: 1040 dpm/g/mL; kidney: 2190 dpm/g/mL; p<0.01 for
both) compared with vehicle (liver: 610 dpm/g/mL; kidney: 1030 dpm/g/mL).
Glucose uptake into muscle and adipose tissue was not affected by any
treatment. Improvements in liver triglyceride content were also shown with
EMPA (9.1%; p<0.05), LINA (12.1%; p<0.01) and EMPA+LINA (5.7%; p<0.01)
compared with vehicle (14.6%). In conclusion, EMPA+LINA is superior to
the respective monotherapies in improving insulin sensitivity, in particular,
during conditions of severe insulin resistance.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1097-P
Single-/Multiple-Dose Pharmacokinetics (PK) and Pharmacodynamics (PD) of Omarigliptin, a Once-Weekly Dipeptidyl Peptidase-4
(DPP-4) Inhibitor, in Healthy Subjects
POSTERS
Clinical Diabetes/
Therapeutics
RAJESH KRISHNA, CAROL ADDY, DANIEL TATOSIAN, XIAOLI S. HOU, ISAIAS N.
GENDRANO, ASHLEY N. MARTUCCI, JOHN A. WAGNER, S. AUBREY STOCH,
Whitehouse Station, NJ
1099-P
Omarigliptin is an oral, once-weekly, DPP-4 inhibitor being developed
for the treatment of type 2 diabetes mellitus. Two studies were conducted
to evaluate safety, tolerability, PK and PD following single-/multipledose administration in healthy subjects. Two double-blind, randomized,
placebo-controlled, multiple-panel, rising-dose studies were conducted.
Male subjects received single doses (0.5-400 mg; n=6/panel), multiple
doses (10, 25, 50, and 100 mg; n=6/panel) once weekly for three weeks,
or matching placebo (n=2/panel) in the fasted state. Plasma was obtained
to evaluate concentrations of omarigliptin, DPP-4 activity and active
glucagon-like peptide (GLP)-1. Omarigliptin was generally well tolerated.
There were no hypoglycemic events and no significant changes in safety
parameters. Absorption was rapid with median Tmax of 1-3 hours and steady
state plasma concentrations were achieved after ~2-3 weeks. Weekly AUC
and Cmax displayed dose proportionality within the dose range studied at
steady state. At steady state, ~71% of the 10-mg dose was excreted in
urine, with an average renal clearance of ~2 L/hr. The point estimates of
treatment difference (active vs. placebo) in DPP-4 inhibition ranged from
77%-89% at 168 hrs following the last of 3 once-weekly doses over the dose
range studied. Omarigliptin administration resulted in ~2-fold increases in
weighted average post-prandial active GLP-1. Administration of omarigliptin
was generally well tolerated in healthy subjects, and the PK profile supports
once-weekly dosing. Omarigliptin acts by stabilizing active GLP-1, which is
consistent with its mechanism of action as a DPP-4 inhibitor.
Efficacy and Safety of Lobeglitazone Monotherapy in Patients With
Type 2 Diabetes Mellitus over 24 Weeks: Multicenter, Randomized,
Double-Blind, Parallel-Group, Placebo Controlled Study
SIN GON KIM, DOO MAN KIM, JEONG-TAEK WOO, HAK CHUL JANG, CHOON
HEE CHUNG, KYUNG SOO KO, JEONG HYUN PARK, YONG SOO PARK, SANG JIN
KIM, DONG SEOP CHOI, Seoul, Republic of Korea, Bundang, Republic of Korea,
Wonju, Republic of Korea, Pusan, Republic of Korea, Guri, Republic of Korea, Cheonan, Republic of Korea
Lobeglitazone is a novel PPAR- γ agonist with a thiazolidinedione structural
motif. The aim of this study was to assess the glucose-lowering and lipidmodifying effects as well as the safety profile of lobeglitazone compared to
placebo as a monotherapy in patients with type 2 diabetes.
In this 24 week, multicenter, randomized, double-blind, parallel-group,
placebo control, therapeutic confirmatory study, 173 patients were randomly
assigned (a 2:1 ratio) to 0.5mg lobeglitazone (n= 115) or matching placebo
(n= 58) orally once daily. The primary endpoint was the change in HbA1c
from baseline to the end of treatment. The secondary endpoints included
various glycemic parameters, lipid parameters and safety profile. This study
is registered with ClinicalTrials.gov number NCT01001611.
At 24 weeks, a significant reduction in HbA1c was observed with lobeglitazone versus placebo (-0.44% vs 0.16%, mean difference -0.6%,
p<0.0001). The goal of HbA1c <7% was achieved significantly more in the
lobeglitazone group compared to the placebo group (44% vs 12%, p<0.0001).
Fasting plasma glucose (p <0.0001), homeostasis model assessment (HOMA)
insulin resistance index (p=0.002) and quantitative insulin sensitivity check
index (QUICKI, P<0.0001) were also improved in the lobeglitazone group. In
addition, lobeglitazone treatment significantly improved triglycerides, HDL
cholesterol, small dense LDL cholesterol, free fatty acid, Apo-B and Apo-CIII
compared to placebo (p<0.01, respectively). More weight gain was observed
in the lobeglitazone group than in the placebo group (0.89kg vs - 0.63kg,
mean difference 1.52kg, p<0.0001). The safety profile was comparable
between the two groups and lobeglitazone was also well tolerated.
Lobeglitazone 0.5 mg showed a favorable balance in the efficacy and
safety profile. The results support a potential role of lobeglitazone in treating
type 2 diabetes.
Supported by: Merck, Sharp & Dohme
1098-P
Efficacy and Safety of Canagliflozin (CANA) in Subjects With Type
2 Diabetes Mellitus (T2DM) on Metformin (MET) and Pioglitazone
(PIO) Over 52 Weeks
THOMAS FORST, ROBERT GUTHRIE, RONALD GOLDENBERG, JACQUELINE YEE,
UJJWALA VIJAPURKAR, GARY MEININGER, PETER STEIN, Mainz, Germany, Columbus, OH, Thornhill, ON, Canada, Raritan, NJ
CANA is an SGLT2 inhibitor in development for the treatment of T2DM.
This randomized, double-blind study enrolled subjects with T2DM on MET
and PIO (N = 342) and included a 26-week core period (CANA 100 and 300
mg vs placebo [PBO]) and a 26-week extension period (n = 275; mean age,
56.9 y; A1C, 7.9%; fasting plasma glucose [FPG], 162.2 mg/dL; BMI, 32.5 kg/
m2; PBO group switched to sitagliptin 100 mg [PBO/SITA]). Efficacy data at
52 weeks are reported for CANA 100 and 300 mg (SITA used to maintain
double-blind and as a control group, not as efficacy comparator); safety data
are shown for both CANA doses and PBO/SITA. At Week 52, CANA 100 and
300 mg lowered A1C and FPG from baseline with a substantial proportion of
subjects reaching A1C <7.0%; reductions in body weight and systolic BP, and
increases in HDL-C, LDL-C, and triglycerides were also seen.
Overall AE rates were lower with CANA 100 mg than CANA 300
mg and PBO/SITA (70%, 76%, 77%). Rates of serious AEs, AE-related
discontinuations, UTIs, and hypoglycemia were similar across groups.
Higher rates of AEs related to osmotic diuresis (ie, thirst, pollakiuria; <7%
per AE), reduced intravascular volume (ie, postural dizziness, orthostatic
hypotension; <2% per AE), and genital mycotic infections were seen in the
pooled CANA group versus PBO/SITA. In summary, CANA improved glycemic
control, reduced body weight, and was generally well tolerated in subjects
with T2DM on MET and PIO over 52 weeks.
Supported by: Chong Kun Dang Pharmaceutical Corporation
1100-P
Small-Molecule Inducers of the Beta-Cell Master Gene Pax4 in
Pancreatic Alpha Cells
KAIHUI HU HE, JAMES SPOONAMORE, BRIDGET K. WAGNER, Cambridge, MA
Type 1 diabetes is a severe metabolic disease caused by selective
destruction of pancreatic insulin-producing beta cells. Small molecules that
restore beta-cell mass or function may enable insulin independence, and
improve the quality of life of type 1 diabetes patients. Recently, efforts to
replenish beta-cell mass have focused on reprogramming other pancreatic
cell types into beta cells. Previous in vivo studies in mice have shown that the
misexpression of just one transcription factor, Pax4, in alpha cells converted
them into beta cells, both during embryogenesis and adulthood. To answer
the questions of whether small-molecule induction of Pax4 causes a similar
alpha-to-beta conversion in mouse islets, and whether this result translates
to human islets, we developed a qPCR-based assay for high-throughput
screening to identify small molecules capable of increasing Pax4 expression
in the mouse alpha-TC1 cell line.
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
Key secondary endpoints were changes from baseline in insulin dose and
HbA1c at week 78.
EMPA significantly reduced HbA1c at week 18 and 78, and insulin dose at
week 78, vs PBO (Table). Further analyses showed reductions in FPG, body
weight, and systolic BP (Table). Hypoglycemia (glucose ≤70 mg/dL and/or
requiring assistance) was reported similarly in 36.1% of patients on EMPA
10 mg and 25 mg and 35.3% on PBO; 2 patients on EMPA 25 mg required
assistance. AEs consistent with urinary tract infection were reported in
14.8%, 11.6% and 8.8% on EMPA 10 mg, EMPA 25 mg and PBO, respectively.
AEs consistent with genital infection were reported in 7.7%, 5.2% and 1.8%
on EMPA 10 mg, EMPA 25 mg and PBO, respectively.
In conclusion, EMPA 10 mg and 25 mg for 78 weeks as add-on to basal
insulin improved glycemic control, led to reductions in body weight without
increase in hypoglycemia risk, and were well tolerated except for increased
genitourinary infections.
Hydrolysis probe-based detection of Pax4 mRNA resulted in a robust assay,
with a Z’-factor of 0.7. We screened nearly 100,000 compounds derived from
diversity-oriented synthesis (DOS) at the Broad Institute, treating cells for 3
days before cell lysis and qPCR detection. We reasoned that the structural
diversity of DOS libraries, representing multiple chemical scaffolds, may
increase the likelihood of targeting “undruggable” transcription factors,
such as Pax4. Eighty compounds (hit rate 0.1%) showed significant increase
in signal by qPCR, and retesting in cell lines and primary islets is underway.
Small molecules identified in this screen may serve as tools to demonstrate
alpha-to-beta transdifferentiation in human cells for the first time, and could
provide a way to restore functional beta-cell mass in type 1 diabetes.
Supported by: JDRF
1101-P
Real-Life Effectiveness of Vildagliptin Compared to Sulfonylureas
in Type 2 Diabetes Patients in Germany
Clinical Diabetes/
Therapeutics
Metformin is an established treatment for type 2 diabetes mellitus
(T2DM) patients but therapy intensification is usually required over time.
The EDGE-study compared effectiveness and safety of vildagliptin and
other oral antidiabetic drugs in 45868 patients with T2DM not controlled by
monotherapy under real life conditions. Add-on treatment was chosen by the
physician based on patient’s need. Effectiveness was assessed by HbA1c
drop and by a composite endpoint (HbA1c <7.0% without hypoglycemia and
weight gain) after 12 months of treatment. Here, results for 8887 patients in
Germany receiving vildagliptin or sulfonylurea (SU) add-on to metformin are
presented. 7410 patients (age: 62.6±11.1 yr; baseline HbA1c: 7.8±1.6; BMI:
30.8±5.5 kg/m²) received study medication (metformin+ vildagliptin (4960) or
metformin+SU (819)). HbA1c decreased significantly greater with vildagliptin
compared to SU (vildagliptin:-0.69%; SU:-0.46%; Δ-0.23%; p<0.001) and a
higher proportion of vildagliptin patients reached the composite endpoint
(vildagliptin:25.5%; SU:17.7%; p< 0.001). The incidence of hypoglycemic
events was 4-fold higher in the SU cohort when compared to the vildagliptin
cohort. The data suggest, that in real life clinical practice vildagliptin is
associated with a greater HbA1c-drop, less hypoglycemic events and a
higher proportion of patients reaching target HbA1c without hypoglycemia
and weight gain compared to SU.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1103-P
Tofogliflozin Improves Insulin Resistance as well as Glucose Tolerance by Ameliorating Fatty Liver and Obesity
ATSUSHI OBATA, NAOTO KUBOTA, TETSUYA KUBOTA, HIROYUKI SATO, YOSHITAKA SAKURAI, MASANORI FUKAZAWA, MASAYUKI SUZUKI, KIYOFUMI HONDA, YOSHIYUKI SUZUKI, SACHIYA IKEDA, KOHJIRO UEKI, TAKASHI KADOWAKI,
Tokyo, Japan, Bunkyo-ku, Japan, Gotemba, Japan
SGLT2 is mainly present in S1 segment of renal proximal tubule and
accounts for approximately 90% of total urinary glucose reabsorption. To
elucidate the anti-diabetic effects of SGLT2 inhibitors, we conducted long
term administration of Tofogliflozin (Tofo), a novel SGLT2 inhibitor, to diet
induced obese model mice. C57BL/6J mice were fed a high fat diet or a
high fat diet which contains Tofo for 8 weeks. Although food intake was
increased, body weight and fat mass were significantly decreased in Tofo
treated mice.
Blood glucose levels were significantly lower in Tofo treated mice with
reduction of serum insulin levels. OGTT conducted after drug washout
revealed improved glucose tolerance in Tofo treated mice with significantly
lower insulin levels. HOMA-R was also significantly improved in Tofo treated
mice. In addition, Tofo treated mice demonstrated elevated serum free fatty
acid levels and diminished adipocyte size, which indicated accelerated
lipolysis in Tofo treated mice. Reduced respiratory quotient and elevated
serum ketone body suggested acceleration of β-oxidation in Tofo treated
mice. In fact, CPT1α expression levels were significantly increased in the
1102-P
Empagliflozin as Add-On to Basal Insulin for 78 Weeks Improves
Glycemic Control With Weight Loss in Insulin-Treated Type 2 Diabetes (T2DM)
JULIO ROSENSTOCK, ANTE JELASKA, FEI WANG, GABRIEL KIM, ULI C. BROEDL,
HANS J. WOERLE, Dallas, TX, Ridgefield, CT, Ingelheim, Germany
Empagliflozin (EMPA) is a selective SGLT2 inhibitor in development for the
treatment of T2DM. We assessed the efficacy and safety of EMPA added-on
to basal insulin in T2DM patients (mean age 58.8 yrs; HbA1c 8.2%; BMI 32.2
kg/m2) randomized to double-blind EMPA 10 mg (n=169) or 25 mg qd (n=155)
or placebo (PBO; n=170) for 78 weeks. Basal insulin dose remained constant
for the first 18 weeks, then adjustments were allowed at investigator
discretion. Primary endpoint was change from baseline in HbA1c at week 18.
ADA-Funded Research
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MARKUS DWORAK, JEAN-BERNARD GRUENBERGER, GIOVANNI BADER, Nuernberg, Germany, Basel, Switzerland
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
liver of these mice. Decreased gene expressions of SCD-1, FAS, DGAT-1 and
DGAT-2 were consistent with reduced liver triglyceride contents. As food
intake of Tofo treated mice was increased, we also conducted a pair feeding
experiment by adjusting the total amount of daily food intake to exclude
the influence of overdosing. The pair feeding experiment revealed more
significant results compared to the ad libitum experiment.
Moreover, the expression levels of TNFα, MCP-1 and IL-6 in white adipose
tissue were decreased in Tofo treated mice. In conclusion, Tofo may shift
the energy consumption from glucose to lipid by increasing urinary glucose
excretion and improve insulin resistance by reducing fat mass and liver triglyceride contents and ameliorating inflammation in white adipose tissue.
1104-P
Empagliflozin in Patients With Type 2 Diabetes Mellitus (T2DM) and
Renal Impairment (RI)
POSTERS
Clinical Diabetes/
Therapeutics
ANTHONY H. BARNETT, AMBRISH MITHAL, JENNY MANASSIE, RUSSELL
JONES, HENNING RATTUNDE, HANS J. WOERLE, ULI C. BROEDL, Birmingham,
United Kingdom, Delhi, India, Berkshire, United Kingdom, Ingelheim, Germany
A Phase III trial investigated the efficacy and safety of empagliflozin
(EMPA) as add-on to existing therapy for 52 weeks in patients with T2DM
and RI. Patients with mild RI (eGFR [MDRD equation] ≥60 to <90 mL/min/1.73
m2; n=290; mean age 62.6 years; mean BMI 31.5 kg/m2) received EMPA 10 or
25 mg qd or placebo (PBO). Patients with moderate RI (eGFR ≥30 to <60 mL/
min/1.73 m2; n=374; mean age 64.9 years; mean BMI 30.2 kg/m2) received
EMPA 25 mg qd or PBO. The primary endpoint was change from baseline in
HbA1c at week 24. Exploratory endpoints included changes from baseline in
fasting plasma glucose (FPG), weight and blood pressure (BP) at week 24.
EMPA significantly reduced HbA1c vs PBO at week 24. Further analyses
showed significant reductions in FPG, weight and BP. At week 24, adverse
events (AEs) were reported by 79.6%, 75.4% and 72.7% of all patients
(including an exploratory group with severe RI [n=74] on EMPA 25 mg or
PBO) on EMPA 10 mg, 25 mg and PBO, respectively. Hypoglycemia (plasma
glucose ≤70 mg/dL and/ or requiring assistance) was reported in 23.5% of
patients on EMPA 10 mg, 22.1% on EMPA 25 mg and 22.9% on PBO. AEs
consistent with urinary tract infection were reported in 10.2% of patients on
EMPA 10 mg, 9.0% on EMPA 25 mg and 8.2% on PBO. AEs consistent with
genital infection were reported in 6.1% of patients on EMPA 10 mg, 2.5% on
EMPA 25 mg and 1.3% on PBO.
To conclude, in patients with T2DM and mild or moderate RI, EMPA
reduced HbA1c, weight, and BP vs PBO, and was well tolerated.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1105-P
Dapagliflozin as Monotherapy in Drug-Naïve Asian Patients With
T2DM Inadequately Controlled on Diet and Exercise
LINONG JI, JIANHUA J. MA, HONGMEI LI, TRACI A. MANSFIELD, CAROLINE L.
T’JOEN, NAYYAR IQBAL, AGATA PTASZYNSKA, JAMES F. LIST, Beijing, China,
Nanjing, China, Shanghai, China, Princeton, NJ, Braine-l’Alleud, Belgium
Dapagliflozin (DAPA), a selective SGLT2 inhibitor, improves glycemic
control in diverse patient populations, as monotherapy or in combination
with other glucose-lowering drugs. We assess DAPA as monotherapy in
drug-naïve Asian patients inadequately controlled on diet and exercise
(HbA1c 7.0-10.5%) in a 24-week double-blind study (NCT01095653) that
randomized patients to placebo (PBO; N=132) or DAPA (5 or 10 mg; N=128 and
133, respectively) groups. Baseline characteristics were balanced across
groups. Most patients (89%) were Chinese. Median duration of T2DM was
0.2 years. At week 24 (LOCF), DAPA 5 and 10 mg provided dose-dependent,
statistically significant reductions in HbA1c vs PBO (primary endpoint) and in
FPG, PPG, body weight and proportion of patients with HbA1c <7% (secondary
endpoints) (Table). Adverse events (AEs) were balanced across groups. Few
patients had serious AEs or AEs leading to discontinuation. Hypoglycemia
was uncommon (1.5, 0.8 and 0.8% in the PBO, DAPA 5 mg and 10 mg groups,
respectively); none led to discontinuation. Genital infections were more
common with DAPA; 0.8, 3.1 and 4.5% of PBO, DAPA 5 mg or 10 mg patients
respectively. UTIs occurred in 3.0, 3.9 and 5.3% of patients, respectively. No
AEs of renal failure or pyelonephritis and no deaths occurred. In summary,
DAPA as monotherapy in drug-naïve Asian patients was well-tolerated,
significantly improving glycemic control with the additional benefit of
modest weight loss.
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was generally well tolerated, and there were no hypoglycemic events. PK
profiles in subjects with and without T2DM were similar to what has been
observed in non-obese subjects (historical data) and are supportive of onceweekly dosing. Trough DPP-4 activity was inhibited by ~90%, post-prandial
(PP) 4-hour weighted mean active GLP-1 concentrations were increased ~2fold, and post-meal glucose was significantly reduced relative to placebo
in the treatment population. Omarigliptin was generally well tolerated in
the treatment population and was associated with a significant reduction
in PP glucose, which was achieved through inhibition of DPP-4 and increased
active GLP-1. Omarigliptin may provide an important once-weekly treatment
option for patients with T2DM.
Dapagliflozin Efficacy and Safety at 24 weeks in Asian Patients
Outcomes at 24 weeks
Placebo
Dapagliflozin−5mg Dapagliflozin−10mg
(N=132)
(N=128)
(N=133)
…
HbA1c, %
…
122
…
n
127
8.15 (0.75)
127
BL mean (SD)
8.33 (0.93)
−1.04
8.28 (0.93)
Change−from−BL*
−0.29 (−0.43,−0.16) (−1.18,−0.90)
−1.11 (−1.24,−0.98)
(95%CI)
…
−0.75
−0.82 (−1.01,−0.63)†
Difference−vs−PBO
(95%CI)
…
(−0.94,−0.56)†
FPG, mg/dL
…
n
131
…
…
BL mean (SD)
166.6 (42.6)
127
128
Change−from−BL*
2.5
154.2 (31.8)
161.8 (43.0)
(95%CI)
(−1.9,6.9)
−25.1 (−29.6,−20.6) −31.6 (−36.1,−27.2)
Difference−vs−PBO
…
−27.7 (−34.0,−21.4)‡ −34.2 (−40.4,−27.9)‡
(95%CI)
…
2-hr PPG§, mg/dL
…
…
…
n
105
100
105
BL mean (SD)
250.4 (63.6)
224.0 (58.4)
230.3 (67.4)
Change−from−BL*
1.1 (−7.9,10.1) −46.8 (−56.0,−37.6) −54.9 (−63.8,−46.0)
(95%CI)
…
−47.9 (−60.8,−35.0)‡ −56.0 (−68.7,−43.3)‡
Difference−vs−PBO
…
(95%CI)
Body weight, kg
n
…
…
…
BL mean (SD)
132
128
128
Change−from−BL*
72.18 (13.23)
68.89 (11.43)
70.76 (11.70)
(95%CI)
−0.27 (−0.72,0.18) −1.64 (−2.09,−1.18) −2.25 (−2.70,−1.80)
Difference−vs−PBO
…
−1.37 (−2.01,−0.73)‡ −1.98 (−2.62,−1.34)‡
(95%CI)
…
Pts w HbA1c<7%
…
…
…
n
127
122
127
Proportion#
21.3% (14.8,27.8)
42.6%
49.8%
(95%CI)
…
(34.2,51.1)
(41.9,57.7)
Difference−vs−PBO
…
21.3%
28.5%
(95%CI)
(11.1,31.6)‡
(18.6,38.3)‡
…
…
…
Safety data
84 (63.6)
79 (61.7)
81 (60.9)
≥1 AE, n (%)
1 (0.8)
3 (2.3)
3 (2.3)
AE→disc, n (%)
≥1 SAE, n (%)
2 (1.5)
5 (3.9)
4 (3.0)
SAE→disc,n(%)
0
1 (0.8)
2 (1.5)
≥1 hypo, n (%)
2 (1.5)
1 (0.8)
1 (0.8)
*Data are adjusted mean change from baseline at 24 weeks derived from
analysis of covariance with treatment group as an effect and baseline value
as a covariate using last observation carried forward (LOCF) and excluding
data after rescue therapy. †p<0.0001 vs placebo for primary endpoint tested
at alpha=0.027 applying Dunnett’s adjustment. ‡p<0.0001 vs placebo for secondary endpoints tested following a sequential procedure at alpha=0.05. §As
measured after ingestion of liquid meal. #Data are proportions adjusted for
baseline HbA1c derived from logistic regression using LOCF and excluding
data after rescue therapy; BL, baseline; disc, discontinuation; FPG, fasting
plasma glucose; hr, hour; hypo, hypoglycemia; N, number of randomized
patients who took at least one dose of double-blind study medication; n,
number of randomized patients with non-missing baseline and week 24
(LOCF) values; PBO, placebo; PPG, post-prandial plasma glucose
Supported by: Merck, Sharp & Dohme
1107-P
Saxagliptin Is Well Tolerated and Improves Glycemic Control in
Adult Diabetes Patients With GAD Antibodies
1108-P
Pharmacokinetics (PK) and Pharmacodynamics (PD) of PF-04991532,
a Hepatoselective Glucokinase Activator (GKA), Administered as
Monotherapy in Japanese and Non-Japanese T2DM Patients
DAVID KAZIERAD, ARTHUR BERGMAN, JEFFREY A. PFEFFERKORN, XIN WANG,
TIMOTHY ROLPH, JAMES M. RUSNAK, Cambridge, MA, Groton, CT
The purpose of this study was to investigate the PK, PD dose response
and safety/tolerability of multiple oral doses of PF-04991532. Twice
daily doses of placebo, 25, 75, 150 or 300 mg PF were administered to
T2DM treatment naïve patients or patients washed off a single oral
diabetic agent in a randomized fashion for 14 days (N=8 Japanese and
N=8 non-Japanese subjects per treatment group). PF-04991532 AUC and
C max increased proportionally with dose, and Tmax values ranged from
1-2 hours. The pharmaco kinetic profile was generally similar between
Japanese and non-Japanese subjects. PF-04991532 was associated
with reductions in mean daily glucose (MDG), fasting plasma glucose
(FPG) and glucose excursion following a meal tolerance test (MTT) by
Day 14 of dosing, with the largest MDG reductions occurring at the
highest doses studied. Additionally, there was a trend for larger MDG
reductions (~2-fold at the 300-mg BID dose) in Japanese subjects (N=38
naïve, N=2 washout) compared to non-Japanese subjects (N=12 naïve,
N= 28 washout). PF-04991532 was found to be safe and well tolerated
at all doses and there were no clinically meaningful changes in lab
safety values, vital signs or ECG results. In conclusion, PF-04991532 was
associated with robust effects on plasma glucose following 2 weeks of
dosing to patients on no other anti-diabetic agents.
Supported by: Bristol-Myers Squibb/AstraZeneca
1106-P
Pharmacokinetic (PK) and Pharmacodynamic (PD) Effects of Multiple-Dose Administration of Omarigliptin, a Novel Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor, in Obese Subjects With and
Without Type 2 Diabetes Mellitus (T2DM)
CAROL ADDY, DANIEL TATOSIAN, XIAOLI S. HOU, ISAIAS N. GENDRANO, ASHLEY MARTUCCI, MICHELLE GROFF, JOHN A. WAGNER, S. AUBREY STOCH,
Whitehouse Station, NJ
Omarigliptin is a potent, oral, long-acting DPP-4 inhibitor that is being
developed as a once-weekly treatment for T2DM. This study was aimed to
investigate the PK and PD effects of omarigliptin in obese subjects with and
without T2DM. This was a randomized, double-blind, placebo-controlled,
multiple-dose study of 50-mg omaragliptin given once weekly for 4 weeks.
Subjects included 24 obese but otherwise healthy subjects (n=18 active/
n=6 placebo) and 8 obese subjects with T2DM (n=6 active/n=2 placebo;
treatment-naïve, HbA1c ≥6.5% and ≤10.0%). Subjects were 45-65 years
of age with 30 ≤ body mass index ≤ 40 kg/m2. Blood sampling occurred
at select time points to evaluate the PK of omarigliptin, DPP-4 activity,
active glucagon-like peptide (GLP)-1, and plasma glucose. Omarigliptin
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Latent autoimmune diabetes in adults (LADA) is recognized by the
presence of glutamic acid decarboxylase (GAD) antibodies, and there is a
need for effective therapies for these patients. Patients from 5 placebo
(PBO)-controlled studies from the saxagliptin (SAXA) phase 3 program were
pooled and classified by GAD status (GAD-positive: values ≥ lower limit
of quantitation [LLOQ]; GAD-negative: values <LLOQ). To assess similarity
in SAXA efficacy by GAD status, we analyzed treatment effects (glycated
hemoglobin [A1C], fasting plasma glucose [FPG], 120-min postprandial
glucose [PPG], adverse events [AEs], serious AEs, hypoglycemia) using
analysis of covariance, with test for treatment by subgroup interaction.
The GAD-positive group included 98 SAXA patients and 35 PBO patients;
the GAD-negative group included 1849 SAXA and 727 PBO patients. Age,
sex, and race were balanced across subgroups. For GAD-positive and GADnegative patients, baseline mean A1C was 8.2% in both subgroups, mean
FPG was 177 and 170 mg/dL, and mean C-peptide was 3.3 and 3.4 nmol/L.
SAXA showed greater decreases from baseline than PBO, with consistent
treatment effects in GAD-positive and GAD-negative patients: mean change
from baseline A1C was ‒0.64% and ‒0.62%, respectively (P=0.93) and PPG
was ‒39.1 and ‒39.7 mg/dL, respectively (P=0.97). Differences in achieving
A1C <7% were also consistent between GAD-positive and GAD-negative
patients. There was a larger treatment effect for FPG for GAD-positive vs
GAD-negative patients (‒33.9 vs. ‒13.8 mg/dL; P<0.01). General similarity
was shown with SAXA vs PBO for both GAD categories for incidence of AEs
(65% vs 80% for GAD-positive; 73% vs 70% for GAD-negative), serious AEs
(2.0% vs 5.7% and 3.5% vs 3.4%, respectively), and hypoglycemic events
(5.1% vs 5.7% and 7.4% vs 6.5%, respectively). SAXA was effective and
generally well tolerated in patients with type 2 diabetes regardless of GAD
status. These data suggest that SAXA is effective in patients with LADA.
Clinical Diabetes/
Therapeutics
PAOLO POZZILLI, RAFFAELLA BUZZETTI, ROBERT FREDERICH, NAYYAR IQBAL,
BOAZ HIRSHBERG, Rome, Italy, Princeton, NJ
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
PF-04991532 Day 14 Pharmacodynamic Effects
Dose
MDG Change from
FPG Change from
Glucose AUC ratio
baseline [90% CI]
baseline [90% CI]
following MTT
(mg/dL)
(mg/dL)
(active/placebo)[90% CI]
25 mg -41.8 [-23.6, -60.0] -27.0 [-13.4, -40.6]
0.87 [0.81, 0.93]
75 mg -30.2 [-11.9, -48.4] -24.0 [-10.3, -37.6]
0.91 [0.85, 0.97]
150 mg -34.5 [-16.3, -52.7] -17.6 [-3.9, -31.2]
0.87 [0.81, 0.93]
300 mg -55.9 [-37.6, -74.2] -21.4 [-7.8, -35.1]
0.78 [0.73, 0.83]
1109-P
No Effect of Exenatide or Sitagliptin Therapy on β-Cell Secretory
Capacity in Early Type 2 Diabetes
POSTERS
Clinical Diabetes/
Therapeutics
LALITHA GUDIPATY, CARISSA FULLER, NORA ROSENFELD, MICHEAL R. RICKELS,
Philadelphia, PA
The main pathophysiologic abnormalities in Type 2 Diabetes (T2D) are
impaired tissue sensitivity to insulin action (i.e. insulin resistance) and
impaired β cell insulin secretion. The impaired β-cell insulin secretion in
T2D is currently best explained by a combination of reduced β-cell mass
and a functional defect in insulin secretion from the available β-cells.
Presently no anti-diabetogenic agent has been shown to prevent or reverse
the progressive decline in β-cell insulin secretion, novel agents such as
glucagons-like peptide-1 (GLP-1) hold some promise as GLP-1 enhances β
cell insulin secretion and inhibits α-cell glucagon secretion in a glucosedependent fashion while exerting extra-pancreatic effects of GLP-1, most
notably appetite suppression and delayed gastric emptying to limit glucose
excursions following a meal.
To evaluate GLP-1 effects on β-cell secretory capacity in vivo early in the
progression of T2D, we performed glucose-potentiated arginine tests in 47
subjects with early T2D or pre-diabetes randomized receive GLP-1 analog
exenatide, DPP4 inhibitor sitagliptin (allows for 2-fold increase in levels of
active GLP-1) or a comparator insulin secretagogue glimepiride for 6 months.
The acute insulin responses to 5 g IV arginine were measured at baseline
and after 6 months of therapy during fasting (AIRarg) and 230 mg/dl (AIR pot)
and 340 mg/dl (AIR max) glucose clamps. From before to after 6 months of
therapy, there was no difference in the acute insulin responses to arginine
with either exenatide or sitagliptin therapy. The mean difference after 6
months in AIRmax was -37 ± 180 uU/mL in the exenatide group vs. 8 ± 72
uU/mL in the sitagliptin group. This was not statistically different from the
comparator insulin secretagogue, glimepiride where the mean difference in
AIRmax was 57 ± 126 uU/mL. These data indicate that exenatide or sitagliptin
therapy that increase GLP-1 levels do not have a significant effect on β cell
secretory capacity in early Type 2 diabetic subjects.
1111-P
Ultrasonography Modifications of Visceral and Subcutaneous Adipose Tissue After Pioglitazone or Glibenclamide Therapy Combined
With Rosuvastatin in Type 2 Diabetic Patients Not Well Controlled
by Metformin
PAMELA MAFFIOLI, ANGELA D’ANGELO, TIZIANO PERRONE, ELENA FOGARI,
GIUSEPPE DEROSA, Pavia, Italy
The aim of this study was to compare pioglitazone or glibenclamide
alone and in combination with rosuvastatin on hepatic steatosis in type 2
diabetic patients. After 3 months of metformin, patients were randomised to
pioglitazone 15 mg twice a day or glibenclamide 5 mg twice a day for six months,
then rosuvastatin was added for other six months. Patients underwent an
ultrasound examination to evaluate steatosis degree, subcutaneous adipose
tissue (SAT) and visceral adipose tissue (VAT) diameter, an euglycemic
hyperinsulinemic clamp to evaluate glucose infusion rate (GIR), and a blood
sample collection to evaluate: glycemic control, fasting plasma insulin (FPI),
lipid profile, adipocytokines at randomisation, and after 6, and 12 months.
Both pioglitazone and glibenclamide improved glycemic control. Pioglitazone
reduced FPI, while glibenclamide increased it. Pioglitazone increased GIR
compared to glibenclamide therapy. Pioglitazone reduced total cholesterol,
and triglycerides, and increased high density lipoprotein cholesterol. When
rosuvastatin was added, there was a greater improvement with pioglitazone
and rosuvastatin. Adiponectin was increased by pioglitazone, with a further
increase when rosuvastatin was added. A significant decrease of leptin, and
interleukin-6 was recorded with pioglitazone; a similar trend was maintained
after rosuvastatin addition.
The addition of rosuvastatin to pioglitazone decreased tumor necrosis
factor-α. Pioglitazone + rosuvastatin were superior to glibenclamide +
rosuvastatin in reducing high sensitivity C-reactive protein. Only pioglitazone
decreased ultrasound parameters, and the addition of rosuvastatin further
decreased them. We can conclude that pioglitazone was more effective than
glibenclamide in improving inflammation and the hepatic steatosis indices.
Supported by: Pennsylvania Dept. of Health
1110-P
Canagliflozin (CANA) Lowers A1C and Blood Pressure (BP) Through
Weight Loss-Independent (WL-I) and Weight Loss-Associated (WLA) Mechanisms
LAWRENCE BLONDE, JOHN WILDING, JEAN-LOUIS CHIASSON, DAVID POLIDORI, GARY MEININGER, PETER STEIN, New Orleans, LA, Liverpool, United Kingdom, Montreal, QC, Canada, San Diego, CA, Raritan, NJ
1112-P
CANA is an SGLT2 inhibitor that increases urinary glucose excretion, leading
to decreased A1C and weight loss (WL) in subjects with type 2 diabetes.
Systolic BP (SBP) also decreases, possibly due in part to diuresis. WL alone
reduces A1C and SBP; WL-I and WL-A effects of CANA were estimated using
a pooled analysis of 4 previously reported 26-week Phase 3 studies (N =
2250). Each study had 3 groups: placebo (PBO), CANA 100 mg, CANA 300 mg.
Mean baseline values of A1C = 8.0%, body weight (BW) = 89 kg, and SBP =
128 mmHg were similar across groups. Within each group, mean changes in
A1C and SBP were calculated for each decile of WL and ANCOVA analysis
was done with ΔA1C or ΔSBP as response and ΔBW (%) as covariate. Greater
reductions in A1C and SBP were seen with greater WL, with similar slopes
in each group (Figure). WL-I effects were defined as the vertical distance
between lines (ie, difference in response observed when WL is the same in
each group). Total PBO-subtracted mean reduction in A1C was 0.72% with
CANA 100 mg (0.60% [85%] of the effect was WL-I) and 0.90% with CANA
300 mg (0.75% [85%] WL-I). Total PBO-subtracted reduction in SBP was 3.5
mmHg with CANA 100 mg (2.0 mmHg [57%] WL-I) and 4.7 mmHg with CANA
300 mg (2.7 mmHg [59%] WL-I); relative contributions of fat and fluid loss
to WL-A effects cannot be determined from these data. CANA lowers both
A1C and BP through WL-I and WL-A mechanisms; a greater proportion of the
reduction in A1C is WL-I compared to SBP.
The Effect of Vildagliptin Relative to Sulphonylureas in Muslim Patients With Type 2 Diabetes Fasting During Ramadan: The VIRTUE
Study
MONIRA AL AROUJ, AHMED A.K. HASSOUN, RITA MEDLEJ, FARUQUE M. PATHAN, INASS SHALTOUT, MANOJ S. CHAWLA, PARNIA GERANSAR, SASHKA
HRISTOSKOVA, SHELLEY DITOMMASO, MAHOMED Y. KADWA, Dasman, Kuwait,
Dubai, United Arab Emirates, Beirut, Lebanon, Dhaka, Bangladesh, Cairo, Egypt,
Mumbai, India, Basel, Switzerland
VIRTUE was a prospective, observational study that assessed the risk of
hypoglycemic events (HE) in patients with type 2 diabetes mellitus (T2DM)
who fast during Ramadan. The study enrolled Muslim patients with T2DM
in two cohorts: vildagliptin (n=684) or sulphonylurea (SU; n=631), both
given either as monotherapy or dual therapy with metformin. Patients
were recruited from 10 countries in the Middle East and Asia. Mean HBA1c
was 7.34% and 7.44% in the vildagliptin and SU cohorts, respectively. The
primary endpoint was the proportion of patients with ≥1 HE during Ramadan.
Secondary endpoints included change in HbA1c, change in body weight,
treatment adherence and overall safety.
The study showed that significantly (p<0.001) fewer patients experienced 1
or more HE with vildagliptin (n=36/669, 5.4%) compared with SU (n=123/621,
&
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index; (iii) having a trial duration of at least 12 weeks. Finally, a total of 16
articles reporting 22 comparisons met inclusion criteria, which included 6,567
study participants, 3,560 treated with sitagliptin and 3,007 treated with
placebo or a comparator drug. In all studies, HOMA-IR and HOMA-β were
analyzed as weighted mean differences (WMD) under a fixed effects model
because no heterogeneity was found. The meta-analysis showed HOMAIR and HOMA-β was significantly improved (WMD = -0.3, 95% confidence
interval (CI), -0.5 to -0.1; WMD = 11.7, 95%CI, 9.9 to 13.5, respectively). There
was possible publication bias in the analysis of HOMA-β (Egger’s regression
test: P=0.05), but not in HOMA-IR (P=0.92). In conclusion, it is suggested
that sitagliptin may have a beneficial effect on insulin resistance as well as
beta-cell function.
19.8%). No patients reported a grade 2 HE (requiring third-party assistance)
with vildagliptin compared with 4 patients receiving SUs (p=0.053). The
mean change in HbA1c, pre- to post-Ramadan, was -0.24% in the vildagliptin
group compared with +0.02% in the SU group (-0.26% between treatment
difference; p<0.001). Greater body weight reductions were observed with
vildagliptin compared with SU (-0.76 vs. -0.13 kg; -0.63kg between treatment
difference; p<0.001). Treatment adherence was high with a similar number of
missed doses between cohorts. A higher proportion of SU-treated patients
experienced adverse events compared with vildagliptin (22.8% vs. 10.2%),
with the difference driven by hypoglycemia, which was the most common
adverse event.
In conclusion, vildagliptin therapy was associated with significantly fewer
patients experiencing hypoglycemia compared with SU therapy in this
large cohort of fasting patients with T2DM. This outcome is particularly
meaningful when viewed in the context of good glycemic and weight control
accompanied by favorable tolerability observed in vildagliptin-treated
patients who fast.
1115-P
Glycemic Control of Pioglitazone in a Diabetic Rat Model Is Improved when Combined With Empagliflozin
Dipeptidyl Peptidase-4 Inhibitor Ameliorates PPARγ Agonist-Induced Body Weight Gain via Reduction in Body Fat Mass, but Not
Fluid Volume
TAKAHIRO MASUDA, JAN CZOGALLA, AKIKO EGUCHI, MICHAEL A. ROSE, MARIA GERASIMOVA, VOLKER VALLON, La Jolla, CA
Peroxisome proliferator-activated receptor γ (PPARγ) agonists, like
pioglitazone (PG) are effective anti-diabetic drugs, but induce fluid retention
and body weight (BW) gain. Dipeptidyl peptidase-4 (DPP-4) inhibitors are
new anti-diabetic drugs that enhance renal Na+ and fluid excretion. We
therefore examined whether the DPP-4 inhibitor alogliptin (AL) ameliorates
PG-induced BW gain. Male SV129 mice were treated with vehicle (VE;
repelleted diet), PG (220 mg/kg diet), AL (300 mg/kg diet) or combination of
PG and AL (COM)(n=8-10 per group) for 14 days. * P<0.05 vs VE; # P<0.05 vs
PG. PG increased, and AL lowered BW vs VE (delta BW: 4.2±0.8*, -0.1±0.5*,
and 1.7±0.3 %). COM (0.8±0.8 % #) prevented the increase in BW observed
in PG alone. COM decreased hematocrit to a greater degree than PG alone
(46.9±0.9 # vs 49.9±0.3 %; each *) while AL had no effect vs VE (50.4±0.3
vs 50.8±0.3 %). PG tended to increase and COM significantly increased fluid
content of abdominal fat pads vs VE (9.1±0.9, 9.5±0.6*, 7.4±1.0 %). COM
increased body fluid content determined by bioimpedance spectroscopy
(BIS) to a similar degree as PG (in absolute terms and related to BW; each by
10-20% vs VE; each *). BIS revealed that AL had no effect on fat mass (FM) vs
VE (FM/BW: 22.4±1.4 vs 20.5±1.9 %), but COM decreased FM to lower levels
than PG (7.6±1.0 # vs 13.7±2.4 %; each *; similar results were obtained for
absolute values). The latter was confirmed by MRI. AL, but not PG, modestly
decreased food intake (by 6-8%*) and plasma free fatty acid concentrations
(FFAs) (by 25-36%*). Vice versa, PG, but not AL, increased mRNA expression
of thermogenesis mediator uncoupling protein 1 (UCP1) in epididymal
white adipose tissue (by 808-1160%*). In summary, DPP-4 inhibition did not
attenuate PPARγ agonist-induced fluid retention, but prevented BW gain via
a further reduction in FM. The latter may involve distinct and complementary
effects on determinants of FM like plasma FFAs and adipose tissue UCP1
expression.
1116-P
Response to Dapagliflozin by Baseline HbA1c in Head-to-Head Comparisons
ROBERT R. HENRY, ALEXANDER V. MURRAY, MICHAEL A. NAUCK, KATJA
ROHWEDDER, EVA JOHNSSON, SHAMIK J. PARIKH, AGATA PTASZYNSKA, San
Diego, CA, Greensboro, NC, Bad Lauterberg, Germany, Wedel, Germany, Wilmington,
DE, Princeton, NJ
Dapagliflozin (DAPA), a selective SGLT2 inhibitor, reduces hyperglycemia
by removing excess blood glucose via the urine. The objective of this
analysis was to directly compare the glycemic efficacy of DAPA with other
oral antidiabetic drugs (OADs) across a wide range of baseline HbA1c. DAPA
was compared with other OADs in 2 randomized, double-blind clinical trials:
Study 1 (NCT00660907), a 52-week trial of DAPA (≤10 mg) vs glipizide (GLIP,
≤20 mg) as add-on to metformin (MET); Study 2 (NCT00859898), a 24-week
trial of DAPA 10 mg vs MET extended release 2000 mg as monotherapies.
Mean baseline HbA1c was 7.7% (Study 1) and 9.1% (Study 2). Non-inferiority
of DAPA to comparators for changes in HbA1c (primary endpoint) was
previously described. Here we present analyses by baseline HbA1c levels
(Figure). Both DAPA and comparators provided greater reductions in
HbA1c in the higher baseline HbA1c subgroups. Furthermore, within each
study, reductions by DAPA and comparator were similar for each baseline
HbA1c category. In both studies, DAPA had a low intrinsic propensity for
hypoglycemia (Study 1: DAPA 3.5% vs GLIP 40.8%; Study 2: DAPA 0.9% vs
MET 2.9%), consistent with the insulin-independent mechanism of action.
In summary, as with the overall populations, DAPA demonstrated glycemic
responses similar to other OADs in subgroups stratified by baseline glycemic
control, producing larger reductions in HbA1c for individuals starting with
higher baseline levels.
Supported by: Takeda Pharmaceuticals U.S.A., Inc.
1114-P
Effects of Sitagliptin on Insulin Sensitivity and Beta-Cell Function
by the Homeostasis Model Assessment in Patients With Type 2 Diabetes: A Meta-Analysis
TAKAFUMI TSUCHIYA, MISATO KAWANISHI, SHINTAROU SAKURAI, TATSUHIKO
SUZUKI, KENNICHIROU HORI, TOMOKO TERASAWA, RIKA NARUSE, KENJI
HARA, KOHZO TAKEBAYASHI, TOSHIHIKO INUKAI, Koshigaya, Japan
The homeostatic model assessment is a method used to quantify insulin
sensitivity and beta-cell function. The objective of this study is to evaluate
the impacts of a dipeptidyl peptidase-4 (DPP-4) inhibitor, sitagliptin, on
markers of insulin sensitivity and beta-cell function in patients with type
2 diabetes mellitus. For a meta-analysis, randomized controlled trials
using sitagliptin as an add-on therapy or a monotherapy treating type 2
diabetes mellitus were identified through electronic searches up to and
including December 2011. Studies were included if they met the following
inclusion criteria: (i) randomized controlled trials that compared sitagliptin
with placebo or a sitagliptin/metformin combination drug with metformin
monotherapy in adult people with type 2 diabetes; (ii) reporting homeostatic
model assessment of insulin resistance (HOMA-IR) or of beta-cell (HOMA-β)
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Empagliflozin is a novel, potent and selective sodium glucose cotransporter 2 (SGLT2) inhibitor in clinical development for the treatment of
type 2 diabetes. We investigated whether empagliflozin could be used in
combination with pioglitazone, an insulin sensitizer, to improve glycemic
control in type 2 diabetic animals (ZDF rats).
ZDF rats were treated once daily for 15 days with empagliflozin (1 mg/kg),
pioglitazone (10 mg/kg) or both these drugs or vehicle. At day 15, blood glucose
level increased by 18.6% in the control group, but decreased significantly
by 36.9% (p<0.001) and 48.2% (p<0.05) vs control with empagliflozin and
pioglitazone monotherapy, respectively, and by 75.7% (p<0.001) vs control
with the combination. At the end of the study, fed blood glucose levels were
26.7mM, 16.9mM and 13.8mM in the control, empagliflozin and pioglitazone
groups, respectively, and 6.5mM in the combination group. HbA1c increased
from 3.19% to 5.79% between day 0 and day 15 in the control group. The
increase in HbA1c was significantly less in the empagliflozin and in the
pioglitazone group than in the control group, while the combination group
had the lowest increase. Baseline-corrected changes in HbA1c were 2.6%,
1.94%, 1.03% and 0.5% with vehicle, empagliflozin, pioglitazone and the
combination, respectively.
This study shows that empagliflozin, with a mechanism of action that is
independent of insulin pathways and beta-cell function, can be combined
with an insulin sensitizer to improve glycemic control in animal model of
type 2 diabetes.
In conclusion these results suggest that, empagliflozin, could be combined
with pioglitazone for a better control of glucose homeostasis in type 2
diabetic patients.
1113-P
Clinical Diabetes/
Therapeutics
LEO THOMAS, ROLF GREMPLER, MICHAEL MARK, ERIC MAYOUX, GERD LUIPPOLD, Biberach, Germany
Supported by: Novartis Pharma AG
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
Blood Glucose (mmol/L*min)
Insulin (pmol/L*min)
Intact Proinsulin (pmol/L*min)
GLP-1 (pmol/L*min)
PAI-1 (ng/mL*min)
cGMP (pmol/L*min)
ADMA (µmol/L*min)
Glimepiride
-522±111 *
22595±560 *
1359±642
-7±185
863±455
92±98
-1.8±2.7
Linagliptin
-309±68 *
-8007±4204 $
-1771±426 *,$
4149±658 *,$
-410±261 $
111±128
-4.1±2.3
Change from baseline in the pp AUC (mean±SEM; *=p<0.05 vs. baseline;
$ =p<0.05 between groups)
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1118-P
Glucagon Receptor Antagonist LGD-6972 Is Efficacious in Streptozotocin-Induced Diabetic Mice
Glucagon plays an important role in insulin dependent diabetes and
glucagon receptor (GCGR) antagonism has been effective in clinical
trials with T2DM patients. Glucagon is also critical in insulin deficient,
streptozotocin (STZ) treated mice as observed in experiments with GCGR -/mice. We examined whether pharmacological antagonism of the GCGR
would have similar effects in STZ treated mice.
LGD-6972 is a potent and selective antagonist of the GCGR that has
previously demonstrated activity in pre-clinical models of T2DM. Male
BALB/c mice were injected with STZ and left untreated until hyperglycemia
was confirmed. Hyperglycemic mice were orally dosed with LGD-6972 or
vehicle for 28 days. Non-fasting blood glucose was significantly reduced in
LGD-6972 treated mice (average = 80 mg/dL throughout the experiment).
Larger effects were observed on fasting blood glucose (Vehicle: 382 mg/
dL, LGD-6972: 234 mg/dL, non-diabetic controls: 118 mg/dL). An oral glucose
tolerance test revealed a large increase in glucose levels and a slow recovery
to baseline levels in STZ mice relative to non-diabetic controls, consistent
with an insulin deficient state. LGD-6972 treated mice had lower glucose
levels than STZ mice throughout the glucose tolerance test (average decrease
of 100 mg/dL) but displayed a similar delayed return to baseline. Terminal
measurements of HbA1c, 3-hydroxybutyrate, and free fatty acids (FFA) were
significantly elevated in STZ mice indicating prolonged hyperglycemia and
ketoacidosis. LGD-6972 partially restored HbA1c and 3-hydroxybutyrate
to non-diabetic levels but did not alter FFA levels.In addition to efficacy
observed in T2DM patients, pharmacological inhibition of GCGR may be an
effective treatment for T1DM and could potentially be used in an insulinsparing regimen. GCGR antagonism was not able, however, to completely
normalize the hyperglycemic state, unlike the effects observed with GCGR -/mice. Further studies to investigate these differences may be useful.
POSTERS
Clinical Diabetes/
Therapeutics
ERIC G. VAJDA, LIN ZHI, KEITH B. MARSCHKE, La Jolla, CA
Supported by: Bristol-Myers Squibb/AstraZeneca
1119-P
The Beneficial Effect of Metformin on β-Cell Function and its Relationship to Insulin Sensitivity in Lean Subjects With Newly Diagnosed Type 2 Diabetes
1117-P
Linagliptin Improves Beta Cell Function and Vascular Biomarkers in
Patients With Type 2 Diabetes
YAN BI, DALONG ZHU, HUIJIE YANG, GUOYU TONG, Nanjing, China
MICHAEL MITRY, ANDREAS PFÜTZNER, THOMAS FORST, Mainz, Germany
Studies with metformin have suggested beneficial effects on β-cell
function in obese patients, but it remains unclear whether a similar effect
is observed in non-obese individuals. Here we investigated the effects
of metformin or glipizide GITS on β-cell function in lean and overweight
patients with newly diagnosed type 2 diabetes.
160 newly diagnosed patients with fasting plasma glucose 7.0-13.0
mmol/l and body mass index < 30 kg/m2 were randomized to metformin
or glipizide GITS and treated for 24 weeks. β-Cell function (insulinogenic
index as measured by the ratio of area under the curve (AUC) of insulin and
C-peptide to glucose AUC) and insulin sensitivity (Matsuda index ISIM) were
assessed during the standard meal tolerance test before and after therapy.
Analysis was done by intention-to-treat.
We found that HbA1c was significantly reduced to a similar extent with
metformin and glipizide GITS treatment (-1.7±1.3% metfromin vs. -2.0±1.5%
glipizide GITS, P=0.256). Plasma adiponectin and glucagon-like peptide-1
response were markedly increased from baseline in two groups. Metformin
significantly increased ISIM from baseline (P=0.029), but subgroup analysis
identified that the increase in ISIM in lean subgroup was not significant
(P=0.134). When corrected for alterations in insulin sensitivity, parameters
regarding insulin secretion were improved significantly (P<0.05) and
comparable with metformin and glipizide GITS, which the trends persisted
across lean and overweight subgroups with each treatment.
Postprandial metabolism and the amelioration of endothelial function are
major components in the development of vascular complications in T2DM.
The goal of this study was to investigate the effects of Linagliptin compared
to Glimepiride on beta cell function and several vascular biomarkers in the
postprandial state.
Thirtynine patients on metformin treatment (age: 64±7 years; duration
of DM: 7.9±4.5years, 27 male; HbA1c: 57.2±6.9 mmol/mol; mean±SD) were
randomized to add Linagliptin 5mg (n=19) or Glimepiride up to 4 mg (n=20) for
a study duration of 12 weeks. Blood glucose, insulin, intact proinsulin, GLP-1,
PAI-1, c-GMP, and ADMA levels were measured fasting and postprandial
(pp) at 30 minutes intervals for a duration of 5 h. The areas under the curve
(AUC0-300min) were calculated.
HbA1c, fasting and pp glucose levels improved in both groups. Insulin,
intact proinsulin, and PAI-1 levels increased during treatment with
Glimepiride and decreased during treatment with Linagliptin. In both groups
a slight increase in pp c-GMP and a slight decrease in pp ADMA could be
observed (n.s.). A linear correlation could be observed between pp intact
proinsulin and pp c- GMP (r=-0.14; p<0.0001), and between pp GLP-1 and pp
PAI-1 (r=-0.08; p=0.003).
In addition to metformin Linagliptin significantly improves pp beta cell
function and reduces pp PAI-1 levels vs. Glimepiride.
&
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Therefore, metformin’s beneficial effects on β-cell function were
observed in both lean and overweight subjects with newly diagnosed type
2 diabetes, and which were independent of the change in insulin sensitivity,
in part, in lean subjects. This study provides evidence-based data to support
metformin use in non-obese patients with type 2 diabetes as an agent which
can improve both insulin sensitivity and β-cell function.
1121-P
The Hepatoselective Glucokinase (GK) Activator PF-04991532 Provides Additive Improvements in Glycemic Control With Exercise in
Goto-Kakizaki Rats
Drugs that exert additional glycemic control in combination with exercise
training have the potential to improve patient outcomes. Recently, metformin
was reported to show a lack of benefit in combination with exercise relative
to either treatment alone in pre-diabetic subjects. Pharmacologic agents
which improve glycemic control and complement the increased peripheral
glucose disposal derived from exercise training have the potential to show
additive benefit with physical activity. We hypothesized that PF-04991532,
a hepatoselective glucokinase activator which improves hepatic glycemic
control, would exert additive benefit in combination with exercise training.
In the present study, the interplay between PF-04991532 and exercise
training was examined. Male Goto-Kakizaki rats were exercised for 12
wks at ~50% peak power (1 hr/day, 5 days/wk). This exercise intervention
was weight neutral but significantly improved markers of glycemic control
[fasting plasma glucose (FPG), fasting insulin and HOMA-IR] relative to
sedentary controls. 48-hrs following the last exercise session, a single oral
dose of PF-04991532 (60 mg/kg) or vehicle was administered by oral gavage.
An oral glucose tolerance test was performed 1-hr post compound dose.
PF-04991532 produced improvements in fasting insulin levels, FPG, postprandial glucose and HOMA-IR in both exercise trained and sedentary rats.
The effect of PF-04991532 was additive with exercise training in improving
fasting insulin levels, FPG, post-prandial glucose and HOMA-IR. Improvements
in post-prandial insulin glucose ratio (a marker for insulin sensitivity) were
only observed in exercised but not non-exercised rats, and this effect was
potentiated by PF-04991532.These data suggest that PF-04991532 may
work additively with exercise to improve glucose homeostasis; subsequent
studies will evaluate the effect of chronic GK activation in combination with
exercise training.
CHRISTOPHER KOVACS, VEERASWAMY SESHIAH, ROS SWALLOW, RUSSELL
JONES, HENNING RATTUNDE, HANS J. WOERLE, ULI C. BROEDL, St. John’s, NL,
Canada, Chennai, India, Berkshire, United Kingdom, Ingelheim, Germany
A Phase III trial investigated the efficacy and safety of empagliflozin
(EMPA) in patients with T2DM on a stable pioglitazone regimen with or
without metformin. Patients (mean age 54.5 [SD 9.8] years; mean BMI 29.2
[SD 5.5] kg/m2) were randomized and treated double-blind with EMPA 10
mg (n=165), 25 mg qd (n=168) or placebo (PBO; n=165) for 24 weeks. Primary
endpoint was change from baseline in HbA1c at week 24. Key secondary
endpoints were change from baseline in FPG and weight at week 24.
EMPA significantly reduced HbA1c, FPG, and weight versus PBO. Further
analyses showed significant reductions in blood pressure (BP) vs PBO.
Weight loss of >5% was achieved by 18.8% of patients on EMPA 10 mg,
13.7% on EMPA 25 mg and 5.5% on PBO. Adverse events (AEs) were
reported by 67.3%, 71.4% and 72.7% of patients on EMPA 10 mg, 25 mg
and PBO, respectively. Hypoglycemia (plasma glucose ≤70 mg/dL and/or
requiring assistance) was reported in 1.2% of patients on EMPA 10 mg, 2.4%
on EMPA 25 mg and 1.8% on PBO; none required assistance. AEs consistent
with urinary tract infection were reported in 17.0% of patients on EMPA 10
mg, 11.9% on EMPA 25 mg and 16.4% on PBO. AEs consistent with genital
infection were reported in 8.5% of patients on EMPA 10 mg, 3.6% on EMPA
25 mg and 2.4% on PBO.
To conclude, EMPA 10 mg and 25 mg for 24 weeks as add-on to pioglitazone
with or without metformin reduced HbA1c, FPG, weight and BP versus PBO,
and was well tolerated in patients with T2DM.
1122-P
Effect of Canagliflozin (CANA) 300 mg on C-peptide Clearance
(CL Cpep)
SUE SHA, DAVID POLIDORI, TIM HEISE, JAYA NATARAJAN, EUNICE ARTIS,
SHEAN-SHENG WANG, NICOLE VACCARO, PAUL ROTHENBERG, ALIN STIRBAN,
Raritan, NJ, San Diego, CA, Neuss, Germany
CANA, a sodium glucose co-transporter 2 (SGLT2) inhibitor, lowers plasma
glucose and A1C in type 2 diabetic subjects by increasing urinary glucose
excretion. In clinical trials, CANA doses ≥100 mg improved indices of β-cell
function (βCF) based on circulating C-peptide and glucose concentrations (eg,
HOMA2-%B and meal tolerance test-based indices). However, as C-peptide
is mostly cleared renally, these results could be confounded if CANA
affects CLCpep. Therefore, this 2-period crossover study assessed whether
a single 300 mg CANA dose alters CLCpep in 10 healthy subjects (mean age =
36 y, body weight = 79 kg). After an overnight fast, subjects received iv
injection of 150 µg of synthetic human C-peptide 3 h after CANA or placebo
(P) dosing and 1 h after initiating a constant iv somatostatin infusion to
suppress endogenous C-peptide secretion. Serum C-peptide was measured
frequently for 3 h; profiles were fitted to a 2-compartment model to obtain
CLCpep. Urinary C-peptide was measured to calculate renal clearance (CLR).
Serum C-peptide profiles were similar following CANA or P treatment (Fig).
CLCpep was comparable with CANA and P (mean [SD] = 190 [37] vs. 197 [30]
mL/min; ratio (CANA/P) [90% CI] = 96% [93%; 99%]). CLR and other kinetic
parameters were similar between treatments. CANA was well tolerated.
These results show that CANA 300 mg does not meaningfully alter CLCpep
and confirm that C-peptide-based measurements of insulin secretion are
appropriate for assessing βCF in CANA-treated subjects.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
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1120-P
Empagliflozin as Add-On to Pioglitazone With or Without Metformin
Improves Glycemic Control in Patients With Type 2 Diabetes (T2DM)
Clinical Diabetes/
Therapeutics
TRENTON T. ROSS, DAVID A. BEEBE, DEREK M. ERION, PAUL A. AMOR, YIMIN
ZHU, GREGORY J. TESZ, QINGYUN YAN, SANTOS CARVAJAL-GONZALEZ, TIMOTHY P. ROLPH, JEFFREY A. PFEFFERKORN, WILLIAM P. ESLER, Cambridge, MA
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1125-P
1123-P
POSTERS
Clinical Diabetes/
Therapeutics
higher with CANA 300 mg (12.5%). There were no severe hypoglycemic
episodes. In conclusion, CANA added to ongoing SU monotherapy produced
significant improvements in a number of efficacy parameters important in
T2DM management with an increased incidence of several specific AEs
probably related to SGLT2 inhibition.
Plasma Aminoacids Following a Mixed Meal in T2D Patients: Effect
of Sitagliptin Treatment
The Effect of High Dose Vitamin D Supplementation on Glycemic
Control in Healthy Type 2 Diabetic Patients
ELZA MUSCELLI, SILVIA FRASCERRA, ARTURO CASOLARO, SIMONA BALDI,
WALT GALL, ELE FERRANNINI, Pisa, Italy
OHK HYUN RYU, SUNGHWA LEE, MOON-GI CHOI, JAE MYUNG YU, DOO-MAN
KIM, SUNG-HEE IHM, HYUNG JOON YOO, Chuncheon, Republic of Korea, Seoul,
Republic of Korea, Pyungchon, Republic of Korea
Aminoacid (AA) metabolism is altered in T2D, and fasting levels of
α-hydroxybutyrate (α-HB), a biomarker for insulin resistance and incident
diabetes, have been suggested to track AA metabolism. We investigated
the changes in AA and α-HB induced by a mixed meal (MTT) and the effects
of chronic sitagliptin treatment.
Forty-seven T2D patients (age 56±7 yrs, BMI 29.9±4.2 kg/m2) were
randomized to sitagliptin (100 mg/d) or placebo for 6 weeks. Seven age- and
BMI-matched nondiabetic subjects served as control (CT). During a 5-hr
MTT, plasma branched-chain AA (BCAA) peaked earlier in T2D than in CT
(75[25] vs 62[3] mmol/L over 2 hrs, median[interquartile range], p=0.05), and
rose higher (31[23] vs 19[24] mmol/L, ∂AUC over 5 hrs, p=0.05). Fasting α-HB
was higher in T2D than CT (7.5[2.7] vs 5.9[1.3] µg/mL, p=0.04), increased at
60 min in T2D but not CT, and its ∂AUC over 2 hrs postMTT was higher in
T2D (24[99] vs -41[86] µg/mL, p=0.005). Plasma FFA declined sharply during
MTT, but their AUC was greater in patients (53±16 vs 35±10 mEq/L over 3
hrs, p=0.005). Sitagliptin treatment was associated with lower fasting and
postmeal glycemia, and improved β-cell sensitivity (52.9[52.1] vs 31.1[35.9]
pmol.min-1.m-2.mM-1, p=0.002) and insulin sensitivity (273[69] vs 239[69]
mL.min-1.m-2, p=0.0002). As compared to placebo, both BCAA (∂AUC
-6.4[21.1] vs 3.4[17.9] mmol.L-1.5h, p=0.01) and α-HB (∂AUC -114[250] vs
114[428] µg.mL-1.2h, p=0.002) decreased with sitagliptin, and meal-induced
FFA suppression was greater. Changes in BCAA and α-HB AUCs were both
reciprocally related to changes in insulin sensitivity (rho=-0.50 and -0.35,
respectively, p≤0.03)
T2D is associated with a hyperaminoacidemic response to a mixed
meal, which circulating α-hydroxybutyrate levels track. Sitagliptin-induced
glycemic improvement was associated with consensual reductions in BCAA
and α-HB excursions (as well as FFA suppression) in parallel with improved
insulin sensitivity, confirming that α-HB is a readout of metabolic overload.
Background: Vitamin D deficiency is very common in Korea.Epidemiologic
studies showed the striking inverse relationship between vitamin D level
and insulin resistance/glucose intolerance. But there are few interventional
studies that evaluate the glucose-lowering effect in diabetic patients.
Aims: We investigated the glucose-lowering effect of high dose vitamin D
in type 2 diabetic patients.
Methods: We enrolled type 2 diabetic patients who took antidiabetic
agents or managed diabetes by lifestyle modification. The participants was
also satisfied the following criteria: age (<70 years) and HbA1C (<8.5%).
We excluded patients who took vitamin D or calcium supplements. We
also excluded chronic kidney disease patients (in men: Cr>1.5mg/dL, in
women: Cr>1.4mg/dL), and physically disabled patients. We randomized
158 participants into 2 groups: intervention group (n=79) (Vitamin D 2000IU/
day+Calcium 200mg/day) or placebo group (Calcium 200mg/day) (n=79).
Results: There were no difference in baseline characteristics, such as
HbA1c (HbA1c 7.29±0.59% vs 7.30±0.61%),vitamin D level (10.1±3.9ng/ml
vs 10.8±5.1ng/ml) diabetes duration, oral antidiabetic agents, and outdoor
physical activity in placebo and intervention group, respectively. Although
the achieved vitamin D level was different (15.6±7.1 vs 30.2±10.8ng/ml;
P<0.001), there were no difference in HbA1c (7.27±0.87% vs 7.40±0.90%;
P=0.415) between placebo and intervention group.
Conclusions: In healthy type 2 diabetic patients, long-term supplementation
of high dose vitamin D was no effect in glycemic control.
1124-P
Canagliflozin (CANA) in Subjects With Type 2 Diabetes Mellitus
(T2DM) Inadequately Controlled on Sulfonylurea (SU) Monotherapy:
A CANVAS Substudy
GREG FULCHER, DAVID MATTHEWS, VLADO PERKOVIC, KENNETH W. MAHAFFEY, ROBERT WEISS, JULIO ROSENSTOCK, GEORGE CAPUANO, MEHUL
DESAI, WAYNE SHAW, FRANK VERCRUYSSE, GARY MEININGER, BRUCE NEAL,
Sydney, Australia, Oxford, United Kingdom, Durham, NC, Auburn, ME, Dallas, TX,
Raritan, NJ, Beerse, Belgium
1126-P
Phase 1 Clinical Evaluation of the CCR2 Antagonist CCX872-B
PIROW BEKKER, TREVOR CHARVAT, SHICHANG MIAO, LISA LOHR, TIMOTHY
SULLIVAN, ZHENHUA MIAO, JAY POWERS, JUAN JAEN, THOMAS J. SCHALL,
Mountain View, CA
Within a pre-specified substudy of the Canagliflozin Cardiovascular
Assessment Study (CANVAS), we evaluated the efficacy, safety and
tolerability of CANA in subjects with T2DM inadequately controlled on SU
monotherapy (n = 127; 45 placebo [PBO], 42 CANA 100 mg and 40 CANA 300
mg). The primary endpoint was change from baseline in HbA1c at week 18.
Mean baseline age was 65 y, males (57%), HbA1c 8.4%, BMI 29.9 kg/m2, FPG
10.0 mmol/L, systolic blood pressure (SBP) 136.3 mmHg and eGFR 69.3 mL/
min/1.73 m2. At randomization, 35% were taking glimepiride, 29% glyburide/
glibenclamide and 27% gliclazide modified release (ND). Compared to
PBO, both CANA doses significantly improved glycemia (Table). The overall
incidence of adverse events (AEs) with CANA 100 mg (26.2%) was lower
relative to PBO (64.4%) and CANA 300 mg (45%). Specific AEs of male and
female genital infections, pollakiuria, and thirst were more common with
CANA. AEs leading to discontinuation in the CANA groups were low (300
mg; 2.5%, 100 mg; 2.4%), with none reported in the PBO group. Documented
hypoglycemia was similar with CANA 100 mg (4.1%) and PBO (5.8%) and
CCX872-B is an orally administered, specific antagonist of the C-C
chemokine receptor 2 (CCR2). This receptor and its most prominent
chemokine ligand MCP-1 (also called CCL2) have been implicated in a variety
of diseases, including various forms of renal inflammation/fibrosis and type
2 diabetes. We have shown that CCX872-B is effective in improving renal
disease, as measured by albuminuria and several histologic measurements
such as podocyte number, glomerular size, glomerular basement membrane
thickness, and macrophage infiltration in several mouse models of diabetic
nephropathy, including the db/db, BTBR ob/ob, and eNOS-/-db/db mouse
models. CCX872-B also reduces hyperglycemia in mouse models of diabetes,
such as the db/db mouse model. We describe the results of a randomized,
double-blind, placebo-controlled, single- and multiple ascending dose Phase
1 clinical trial in 40 healthy volunteers. The primary objective of the trial
is to evaluate the safety and tolerability of orally administered CCX872-B.
Secondary objectives include evaluation of the pharmacokinetic (PK) and
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pharmacodynamic profiles of CCX872-B. Oral doses of 3 mg up to 300 mg
CCX872-B or placebo are given in sequential single and 7-day multiple dose
periods in the trial. CCX872-B is given as hard gelatin capsules. A total of
40 subjects have been enrolled. CCX872-B was well tolerated at all dose
levels tested in the study. No serious adverse events and no withdrawals
from the study due to adverse events have been observed. The preliminary
PK profile indicates that CCX872 plasma concentrations increased relatively
dose-proportionately. CCX872-B appeared to be readily absorbed following
oral dosing. The Tmax was 2 to 3 hours, Cmax ranged from 148 ng/mL at 3 mg
to 12800 ng/mL at 300 mg CCX872-B, AUCinf ranged from 2830 hr.ng/mL to
270000 hr.ng/mL, and t1/2 was approximately 35 hours. In summary, orally
administered CCX872-B was well tolerated in humans at doses ranging from
3 mg to up to 300 mg. CCX872-B has an excellent human PK profile.
Lipid parameters did not consistently improve with either compound; mild
increases in triglycerides and VLDL-cholesterol (vs. PBO) with RO838 were
not significant.
Both compounds were well tolerated. Slight changes in systolic blood
pressure seen with 5 mg RO151 (decreases in day, night and 24h values) and
200 mg RO838 (increases in semi-supine values which were not repeated
in the 24 hour ABPM) were not significant. Increased concentrations of
ACTH and adrenal androgen precursors were found with RO151, but not with
RO838.
In conclusion, modest metabolic improvements were seen, particularly
with the higher dose of RO151. Longer studies are needed to investigate
potential benefits and risks of these compounds.
1127-P
Administration of a GPR40 (FFAR1) Agonist plus Metformin Produces Glucose Normalization and Insulin Sensitization in a Preclinical
Model of Insulin Resistance
1129-P
CS-1050, a Novel PPARγ Ligand, Does Not Elicit the Cardiac Side
Effects Associated With Thiazolidinediones
LY2881835 is a potent, efficacious, and selective GPR40 agonist which
lowers glucose levels and enhances insulin secretion when examined in
preclinical models of T2D. In contrast, metformin (MET) lowers glucose
levels via multiple mechanisms including insulin sensitization and reduced
hepatic glucose production. LY2881835, MET, or LY2881835 plus MET were
administered orally to Zucker fa/fa rats, a rodent model of insulin resistance,
for 14 days. OGTTs were performed on days 1, 7 and 14 with fasting glucose
levels measured 60 minutes following drug administration, i.e., just prior to
administration of the oral glucose bolus. On days 1, 7, and 14 the AUCs for
glucose were significantly lower in animals receiving LY2881835 or MET
compared to the vehicle-treated fa/fa controls and equal to glucose AUCs
for the learn controls. However, glucose AUCs for animals receiving the
combination of LY2881835 plus MET were significantly lower compared to
glucose AUCs for both the fa/fa and lean controls. Glucose levels, fasting
and during the OGTTs, were never below 97 mg/dl for any animal receiving
treatment during the study. These results demonstrate that the combination
of LY2881835 plus MET normalizes glucose levels in a preclinical model of
insulin resistance without producing hypoglycemia. Insulin AUCs during
the OGTTs were elevated in animals receiving LY2881835 and decreased in
animals receiving MET (trends, not significant) reflecting their differences
in glucose lowering mechanisms. Animals receiving LY2881835 plus MET
demonstrated insulin AUCs that were significantly lower than those in
animals receiving only LY2881835 on days 7 and 14. The enhanced insulin
sensitization with combination therapy may explain the significantly lower
glucose in these animals. In summary, LY2881835 plus MET produces
normalization of glucose levels during an OGTT in a preclinical model of
insulin resistance without a risk of hypoglycemia.
Type 2 diabetes (T2DM) is increasing in epidemic proportions and requires
multiple therapeutic options, including insulin sensitizers. Thiazolidinediones
(TZD), such as rosiglitazone (RSG), are highly useful to enhance insulin
sensitization, but have detrimental effects of edema leading to heart failure
and weight gain limiting their use. CS-1050, a derivative of cercosporamide,
is a potent and selective non-TZD PPARγ partial agonist. Similar to RSG,
CS-1050 has anti-diabetic effects but, unlike RSG, CS-1050 did not induce
plasma volume increase or cardiac enlargement in rat models of T2DM.
We studied cardiac side effects of CS-1050 and RSG in 3-month-old male
B6.129S2-Serpine1tm1Mlg/J mice lacking plasminogen activator inhibitor-1,
infused with angiotensin II (AngII; 2.5 ug/kg/min) via subcutaneous osmotic
pumps, which caused cardiac hypertrophy and extensive fibrosis. Seven
days after AngII infusion, mice were assigned to: 1) control (n=20); 2) 0.6g
RSG/kg chow (n=30); or 3) 1.0g CS-1050/kg chow (n=19) for 27 days. Survival
rates in CS-1050 (84%) and control (90%) mice were higher than RSG-treated
mice (53%, p<0.05). Echocardiography at day 21 revealed reduced ejection
fraction in RSG-treated mice (38%, p<0.05) compared to CS-1050 (49%)
and control mice (51%). Heart weight and trichrome-stained fibrosis were
similar in all groups. Expression of marker genes for heart failure (Anp),
fibrosis (Tgfβ) and extracellular matrix genes were not significantly different
among the groups. However, mRNA levels of arrhythmia gene K+ channel
Kcna5 were decreased (p<0.05) in RSG vs. CS-1050 and control mice. In
this model of cardiac fibrosis and hypertrophy, RSG increased mortality,
depressed cardiac function and decreased expression of a key gene involved
in maintenance of cardiac rhythm, while CS-1050 did not have these effects.
The selective PPARγ partial agonist CS-1050 may have a different cardiac
safety profile than TZDs for the treatment of T2DM.
1130-P
An Integrated Analysis of Weight Loss With Combination Naltrexone/Bupropion Therapy by BMI (Obesity) Classification
1128-P
Metabolic Effects and Safety of Two Selective 11β-HSD1 Inhibitors
(RO5093151 (RO151) and RO5027838 (RO838) in Metformin-Treated
Patients With Type 2 Diabetes (T2D)
CAROLINE APOVIAN, COLLEEN BURNS, BRANDON WALSH, KRISTIN TAYLOR,
Boston, MA, La Jolla, CA
Naltrexone sustained-release (SR) / bupropion SR (NB) significantly
reduced body weight vs placebo (PBO) in the four, 56-week, Phase 3 trials of
overweight/obese patients (BMI ≥27 and ≤45 kg/m2). This integrated analysis
investigated weight loss in these 4 trials when stratified by baseline BMI
(obesity class): Class-I (30.0-34.9 kg/m2), Class-II (35.0-39.9 kg/m2), ClassIII (≥40 kg/m2). Treatment group differences (LS mean±SE) in the modified
ITT-LOCF population (≥1 post-baseline weight on study drug) were evaluated
by ANCOVA with treatment, study, and baseline values as covariates.
Baseline characteristics (mean±SD) were similar between treatment arms
(NB [n=2043] or PBO [n=1319): 81% female; 79% Caucasian; 46±11 y; 36±4
kg/m2; obesity Class-I: 37%, Class-II: 36%, Class-III: 25%. Completion rate
was 66% for NB and 59% for PBO. At Week 56, NB resulted in significantly
greater weight loss vs PBO (-7.0 ±0.2% NB vs -2.3±0.2% PBO; p<0.001) and
proportion of patients who attained ≥5% weight loss (53% NB vs 21%
PBO; p<0.001). NB patients experienced favorable shifts in BMI class from
baseline relative to PBO (NB vs PBO: improved = 45% vs 20%, no change =
53% vs 74%, worsened = 2% vs 6%; p<0.001), and a larger proportion of NB
vs PBO subjects shifted to a non-obese BMI from Class-I obesity (17% NB
vs 6% PBO) and Class-II obesity (3% vs 1%). Of note, weight loss with NB
was similar across the 3 obesity classes (NB range: -6.1% to -7.3%; PBOcorrected range: -4.0% to -5.0%, all p<0.001), as was achievement of ≥5%
weight loss (NB range: 49% to 54%, odds ratio relative to PBO: 3.5 to 4.3;
LINDA MORROW, TIM HEISE, MARCUS HOMPESCH, THOMAS R. PIEBER, HANSULRICH HAERING, CHRISTOPH KAPITZA, MARKUS ABT, MARKUS RAMSAUER,
SABINE FUERST-RECKTENWALD, Chula Vista, CA, Neuss, Germany, Graz, Austria,
Tübingen, Germany, Basel, Switzerland
Two selective 11β-HSD1 inhibitors (RO151 and RO838) were assessed in
a randomized, controlled study in patients with T2D who either received
placebo (PBO) (21 pts), RO151 5mg BID (24 pts) or 200mg BID (20 pts), or
RO838 50 mg QD (21 pts) or 200mg QD (24 pts) for 28 days plus a stable
dose of metformin. Metabolic assessments (including oral glucose tolerance
and/or standardized meal tests) and safety assessments (including ACTH
stimulation test) were done at baseline and around 14 and 28 days of
treatment.
Key demographics at baseline were similar between groups (mean
ranges: age 53-57 yrs, BMI 32-33 kg/m2, diabetes duration 6.5-9.4 yrs,
FPG 170 -174 mg/dL ). Despite the short treatment duration, both RO151
and RO838 showed trends for improved HbA1c. Improvements in several
insulin sensitivity parameters were seen with 200 mg RO151 but were
not significant. While there was a slight decrease in body weight with
PBO (-0.28 kg), greater reductions (-0.86 to -1.67 kg) occurred in all active
treatment groups (reaching statistical significance vs.PBO in the RO151
200mg BID group only (LSmean -1.39 kg, 95% CI -2.54, -0.23 kg; p=0.019).
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YANYUN CHEN, MIN SONG, PRANAB MAITI, CHAFIQ HAMDOUCHI, ANNE REIFEL MILLER, Indianapolis, IN, Bangalore, India
Clinical Diabetes/
Therapeutics
MARICELA R. RAMIREZ, ALAN R. COLLINS, YUELAN REN, CHRISTOPHER J.
LYON, MASANORI KUROHA, KAZUSHI ARAKI, JUN TANAKA, SATOKO WAKIMOTO, NAOKO NAKAI, TAKAHIRO NAGAYAMA, JUN OHSUMI, HUBERT CHOU,
WILLA HSUEH, Houston, TX, Tokyo, Japan, Edison, NJ
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
all p<0.001). The safety/tolerability profile of NB32 was consistent with
its individual components; the most common adverse events were nausea
(32%), constipation (19%), headache (18%), and vomiting (11%). Thus, the
clinically significant weight loss associated with NB was consistent across
a wide BMI range, and resulted in an approximately 3-fold greater transition
from Class-I/II obese to non-obese BMI.
1131-P
LX4211 Efficacy Improves With Increasing Baseline Hemoglobin
A1C
POSTERS
Clinical Diabetes/
Therapeutics
IKE OGBAA, HALLIE ROZANSKY, PABLO LAPUERTA, BRIAN ZAMBROWICZ, PHILLIP BANKS, KENNY FRAZIER, ARTHUR SANDS, The Woodlands, TX
Baseline hemoglobin A1C (A1C) influences the choice of antidiabetic
therapy, as well as its efficacy, in patients with type 2 diabetes (T2DM).
An unmet medical need remains for antidiabetic agents, with low intrinsic
risk for causing hypoglycemia, which can provide clinically meaningful A1C
reductions across a wide range of baseline A1Cs. LX4211 reduces A1C in a
glucose dependent manner through dual inhibition of SGLT1 and SGLT2, the
major sodium-glucose transporters in the gastrointestinal tract and kidney.
In a 12-week dose-ranging study, 299 patients with inadequately controlled
T2DM on metformin were randomly assigned to receive LX4211 (doses of
75 mg qd, 200 mg qd, 200 mg bid, or 400 mg qd) or placebo. The primary
endpoint was change in A1C. Mean demographics were: age 55.9 years, A1C
8.1%, and body mass index 33.1 kg/m2. We report a subgroup analysis of A1C
Supported by: Novartis Pharma AG
1133-P
Saxagliptin Reduces A1C and Is Well Tolerated in Patients With
Type 2 Diabetes Receiving Concomitant Statin Therapy
BRIAN BRYZINSKI, ELSIE ALLEN, WILLIAM COOK, BOAZ HIRSHBERG, Wilmington, DE, Princeton, NJ
The JUPITER study and other trials have reported an increased risk for
development of diabetes with statin treatment. Given these findings, we
examined whether glycemic control with saxagliptin (SAXA) 2.5 and 5 mg/d
was affected by concomitant statin therapy. Pooled data from 9 placebocontrolled phase 3 studies with a primary 24-week treatment period were
analyzed (4 monotherapy, 2 add-on to metformin, and 1 each of add-on
to sulfonylurea, thiazolidinedione, or insulin). Safety was assessed in 11
studies and in an extended pool of 20 phase 2/3 studies. Greater mean
reductions in glycated hemoglobin (A1C) with SAXA, compared with control,
were observed for patients with any statin use and no statin use (Table).
No treatment group-by-baseline statin use interaction was observed
(interaction P=0.47). The proportions of patients with adverse events (AEs)
in the treatment groups were comparable with or without statin use. Serious
AEs, deaths, and symptomatic confirmed hypoglycemia (fingerstick glucose
≤50 mg/dL) were few and similar in patients with any statin use compared
with no statin use. Similar safety findings were observed in the extended
safety pool. SAXA improves glycemic control and is generally well tolerated
in patients with type 2 diabetes and is not affected by concomitant statin
therapy.
reductions in patients stratified by baseline median A1C: >7.8% or ≤7.8%.
LX4211 led to robust reductions in A1C with greater reductions achieved in
patients with higher baseline A1C levels in all active treatment groups.
1132-P
Efficacy and Safety of Vildagliptin in Triple Combination With Metformin Plus Sulfonylurea in Subgroup of Patients With T2DM and
Baseline HbA1c ≤8%
VALENTINA LUKASHEVICH, MAKO ARAGA, WOLFGANG KOTHNY, East Hanover,
NJ
The broadly used combination of metformin (Met) and sulfonylurea (SU)
often fails to bring patients to glycemic goal and the addition of a third oral
antidiabetic drug (OAD) or insulin is required. Our previously reported doubleblind placebo-controlled 24-week study in T2DM patients inadequately
controlled with Met plus SU (HbA1c ≥7.5% and <11%) demonstrated that
the addition of vildagliptin (Vilda) 50 mg bid reduced HbA1c by 1.0% from a
baseline of 8.8%. We now assessed which patient population could actually
achieve glycemic control with this triple combination. We present the
efficacy and safety of Vilda in a subgroup of patients with baseline HbA1c
≤8% (N=84).
In this subgroup with background demographic characteristics similar to
the overall study population, Vilda demonstrated a reduction in HbA1c of
0.6% compared to an increase of 0.2% with placebo (Figure). Significantly
more Vilda patients (38.6%) achieved an HbA1c target of <7.0% vs. placebo
(13.9%) (p=0.014). Overall, Vilda demonstrated a good safety profile with low
and comparable to placebo incidence of hypoglycemia.
Vilda could be successfully used as a third OAD in patients with T2DM
and HbA1c ≤8% failing on Met plus SU, as a significant part of this patient
population could achieve HbA1c treatment target before initiating an insulin
therapy.
Supported by: Bristol-Myers Squibb/AstraZeneca
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confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL, ≤1%) were few and
similar across treatment and CV risk groups. Two patients in the high CV risk
PBO group died. SAXA is effective, with overall AEs similar to PBO and no
increased risk of hypoglycemia in high CV risk patients.
1134-P
Saxagliptin (SAXA) as Add-On to Metformin (MET) + Sulfonylurea
(SU): Outcomes Stratified by Baseline A1C and Patient Characteristics
ROBERT G. MOSES, SANJAY KALRA, JOHN MONYAK, HELEN YEH, Wollongong,
Australia, Karnal, India, Wilmington, DE
Supported by: Bristol-Myers Squibb/AstraZeneca
1136-P
Association Between PPAR-γ Gene Polymorphism and Response to
Pioglitazone Therapy in Bangladeshi T2DM Subjects
MASUMA PARVIN, AK AZAD CHOWDHURY, TAPASH ROY, BEGUM ROKEYA,
Dhaka, Bangladesh, London, United Kingdom
Present study was undertaken to assess association between PPAR-γ gene
variants and response to pioglitazone with T2DM subjects in Bangladesh.
Evaluating case history 77 patients were randomized to receive pioglitazone
(30 mg once daily) for three months. DNAs were extracted from whole blood
of patients, amplified with exon B using primers forward: 5-ACT CTG GGA
GAT TCT CCT ATT GGC and primers reverse 5-CTG GAA GAC AAA CTA CAA
GAG introducing HaeIII recognition site for digestion and size polymorphism
to distinguish alleles. 61 patients [HbA1c 7.2±0.7%, M ±SD] completed study.
Outcome measures included BMI, HbA1c, fasting (FBG) and 2 hours blood
glucose (2hBG), insulin levels, total cholesterol (TC), high (HDL-C) and low
density lipoprotein cholesterol (LDL-C),triglyceroides, SGPT and creatinine
for each month. Response to therapy was defined as either ≥10% decrease
in Fasting Blood Glucose (FBG) or ≥1% decrease in HbA1c after 3 months
treatment. Frequencies and response rate were 29.5% and 83.33% in
Pro12Ala, 70.5% and 76.74% in Pro12Pro variants respectively. No Ala12Ala
was found. In Pro12Pro HbA1c was reduced from 7.2 to 6.8 (p <0.005), Fasting
Serum Insulin [µU/ml] from 15.9±8.0 to 11.0±5.6 (p <0.006). Enhancement in
HOMA%S from 48.0 to 73.0 (p <0.000), QUICKI from 0.51 to 0.58 (p <0.001),
decrease of HOMA IR from 5.3 to 2.7 (p <0.001) were observed. LDL-C (mg/
dl) reduction (p <0.046) and BMI [kg/m2] enhancement from 27.1 to 27.5 (p
<0.002) were in Pro12Pro. In Pro12Ala reduction of HbA1c from 7.4 to 6.5 (p
<0.036), increase of HOMA%B from 146.8 to 169.0 (p <0.515) and other nonsignificant positive changes were noticed. In conclusion, before treatment
no difference in baseline bio-markers between two groups was observed
but after treatment Pro12Ala differed significantly from Pro12Pro and was
better in FBG (p <0.039), HOMA% B (p <0.006), BMI (p <0.094) and FSI (p
<0.093) with lower risk. Pro12Ala achieved lower FBG and more active β cell
function compared to Pro12Pro variants.
Supported by: Bristol-Myers Squibb/AstraZeneca
1135-P
Saxagliptin (SAXA) Reduces A1C and Is Well Tolerated in Patients
With Type 2 Diabetes (T2DM) and High Framingham 10-Year Cardiovascular (CV) Risk
ENZO BONORA, ELSIE ALLEN, BRIAN BRYZINSKI, BOAZ HIRSHBERG, WILLIAM
COOK, Verona, Italy, Princeton, NJ, Wilmington, DE
Recent trial results in patients with T2DM suggest that glycemic targets
should be personalized and the burden of hypoglycemia and comorbid
conditions, such as CV disease, carefully considered. A post hoc analysis
was performed of data pooled from 5 phase 3, placebo (PBO)-controlled,
24-week studies of SAXA (2 of SAXA 5 mg/d monotherapy and 1 each
of SAXA 5 mg/d add-on to metformin, glyburide, or thiazolidinedione),
stratified by Framingham 10-year CV risk score (<20% vs ≥20%). Patients
(52% women) had a mean age of 55 (range, 18-77) years and a mean body
mass index of 30 (range, 17-45) kg/m2. Week 24 improvements in glycated
hemoglobin (A1C), fasting plasma glucose, and 2-hour postprandial glucose
were greater with SAXA vs PBO (Table). Differences between CV risk groups
were investigated, with no important differences between groups based on
Framingham risk. More patients achieved A1C <7% with SAXA vs PBO in
both CV risk groups. In the high CV risk group, the proportion of patients
with adverse events (AEs) was similar with SAXA (74%) and PBO (73%).
Serious AEs (2%-5%) and reported hypoglycemia (7%-8%) and symptomatic
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Therapeutics
In a placebo (PBO)-controlled, 24-week phase 3b trial in patients with
T2DM inadequately controlled with MET+SU (NCT01128153), adding SAXA 5
mg/d to MET+SU significantly reduced A1C vs PBO. A post hoc analysis was
performed with data stratified by patient age (<65 y, ≥65 y), race (white vs
Asian), baseline A1C (<8%, 8%-<9%, ≥9%), and BMI (<30 kg/m2, ≥30 kg/m2).
Across categories of age (interaction P value=0.40), race (P=0.36), baseline
A1C (P=0.12), and BMI (P=0.99), A1C was reduced more with SAXA vs PBO
(Tables 1, 2). Adverse events were comparable across treatment groups
and categories and were reported by 58%-85% of patients. Symptomatic
confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL) was reported by 2
Asian patients receiving SAXA, with baseline A1C <8% and BMI <30 kg/m2.
When added to MET+SU, SAXA improves A1C across categories of age,
race, baseline A1C, and BMI and is generally well tolerated.
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
-53.7 ± 8.6 mg/dL (p<0.0001). In summary, this pooled analysis from a large,
global Phase 3 program shows that once-daily linagliptin improves measures
of β-cell function relative to placebo. The effect of long-term treatment with
linagliptin on β-cell function remains to be determined.
1137-P
WITHDRAWN
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1139-P
Urinary Tract Infection (UTI) With Canagliflozin (CANA) in Subjects
With Type 2 Diabetes Mellitus (T2DM)
CANA, an SGLT2 inhibitor, inhibits renal glucose reabsorption, resulting
in increased glucosuria. The impact of this on UTI was assessed in subjects
with T2DM in placebo (PBO)-controlled, Phase 3 studies of CANA using
a UTI case report form to characterize the presentation and severity of
events. Findings are reported for pooled analyses of subjects from four 26wk studies (DS1; N = 2,313) and subjects with moderate renal impairment
(eGFR ≥30 and <60 mL/min/1.73 m2) from four 18- or 26-wk studies (DS2;
N = 1,085), and for the CANagliflozin cardioVascular Assessment Study
(CANVAS; 52-wk interim safety analysis) in subjects with a history or high
risk of cardiovascular disease (N = 4,327); subjects with a history of UTI were
not excluded from these studies.
Across datasets analyzed, the proportion of subjects with UTI was slightly
higher with CANA than PBO, with no increase in recurrent or serious events
or in UTI-related discontinuations; upper UTI rates were low and similar
across groups. UTI was more common in women than men, but the increased
incidence with CANA was consistent between genders. UTIs generally
occurred within 26 wks of starting CANA, with a subsequent attenuation
in incidences. Median time to first symptomatic UTI tended to be earlier
with CANA, but median duration and severity of symptoms of UTIs were
similar with CANA and PBO. In summary, a slight increase in UTI rates, with
no increase in serious or upper UTI, was seen with CANA in subjects with
T2DM.
POSTERS
Clinical Diabetes/
Therapeutics
LINDSAY E. NICOLLE, GEORGE CAPUANO, ALBERT FUNG, KEITH USISKIN, Winnipeg, MB, Canada, Raritan, NJ
1138-P
The Dipeptidyl Peptidase (DPP)-4 Inhibitor Linagliptin Improves
β-Cell Function and Postprandial Glucose in Type 2 Diabetes (T2D)
SANJAY PATEL, TIM HEISE, MARTIN LARBIG, SONJA WEBER, THOMAS SECK,
UWE HEHNKE, HANS J. WOERLE, KLAUS DUGI, Bracknell, United Kingdom, Neuss,
Germany, Ingelheim, Germany
In patients with T2D, progressive deterioration of β-cell function
contributes to the development of hyperglycemia. Treatment with incretinbased therapies may potentially improve β-cell function and delay this
progressive deterioration. Here we investigated the effect of the DPP4 inhibitor linagliptin on β-cell function, as assessed by changes in
Homeostasis Assessment Model (HOMA)-%β index and incremental 2-hour
postprandial glucose (PPG) levels after a meal tolerance test. Data from
six randomized, 24-week, placebo-controlled, Phase 3 trials of linagliptin 5
mg qd were pooled for this analysis. In total, 2960 patients were available:
linagliptin, n=2077; placebo, n=883. Mean ± SD baseline characteristics for
this pooled dataset were as follows: age, 56.5 ± 10.2 years; BMI, 29.2 ± 5.1
kg/m2; HbA1c, 8.2 ± 0.9%; FPG, 167.1 ± 44.9 mg/dL. The % of patients with
T2D >5 years was 53.8%. Mean drug exposure was 163 ± 33 days. Subgroup
analyses were conducted in patients who had baseline and week-24 data
for HOMA-%β (n=1770) and PPG (n=224) assessments. Mean ± SD baseline
HOMA-%β and PPG for linagliptin vs placebo were 54.6 ± 101.6 vs 49.4 ± 47.7
(mU/L)/(mmol/L) and 267.3 ± 73.7 vs 253.2 ± 73.6 mg/dL, respectively. After
24 weeks’ treatment, the adjusted mean ± SE change from baseline in HOMA%β with linagliptin vs placebo was 16.7 ± 4.3 vs 0.2 ± 5.1 (mU/L)/(mmol/L);
the placebo-adjusted mean change for linagliptin was 16.5 ± 4.6 (mU/L)/
(mmol/L) (p=0.0003). Similarly, after 24 weeks’ treatment, the adjusted mean
± SE change from baseline in PPG with linagliptin vs placebo was -44.6 ± 6.0
vs 9.1 ± 7.9 mg/dL; the placebo-adjusted mean change for linagliptin was
1140-P
Potent Anti-Hyperglycemic Effects of Panax Notoginseng Extract
Containing Dammarane-Type Triterpenes in Human Subjects
MITSURU NOMURA, HIDEAKI IWASAKI, NORIYUKI SUZUKI, AYUMI MURATA,
TAKU IWAMOTO, KUMIKO KITAMURA, YUSUKE TAKAMURA, MISAO KOIDE, MICHIAKI MURAKOSHI, HOYOKU NISHINO, Odawara, Japan, Kyoto, Japan
The root of Panax notoginseng has been used as an herbal treatment
in traditional Chinese medicine for centuries, and a group of saponins is
considered as the major active ingredients. Since saponins are converted
into dammarane-type triterpenes as aglycones during the digestion process,
we produced a dammarane-type triterpene extract (DTE) from the root of
Panax notoginseng in which all sugars were fully removed from saponins.
Previously we reported that DTE has hyperglycemia inhibitory effect in
mouse obese/diabetic models by enhancement of glucose uptake in skeletal
muscle (0109-LB, ADA 71st Scientific Sessions, 2011). Panaxatriol, one of
the dammarane-type triterpenes in DTE, has been found to improve whole
&
For author disclosure information, see page 829.
A296
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ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1141-P
MIAN WU, JUNXI LU, YAN HUANG, KAIFENG GUO, HAOYONG YU, LEI ZHANG,
YUQIAN BAO, HAIBING CHEN, WEIPING JIA, Shanghai, China
Aims: At present, conclusive opinions does not exist to support the
tenet that vitamin D is associated with type 2 diabetes mellitus (DM) or
its supplementation improve glucose metabolism of type 2 DM. In addition,
reports about Chinese population were quite limited. So this study aimed to
elucidate the relationship between serum 25-hydroxyvitamin D3 (25(OH)D3)
level and β-cell function in Chinese subjects, and the effect of vitamin D3
supplementation on patients with type 2 DM.
Methods: Two human studies were performed: (1) a cross-sectional study
of 78 healthy, glucose-tolerant volunteers and 399 type 2 DM subjects, in
whom data were used to assess the relationship between serum 25(OH)
D3 level and β-cell function; and (2) a longitudinal study of 22 type 2 DM
patients treated with 800 IU cholecalciferol per day for 6 months and a
control group of 22 matched type 2 DM patients, baseline and follow-up
records were collected to explore the effects of intervention. C-peptide and
its derivatives were used to assess β-cell function.
Results: In the cross-sectional study, serum 25(OH)D3 was independently
correlated with β-cell function in men. However, the correlation between
serum 25(OH)D3 and β-cell function in female group was quenched after
adjustment for a number of confounding factors. In the longitudinal study,
serum fasting C-peptide (FCP) was significantly increased (P = 0.030) in 22
type 2 DM patients after supplementation with cholecalciferol, whereas
there was no statistical change in the control group (P = 0.811).
Conclusions: There was a sex difference in the relationship between
serum 25(OH)D3 and β-cell function in a Chinese population. Treatment with
800 IU cholecalciferol daily for 6 months increased insulin secretion.
P value
1143-P
DPP4 Inhibition Ameliorates Intramuscular Fat Content in Patients
With IGT or Type 2 DM: Comparing Alogliptin and Voglibose
MASANOBU TSUCHIYA, HIROSHI MAEGAWA, Yanai, Japan, Otsu, Japan
We reported that the DPP4 inhibitor, Alogliptin treatment(ALO) ameliorates
both liver fat content andLDL-size, but Voglibose treatment (VOG) does
not. To clarify whether ALO maydecrease intramuscular fat content, the 37
patients comprised of 25 IGT and 12 DM were recruited. The 37 patients
were randomly assigned to the treatment for 12weeks with either ALO
(25mg daily) or VOG (0.6mg daily). A 75-g OGTT,laboratory measurements and
computedtomography (CT) to determine intramuscular CT values (Hounsfield
unit,HU) were performed at baseline and after the treatment. Earlyinsulin
secretion and postprandial hyperglycemia were assessed by delta IRI / deltaPG
for 30. Intramuscular fat content was evaluated by Psoas major muscle CT
values and Paraspinal muscle CT values in terms of the mean values for two
different sites respectively. 12 weeks after the treatment, ALO significantly
decreased plasma glucose level at 0min (P<0.05), 30 min (P<0.05), 60 min
(P<0.01) and 120min (p<0.001) after the glucose load and also showed higher
IRI/ PG(0.65±0.37, 1.27±1.31, P<0.05). VOG significantly decreased plasma
glucose level at 120m (P<0.001). ALO showed higher Psoas major muscle
CT values (48.6± 5.7, 51.1 ± 4.8 HU, P<0.01), Paraspinal muscle CT values
(53.2 ± 5.4, 54.5 ± 5.3 HU, P<0.01), HDL-c (P<0.05) and had lower triglyceride
(P<0.01), as compared with those of the baseline but VOG does not. In this
treatment, before and after treatment, there were no differences in BMI,
HOMA-R, adiponectin, abdominal visceral fat area, subcutaneous fat area in
both groups. In conclusion, DPP4 inhibition may decrease intramuscular fat
content in patients with IGT or type 2 DM.
1142-P
Comparative Effects of Aleglitazar- a PPAR-α/γ Agonist- versus
Pioglitazone on Glycemia, Insulin Sensitivity and Lipids in Patients
With Type 2 Diabetes and Stage 3 Chronic Kidney Disease
MARKOLF HANEFELD, GIANCARLO VIBERTI, KLAS MALMBERG, NADEJDA MUDIE, TERESA URBANOWSKA, SYLVIE MEYER REIGNER, MATTHIAS HERZ, Dresden,
Germany, London, United Kingdom, Stockholm, Sweden, Basel, Switzerland
Aleglitazar (ALE) is a balanced PPAR-α/γ agonist in Phase III for cardiovascular risk reduction following acute coronary syndrome in patients with
type 2 diabetes (T2D). As well as evaluating renal effects of ALE in stage 3
chronic kidney disease in patients with T2D, this Phase IIb study (AleNephro)
assessed effects on glycemia, insulin sensitivity and lipids vs the established
PPAR-γ agonist, pioglitazone (PIO). Patients were randomized to 52 weeks’
double-blind treatment with ALE 150 µg/d or PIO 45 mg/d in addition to
pre-existing diabetes therapy (5%, drug-naïve; 44%, monotherapy; 51%,
combination therapy), and 8 weeks’ follow-up. Endpoints included change
from baseline in HbA1c, homeostasis model assessment of insulin resistance
(HOMA-IR), C-peptide and lipids at 52 weeks. Similar HbA1c reductions were
seen with ALE vs PIO (Table), with greater reductions (> 1%) in patients with
HbA1c > 7.5% at baseline. In both treatment groups, reductions in HbA1c
were similar in patients taking/not taking metformin at baseline but greater
in those on sulfonylurea at baseline vs those without. Similar reductions in
HOMA-IR and C-peptide and greater improvements in lipids were seen with
ALE vs PIO (Table). In AleNephro, while ALE 150 µg/d had comparable effects
to PIO 45 mg/d on diabetes control and insulin sensitivity, a significantly
better effect was seen on atherogenic dyslipidemia.
&
PIO 45 mg
(n = 152)
HbA1c, %
All patients
Baseline
7.5 ± 0.9
7.6 ± 0.9
0.41
Absolute change at EOT (95% CI)
-0.67 (-0.87, -0.48) -0.76 (-0.96, -0.56)
Patients with baseline HbA1c > 7.5†
Baseline
8.5 ± 0.8
8.4 ± 0.8
Absolute change at EOT (95% CI)
-1.02 (-1.38, -0.66) -1.23 (-1.59, -0.87) 0.24
HOMA-IR (calculated), µU/mL*mg/dL‡
Baseline
3.15 (1.99-5.82)
3.37 (2.16-4.98)
0.26
% change at EOT (95% CI)
-47.1 (-54.3, -38.7) -42.3 (-50.1, -33.2)
C-peptide, ng/mL
Baseline
3.33 ± 1.83
3.15 ± 1.67
0.22
Absolute change at EOT (95% CI)
-0.85 (-1.13 -0.58) -0.68 (-0.95, -0.40)
Triglycerides, mg/dL§
Baseline
204.1 ± 143.3
192.1 ± 105.2
< 0.001
% change at EOT (95% CI)
-33.6 (-41.1, -26.1) -14.1 (-21.7, -6.5)
HDL-C, mg/dL§
Baseline
46.4 ± 12.7
47.3 ± 12.5
< 0.001
% change at EOT (95% CI)
22.0 (17.4, 26.6)
11.6 (6.9, 16.3)
LDL-C, mg/dL‡§
Baseline
104.0 (82-130)
112.0 (90-135)
0.04
% change at EOT (95% CI)
-7.3 (-13.2, -1.0)
-0.3 (-6.8, 6.6)
Data from safety analysis set. ALE = aleglitazar, PIO = pioglitazone, EOT = end
of treatment.
* Mean ± SD values provided apart from median (interquartile range) for
HOMA-IR and LDL-C at baseline. † At baseline: ALE, n = 58; PIO, n = 70. ‡
Analysis on log transformed scale. § Data from full analysis set: ALE, n = 149;
PIO, n = 148.
Oral Supplementation With Cholecalciferol 800 IU Improved β-Cell
Function in Chinese Type 2 Diabetic Patients
ADA-Funded Research
ALE 150 µg
(n = 149)
1144-P
Empagliflozin Monotherapy for 12 Weeks Improves Glycemic Control in Japanese Patients With Type 2 Diabetes (T2DM)
TAKASHI KADOWAKI, MASAKAZU HANEDA, NOBUYA INAGAKI, ATSUSHI TANIGUCHI, MASASHI SAKAMOTO, KAZUKI KOIWAI, HENNING RATTUNDE, HANS
J. WOERLE, ULI C. BROEDL, Tokyo, Japan, Asahikawa, Japan, Kyoto, Japan, Ingelheim, Germany
A Phase II trial investigated the efficacy and safety of empagliflozin
(EMPA) monotherapy in Japanese patients with T2DM. Patients (mean age
57.5 [SD 9.9] years; mean BMI 25.5 [SD 3.9] kg/m2) were randomized doubleblind and treated with EMPA 5 mg (n=110), 10 mg (n=109), 25 mg (n=109) or
50 mg (n=110) qd or placebo (PBO; n=109) for 12 weeks. The primary endpoint
was change from baseline in HbA1c at week 12. Secondary endpoints were
the proportion of patients with baseline HbA1c ≥7% who reached HbA1c <7%
and change from baseline in FPG at week 12.
For author disclosure information, see page 829.
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A297
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Parameter*
Clinical Diabetes/
Therapeutics
body insulin resistance by using the hyperinsulinemic-euglycemic clamp in
mice and enhance phosphorylation of Akt in skeletal muscle (1933-P, ADA
72nd Scientific Sessions, 2012). The aim of this study was to evaluate the
anti-hyperglycemic effects of DTE in human subjects. Using a double-blind,
placebo-controlled design, Japanese men and women (n=53; aged 39-69
years) with slightly higher blood glucose levels (FBG: 79.0-135.0 mg/dL, HbA1c:
5.0-6.5 %, GA: 11.6-18.1 %), consumed 180 mg/d DTE or placebo tablets for
16 weeks. The time for ingestion of test tablets was not limited, but it was
recommended that the subjects take test tablets after breakfast to maintain
compliance. The blood-sugar monitoring revealed a significant reduction in
FBG (-2.73±6.17 mg/dL) in the DTE group, as compared with that in the placebo
controls (+1.07±6.66 mg/dL; P=0.036). Throughout this study, no adverse
effects were observed. For confirmation of safety, 16 healthy subjects were
given DTE tablets for 16 weeks. And none indicated changes in hematological
and relevant biochemical parameters were apparent. From these results, DTE
appears to be a promising agent for the control of blood-sugar level.
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1146-P
Efficacy of Concomitant Therapy in Japanese Type 2 Diabetes Mellitus Patients With Insulin and Sitagliptin, a DPP-4 Inhibitor
TOMOKO NAKAGAMI, RISA IDE, NAOKO IWASAKI, MAKIKO OGATA, JUNKO
OYA, MARI OSAWA, NOBUE TANAKA, HIROKO TAKAIKE, ASAKO SATO, JUNNOSUKE MIURA, YASUKO UCHIGATA, Tokyo, Japan
This open-label observational study has examined the efficacy of the
additional administration of sitagliptin with respect to lowering HbA1c and
body weight (BW) in type 2 diabetes (T2DM) patients insufficiently glycemic
controlled by insulin. The study comprises 64 T2DM patients with mean
age 59±15 years old, duration of DM 20±7 years, and BMI 25.8±4.4 kg/m2.
Plasma glucose (PG), C-peptide (CPR) and glucagon on meal tolerance test
(MTT), HbA1c and BW were compared between just before and 4 months
after the administration by paired t-test. Multivariate stepwise logistic
regression model with backward form was used to identify characteristics
of the patients in whom HbA1c lowered without BW gain by this regimen.
Four months after the administration, there were significant decreases in
mean HbA1c (8.6±1.2 to 7.8±1.2%) and mean PG at 60 min (244.2±62.0 to
215.0±61.9 mg/dL) and 120 min (231.5±72.2 to 198.3±67.5 mg/dL) on MTT (all
p<0.001); significant increases in mean CPR before (1.1±0.8 to 1.2±0.8 ng/
mL) and 60 min (1.7±1.10 to 1.8±1.1 ng/mL) on MTT (all p<0.05); and significant
decreases in mean glucagon at 60 min (88.3±27.8 to 81.0±25.1 pg/mL) and
120 min (85.7±30.7 to 79.5±27.4 pg/mL) on MTT (all p<0.05). There was no
change in the basal insulin dose after 4 months, but the additional insulin dose
showed a significant decrease (0.26±0.20 to 0.25±0.19 units/kg, p=0.005).
There was no significant change in mean BW and no severe hypoglycemia.
Eventually, HbA1c decreased in 50 patients among 64, but 29 of 50 increased
their BW. Logistic regression analysis showed that the patients in whom
HbA1c lowered without BW gain independently related to CPR (1.0 ng/mL) at
60 min and 120 min on MTT at the pre-administration phase with odds ratios
(95% CI) of 9.8 (1.2-82.3) and 0.1 (0.02-0.6), respectively and did not relate
to glucagon level. Additional administration of sitagliptin may be effective
in insulin treated T2DM patients who have non-delayed pattern of insulin
secretion.
POSTERS
Clinical Diabetes/
Therapeutics
EMPA significantly reduced HbA1c and FPG vs PBO; more patients reached
HbA1c <7% with EMPA than with PBO. Further analyses showed significant
reductions in weight vs PBO with all doses of EMPA, and significant
reductions in systolic blood pressure (SBP) vs PBO with all doses except
EMPA 5 mg. Adverse events (AEs) occurred in 32.7%, 37.6%, 36.7%, 38.2%
and 42.2% of patients on EMPA 5 mg, 10 mg, 25 mg, 50 mg and PBO,
respectively. Hypoglycemia (plasma glucose ≤70 mg/dL and/or requiring
assistance) was rare; none required assistance. AEs consistent with urinary
tract infection were reported in 1 patient (0.9%) each on EMPA 10, 25, 50 mg
and PBO and 0 on EMPA 5 mg. AEs consistent with genital infection were
reported in 1 patient (0.9%) each on EMPA 5, 10, and 50 mg and 0 on EMPA
25 mg or PBO.
To conclude, EMPA as monotherapy for 12 weeks significantly reduced
HbA1c, FPG, weight and SBP versus PBO, and was well tolerated in Japanese
patients with T2DM.
1147-P
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
SNPs Related to the Glucose Lowering Effect of Metformin: Do they
Affect Plasma Concentrations of Metformin (MPC) and their Effects
on Insulin Requirements (DDI)?
1145-P
MATTIJS OUT, ADRIAAN KOOY, MATTHIJS L. BECKER, RON H.N. VAN SCHAIK,
PHILIPPE LEHERT, COEN D.A. STEHOUWER, Hoogeveen, Netherlands, Rotterdam,
Netherlands, Louvain, Belgium, Maastricht, Netherlands
WITHDRAWN
Several genes involved in the pharmacokinetics and pharmacodynamics
of metformin may influence the glucose-lowering effect of metformin.
However, their clinical importance is yet unknown. In the population of
the HOME trial (a placebo-controlled, randomised trial with patients with
type 2 diabetes, treated with insulin) we genotyped 4 single nucleotide
polymorphisms (SNPs) of such genes to detect their potential influence on
MPC. Furthermore, we studied the potential of these SNPs and the MPC
to predict the reduction of DDI, an important action of metformin in insulin
therapy.
We genotyped 164 metformin users of the HOME trial for polymorphisms
in the genes coding for organic cation transporter 1 (OCT1, rs12208357 and
rs622342), multidrug and toxin extrusion 1 transporter (MATE1, rs2289669)
and Ataxia Telangiectasia Mutated (ATM, rs11212617). The daily dose of
metformin (DDM) and DDI have been reported previously (Arch Int Med
2009). MPC was measured using HPLC-UV.
Stepwise linear analysis showed that the SNP rs11212617 (ATM) had a
significant effect on MPC (p < 0.001), but not on DDI. Other SNPs studied did
not affect MPC or DDI (P values ranging between 0.30-0.92 and 0.40-0.72,
respectively).
Overall, we found a significant relationship between MPC and DDI (most
pronounced after adjustment for renal clearance): an increase of MPC with
1mg/ml was associated with a decrease of DDI with 3.51 IU (95% CI: -6.70
to -0.32; p=0.01). DDM predicted the MPC (p<0.001) and was strongly
correlated with a reduction of DDI: an increase of DDM with 1 gram/day
was associated with a mean decrease of DDI with 10.57 IU (95% CI: -17.20
to -3.94; p<0.001).
Of the SNPs studied, only the ATM SNP has an effect on MPC, but its
clinical relevance is unclear, since this SNP has no effect on DDI. DDM is a
strong predictor of the effect of metformin on DDI, independent of all SNPs
studied.
Supported by: Altana AG; Lifescan, Inc.; E. Merck/Santé; Merck Sharpe & Dohme;
Novo Nordisk, Inc.
&
For author disclosure information, see page 829.
A298
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ADA-Funded Research
1150-P
Efficacy and Safety of Alogliptin in Subjects With Type 2 Diabetes: A
Multicenter, Randomized, Double-Blind, Placebo-Controlled, Phase
3 Study in Mainland China, Taiwan and Hong Kong
ELIZABETH ROUND, YUE SHENTU, GREGORY T. GOLM, EDWARD A. O’NEILL, IRA
GANTZ, SAMUEL S. ENGEL, KEITH D. KAUFMAN, BARRY J. GOLDSTEIN, Whitehouse Station, NJ
CHANGYU PAN, PING HAN, QIUHE JI, CHENGJIANG LI, JUMING LU, JINKUI
YANG, WENHUI LI, JIAOE ZENG, JULIANNA CHAN, AN-TSZ HSIEH, Beijing, China,
Shenyang, China, Xi’an, China, Hangzhou, China, Wuhan, China, Sha Tin, Hong Kong,
Taipei, Taiwan
Patients being treated with a sulfonylurea (SU) in combination with
metformin (MET) for at least 10 weeks were randomized in a 1:1 ratio to
sitagliptin (SITA) 100 mg/day or placebo (PBO) for 24 weeks in a multicenter,
double-blind study. Of 427 patients randomized, 388 (90.9%) completed the
study. At Week 24, the least squares mean (95% confidence interval [CI])
changes from baseline in HbA1c (%, SITA, -0.84 [-0.97, -0.71] vs. PBO, -0.16
[-0.28, -0.03]), 2-hour post-meal glucose (mg/dL, SITA, -36.8 [-45.2, -28.4] vs.
PBO, -3.3 [-11.7, 5.0]) and fasting plasma glucose (mg/dL, SITA, -13.2 [-18.8,
-7.7] vs. PBO, 5.3 [-0.2, 10.9]) were greater with SITA vs. PBO (p<0.001). The
incidence of drug-related adverse events was numerically greater with SITA
(n=13, 6.2%) vs. PBO (n=5, 2.4%). The between-group difference in drugrelated adverse events (95% CI) was 3.8% (-0.0, 8.2). This difference was
driven mostly by a higher incidence of drug-related hypoglycemia (HYPO)
with SITA (n=12, 5.7%) vs. PBO (n=4, 1.9%); these findings are consistent
with previous observations, where a drug not known to cause HYPO
increases the incidence of hypoglycemic events when added to SU. The
overall incidence of symptomatic HYPO with SITA was n=27 (12.9%) and
with PBO was n=7 (3.3%). The between-group difference in the overall
incidence of symptomatic HYPO (95% CI) was 9.6% (4.6, 15.1), p<0.001. The
two treatment groups were generally similar in other aspects of their safety
profiles. Changes in body weight were small in both groups at Week 24; the
between-group difference (95% CI) of -0.2 (-0.7, 0.3) kg was not significant
(p=0.521). In this study, SITA 100 mg/day was generally well tolerated and
provided good glycemic efficacy when added to the combination of SU and
MET in patients with type 2 diabetes.
This multicenter clinical trial in Mainland China, Taiwan and Hong Kong
was done to determine the efficacy and safety of once-daily oral Alogliptin
(AL) as monotherapy, add-on to ongoing metformin (M) therapy, and add-on to
pioglitazone (P) therapy (with or without M) in patients with type 2 diabetes.
A total of 506 subjects (185 in the monotherapy group, 197 in the add-on
to M therapy group, and 124 in the add-on to P group) were randomized
to receive AL 25mg QD or placebo (PBO) QD for 16 weeks. The primary
endpoint was change from baseline (BL) in HbA1c at week 16. The secondary
endpoints were change in fasting plasma glucose (FPG), incidence of marked
hyperglycemia, clinical HbA1c response, and change in body weight from BL.
For monotherapy, the decrease of HbA1C from BL to week 16 in the AL and
PBO arms were 0.99% and 0.42%, respectively (P<0.001). For the add-on to
M group, AL decreased HbA1c by 0.91% compared to PBO 0.22% (P<0.001).
For add-on to P group, AL decreased HbA1c by 0.76% vs PBO 0.25% (P<0.001).
The decreases in FPG were greater in the AL arms than in the PBO arms. The
percentage of subjects able to achieve an HbA1c target of ≤ 6.5%, ≤7.0% and
≤7.5% were all significantly higher (P<0.001) in the AL arms than in the PBO
arms. AL treatment showed lower incidence of hyperglycemia than PBO in
all groups. No weight gain was observed in either the AL or PBO arms, with
weight loss occurring in both arms in all groups. Pooled analysis showed that
the percentage of subjects who experienced hypoglycemia was 1.6% in the
AL arm vs 0.8% in PBO arm. All episodes of hypoglycemia were considered
mild or moderate. No significant changes were observed between the AL
and PBO arms in the laboratory parameters compared with BL. AL 25mg QD
significantly reduced HbA1c and FPG, and enhanced clinical HbA1c response
compared to PBO when used as monotherapy, add-on to M, and add-on to P.
AL 25mg QD showed a safety profile similar to PBO.
Supported by: Merck, Sharp & Dohme
1149-P
Early Improvement in Control of Eating Is Associated With LongTerm Weight Loss—Integrated Analysis of Four Phase 3 Trials of
Combination Naltrexone/Bupropion Treatment
Supported by: Takeda Global Research & Development Center (Asia) Pte. Ltd.
KEN FUJIOKA, BRANDON WALSH, COLLEEN BURNS, PRESTON KLASSEN, La
Jolla, CA
Early Onset of Increased Hypoglycemic Incidence With Glipizide
(GLIP) vs. Saxagliptin (SAXA) in Type 2 Diabetes Patients on Metformin
1151-P
Combination treatment with naltrexone sustained-release (SR) / bupropion
SR (NB) results in substantial and sustained weight loss that is postulated
to be partially mediated by effects on the mesolimbic dopaminergic reward
system that modulate control of eating behavior. In the Phase 3 trials of
NB in overweight/obese individuals, eating behavior was evaluated with
the Control of Eating Questionnaire (CoEQ, twenty 100mm visual analog
scales) at baseline and Weeks 8, 16, 28, and 56. This integrated analysis of
all four Phase 3, 56-week clinical trials of NB in overweight/obese patients
(BMI ≥27 and ≤45 kg/m2) evaluated the change in CoEQ question 19 (CoEQ
19: “Generally how difficult has it been to control your eating?”) and the
relationship between changes in CoEQ 19 and body weight. Treatment group
differences (LS mean±SE) in the modified ITT-LOCF population (≥1 postbaseline weight on study drug) were evaluated by ANCOVA with treatment,
study, and baseline values as covariates. Baseline characteristics (mean±SD)
were similar between treatment arms (NB [n=2043] or placebo [PBO; n=1319]):
81% female, 79% Caucasian, 46±11 y, 36.3±4.3 kg/m2. Completion rate was
66% for NB and 59% for PBO. At Week 56, weight loss was significantly
greater with NB (-7.0±0.2%) vs PBO (-2.3±0.2%; p<0.001). NB-treated
subjects reported significantly greater improvement in CoEQ 19 at all time
points (p<0.001 vs PBO), with the greatest effect observed at Week 8 (-23.3
vs -13.5 mm; p<0.001). In both groups, reduction in CoEQ 19 at Week 8 was
positively correlated with body weight reduction at Week 56 (r=0.20 (NB),
r=0.22 (PBO); both p<0.001), such that the quartile of NB subjects with the
greatest CoEQ 19 improvement at Week 8 (> 43 mm) exhibited -9.4% mean
weight change at Week 56. These results suggest that NB is associated with
rapid improvement in control of eating behavior that may, in part, contribute
to the weight loss associated with treatment.
ADA-Funded Research
&
ROBERT FREDERICH, SHAMIK J. PARIKH, ELSIE ALLEN, BRIAN BRYZINSKI, WILLIAM COOK, BOAZ HIRSHBERG, Princeton, NJ, Wilmington, DE
A goal of diabetes therapy is to achieve glycemic control without
hypoglycemia. In a double-blind, 52-week (with 52-week extension) trial
(NCT00575588), patients with A1C 6.5%-10.0% on metformin (MET ≥1500
mg/d) were randomized 1:1 to SAXA 5 mg/d or GLIP 5-20 mg/d (titrated to
optimal effect or highest tolerable dose in 18 weeks). Hypoglycemic episodes
were recorded in patient diaries per protocol.
1. Despite titration, a much higher fraction of those randomized to GLIP
experienced hypoglycemic events and had a higher number of total events
vs those randomized to SAXA.
2. Severity of events judged by discontinuation and fingerstick glucose
was greater in those randomized to GLIP.
3. For those randomized to GLIP, 38.4% had ≥1 hypoglycemic event. Of
these, 65% had their first event within the first 10 weeks. Only 15 (3.5%) of
those randomized to SAXA experienced ≥1 event, about half (n=7) with an
event in the first 10 weeks.
For author disclosure information, see page 829.
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A299
POSTERS
1148-P
Safety and Efficacy of Sitagliptin Added to the Combination of Sulfonylurea and Metformin in Patients With Type 2 Diabetes Mellitus
and Inadequate Glycemic Control
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1153-P
Withdrawing GLP-1 Analog, Liraglutide on Drug-Naive Type 2 Diabetes Patients—Does it Induce Glycemic Remission?
HITOMI FUJII, MITSUTOSHI KATO, NORIKO KATO, KAZUO KANNO, HIROKO
KONDO, HIROSHI TAKAMURA, DAISUKE MATSUDA, MASAYUKI SHIGETA,
YUKO WATANABE, TAKAICHI MIYAKAWA, AKIO UEKI, TAKAFUMI KITAOKA,
Tama, Japan, Katsushika-ku, Japan, Mitaka, Japan, Kodaira, Japan, Fussa, Japan,
Higashiyamato, Japan
Objectives: The GLP-1 analog Liraglutide has been prescribed for two years
in Japan. To evaluate the efficacy and safety of Liraglutide, we conducted a
multi-centered, observational study involving eight diabetes clinics in Tokyo
and approved by the IRB of West Tokyo Clinical Diabetes Study Group.
Methods: Type 2 diabetes patients on diet and exercise, not taking oral
hypoglycemic agents, were recruited. They injected with 0.9mg per day (the
maximum dose covered by Japanese national insurance) of Liraglutide with
a target to reduce HbA1c levels to less than 7.0 %. Diabetologists decided to
stop injection if their HbA1c level reduced to less than 6.2%.
Results: 45 registered. 32 were male. Average age: 53.8±12.6; Duration
of illness: 3.7±3.2 years; BMI: 25.8±5.81; HbA1c at start: 11.2±1.90 %.
22 (47.8%) and 20(43.5% of the cases) subjects achieved the target
HbA1c levels at month 6 and 12 respectively. During 12 months, 18
were stopped injection because of achieving HbA1c less than 6% twice
consecutive times (Group1: withdrawal). Nine stopped visiting (Group2:
stopped coming) Eight cases were changed the treatment because of
poor response to Liraglutide (Group 3: changed treatment). Residual 11
continued Liraglutide injection (Group 4: continuing). Among group1,
after stopping Liraglutide, 3 out of 18 started Sulfonylureas, DPP-4
Inhibitors, and biguanides within 6 months. In group 3, 3 started insulin,
2 started exenatide, and others stated oral agents. Comparing basic
characteristics of groups, group1 tended to have shorter duration of
illness, larger waist circumference and higher insulin secretion.
Conclusion: In conclusion, 0.9mg of Liraglutide per day was effective for
patients who were drug-naïve and had relatively short duration of illness.
More than 40% of the patients were able to achieve and sustained HbA1c
level less than 7%.
1152-P
POSTERS
Clinical Diabetes/
Therapeutics
Supported by: Bristol-Myers Squibb/AstraZeneca
Real-World Improvements in A1C With Colesevelam in an Electronic
Medical Records Dataset
RICHARD A. HANSEN, JOEL F. FARLEY, MATTHEW L. MACIEJEWSKI, XIN YE,
CHUNLIN QIAN, BENJAMIN J. POWERS, Auburn, AL, Chapel Hill, NC, Durham, NC,
Parsippany, NJ, Boise, ID
Colesevelam HCI, added to other anti-diabetic therapy, reduced A1C by
~0.5% compared to placebo in randomized clinical trials (RCTs). Evidence
on real-world effectiveness is unknown. We used GE Centricity electronic
medical records data from 2000-2011 to evaluate A1C changes in realworld clinical practice among patients with type 2 diabetes mellitus (T2DM)
initiating colesevelam.
A retrospective cohort of patients with T2DM was examined to evaluate
changes in A1C associated with colesevelam initiation. Patients were
included if they were 18 years or older, diagnosed with T2DM, and had
database activity 395 days before and after colesevelam initiation. The
sample was further restricted to patients with a baseline A1C > 7% within
90 days prior to starting colesevelam and at least one A1C result between
42 to 210 days after initiation. Three time intervals were created for A1C
measurement, including 16-weeks (days 42-140), 26-weeks (days 42-210),
and 52-weeks (days 42-395) following therapy initiation. The last observed
A1C lab measurement during each interval was used to define change
from baseline. Mean change in A1C was examined using paired t-tests and
compared with RCT results.
Of 1,709,393 patients in the GE database with T2DM, 1,769 met
inclusion criteria. The cohort was 58% female, 38% age 65 and older,
and 54% white. For the 16-week endpoint (N=1,405), A1C dropped from
a mean of 8.22% to 7.75% (mean change -0.46%; P<0.001). For the 26and 52-week endpoints (N=1,769), A1C dropped from a mean of 8.24% to
7.81% (mean change -0.44%; P<0.001) and 8.24% to 7.78% (mean change
-0.47%; P<0.001), respectively.
The 0.44% to 0.47% A1C reduction observed in this study was similar to
the reduction observed in RCTs, supporting the real-world effectiveness of
colesevelam in reducing A1C. Planned subsequent analyses will compare
colesevelam effectiveness with alternative treatment strategies and adjust
for other covariates to fully consider aspects of treatment in real-world
clinical practice.
1154-P
Effect of Metformin on Weight
Gain and Diastolic Blood Pressure in
WITHDRAWN
Type 1 Diabetes (T1D)
ESTHER S. O’SULLIVAN, FIONA MACNAIR, RONAN J. CANAVAN, MALACHI J.
MCKENNA, DONAL O’SHEA, Dublin, Ireland
Metformin is commonly added to insulin therapy in T1D patients that are
thought to have insulin resistance, but data to support this is limited.
We examined medical records of 61 patients with T1D on Metformin,
mean age 50.5 (25.8 to 87.7), 33 females; mean duration of T1D 21.0 years
(0.8 to 45.8); total T1D person years 1155.1, total Metformin person years
275.7 (0.02 to 20.4).
Total insulin, basal and bolus doses, HbA1c, weight, systolic and diastolic
BP(sBP, dBP),total cholesterol (TC), triglycerides (TGs), HDL and LDL results
were compared at baseline with the corresponding measurements just
before the addition of Metformin, and with the most recent data available.
The change in each parameter is expressed as rate of change prior to, and
after the commencement of Metformin.
The rate of weight gain after the addition of Metformin was -0.1kg
per year, compared with 2.7kg per year before Metformin was added
(p=0.02). The rate of change of dBP was also significantly better -2.0
vs 0.4mmHg/yr respectively, p=0.045. There were trends toward
improvements in TC (p=0.08) and LDL (p=0.07) and reduced total insulin
dose (-4.1 IU/yr vs 1.4 IU/yr p=0.2). Overall total and bolus insulin doses
only changed significantly between baseline and starting Metformin,
there was no overall change in HbA1c (figure 1).
Our data although limited to retrospective analysis demonstrates the
potential benefits to weight and dBP from the addition of Metformin in T1D.
Supported by: Daiichi Sankyo, Inc.
&
For author disclosure information, see page 829.
A300
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1155-P
1157-P
Effects of Age, Gender and Obesity on the Single Dose Pharmacokinetics (PK) of Omarigliptin, a Novel Once-Weekly Dipeptidyl Peptidase-4 (DPP-4) Inhibitor
WITHDRAWN
Supported by: Merck, Sharp & Dohme
1158-P
1156-P
A Novel Tripeptide Diapin Effectively Lowers Blood Glucose Levels
in Type 2 Diabetes Mice by Increasing Blood Levels of Insulin and
GLP-1
Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor, Sitagliptin Compared With Alpha-Glucosidase Inhibitor in Japanese Patients With Type 2 Diabetes Treated With Sulfonylurea Alone (SUCCESS2): A Multicenter, Randomized, Open-Label, Clinical Trial
JIFENG ZHANG, ZHONGMIN A. MA, YUQING EUGENE CHEN, Ann Arbor, MI
The prevalence of type 2 diabetes (T2D) is rapidly increasing worldwide
and it is urgent to develop innovative therapeutic approaches for preventing
such condition since several effective therapies, such as insulin and GLP1 require injections, which are costly, inconvenient, and less patient
compliance. Many studies reported that co-injection of protein hydrolysates
and amino acids can substantially increase plasma insulin responses and
reduce the prevalence of hyperglycemia in T2D patients. Here, we report
an identification of a novel tripeptide with significantly potential to treat
T2D. The peptide, referred to as Diapin, is comprised of three natural
L-amino acids. Glucose tolerance tests showed that orally administration
of Diapin effectively inhibits blood glucose rise after oral glucose loading
in both T2D mouse models, including KKay, db/db, and ob/ob mice and in
normal C57BL/6J mice. In addition, Diapin reduces random blood glucose in
KKay diabetic mice in a time- and dose-dependent manner. The amino acid
composition of Diapin or the dipeptides with same amino acid composition,
however, has no significant effect on blood glucose of 57BL/6J mice.
Furthermore, we found that serum GLP-1 and insulin levels in diabetic
models with Diapin treatment are significantly increased compared to that in
the controls. A pharmacokinetic study using 13C-labeled Diapin has shown
that Diapin exists in the blood stream at low concentrations. In summary, our
finding has established a novel concept that a peptide with minimum of three
amino acids has potential to improve glucose homeostasis and Diapin shows
promise as a novel pharmaceutical anti-diabetic agent to treat patients with
T2D, possible in the mechanism of its dual effects on both GLP-1 and insulin
secretion.
KAZUKI KOBAYASHI, HIDETAKA YOKOH, YASUNORI SATO, MINORU TAKEMOTO,
DAIGAKU UCHIDA, AZUMA KANATSUKA, NOBUICHI KURIBAYASHI, KENICHI
SAKURAI, TAKASHI TERANO, NAOTAKE HASHIMOTO, HIDEKI HANAOKA, KO
ISHIKAWA, SHUNICHIRO ONISHI, KOUTARO YOKOTE, THE SUCCESS STUDY
GROUP, Chiba, Japan, Kisarazu, Japan, Funabashi, Japan, Yachiyo, Japan
Dipeptodyl peptidase-4 inhibitors (DPP-4i) have been used widely, but its
most appropriate position in medication of type 2 diabetes has not been well
established. We compared the efficacy and safety of sitagliptin (Sita), a DPP-4i
and α-glucosidase inhibitor (αGI) in Japanese patients with type 2 diabetes
(T2DM) in the setting of combination therapy with sulfonylurea (SU).
A multicenter, prospective, randomized, open-label trial was conducted
at 37 hospitals and clinics in Chiba prefecture in Japan from January 2011
to June 2012. The one hundred and twenty participants were 20-79 years
old patients with T2DM who had inadequate glycemic control (glycated
haemoglobin A1c [HbA1c] 6.9-8.8%) with 2 mg/day or less glimepiride (Gri)
alone. They were randomly assigned to two groups, and either Sita (50 mg
daily) or αGI (0.6 mg voglibose or 150 mg miglitol daily) was added onto
Gri. The primary endpoint was the difference of change in HbA1c (ΔHbA1c)
between the two groups at 12 weeks (w).
Mean values of HbA1c at baseline was 7.6-7.7% in both group. At 12w,
HbA1c was reduced by -0.72% in Sita and -0.28% in αGI group. The difference
of ΔHbA1c Sita compared to αGI group was -0.49% (95% CI -0.66 to -0.32,
p<0.0001) indicating the superiority of efficacy of Sita. At 24w, ΔHbA1c was
similar between the two groups (-0.49%; 95% CI -0.34 to 0.16, p=0.47).
Gastrointestinal symptoms were more common with αGI than with Sita (20
patients [37%] and 5 [8.6%], respectively, p=0.0003). Minor hypoglycemia
occurred in about 4-5% of patients in each group.
Sita was superior to αGI for reduction of HbA1c at 12w, and not inferior
at 24w after administration on Japanese patients with T2DM treated with
a small dose of Gri alone. It was also well tolerated with minimum risk of
gastrointestinal symptoms and hypoglycemia.
Supported by: Waksman Financial Group
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A301
POSTERS
Omarigliptin is being developed as a potent, once-weekly, oral DPP4 inhibitor for the treatment of type 2 diabetes mellitus. The aim of this
study was to evaluate the effects of age, gender and obesity on the PK
of omarigliptin. This was a double-blind, randomized, placebo-controlled
study. A single 10-mg oral dose of omarigliptin (n=6/panel) or placebo (n=2/
panel) was administered in the fasted state to healthy elderly men and
women, healthy young obese [30 ≤ body mass index (BMI) ≤ 35 kg/m2] men
and women, and to healthy young women of non-childbearing potential.
Plasma was collected at selected post-dose time points for evaluation of
omarigliptin concentrations. PK parameters were compared to historical
data from a previously conducted single-dose study in young, non-obese
male subjects. Omarigliptin was generally well tolerated and there were
no serious adverse events or hypoglycemic events. There were no clinically
significant differences in omarigliptin AUC0-∞ based on age, gender or
BMI (young female vs. young male, pooled elderly vs. pooled young, young
obese vs. young non-obese subjects, and pooled female vs. pooled male).
Omarigliptin Cmax values were ~40% higher in females vs. males, regardless
of age, but were similar in elderly vs. young subjects within each gender. Cmax
was ~24% lower for young obese vs. young non-obese females; however,
Cmax was similar in young obese vs. young non-obese males. Omarigliptin
was generally well tolerated. Demographic factors and BMI do not have
a clinically meaningful effect on omarigliptin PK. The data suggest that
omarigliptin dose adjustment is not needed on the basis of age, gender or
body weight.
Clinical Diabetes/
Therapeutics
CAROL ADDY, DANIEL TATOSIAN, XIAOLI S. HOU, ISAIAS N. GENDRANO, ASHLEY MARTUCCI, JOHN A. WAGNER, S. AUBREY STOCH, Whitehouse Station, NJ
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1159-P
1161-P
Efficacy and Safety of Linagliptin Monotherapy in Asian Patients
With Inadequately Controlled Type 2 Diabetes Mellitus: A 24-Week,
Randomized, Phase III Clinical Trial
Effect of Colesevelam HCl (COL) as an Add-On to Pioglitazone (PIO)
on Lipid Particles in Type 2 Diabetes Mellitus (T2DM)
MICHAEL R. JONES, DANIEL M. FORD, MERAV BAZ-HECHT, BEN TAO, KENNETH
E. TRUITT, HUBERT S. CHOU, Parsippany, NJ, Edison, NJ
POSTERS
Clinical Diabetes/
Therapeutics
YUHONG CHEN, GUANG NING, CHANGJIANG WANG, YAN GONG, HANSJUERGEN WOERLE, WEIQING WANG, Shanghai, China, Hefei, China, Ingelheim,
Germany
Previous studies evaluated the effects of COL in combination with
metformin-, sulfonylurea-, or insulin-based therapy, but it had not previously
been extensively studied in combination with thiazolidinediones. A study
was recently conducted to evaluate COL as an add-on to PIO-based therapy
in adults with T2DM who had inadequate glycemic control (hemoglobin
A1C ≥7.5% to ≤9.5%) on a stable dose of PIO (30 or 45 mg/day), with or
without 1-2 other oral antidiabetes agents (metformin, a sulfonylurea, or
a dipeptidyl peptidase-4 inhibitor). Patients were randomized to receive
COL 3.75 g/day (n=280) or placebo (PBO; n=282) in addition to their existing
PIO-based therapy for 24 weeks. In addition to the typical glycemic and
lipid parameters, changes in lipid particle concentrations and sizes were
determined by nuclear magnetic resonance spectroscopy. At Week 24, with
last observation carried forward, COL versus PBO produced a significant
reduction in total LDL particle concentration (LDL-P; least squares [LS] mean
treatment difference -126 nmol/L; P<0.0001); significant (P<0.05) reductions
were also seen in subfractions of large (-50 nmol/L), medium small (-14
nmol/L), small (-75 nmol/L), and very small (-61 nmol/L) LDL-P. There were
increases in VLDL particle size (LS mean treatment difference +2.0 nm)
and associated increases in concentrations of large VLDL and chylomicron
particles (+1 nmol/L) and medium VLDL particles (+7 nmol/L; all P<0.001),
and a reduction in small VLDL particle concentration (-4 nmol/L; P<0.01).
With COL versus PBO there was also increased HDL particle size (LS mean
treatment difference +0.06 nm), associated with an increase in large HDL
particle concentration (+0.6 µmol/L; both P<0.01). In conclusion, the addition
of COL to PIO-based therapy resulted in generally favorable changes to the
lipoprotein particle profile compared with PBO in patients with T2DM.
This randomized, Phase III, placebo-controlled, double-blind 24-week
study evaluated the efficacy and safety of the DPP-4 inhibitor linagliptin
as monotherapy in patients with inadequately controlled type 2 diabetes
mellitus (T2DM) in Asian countries (NCT01214239).
Patients who were treatment naïve or who had been treated with 1
antidiabetes drug were randomized to either linagliptin 5 mg daily or placebo
following 4-week washout of prior drugs. The primary endpoint was change
from baseline in mean HbA1c after 24 weeks.
A total of 300 Asian patients with T2DM (China n=261, Malaysia n=22 and
the Philippines n=17) were randomized to linagliptin (n=201) or placebo (n=99)
at a 2:1 ratio. Baseline characteristics were well matched between groups,
with mean (SD) HbA1c of 7.95 ± 0.89% in the linagliptin group and 8.09 ±
0.91% in the placebo group. Following 24 weeks of treatment, adjusted
mean (SE) HbA1c decreased by −0.68 ± 0.07% in the linagliptin group and
−0.18 ± 0.10% in the placebo group (placebo-corrected difference, −0.50 ±
0.11; 95% CI: −0.71, −0.28; P<0.0001). In the pre-defined subgroup of patients
with baseline HbA1c ≥8.5%, the placebo-corrected decrease in HbA1c was
−0.91 ± 0.20% (P<0.0001). Placebo-corrected adjusted mean (SE) change
in FPG with linagliptin was −9.6 ± 3.8 mg/dL (95% CI: −17.1, −2.2; P=0.01).
Results for the pre-defined Chinese subgroup were similar to the overall
Asian population. Linagliptin was well tolerated. Adverse events occurred
in 28.0% of linagliptin patients and 28.3% of placebo patients, while drugrelated AEs occurred in 3.0% of linagliptin patients and 2.0% of placebo
patients. Investigator-defined hypoglycemic events were reported in 0.5%
and 0.0% of linagliptin and placebo patients, respectively.
In conclusion, in Asian patients and a Chinese subgroup with inadequately
controlled T2DM, linagliptin 5 mg as monotherapy was efficacious and well
tolerated over 24 weeks.
1162-P
WITHDRAWN
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1160-P
Change in HbA1c after 24 Weeks as a Function of Baseline HbA1c:
Comparison Between Vildagliptin and Sulfonylureas in Interventional Clinical Trials and Real-Life Conditions
GIOVANNI BADER, ANJA SCHWEIZER, JAMES E. FOLEY, Basel, Switzerland, East
Hanover, NJ
T2DM patients have been shown to achieve lower HbA1c levels with
vildagliptin (Vilda) than sulfonylureas (SUs) as add-on to metformin under
real-life conditions (RLC) (EDGE observational study) despite similar efficacy
in interventional controlled clinical trials (ICCT) and the known superior
pharmacological action of SUs. The aim of this post hoc analysis was to
study the predictors of HbA1c change after 24 weeks of treatment in ICCT
and RLC and the interplay of treatments with predictors of HbA1c change
after 24 weeks.
We pooled data from 5 clinical trials carried out in 4480 patients [Vilda,
N=2788 or SUs, N=1692 (glimepiride, n=1259; gliclazide, n=433)] and
compared with a large sample of patients extracted from the EDGE study
(Vilda, N=7002 or SUs, N=3702). The impact of baseline (BL) HbA1c, age,
gender, and weight on change in HbA1c after 24 weeks were assessed by
linear regression model.
Overall, 30% of the change in HbA1c was correlated to BL HbA1c [slope
-0.52 (95% CI: -0.53, -0.51; p<0.001)], while age, gender, and BL weight
were poorly correlated. With Vilda the slope was -0.55 (95% CI: -0.56,
-0.53; p<0.001) and no interaction was detected between BL HbA1c and
study setting (ICCT or RLC). With SUs the slope was -0.54 (95% CI: -0.56,
-0.52; p <0.001). However, there was a stronger association between
HbA1c change and BL in the ICCT as compared with RLC as shown by the
significant interaction effect [regression coefficient -0.32 (95% CI: -0.37,
-0.27; p<0.001)].
This study confirms a strong association between change in HbA1c and
BL HbA1c. Moreover, the data suggest that with Vilda the association
under RLC is consistent with the ICCT, while with SUs this association
appears to be blunted under RLC. Albeit speculative, these data suggest
that pharmacologically SUs are very efficacious, but under RLC doses may
be limited due to fear of hypoglycemia and weight gain associated with
defensive eating to avoid hypoglycemia.
Supported by: Novartis Pharma AG
&
For author disclosure information, see page 829.
A302
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
KOHEI KAKU, ARIHIRO KIYOSUE, SATOSHI INOUE, NAOHIKO UEDA, TAKUTO
TOKUDOME, JISIN YANG, ANNA MARIA LANGKILDE, Okayama, Japan, Tokyo,
Japan, Osaka, Japan, Mölndal, Sweden
PBO
(N=87)
HbA1c
BL, % (SD)
All patients
Adj. mean change from BL, % (SE)
(P value vs PBO)
Patients with BL HbA1c < 7%
Adj. mean change from BL, % (SE)
Patients with BL HbA1c ≥ 7%–< 8%
Adj. mean change from BL, % (SE)
Patients with BL HbA1c ≥ 8%–< 9%
Adj. mean change from BL, % (SE)
FPG
BL mean, mg/dL (SD)
Adj. mean change from BL, mg/dL (SE)
(P value vs PBO)
BW
BL mean, kg (SD)
Adj. mean change from BL, kg (SE)
(P value vs PBO)
*Significant P value P<0.05.
5 mg DAPA
(N=86)
Clinical Diabetes/
Therapeutics
This phase III study (NCT01294423) evaluated the efficacy and safety of
the selective sodium-glucose cotransporter 2 inhibitor dapagliflozin (DAPA)
in Japanese patients with type 2 diabetes mellitus (T2DM) inadequately
controlled with diet or exercise. Patients (N=261, 34-81 y, with modestly
elevated mean baseline [BL] HbA1c 7.5%) received placebo (PBO) or DAPA
(5 or 10 mg) QD for 24 weeks. Estimated glomerular filtration rate at BL was
≥ 45–< 60 mL/min/1.73 m2 in 28% of patients. Adjusted mean reductions
from BL in HbA1c, fasting plasma glucose (FPG) and body weight (BW) were
significantly greater with DAPA (5 mg and 10 mg) vs PBO (Table). Similar to
other DAPA trials, greater HbA1c reductions were observed in patients with
higher BL HbA1c. Overall, 47.7% and 64.8% of patients with DAPA 5 and 10
mg and 51.7% with PBO experienced ≥ 1 adverse event (AE).The majority of
AEs were mild or moderate in intensity and unrelated to study treatment.
Hypoglycemia was reported by 2 patients with DAPA 10 mg. Four patients
reported events suggestive of genital infection (DAPA 10 mg, 2; DAPA 5 mg,
1; PBO, 1) and 4 reported events suggestive of urinary tract infection (DAPA
10 mg, 2; PBO, 2). No events of pyelonephritis were reported. In summary,
DAPA (5 and 10 mg) was well tolerated and effective in reducing HbA1c,
FPG, and BW over 24 weeks in Japanese patients with T2DM inadequately
controlled with diet and exercise.
10 mg DAPA
(N=88)
7.50 (0.63)
-0.06 (0.06)
7.50 (0.72)
-0.41 (0.06)
(< 0.0001)*
7.46 (0.61)
-0.45 (0.06)
(< 0.0001)*
(n=21)
-0.02 (0.12)
(n=45)
–0.12 (0.08)
(n=19)
–0.03 (0.13)
(n=20)
-0.16 (0.12)
(n=50)
–0.33 (0.08)
(n=12)
–0.73 (0.16)
(n=19)
-0.12 (0.12)
(n=49)
–0.38 (0.08)
(n=19)
–0.94 (0.13)
139.8 (21.7)
5.8 (2.2)
137.5 (24.4)
–8.6 (2.2)
(< 0.0001)*
138.7 (22.3)
–13.7 (2.2)
(< 0.0001)*
1165-P
Pharmacokinetics (PK) & Pharmacodynamics (PD) of the GPR40
Agonist TAK-875 and Glimepiride Following Co-Administration in
Subjects With Type II Diabetes (T2DM)
MAX TSAI, RONALD D. LEE, MAJID VAKILYNEJAD, WENCAN ZHANG, JOHN
MARCINAK, XUEJUN PENG, Deerfield, IL
This phase 1, single-blind, placebo-controlled, sequential, single-site
study evaluated the effects of multiple oral doses of TAK-875 on the PK of a
single oral dose of glimepiride and effects of a single dose of glimepiride on
steady-state PK and PD of TAK-875 in T2DM subjects.
T2DM subjects (n=30) received a single dose of glimepiride 2 mg on Day 1
followed by TAK-875 50 mg QD on Days 3-19. On Day 18, glimepiride was also
given with TAK-875. Serial plasma PK samples were collected on Days 1-3 &
Days 18-20 for glimepiride and on Days 13-19 for TAK-875 & M-I. Serial PD
samples for markers of fasting glucose, insulin, C-peptide, and glucagon were
collected on Days 17-18. All PK & PD parameters were estimated using noncompartmental methods. PK interactions were assessed by point estimates
and 90% confidence intervals (CIs) of the ratios of the central values for
Cmax and AUC values when treatments were coadministered relative to
each treatment alone using paired t-test. The effects of glimepiride on TAK875 PD response (AUEC) were similarly assessed for each marker.
Glimepiride was absorbed (Tmax ~ 3 hr) and eliminated (T1/2 ~ 7.5 hr)
following dosing of either glimepiride alone or with TAK-875. TAK-875 was
absorbed (Tmax ~ 4 hr) following dosing of either TAK-875 alone or with
glimepiride. The 90% CIs for Cmax and AUC of glimepiride, TAK-875, and M-I
fell within the no-effect range of 0.80 to 1.25.
The mean AUEC values were lower for fasting glucose and higher for other
PD markers after dosing of TAK-875 with glimepiride relative to TAK-875
alone; differences were statistically significant (p<0.005) for all markers.
Co-administration of TAK-875 with glimepiride was well-tolerated with
no hypoglycemia and no effects on the PK of glimepiride, TAK-875, or
M-I. Changes in PD markers with coadministration of glimepiride suggest
a potential synergistic effect between TAK-875 and glimepiride on insulin
secretion mediated via different pathways.
65.96 (12.91) 65.81 (14.37) 69.70 (13.82)
–0.84 (0.26) –2.13 (0.27) –2.22 (0.26)
(0.0003)*
(0.0001)*
Supported by: AstraZeneca/Bristol-Myers Squibb
1164-P
Efficacy and Safety of Canagliflozin (CANA) Monotherapy in Subjects With Type 2 Diabetes Mellitus (T2DM) Over 52 Weeks
KAJ STENLÖF, WILLIAM T. CEFALU, KYOUNG-AH KIM, ESTEBAN JODAR, MARIA ALBA, ROBERT EDWARDS, CINDY TONG, WILLIAM CANOVATCHEL, GARY
MEININGER, Gothenburg, Sweden, Baton Rouge, LA, Goyang, Republic of Korea,
Madrid, Spain, Raritan, NJ
Supported by: Takeda Global Research & Development Center, Inc.
CANA is an SGLT2 inhibitor in development for the treatment of T2DM. This
randomized, double-blind study enrolled subjects with T2DM inadequately
controlled with diet and exercise (N = 584), and included a placebo (PBO)controlled, 26-week core period (CANA 100 and 300 mg vs PBO) and a
26-week extension (n = 451; mean age, 55.5 y; A1C, 7.9%; fasting plasma
glucose [FPG], 165.8 mg/dL; BMI, 31.8 kg/m2; blinded switch of PBO group
to sitagliptin 100 mg [PBO/SITA]). Efficacy data at 52 weeks are reported for
CANA 100 and 300 mg (SITA used only to maintain double-blind and control
group); safety data are shown for CANA and PBO/SITA. At Week 52, CANA
showed numerical, dose-related reductions from baseline in A1C, FPG, and
ADA-Funded Research
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For author disclosure information, see page 829.
Guided Audio Tour poster
A303
POSTERS
body weight; decreases in systolic BP and triglycerides, and increases in
HDL-C and LDL-C, were also seen.
Overall AE rates were 67%, 66%, and 64% with CANA 100 and 300
mg and PBO/SITA. Rates of serious AEs, AE-related discontinuations, and
hypoglycemia were low across groups. Genital mycotic infection rates were
higher in the pooled CANA group than PBO/SITA (females, 10% vs 5%; males,
8% vs 0%). Higher rates of AEs related to osmotic diuresis (5%, 8%, 2%)
and reduced intravascular volume (≤1% per AE) were seen with CANA 100
and 300 mg versus PBO/SITA; UTI rates were 8%, 7%, and 6%. In summary,
CANA monotherapy provided sustained improvement in glycemic control
and body weight reduction, and was generally well tolerated in subjects
with T2DM over 52 weeks.
1163-P
Efficacy and Safety of Dapagliflozin Monotherapy in Japanese Patients With Type 2 Diabetes Inadequately Controlled With Diet and
Exercise
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1166-P
Eating Behavior and Taste Threshold as Possible Predictors of the
Efficacy of DPP-4 Inhibitors
POSTERS
Clinical Diabetes/
Therapeutics
CHIEKO SAKAI, HISASHI SHIMOHIRO, YOSHIE OTA, HIRONORI SAKINADA, TATSUO TAKEUCHI, SHIN-ICHI TANIGUCHI, KEIICHI HANAKI, Yonago, Japan
Extrapancreatic action of GLP-1, especially appetite regulation, has
recently been emphasized. To clarify the association between hypoglycemic
efficacy of DPP-4 inhibitors and indices for food intake such as eating
behavior or taste threshold, we conducted a comparative study on T2D
patients.
Thirty-seven diabetic patients, either medicated (except incretin-based
drugs) or not, were randomly recruited from an outpatient diabetes clinic (25
males, 12 females, age: 61.0±11.5 years, BMI: 25.4±3.7, A1C: 7.9±1.0%). They
were divided into 2 groups depending on whether any DPP-4 inhibitor was
started or not during the study period. The treatment group (n=20), on DPP-4
inhibitor, was further divided into a responder and a non-responder groups
at 1 or 3 months after the start of the treatment.
Eating behavior was evaluated using a 40-item questionnaire categorized
as “diversion eating”, “impulse for eating”, “sensation of eating heartily”,
“quick eating”, “high-fat/fast food preference”, “irregular meal times”,
“hungry sensation”. Thresholds of recognition for 5 basic tastes (sweet,
salty, sour, bitter, umami) were measured using a filter paper disk method.
1) Comparison between before and after the period: There was no
significant weight gain or loss in the treatment group, although significant
gain in the control group. 2) Between the treatment and control groups:
Indices for eating behavior or taste thresholds were comparable. 3)
Between the responder and non-responder groups: A high-fat diet/fast food
preference score measured before the treatment was significantly higher in
the responder than in the non-responder group (11.6±2.8 vs 7.3±2.2, p<0.05).
As for taste, a bitter taste threshold before the treatment was significantly
higher in the responder than in the non-responder group (3.0±1.4 vs 1.0±0.0,
p<0.05).
These results suggest that the efficacy of DPP-4 inhibitors might be
predicted by evaluating the characteristics of eating behavior and taste
threshold in patients with T2D.
Supported by: Tehran University
1168-P
Development and Characterization of Irreversible Inhibitors of Insulin-Degrading Enzyme
SAMER O. ABDUL-HAY, THOMAS BANNISTER, MALCOLM A. LEISSRING, Jacksonville, FL, Jupiter, FL
Insulin-degrading enzyme (IDE) is an atypical zinc-metallopeptidase that
plays an essential role in terminating the insulin response and is also linked
to the pathogenesis of type-2 diabetes mellitus. Despite widespread interest
in IDE spanning more than a half century, pharmacological inhibitors of this
important peptidase have remained elusive. Here we describe the discovery,
optimization and characterization of the first small-molecule inhibitors of IDE.
Using a fluorescence polarization-based IDE activity assay, we conducted an
ultra-high-throughput (1536-well) cell-based compound screening campaign
on a library of ~325,000 small molecules conforming to Lipinski’s Rule of
Five. Potent (IC50 >10 µM) hits were further subjected to counterscreens to
sensitive to cytotoxicity, fluorescence artifacts, and ability to inhibit IDE in
vitro. Among the top hits we identified several isothiazolones that inhibit IDE
with IC50 values in the low micromolar range. Using diverse approaches, we
show that the mechanism of inhibition involves the irreversible modification
of a specific cysteine residue within IDE’s active site (C819), which occurs via
formation of a disulfide bond. Through subsequent structure-activity relation
(SAR) studies, novel variants were synthesized with improved IC50 values
as low as ~100 nM. The resulting compounds represent the first potent
small-molecule inhibitors of IDE, which should have utility both as chemical
probes for interrogating IDE’s role in insulin signaling and also as potential
pharmacophores for future drug development.
1167-P
Cichorium Intybus L. Extract (CI) as an Insulin Sensitizer
AZIN NOWROUZI, YASIN POURFARJAM, AZITA AMIRI, Tehran, Islamic Republic
of Iran, Huntsville, AL
Cichorium intybus L. seed extract (CI) was shown previously to improve
glucose tolerance test (GTT) profile in a group of rats that were made mildly
diabetic using a combination of Streptozotocin (STZ) and Niacinamide (NIA),
called NIA/STZ group. The same effect was not observed in severe diabetic
rats, STZ group (made diabetic using STZ alone) presumably due to the
absence of insulin (INS) in this group of rats. The present study re-examined
the effect of crude chicory seed extract on GTT in the presence and absence
of INS. GTT was performed four times in a fasting group of rats (n=8) with
severe diabetes. The test was performed in separate days by intraperitoneal
administration of Glucose, Glucose + CI, Glucose + INS, or Glucose + CI +
INS. The concentrations of Glucose and CI, which were dissolved in normal
saline, were 2 g and 125 mg, per kg body weight, respectively; 5 U of regular
INS was used for all the rats. Blood sugar was measured in blood from the
tail by a glucometer every 30 minutes. The results showed that blood sugar
decreased under the effect of INS, but CI significantly improved INS action
in lowering blood sugar during two hours of GTT. The results suggest that
the glucose lowering property of chicory depends on the presence of insulin;
CI acts as an insulin sensitizer leading to alleviation of insulin resistance in
target organs in type 2 diabetes mellitus.
1169-P
Improved Liver Histology in a Patient With Non-Alcoholic Steatohepatitis after Treatment With the Glucagon-Like Peptide-1 Receptor Agonist Liraglutide-A Case
ANDERS E. JUNKER, LISE LOTTE GLUUD, FILIP K. KNOP, TINA VILSBØLL, Copenhagen, Denmark
Non-alcoholic steatohepatitis (NASH) affects up to 30% of obese
patients with type 2 diabetes and is expected to be the leading cause of
liver transplantation by 2020. Recent studies have demonstrated beneficial
effects of glucagon-like peptide-1 receptor (GLP-1R) agonists on liver
function tests (LFTs).
A 25-year old obese woman (body weight: 89 kg; body mass index: 32
kg/m2) with a 2-year history of type 2 diabetes (HbA1c: 6.3%) treated with
metformin (1000 mg twice-daily) and insulin (30 IE once-daily) presented
with elevated LFTs (alanine transaminases (ALT): 133 U/l; aspartatetransaminases (AST): 76 U/l) and NASH (liver biopsy: non-alcoholic fatty liver
disease (NAFLD) score 5; hepatocytes with steatosis: 66%). Treatment with
the GLP-1R agonist liraglutide was initiated at 0.6 mg once-daily and uptitrated to 1.8 mg once-daily after two weeks. Seven weeks after liraglutide
initiation the patient had lost 7 kg and ALT had decreased to 66 U/l and AST
to 42 U/l. After 46 weeks of liraglutide treatment LFTs were normalized (ALT:
29 U/l, AST: 25 U/l), histology was improved (NAFLD score 3; hepatocytes
with steatosis: 40%) and glycemia was well controlled (HbA1c: 5.6%)
without insulin treatment. The total weight loss was 16 kg.
Liraglutide markedly improved LFTs and histology in this patient with
NASH and type 2 diabetes. Randomized controlled trials are needed to
evaluate whether the present findings hold promise for the treatment of
NASH.
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Guided Audio Tour poster
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CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1170-P
1172-P
Single Doses of an iBAT (SLC10A2) Inhibitor Suppress 24h Serum
Bile Acid Concentrations and Enhance Bile Acid Synthesis
The Anti-Diabetes Efficacy of Bromocriptine-QR in Type 2 Diabetes
Mellitus (T2DM) Subjects Is Enhanced among those With Elevated
Blood Pressure and Plasma Triglyceride Levels
ROBERT L. DOBBINS, JIANG LIN, ROBIN O’CONNOR-SEMMES, SUSAN L. MCMULLEN, MICHAEL J. BISHOP, LIHONG CHEN, Research Triangle Park, NC, Durham, NC
Figure 1.
1171-P
Bile Acid Sequestrants for Glycemic Control in Type 2 Diabetes: A
Systematic Review With Meta-Analysis of Randomized Controlled
Trials
MORTEN HANSEN, KRISTIAN H. MIKKELSEN, DAVID P. SONNE, LISE L. GLUUD,
TINA VILSBØLL, FILIP K. KNOP, Hellerup, Denmark
These findings suggest that T2DM subjects with higher rather than lower
BP and TG levels may on average respond better to the anti-diabetes effects
of B-QR.
We aimed to evaluate the glucose-lowering effect and safety of bile acid
sequestrants (BASs) in patients with type 2 diabetes.
We conducted a systematic review with meta-analyses of randomized
controlled trials (RCTs). Manual and electronic searches (The Cochrane
Library, MEDLINE and EMBASE) were combined. The interventions assessed
were BASs (colesevelam, colestimide, colestipol or colestyramine) vs.
placebo, oral antidiabetic drugs or insulin. The primary endpoint was change
in HbA1c. Secondary endpoints were changes in fasting plasma glucose
(FPG) and adverse events. Meta-analyses were performed using random
effects models due to an expected clinical heterogeneity between trials.
We included 17 RCTs (10 trials with colesevelam and 7 trials with
colestimide) with a duration of 2 to 52 weeks, including 2,118 patients with
type 2 diabetes. In random effects meta-analysis, BASs had a beneficial
effect on end of treatment HbA1c (weighted mean difference (WMD) [95%
confidence interval (CI)]: -0.59% [-0.70,-0.48]) and end of treatment FPG
(-0.52% [-0.68,-0.37]). No evidence of publication bias or other small study
effects was identified. BASs did not increase the risk of serious adverse
events, but increased the number of non-serious adverse events (relative
risk: 1.89 [1.32,2.67]), constipation being the most common.
This review suggests that BASs improves glycemic control in patients
with type 2 diabetes without increasing the risk of serious adverse events.
ADA-Funded Research
&
1173-P
The Changes of Leukocyte Telomere Length and Telomerase Activity after Intervention of Sitagliptin in Initial Type 2 Diabetes
DELIN MA, YANG YAN, Wuhan, China
The aim of this study was to determine the effect of sitagliptin on
leukocyte telomere length and telomerase activity in initial type 2 diabetic
patients. We selected initial type 2 diabetic patients (n=38) and matched
non-diabetic subjects (n=31) from the outpatient of Tongji Hospital, Tongji
Medical College, Huazhong university of Science and Technology. Leukocyte
telomere length ratio(T/S ratio) was measured using a quantitative PCR
and analyzed. The activity of telomerase was measured by TRAP-ELISA
method. Peripheral insulin resistance (homeostasis model assessment)
was calculated from fasting plasma glucose and fasting plasma insulin.
The results showed that telomere length(T/S ratio) of the type 2 diabetic
patients (1.58±0.57) was significantly shorter than those of control subjects
(3.98±0.90), and was significantly elongated after intervention by sitagliptin.
There was no significant difference between the T2D and control group in
telomerase activity, and the treatment of sitagliptin in T2D group showed
no significant effect on the telomerase activity. Thus, we came to the
conclusion that sitagliptin might protect β-cell in pancreases by elongating
the telomere length in initial type 2 diabetes.
For author disclosure information, see page 829.
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A305
POSTERS
Available evidence suggests that Bromocriptine-QR (B-QR) improves
glycemic control in T2DM subjects via the central nervous system in part
by reducing overactive sympathetic drive (OSD) to the periphery which is
also a contributor to metabolic (insulin resistance) syndrome, particularly to
hypertension and elevated plasma triglyceride (TG) levels thereof. Therefore,
this study investigated whether the anti-diabetes effect of B-QR may be
enhanced in T2DM subjects with BP and TG levels at or above the NCEP ATP
III definition of metabolic syndrome (BP≥ 130/85 mmHg and TG≥ 150 mg/
dl) (surrogate for OSD) versus in those with normal blood pressure without
anti-hypertensive therapy (<120/80 mmHg) and normal TG levels (< 150 mg/
dl). T2DM subjects on sulfonylurea therapy (HbA1c: 9.4) were randomized to
B-QR (N=183) or placebo (N=211) and treated for 24 weeks while fasting and
postprandial plasma glucose and HbA1c levels were monitored. The between
group difference, B-QR versus Placebo, in change from such baseline values
was determined by linear regression adjusting for Weight at baseline for
the entire study population and for subsets after stratification by baseline
BP and TG levels.
Results are summarized in Figure 1.
This clinical trial examined safety, tolerability, pharmacokinetics
and pharmacodynamics of an ileal bile acid transport (iBAT) inhibitor,
GSK2330672, previously shown to improve glucose and triglyceride levels
in Zucker diabetic rats. It was a single blind, randomized, placebo-controlled,
dose escalating, 4-way crossover trial. Each dosing period required a 4
night/3 day clinical admission. Subjects received identical meals each period
and study drug was administered on Day 1 after an overnight fast. Healthy
volunteers (n=17) were randomized to placebo plus 3 doses of GSK2330672.
Groups of 6-7 individuals received 0.1, 0.3, 1, 3, 10, 30 and 60 mg before
breakfast or 30 mg before breakfast and supper. Safety measures included
clinical lab tests, ECGs, vital signs, cardiac telemetry and spirometry testing.
Stool form and frequency of bowel movements were recorded. Fecal
samples were collected for 48 h after start of dosing to assess bile acid
excretion. Blood samples were obtained on Day 1 for assays of GSK2330672,
serum bile acid and 7 alpha-hydroxy-4-cholesten-3-one (C4) concentrations.
The most frequently reported adverse events included headache, dizziness,
diarrhea, abdominal pain/discomfort and flatulence. Side effects were more
likely to be reported at doses ≥30 mg. No clinically meaningful, treatmentrelated findings were observed for safety measures during the study. There
was no measurable plasma GSK2330672 exposure at total daily doses up to
60 mg. Doses of 10mg QD, 60mg QD and 30mg BID significantly increased
fecal bile acids vs. placebo and suppressed the initial peak in serum total bile
acid concentrations that follows 1.5 h after breakfast. Doses of 60mg QD and
30mg BID consistently elevated concentrations of the bile acid precursor,
C4, for 24.5 h. Single dose escalation of GSK2330672, a GI lumen-restricted
iBAT inhibitor, demonstrated significant effects on bile acid excretion and
synthesis at doses that were generally safe and well-tolerated.
Clinical Diabetes/
Therapeutics
ANTHONY H. CINCOTTA, MICHAEL EZROKHI, Tiverton, RI
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
1175-P
Efficacy and Safety of the Dipeptidyl Peptidase-4 Inhibitor, Sitagliptin Compared With α-Glucosidase Inhibitor in Japanese Patients
With Type 2 Diabetes Inadequately Controlled on Metformin or
Pioglitazone Alone (SUCCESS1): A Multicenter, Randomized, Openlabel, Clinical Trial
HIDETAKA YOKOH, KAZUAKI KOBAYASHI, YASUNORI SATO, MINORU TAKEMOTO, DAIGAKU UCHIDA, AZUMA KANATSUKA, NOBUICHI KURIBAYASHI, KENICHI SAKURAI, TAKASHI TERANO, NAOTAKE HASHIMOTO, HIDEKI HANAOKA,
KO ISHIKAWA, SHUNICHIRO ONISHI, KOUTARO YOKOTE, THE SUCCESS STUDY
GROUP, Yachio Chiba, Japan, Funabashi, Japan
Dipeptidyl peptidase-4 (DPP-4) inhibitors have been used widely lately,
but its most appropriate position of DPP-4 inhibitors in combination therapy
in type 2 diabetes has not been well established. Therefore, we examined
the efficacy and safety of a DPP-4 inhibitor, sitagliptin in comparison with
α-glcosidase inhibitor (αGI), a widely used class of hypoglycemic agent
in Japan, in type 2 diabetes in the setting of combination therapy with
metformin or pioglitazone.
A multicenter, prospective, randomized, open-label trial was conducted at
22 hospitals in Japan from January 2011 to June 2012. Participants aged 2079 years with type 2 diabetes who had treated with metformin or pioglitazone
alone but did not achieve target HbA1c (6.9-8.8%) were randomly assigned
to sitagliptin (50 mg daily) or αGI (0.6 mg voglibose or 150 mg miglitol daily).
The primary endpoint was change in HbA1c from baseline at 12 weeks. All
data were analyzed according to the intention-to-treat principle.
Sixty patients entered in the sitagliptin group and 59 in the αGI group.
Mean values of HbA1c at baseline was 7.6% in the both groups. After 12
weeks, sitagliptin treatment led to significant reductions compared with αGI
in difference of HbA1c (−0.49%). Significant difference was found between
two groups at 24 weeks. Gastrointestinal disorders was more common with
αGI than with sitagliptin (23 [40%] patients vs 6 [11%], p=0.0003). Minor
hypoglycemia occurred in about 4% of patients in each group.
Sitagliptin was superior to αGI for reduction of HbA1c, and was well
tolerated with minimum risk of gastrointestinal disorders and hypoglycemia
in type 2 diabetes inadequately controlled on metformin or pioglitazone
alone. These findings support the use of sitagliptin in the setting of
combination therapy with metformin or pioglitazone.
1174-P
POSTERS
Clinical Diabetes/
Therapeutics
Efficacy and Tolerability of Saxagliptin (SAXA) in Patients With
Type 2 Diabetes Mellitus (T2DM) and a History of Cardiovascular
Disease (CVD)
GIANMARIA MINERVINI, WILLIAM COOK, ELSIE ALLEN, Wilmington, DE, Princeton, NJ
Subgroup analysis of data from patients with T2DM and a history of
CVD (previous event or CVD diagnosis) included data from 3 phase 3
studies: SAXA+metformin (MET) vs MET as initial therapy (NCT00327015),
SAXA+MET vs glipizide (GLIP)+MET (NCT00575588), and SAXA vs placebo
(PBO) add-on to insulin (INS)±MET (NCT00757588). Glycemic efficacy
and adverse events (AEs) for SAXA vs PBO or comparator were analyzed
in patients with/without a history of CVD. No treatment-by-subgroup
interactions (P<0.1) were noted for change from baseline in A1C (Table 1). AEs
were comparable across CVD groups and reported by 47%-69% of patients.
Symptomatic confirmed hypoglycemia (fingerstick glucose ≤50 mg/dL) was
reported in 0%-9% of patients, with more episodes reported for patients
receiving GLIP (Table 2). SAXA improves glycemic control and is generally
well tolerated in patients with T2DM regardless of CVD history.
Supported by: Waksman Financial Group
1176-P
Dapagliflozin as Part of Triple Combination Therapy Helps Reduce
HbA1c and Body Weight in Patients With Type 2 Diabetes
SERGE JABBOUR, ELISE HARDY, TJERK W. DEBRUIN, INGRID GAUSE-NILSSON,
KATJA ROHWEDDER, PAULA MARTIN, SHAMIK J. PARIKH, Philadelphia, PA,
Wilmington, DE, Mölndal, Sweden, Wedel, Germany
Dapagliflozin (DAPA) is an SGLT2 inhibitor that reduces hyperglycemia in
patients with type 2 diabetes mellitus (T2DM) through the urinary excretion
of glucose that is also associated with a reduction in body weight (BW).
DAPA has demonstrated efficacy as monotherapy in treatment naïve
patients and in patients inadequately controlled with single oral antidiabetic
drugs (OADs) or insulin (+/- OADs). In the progression of T2DM, second and
even third agents are often needed to intensify therapy. To investigate the
efficacy of DAPA added to two stable medications, we performed subgroup
analyses of four 24 week studies. Primary results from the full populations
of these studies have been presented previously. Patients in the subgroups
received placebo (PBO) or DAPA 10 mg in the presence of either sitagliptin
(SITA) and metformin (MET) (prespecified stratification); or sulfonylurea (SU)
+ MET(HbA1c prespecified analyses no multiplicity testing, BW post hoc
analyses); or insulin (INS) + MET (post hoc analyses). DAPA reduced HbA1c
and BW compared with PBO at 24 weeks in each of the four subgroups
(Table). These results are generally comparable to those observed across
the DAPA program, confirming that, even when added to two different antidiabetic agents, DAPA is effective in reducing glycemia and BW in T2DM.
This observation is consistent with an insulin-independent mechanism of
action that works regardless of residual beta cell function.
Supported by: Bristol-Myers Squibb/AstraZeneca
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A total of 306 Asian patients (China n=264, Malaysia n=17 and the
Philippines n=24) with T2DM were randomized to linagliptin (n=205) or
placebo (n=101) at a 2:1 ratio. Baseline characteristics were well matched
between groups, with mean (SD) baseline HbA1c of 7.99 ± 0.83% in the
linagliptin group and 8.00 ± 0.80% in the placebo group. After 24 weeks,
adjusted mean (SE) HbA1c decreased by −0.66 ± 0.05% in the linagliptin
group and −0.14 ± 0.07% in the placebo group (placebo-corrected difference,
−0.52 ± 0.09%; 95% CI: −0.70, −0.34; P<0.0001). In the pre-defined subgroup
of patients with baseline HbA1c ≥8.5%, the placebo-corrected decrease in
HbA1c was −0.89 ± 0.17% (P<0.0001). Adjusted mean (SE) FPG decreased
by −10.7 ± 2.5 and −1.1 ± 3.5 mg/dL in the linagliptin and placebo groups,
respectively (placebo-corrected difference, −9.6 ± 4.2 mg/dL; 95% CI: −17.8,
−1.3; P=0.02). Results for the pre-defined Chinese subgroup were similar to
the overall Asian population. Linagliptin was well tolerated, with adverse
events occurring in a similar proportion of patients as in the placebo group
(27.3% and 28.0%, respectively). Drug-related AEs were reported for 2.4%
and 0.0% of linagliptin and placebo patients, respectively. Investigatordefined hypoglycemia occurred in 1.0% in both groups.
In summary, linagliptin 5 mg was efficacious and well tolerated over 24
weeks in Asian patients and a Chinese subgroup with T2DM inadequately
controlled on metformin.
DAPA 10 mg
HbA1c (%)
SITA + MET (NCT00984867)
n
113
113
BL HbA1c [% (SD)]
7.87 (0.75)
7.80 (0.81)
a
24-wk Change from BL (95% CI)
-0.02 (-0.15, 0.10) -0.43 (-0.55, -0.30)
Difference from placebo
--0.40 (-0.58, -0.23)b
SU + MET (study 1) (NCT01031680)
n
114
113
BL HbA1c [% (SD)]
8.10 (0.77)
8.06 (0.78)
24-wk Change from BL (95% CI)a
-0.01 (-0.17, 0.15) -0.55 (-0.72, -0.39)
Difference from placebo
--0.54 (-0.73, -0.36)d
SU + MET (Study 2) (NCT01042977)
n
109
105
BL HbA1c [% (SD)]
7.96 (0.80)
8.03 (0.79)
24-wk Change from BL (95% CI)a
-0.07 (-0.26, 0.12) -0.55 (-0.75, -0.36)
Difference from placebo
--0.48 (-0.69, -0.27)d
INS + MET (NCT00673231)
n
77
83
BL HbA1c [% (SD)]
8.43 (0.73)
8.52 (0.79)
a
24-wk Change from BL (95% CI)
-0.31 (-0.47, -0.16) -0.93 (-1.08, -0.78)
Difference from placebo
---0.61 (-0.83, -0.40)d
Body Weight (kg)
SITA + MET (NCT00984867)
n
113
113
BL BW [kg (SD)]
94.2 (20.9)
94.0 (19.8)
a
24-wk Change from BL (95% CI)
-0.47 (-1.00, 0.05) -2.35 (-2.87, -1.82)
Difference from placebo
--1.87 (-2.61, -1.13)b
SU + MET (Study 1) (NCT01031680)
n
114
112
BL BW [kg (SD)]
89.0 (15.5)
87.6 (19.0)
24-wk Change from BL (95% CI) a
0.0 (-0.6, 0.6)
-2.2 (-2.8, -1.6)
Difference from placebo
---2.2 (-2.9, -1.5)d
SU + MET (Study 2) (NCT01042977)
n
110
106
BL BW [kg (SD)]
90.1 (15.2)
93.4 (19.5)
24-wk Change from BL (95% CI) a
-0.8 (-1.5, -0.2)
-1.9 (-2.5, -1.2)
Difference from placebo
---1.1 (-1.8, -0.3)c
INS + MET (NCT00673231)
n
77
83
BL BW [kg (SD)]
98.7 (17.5)
95.7 (16.2)
a
24-wk Change from BL (95% CI)
-0.06 (-0.61, 0.49) -1.77 (-2.30, -1.24)
Difference from placebo
--1.71 (-2.47, -0.95)d
a Adjusted mean change from baseline (LOCF); b prespecified p-value <0.0001
for comparison of DAPA and PBO c Nominal p-value = 0.0047; d Nominal
p-value <0.0001; BL - baseline
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1178-P
MTBL0036, a New Promising Antidiabetic Drug Candidate: In Vivo
Preclinical Studies
MAHA EL HAGE, GÉRARD MOINET, BERNARD FERRIER, RÉMI NAZARET, GUY
MARTIN, AGNÈS CONJARD-DUPLANY, GABRIEL BAVEREL, Lyon, France
The objective of the present study was to establish the characteristics of
the effect of MTBL0036, a new optimized and patented antidiabetic drug
candidate, in 8-12 month-old db/db mice, a good animal model of type 2
diabetes. For this, MTBL0036 was administered per os as a suspension in
2% methylcellulose and the control animals received per os only the vehicle
which itself did not influence glycemia. The glycemia was measured at
various time points after small blood collections by small incisions of the
tail, before and after the oral administration of a glucose load. The glycemia
was measured using a glucometer (Lifescan One Touch Ultra, Lifescan, J&J
Company, USA). The Areas Under the Curve (AUCs) were calculated using
the GraphCalc software.
The reduction (by 25-30%) of the blood glucose level in diabetic mice
treated with 200 mg MTBL0036/kg body weight was observed one hour after
the administration and persisted for at least 4 hours. No anti-hyperglycemic
effect was observed after the administration of 200 mg metformin/kg body
weight. When administered orally 120 min before the glucose load, two doses
of MTBL0036 (25 and 50 mg/kg) reduced by 60% and 80%, respectively,
the AUCs for glucose after the glucose load in 17h-fasted diabetic mice.
Under the same conditions, metformin (50 mg/kg) did not reduce the AUC
for glucose. In fed db/db mice treated for 5 days with a daily dose of 50 mg
MTBL0036/kg, the level of neither insulin nor triglycerides was found to be
elevated. MTBL0036 was found to be eliminated, at least in part, in urine in
an unchanged form.
It is concluded that, in db/db mice, MTBL0036 is more efficacious than
metformin, the gold-standard treatment for type 2 diabetes. In addition, this
promising antidiabetic drug candidate seems to be devoid of hypoglycemic
and cardiovascular risks. Moreover, the risk for interacting with the
metabolism of other drugs seems to be limited.
Supported by: AstraZeneca/Bristol-Myers Squibb
1177-P
Efficacy and Safety of Linagliptin in Asian Patients With Type 2 Diabetes Mellitus Inadequately Controlled on Metformin: A 24-Week,
Randomized, Phase III Clinical Trial
WEIQING WANG, JINKUI YANG, GANGYI YANG, YAN GONG, HANS-JUERGEN
WOERLE, GUANG NING, Shanghai, China, Beijing, China, Chongqing, China, Ingelheim, Germany
This randomized, Phase III, placebo-controlled, double-blind 24-week
study evaluated the efficacy and safety of the DPP-4 inhibitor linagliptin
added to metformin in patients with type 2 diabetes mellitus (T2DM) in
Asian countries (NCT01215097).
Antidiabetes drugs other than metformin were washed out for 4 weeks
prior to randomization to either linagliptin 5 mg daily or placebo added to
metformin. The primary endpoint of the study was change from baseline in
mean HbA1c after 24 weeks.
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A307
POSTERS
PBO
Clinical Diabetes/
Therapeutics
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—ORAL AGENTS
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS
increased after donepezil treatment in both SHR (0.321 ± 0.009 vs. 0.296 ±
0.004, p < 0.02) and WKY (0.339 ± 0.008 vs 0.313 ± 0.008, p < 0.03) when
compared with placebo. There was no significant difference in body weight
among the 4 groups. We conclude donepezil treatment ameliorates IR in SHR
and may potentially be repurposed as adjunctive treatment for diabetes.
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—
PHARMACOLOGIC TREATMENT OF COMPLICATIONS
Guided Audio Tour: Management of Complications of Diabetes (Posters:
1179-P to 1186-P), see page 17.
&
&
1179-P
MASAHIRO OKOUCHI, NAOTSUKA OKAYAMA, TAKASHI JOH, Inazawa, Japan,
Nagoya, Japan
POSTERS
TALI CUKIERMAN-YAFFE, JACKIE BOSCH, LEANNE DYAL, PETER JOHNSTON,
HERTZEL C. GERSTEIN, ON BEHALF OF THE ORIGIN INVESTIGATORS, Ramat Gan,
Israel, Hamilton, ON, Canada, Bridgewater, NJ
Clinical Diabetes/
Therapeutics
1181-P
GLP-1 Analogs Represent a Novel Treatment Strategy for Alzheimer’s Disease in Patients With Type 2 Diabetes
Effect of Basal Insulin Glargine and Omega 3 FA on Cognitive Decline and Dementia in People With Dysglycemia
Diabetic patients commonly develop cognitive impairment of Alzheimer’s
disease type, defined as diabetic encephalopathy, which is involved in
oxidative stress-induced hippocampal neuronal apoptosis. However, the
treatment strategy has not been elucidated. GLP-1, biguanides (BG) or
thiazolidinediones (TZD) have been shown to exert neuroprotective actions
in Alzheimer’s disease. GLP-1 receptors are widely expressed in neurons
throughout the brain, and GLP-1 readily crosses the blood-brain barrier.
Therefore, in vivo and in vitro, the differential neuroprotective effect of
GLP-1, BG or TZD was investigated. First, we compared the difference of
hippocampal atrophy on MRI using VSRAD among 300 type 2 diabetic patients
treated with GLP-1 analogs, BG or TZD, and 200 type 2 diabetic patients
without those medications, and 100 control subjects. Diabetic patients
had more hippocampal atrophy than control subjects. Addionally, diabetic
patients treated with GLP-1 analogs, BG or TZD had less hippocampal atrophy
than diabetic patients without those medications. In vitro, GLP-1 protected
against oxidative stress-induced neuronal apoptosis through activating GLP1 receptor mediated EGFR transactivation, followed by PI3K/Akt/mTOR/GCL
signaling. We also found an increase in progenitor cells or young neurons
in the hippocampal regions after GLP-1 analogs treatment. BG protected
against oxidative stress-induced neuronal apoptosis through inhibiting
PTP opening, cytochrome c release and caspase-9 and -3 activation. TZD
protected against oxidative stress-induced apoptosis in association with the
upregulation of Bcl-2 protein, consequently led to the inhibition of caspase-9
and -3 activation. In conclusion, GLP-1, BG or TZD afford neuroprotection
through enhancing different anti-apoptotic signaling and increasing neural
stem/progenitor cell proliferation. Thus, those treatments represent a
promising treatment modality for diabetic encephalopathy.
Recent evidence suggests that diabetes and nondiabetic dysglycemia are
risk factors for an accelerated rate of cognitive decline. Whether normalizing
glucose levels with insulin glargine and/or administering Omega 3 FA in this
population may slow this is unknown.
The ORIGIN trial which tested the cardiovascular effect of these two
interventions in 12,537 participants with prediabetes or early diabetes
followed for a median of 6.2 years, also assessed the effects of the
interventions on the rate of cognitive decline and the development of
probable dementia. Cognitive function was assessed utilizing the Mini
Mental State Examination & Digit Symbol Substitution. The effect of the
intervention on cognitive function over time; the annualized change in test
scores; and the development of probable dementia defined as either reported
dementia or a MMSE score < 24 were determined.
There was no significant difference in the rate of change in cognitive test
scores in the insulin-glargine comparison versus the standard care group or
in the omega-3 versus the placebo group. Similarly, after adjustment for age,
and the factorialized treatment arm, the incidence of probable dementia did
not statistically differ between either the glargine group and standard care
group or the omega-3 and placebo group (Table).
In people with dysglycemia, insulin mediated normoglycemia and omega-3
had a neutral effect on the rate of cognitive decline and on incident probable
dementia.
&
1182-P
Exenatide Once Weekly: Association between Weight Response,
Glycemic Control, and Markers of Cardiovascular Risk
Supported by: Sanofi (NCT00069784)
&
LAWRENCE BLONDE, LEIGH MACCONELL, WENYING HUANG, RICHARD PENCEK,
New Orleans, LA, San Diego, CA
Exenatide once weekly (EQW) has been shown to improve glycemic
control and body weight (BW) in patients with T2DM. To better describe the
relationship of glycemia, cardiovascular (CV) risk factors, and BW, a post hoc
analysis based on ΔBW quartiles was conducted using pooled data (intentto-treat, N=1830; treated with EQW ± oral antidiabetes medications) from 8
randomized, controlled 24-30 wk trials. LOCF changes from baseline in A1C,
fasting plasma glucose (FPG), BW, lipids and blood pressure were summarized
by BW response quartile. Overall, clinically relevant decreases in A1C (-1.4%),
FPG (-36 mg/dL), BW (-2.4 kg), and systolic blood pressure (SBP; -3 mmHg)
were observed, as were improvements in other CV risk markers. Safety and
tolerability with EQW were consistent with previous reports. Patients in 3
of 4 ΔBW quartiles (75%) showed weight reductions. Clinically relevant A1C
reductions were observed across all ΔBW quartiles. EQW treatment was
also associated with improvement in CV risk factors in at least 3 of 4 ΔBW
quartiles including: total cholesterol, LDL-C, HDL-C, triglycerides, and SBP.
The greatest improvement in cardiovascular risk factors was seen in the
patient quartile with the greatest reduction in weight. In conclusion, clinically
important A1C improvement was seen across all quartiles, including those
with little or no weight loss. The majority of patients achieved reductions in
BW associated with improvements in markers of CV risk.
1180-P
Donepezil, an Acetylcholinesterase Inhibitor Used to Treat Alzheimer Dementia, Ameliorates Insulin Resistance in Spontaneously Hypertensive Rats (SHR)
DONGMEI ZHANG, XIAO JIAN SUN, SOOHYUN P. KIM, STEPHEN L. WILLS, MICHAEL J. QUON, Baltimore, MD, Easton, MD, Bethesda, MD
Donepezil, an acetylcholinesterase inhibitor used to treat Alzheimer
dementia, may improve brain blood flow by raising acetylcholine levels that
stimulate production of nitric oxide (NO). NO from endothelium increases
blood flow in skeletal muscle to determine ~40% of insulin-mediated glucose
uptake. Therefore, we hypothesized donepezil therapy may ameliorate
insulin resistance (IR) in SHR, characterized by hypertension, endothelial
dysfunction, and IR. SHR and WKY littermate control male rats (9 wk
old) were treated with donepezil (10 mg/kg/d in 0.5% methylcellulose) or
placebo (0.5% methylcellulose) by gavage for 12 wk (n = 6/group). After 4
wk, 2 h glucose tolerance tests (GTT, 2 g glucose/kg, i.p.) were conducted.
Improvement in glucose tolerance was noted in SHR treated with donepezil
vs placebo (AUCglucose = 7340 ± 770 vs 11100 ± 1360 (mg/dl)·min, p < 0.008).
No significant differences in GTT were noted among WKY rats. After 12 wk,
2 h insulin tolerance tests (ITT, 0.75 IU insulin/kg, i.p.) were conducted. We
observed a tendency for insulin sensitivity to improve in SHR treated with
donepezil vs placebo (AOCglucose = 6110 ± 170 vs 5540 ± 240 (mg/dl)·min, p
< 0.06). No significant differences in ITT were noted among WKY rats. After
12 wk, fasting insulin was reduced by donezepil treatment when compared
with placebo in both SHR (14 ± 2 vs 21 ± 2 IU/ml, p < 0.03) and WKY (9 ± 1 vs.
15 ± 2, p < 0.014) rats. Fasting glucose was reduced in SHR (105 ± 5 vs. 117 ± 3
mg/dl, p < 0.04) and tended to be reduced in WKY (101 ± 5 vs 112 ± 3, p < 0.09)
when compared with placebo. QUICKI, an index of insulin sensitivity, was
&
For author disclosure information, see page 829.
A308
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS
1183-P
Co-Administration of the DPP-4 Inhibitor Linagliptin and Native
GLP-1 Induce Body Weight Loss and Appetite Suppression
HENRIK HANSEN, GITTE HANSEN, SARAH PAULSEN, MICHAEL MARK, NIELS
VRANG, THOMAS KLEIN, Hørsholm, Denmark, Biberach, Germany
Linagliptin is a dipeptidyl peptidase (DPP)-4 inhibitor approved for
the treatment of type 2 diabetes. DPP-4 inhibitors are weight-neutral,
suggesting that elevation of endogenous incretin levels is not sufficient to
promote weight loss per se. Here we evaluated the effect of subcutaneous
co-administration of linagliptin and native GLP-1(7-36) in rats. In normalweight rats, acute linagliptin treatment (0.5 mg/kg, sc BID) had no effect on
nocturnal food intake, whereas GLP-1 treatment (0.4 mg/kg, sc BID) evoked a
modest and short-lived suppression of food intake. In contrast, linagliptin and
GLP-1 co-administration induced a robust acute anorectic response. In dietinduced obese (DIO) rats, 14 days of linagliptin or GLP-1 monotherapy had no
effect on body weight, whereas continuation with combined linagliptin (0.5
mg/kg, sc BID) and GLP-1 treatment (0.4 mg/kg, sc BID) for an additional
14 days induced a sustained decrease in food intake and body weight
(-6.4 ± 0.8% compared with baseline body weight). Interestingly, the body
weight-lowering effect of combined linagliptin and GLP-1 treatment was
associated with a marked increase in chow preference at the expense of
palatable high-fat-carbohydrate diet intake. In addition, combined linagliptin
and GLP-1 treatment specifically increased preprodynorphin mRNA levels in
the nucleus accumbens. These data demonstrate that combined treatment
with linagliptin and GLP-1 synergistically reduces body weight in obese rats.
This anti-obesity effect is caused by appetite suppression and change in
diet preference, presumably associated with increased dynorphin activity
in dopaminergic forebrain regions involved in reward anticipation and
habit learning. In conclusion, linagliptin and GLP-1 co-administration may
therefore hold promise as a novel therapeutic principle for combined weight
and diabetes management in obese patients.
&
KENNETH CUSI, BEVERLY ORSAK, ROMINA LOMONACO, JOAN FINCH, CAROLINA ORTIZ-LOPEZ, FERNANDO BRIL, NORMA DIAZ, ROSE KAMINSKI-GRAHAM,
CELIA DARLAND, NICOLAS MUSI, AMY WEBB, JEAN HARDIES, FERMIN TIO,
Gainesville, FL, San Antonio, TX
Nonalcoholic steatohepatitis (NASH), the more severe form of fatty liver
associated with necroinflammation and risk of cirrhosis, is common in T2DM.
The only effective therapy to date in this population is pioglitazone (PIO), but
it has been studied only in a small 6-month randomized controlled trial (RCT)
(Belfort et al, NEJM 2006). To examine its long-term safety and efficacy,
we treated 101 patients (pts) with prediabetes or T2DM (51%) and NASH
(age=51±1 yr, BMI: 34.4 ± 0.5 kg/m2, A1c: 6.3 ± 0.1%) for 18 months in a
RCT of diet and PIO vs. diet and placebo. We assessed at 0 and 18 months:
1) Liver histology by biopsy (primary endpoint); 2) Liver fat by magnetic
resonance and spectroscopy (MRS); 3) Total body fat (TBF) by DXA; 4) Liver/
muscle (Rd) insulin sensitivity (insulin clamp with 3-3H glucose); and 5)
fasting hepatic insulin resistance (IR) (HIRi= EGP x fasting plasma insulin
[FPI]) and adipose tissue IR (AdipoIRi= FFA x FPI). Placebo- and PIO-treated
pts were well-matched at baseline for clinical, biochemical and metabolic
characteristics (all NS). Diet plus placebo significantly lowered ALT (61±5
to 44±4 U/L; p<0.01) but this did not translate into any significant change in
liver histology or metabolic parameters. In contrast, PIO compared to placebo
significantly improved LFTs, FPG/A1c, FPI, HOMA and insulin sensitivity in
adipose tissue (AdipoIRi: -37±3% vs. -10±1%; low-dose insulin-suppr of FFA:
66±4% vs. 44±4%), liver (HIRi: 10.5±1 vs. 28±2 mg/kg-1·min-1·µU/ml; lowdose insulin-suppr of EGP: -50±3% vs. -37±3%) and muscle (Rd: 9.3±0.6 vs.
5.3±0.6 mg·kgLBM-1·min-1; all p<0.01 vs. placebo). PIO decreased 60% liver
fat (MRS) and markedly improved steatohepatitis (NAFLD activity score:
4.2±0.2 vs. 2.4±0.2, both p<0.001 vs. placebo), but fibrosis was unchanged.
No pt on PIO discontinued the study due to an adverse event. Conclusion: PIO
treatment for 18 months is safe and effective to reverse metabolic and liver
histological abnormalities in pts with prediabetes/T2DM and NASH.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
&
1184-P
Vitamin B12 Deficiency in the Diabetes Prevention Program Outcome Study (DPPOS)
JILL P. CRANDALL, SHARON L. EDELSTEIN, VANITA ARODA, GEORGE A. BRAY,
SARAH FOWLER, RONALD GOLDBERG, MARY BETH MURPHY, WILLIAM C.
KNOWLER, SANTICA M. MARCOVINA, TREVOR J. ORCHARD, DAVID S. SCHADE,
MARINELLA TEMPROSA, Bronx, NY, Washington, DC, Hyattsville, MD, Baton
Rouge, LA, Rockville, MD, Coral Gables, FL, Memphis, TN, Phoenix, AZ, Seattle, WA,
Pittsburgh, PA, Albuquerque, NM
Vitamin B12 deficiency occurs with long-term metformin treatment,
although it is infrequently recognized. Current guidelines do not recommend
routine B12 testing. We measured vitamin B12 levels in metformin (MET)
and placebo (PLA) participants in the DPPOS, the follow-up to a randomized
clinical trial of diabetes prevention in high-risk adults. B12 levels were
assessed by randomized treatment arm. Years of MET exposure were
computed using protocol-MET exposure and physician-prescribed MET,
reported by participants, for diabetes treatment outside of the protocol.
ADA-Funded Research
&
1185-P
Safety and Efficacy of Long-Term Pioglitazone Treatment for Patients With Prediabetes or T2DM and NASH
Supported by: Burroughs Wellcome Fund
For author disclosure information, see page 829.
Guided Audio Tour poster
A309
POSTERS
&
B12 levels did not differ by age in either MET or PLA. The prevalence of
anemia did not differ by B12 status in DPPOS year 1 (MET or PLA) or year 9
(measured in MET participants only). Total MET-years of exposure was the
only significant predictor of B12 deficiency in a multivariate logistic model
with age, sex, diabetes status, weight change and acid suppressant use. The
OR (95% CI) associated with B12 deficiency per year of MET use was 1.25
(0.98-1.56) in year 1 and 1.11 (1.03-1.20) in year 9 in MET, and 1.56 (0.92-2.63)
and 1.19 (1.07-1.32) in PLA.
Over a mean 13 years follow-up, biochemical vitamin B12 deficiency
occurred in over 7% of participants randomized to MET. Prevalence of deficiency increased with longer duration of metformin use. Anemia is not an
adequate indicator of B12 deficiency. Given the potential neurologic consequences of untreated B12 deficiency, routine testing of MET treated patients
should be considered.
Clinical Diabetes/
Therapeutics
B12 levels and metformin use by DPP treatment group and study visit
DPPOS year 1
DPPOS year 9
(Mean 5 years follow-up) (Mean 13 years follow-up)
MET
PLA
p MET PLA
p
(N=859) (N=856)
(N=753) (N=736)
Total metformin-years of exposure (mean +/- SD) *
2.9 ± 1.7 0.1 ± 0.6 -- 9.5 ± 4.4 1.7 ± 2.8 -Percent with Diabetes
33.2%
39.0% -- 52.3% 59.7% -B12 deficiency (≤203 pg/ml) **
4.3%
2.4% 0.02 7.4% 5.3% 0.12
B12 deficiency or borderline-low B12 (≤298 pg/ml)** 19.1%
9.5% <0.01 20.3% 15.6% 0.02
B12 deficiency (≤203 pg/ml)** among participants
5.2%
NA --- 9.2% NA --currently taking study-provided MET
(*) includes protocol assigned and non-study metformin use; (**) B12 deficiency defined according to American Society of Hematology, 2003.
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS
&
of DAPA on lipids in patients with T2DM are reported here. Data from 3731
patients in 12 phase 2b/3 double-blind controlled trials receiving DAPA 5
or 10 mg or placebo (PBO) for up to 24 weeks were analyzed. Changes in
the plasma lipid profile were studied as exploratory endpoints in these
studies. Demographic and baseline characteristics were balanced between
DAPA and PBO groups. Improved glycemic control with DAPA versus PBO
has been previously reported in these studies. Changes in lipid parameters
from individual trials showed variability across studies. In a 24-week pooled
analysis, changes from baseline in HDL-C were +6.5% and +5.5% for DAPA
5 and 10 mg, respectively and +3.8% for PBO; LDL-C were +0.6% and +2.7%
for DAPA 5 and 10 mg, respectively, and −1.9% for PBO; total cholesterol
were +1.1% and +1.4% for DAPA 5 and 10 mg, respectively, and −0.4% for
PBO. To conclude, DAPA is associated with small mean changes in fasting
lipid parameters versus PBO at 24 weeks; these changes are not clinically
meaningful.
1186-P
Specific miRNA Inhibitors Accelerate Wound Healing in Diabetes
POSTERS
Clinical Diabetes/
Therapeutics
BIAO FENG, LINBO ZHANG, SUBRATA CHAKRABARTI, London, ON, Canada
miRNAs play an important role in the post-transcriptional regulation of
gene expression and controlling various physiological and pathological
processes. Our previous studies showed that miR-200b regulates VEGF
mediated angiogenesis and miR-146a regulates extracellular matrix protein,
fibronectin (FN) production. In this study, we examined the effects of these
two miRNAs in wound healing (WH) in the diabetic and control animals.
Microvascular endothelial cells (ECs) were exposed to low (5mM) and
high (25mM) glucose levels and were tested for VEGF and FN production and
examined for angiogenesis. They were also transfected with miRNA mimics
and inhibitors of these miRNAs and examined similarly. Furthermore, skin
wounds in the mice with or without STZ induced diabetes were treated with
these inhibitors, alone or in combinations. Wound areas were measured and
tissues from the wounds were examined histologically for scar tissue and for
mRNA and miRNA expression by real time RT-PCR.
In the ECs, glucose induced increased VEGF and FN production and
angiogenesis. These mRNA expression and angiogenesis in the ECs exposed
to low concentration glucose were also augmented by miR-200b or miR-146a
inhibitor transfection. In the animals, compared to transfection reagent only,
WH processes were accelerated by miR-200b or miR-146a inhibitor. However,
such acceleration was most pronounced (50% reduction) when these two
inhibitors were combined. In the diabetic animals, although overall WH
process was delayed, combined inhibitor treatment significantly accelerated
such process. Such wound healing was associated with increased VEGF and
FN mRNA production and well developed scar tissues
These results indicated that combination of miR-146a and miR-200b
inhibitors are useful in the accelerating WH both in normal and in diabetic
conditions. miRNA mediated WH may potentially constitute a novel therapeutic approach.
Plasma lipid changes from baseline (%, 95% CI) in the pooled DAPA studies
at 24 weeks
PBO
DAPA 5 mg DAPA 10 mg
(N=1393)
(N=1145)
(N=1193)
TC
.
.
.
n
989
888
834
BL mean, mg/dL
195.22
194.48
195.88
Mean change, %
−0.4%
+1.1%
+1.4%
(95% CI)
(−1.4, +0.6)
(0.0, +2.2)
(+0.2, +2.6)
HDL-C
.
.
.
n
990
889
834
BL mean, mg/dL
44.54
44.79
45.04
Mean change, %
+3.8%
+6.5%
+5.5%
(95% CI)
(+2.8, +4.8)
(+5.3, +7.8)
(+4.3, +6.7)
LDL-C
.
.
.
n
985
884
828
BL mean, mg/dL
114.72
113.24
114.09
Mean change, %
−1.9%
+0.6%
+2.7%
(95% CI)
(−3.5, −0.3)
(−1.2, +2.4)
(+0.8, +4.7)
TG
.
.
.
n
984
886
831
BL mean, mg/dL
187.46
190.40
194.21
Mean change, %
−0.7%
−3.2%
−5.4%
(95% CI)
(−3.0, +1.7)
(−5.8, −0.6)
(−7.9, −2.8)
FFA
.
.
.
n
838
732
694
BL mean, meq/L
0.56
0.58
0.56
Mean change, %
−5.7%
−0.5%
+1.2%
(95% CI)
(−8.9, −2.5)
(−3.7, +2.8)
(−2.4, +5.0)
Data include observations after rescue. N is the number of treated patients. n
is the number of treated patients with non-missing baseline and week 24 values. BL=baseline, CI=confidence interval, DAPA=dapagliflozin, FFA=free fatty
acids, HDL-C=high-density lipoprotein cholesterol, LDL-C=low-density lipoprotein cholesterol, PBO=placebo, TC=total cholesterol, TG=triglycerides.
Supported by: CDA; CIHR
Guided Audio Tour: Cardiovascular Implications of Diabetic Therapies (Posters: 1187-P to 1194-P), see page 17.
&
1187-P
Limiting Cardiac Ischemic Injury by Pharmacologic Augmentation
of Translocation of Glucose Transporter
JINGYING WANG, LIN LENG, LAWRENCE YOUNG, WILLIAM JORGENSEN, JI LI,
RICHARD BUCALA, Buffalo, NY, New Haven, CT
Background: Macrophage migration inhibitory factor (MIF) exerts a
protective effect on ischemic myocardium by activating AMP-activated
protein kinase (AMPK). Small molecules that increase the affinity of MIF for
its receptor have been recently designed, and we hypothesized that such
agonists may enhance AMPK activation and limit ischemic tissue injury.
Methods and Results: Treatment of cardiomyocytes with the candidate MIF
agonist, MIF20, augmented AMPK phosphorylation, increased by 50% the
surface localization of glucose transporter, and enhanced by 25% cellular
glucose uptake when compared to MIF alone. In mouse hearts perfused
with MIF20 prior to no-flow ischemia and reperfusion, post-ischemic left
ventricular function improved commensurately with an increase in cardiac
MIF-AMPK activation and an augmentation in myocardial glucose uptake. By
contrast, small molecule MIF agonism was not effective in cells or tissues
genetically deficient in MIF or the MIF receptor, verifying the specificity of
MIF20 for MIF-dependent AMPK signaling. The protective effect of MIF20
also was evident in an in vivo regional ischemia model. Mice pre-treated
with MIF20 followed by left coronary artery occlusion and reperfusion
showed a significant reduction in infarcted myocardium. Conclusions: These
data support the pharmacologic utility of small molecule MIF agonists in
enhancing AMPK activation in cardiac ischemic injury.
Supported by: Bristol-Myers Squibb/AstraZeneca
&
ULRICH WERNER, K. HISS, DANIEL HEIN, THOMAS HÜBSCHLE, PAULUS WOHLFART, HARTMUT RUETTEN, Frankfurt, Germany
Cardioprotection by the GLP-1 receptor agonist lixisenatide (LIXI) has
recently been described in ex-vivo and in-vivo ischemia/reperfusion rat
studies. Here we assessed the cardioprotective activity of LIXI in a more
severe mouse model of myocardial infarction (MI), induced by permanent
ligation of the left anterior descending coronary artery.
The protective effects of once-daily treatment with LIXI for 4 weeks were
compared with placebo and with sham-operated controls without MI. The
ACE inhibitor ramipril served as reference. Treatment was started 3 days
prior to induction of ischemia. Male C57BL/6 mice (6-7 weeks of age) were
randomized into 5 groups: Sham, MI-control (placebo injection QD); MI-LIXI
10 (10 µg/kg s.c. QD), MI-LIXI 150 (150 µg/kg s.c. QD) and MI-ramipril (2.5 mg/
kg*day in drinking water). Post MI survival was monitored throughout the
study and cardiac function was assessed by pressure-volume loop analysis
at study end.
Four weeks after infarct induction, MI-control animals showed dramatically
reduced global cardiac parameters with significantly depressed systolic
contractility and impaired diastolic function. This was reflected in significantly
increased mortality (survival <60%). Chronic daily injection with LIXI (both 10
and 150 µg/kg) resulted in significant (40-47%) improvements in heart function
Supported by: NIH
&
1189-P
Effects of Lixisenatide on Survival and Cardiac Function in a Mouse
Model of Chronic Myocardial Infarction
1188-P
Dapagliflozin Effects on the Lipid Profile of Patients With Type 2
Diabetes Mellitus
ELISE HARDY, AGATA PTASZYNSKA, TJERK W.A. DE BRUIN, EVA JOHNSSON,
SHAMIK J. PARIKH, JAMES F. LIST, Wilmington, DE, Princeton, NJ
Dapagliflozin (DAPA), an SGLT2 inhibitor, increases urinary glucose
excretion, and improves hyperglycemia in patients with type 2 diabetes
mellitus (T2DM). DAPA also favorably affects cardiovascular risk factors by
reducing weight, blood pressure and uric acid in these patients. The effects
&
For author disclosure information, see page 829.
A310
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ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS
Figure 1.
parameters, such as ejection fraction, stroke volume and cardiac output,
translating into a significantly increased survival rate of >70%. Ramipril also
improved global cardiac parameters but the effect was not superior to that of
LIXI. The survival rate with ramipril, however, was ~90%.
In conclusion, the cardioprotection following ischemia/reperfusion in the
rat which was demonstrated by LIXI in previous studies, could be confirmed
and even extended towards a more aggravated MI induced heart failure
mouse model with permanent coronary artery occlusion.
Supported by: Sanofi
&
1190-P
Sustained Improvement of Postprandial Endothelial Function in
Type 2 Diabetes With Exenatide
Supported by: Novartis Pharmaceuticals Corporation; National Center for Research (UL1RR025758)
&
HIROYOSHI YOKOI, MASATO NAKAMURA, TOSHIYA MURAMATSU, HISAYUKI
OKADA, MASAHIKO OCHIAI, SATORU SUWA, YUTAKA MATSUYAMA, SHINSUKE
NANTO, ON BEHALF OF THE J-DESSERT INVESTIGATORS, Kitakyushu, Japan, Tokyo, Japan, Yokohama, Japan, Hamamatsu, Japan, Izunokuni, Japan, Suita, Japan
Pioglitazone (Pio) is widely used for glycemic control in patients with type2 diabetes mellitus (DM), and is associated with a lower risk of cardiovascular
events according to a meta-analysis of randomized trials.
To evaluate the effect of Pio on ischemic cardiovascular events in Japanese
patients with DM and coronary artery disease, after drug-eluting stent (DES)
implantation, the data from the Japan-Drug Eluting Stents Evaluation; a
Randomized Trial (J-DESsERT) was analyzed. In this prospective, multicenter
trial, 3,533 patients were randomized 1:1 to undergo coronary stenting with
Sirolimus-eluting stents or Paclitaxel-eluting stents. Lesion lengths were
≤46 mm, with vessel diameters from ≥2.5 mm to ≤3.75 mm. Randomization
was stratified based on the presence or absence of DM. Definitions for
allocation into the DM group at the time of this trial were: 1. Previous DM
diagnosis; 2. Currently on diabetic medication (oral hypoglycemic drugs or
insulin injections); 3. HbA1c ≥ 6.5% within 30 days before the procedure.
Patients who met one or more of the above criteria were allocated to the
DM group. A total of 1,692 patients (48%) with DM were analyzed from the
J-DESsERT trial. Cardiac death, myocardial infarction, or stroke, occurred
in 11 of 403 patients (2.7%) receiving Pio and 71 of 1,289 patients (5.5%)
receiving the other therapy, without Pio, at 12 months (P=0.024). Pioglitazone
is associated with a significantly lower risk of death, myocardial infarction,
or stroke in Japanese patients with DM after DES implantation.
Supported by: Amylin Pharmaceuticals, LLC.; Eli Lilly and Company
&
1191-P
Aliskiren Improves Vascular Smooth Muscle Function in the Skin
Microcirculation of Type 2 Diabetic Patients With Normal Renal
Function
JODY DUSHAY, FRANCESCO TECILAZICH, ANTONIOS KAFANAS, MARY MAGARGEE, MICHAEL E. AUSTER, CHARALAMBOS GNARDELLIS, THANH DINH, ARISTIDIS VEVES, Boston, MA, Messolonghi, Greece
&
&
1193-P
Bromocriptine-QR Attenuates the Progression to Both Cardiovascular (CV) Averse Events and Worsening Hyperglycemia in Type 2
Diabetes Mellitus (T2DM) Subjects in Good Glycemic Control
Skin microcirculation endothelium dependent and independent vasodilation
are impaired in T2DM and pre-diabetes. We studied the vascular effects
of daily 150 mg aliskiren, a direct renin inhibitor, in a 12-week randomized,
double-blind, placebo-controlled trial in T2DM and at-risk individuals (1st
degree relative with DM or history of impaired glucose homeostasis or
gestational DM). Forty seven T2DM subjects without vascular complications
[age 58±12 years (mean ± sd), A1c 7.3%±1.2) and 41 at-risk (age 52±11, A1c
5.8±0.3) were enrolled. Twenty six (55%) T2DM and 4 (8%) at-risk subjects
were also treated with ACE inhibitors or Angiotensin II Receptor Blockers.
Aliskiren resulted in lower systolic (p <0.05) and diastolic (p <0.01) blood
pressure and improved forearm skin endothelium-independent vasodilation
in T2DM subjects (p<0.05, Figure 1). No additional effects of aliskiren
were seen in serum or tissue (skin biopsy) markers of inflammation or in
the macrocirculation in either study group. Importantly, there was no
hypotension or change in potassium or creatinine levels with aliskiren
treatment. We conclude that aliskiren is well tolerated and improves blood
pressure and vascular smooth muscle function in skin microcirculation of
T2DM patients with normal renal function.
ADA-Funded Research
1192-P
Impact of Pioglitazone on Cardiovascular Events in Patients With
Type-2 Diabetes Mellitus after Drug-Eluting Stent Implantation
ANTHONY H. CINCOTTA, RICHARD E. SCRANTON, MICHAEL EZROKHI, J. MICHAEL GAZIANO, Tiverton, RI, Boston, MA
The one-year Cycloset Safety Trial (CST) demonstrated the CV safety and
anti-diabetes efficacy of bromocriptine-QR (B-QR) versus placebo in a large
(3070) randomized population of T2DM subjects whose hyperglycemia was
treated with diet, or one or two anti-diabetes medications (including insulin)
(Diabetes Care. 2010 Jul;33(7):1503-8, Endocr Pract. 2012 Nov 1;18(6):93143). The present study however tested whether B-QR may retard both CV and
metabolic disease progression in T2DM subjects already in good metabolic
control (i.e., that had a baseline HbA1c of ≤ 7.0) derived from the CST (BQR N= 1219, placebo N= 615, mean HbA1c: each 6.3). A Cox proportionalhazards regression analysis was used to determine the frequency of major
CV events, pre-specified as a composite of first myocardial infarction, stroke,
coronary revascularization, or hospitalization for angina or congestive heart
failure that occurred after randomization. Both on-treatment (OT) (exposure
time restricted to time on study drug) and intention to treat (ITT) analyses
(exposure time equal to early termination, time to event, or one year) were
conducted. The impact of B-QR on loss of good glycemic control was
For author disclosure information, see page 829.
Guided Audio Tour poster
A311
POSTERS
We previously demonstrated that exenatide (Ex) improved endothelial
function (EF) and plasma triglycerides (TG) 3.5 hours after a single, fatenriched breakfast meal in subjects with impaired glucose tolerance or new
onset diet controlled type 2 diabetes. In this study, we tested whether the
vascular effect of Ex is sustained through multiple meals and whether it is
effective in those with type 2 diabetes of longer duration.
Participants with diagnosed type 2 diabetes of duration < 3 years (n=19)
and > 5 years (n=21) were randomized to receive twice a day for 10 days
in a cross-over fashion Ex (Byetta®; dose per injection: 5 µg for days 1-5,
10 µg for days 6-10) or placebo (Pl) . On day 11 after the morning injection,
participants received fat-enriched breakfast and lunch meals (400 kcal/m2
per meal, 45% fat, 40% carbohydrate, 15% protein) separated by 4 hours. EF
as reactive hyperemia index (RHI) by peripheral arterial tonometry, plasma
glucose, insulin and lipid concentrations were measured before, and every 2
hours after the study drug, for a total 8 hours.
36 participants completed both study periods. Over 8 hours, exenatide
increased RHI (mean percent change in area under the curve ± SD: 10 ± 18,
p=0.008), decreased glucose and TG concentrations (by 16 ± 13 % and 23 ±
21 %, respectively, both p<0.0001), and had no effect on insulin or total,
HDL and LDL cholesterol concentrations. Augmentation of RHI with Ex was
similar in those with diabetes duration > 5 years and < 3 years (12 ± 19 % and
10 ± 17 %, respectively, p=0.8) and remained significant after adjustment for
glucose (p=0.006) and TG (p=0.04) concentrations.
In conclusion, exenatide administration was followed by sustained
improvement of endothelial function over 8-hour period including fatenriched breakfast and lunch meals. The favorable effect of exenatide on
endothelial function was observed regardless of diabetes duration and
was only partially accounted for by sustained reductions in postprandial
triglycerides.
Clinical Diabetes/
Therapeutics
JURAJ KOSKA, JAMES LIU, KALYANI RARAVIKAR, DAWN C. SCHWENKE, ERIC
A. SCHWARTZ, PETER D. REAVEN, Phoenix, AZ
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS
demonstrate any association between insulin sensitivity and these muscle
transcripts, and protein abundance of SDHA (complex II) and UQCRC1
(complex III), and Thr172 phosphorylation of AMPK were unaffected by
testosterone therapy.
In conclusion, we show that in elderly men with subnormal testosterone
levels, insulin sensitivity is not associated with expression of genes involved
in oxidative metabolism, and the beneficial effect of testosterone treatment
on lipid oxidation is not caused by a general increase in the abundance of
genes and enzymes involved in OxPhos and lipid metabolism in skeletal
muscle.
analyzed by assessing among those study subjects not having a change in
concomitant anti-diabetes medication (B-QR N=586, placebo N=328), the
percent whose HbA1c level increased above 7.0 after 52 weeks of therapy
(B-QR N=104, placebo N=84) via Fisher’s Exact Test.
B-QR treatment reduced the time to first CV event by 50% (ITT) (HR: 0.51;
CI 0.28 to 0.96,) and by 52% (OT) (HR: 0.48; CI 0.24 to 0.95). B-QR reduced the
percent of subjects with loss of good glycemic control by 31% (from 26% to
18%, P=0.006) over this one-year study period.
These findings suggest that B-QR therapy to T2DM subjects in good
glycemic control may offer a possible means of retarding progression of both
cardiovascular and metabolic disease among such T2DM subjects.
1194-P
1196-P
Prior Treatment With Dipeptidyl-Peptidase IV Inhibitors Is Associated With Favorable Outcome in Patients With Acute Ischemic
Stroke
Sodium Glucose Cotransport-2 Inhibition With Empagliflozin Attenuates Renal Hyperfiltration in Patients With Type 1 Diabetes
DAVID Z. CHERNEY, BRUCE A. PERKINS, NIMA SOLEYMANLOU, VESTA LAI, MARIA MAIONE, ALANA LEE, NORA FAGAN, HANS-JUERGEN WOERLE, ODD ERIK
JOHANSEN, ULI C. BROEDL, MAXIMILIAN VON EYNATTEN, Toronto, ON, Canada,
Burlington, ON, Canada, Ridgefield, CT, Ingelheim, Germany
KONSTANTINOS TZIOMALOS, STELLA BOUZIANA, ATHINODOROS PAVLIDIS,
MARIANNA SPANOU, VASILIOS GIAMPATZIS, MARIA PAPADOPOULOU, FOTINI GIANNAKIDOU, FOTIOS ILIADIS, TRIANTAFILLOS DIDANGELOS, CHRISTOS
SAVOPOULOS, APOSTOLOS HATZITOLIOS, Thessaloniki, Greece
POSTERS
Clinical Diabetes/
Therapeutics
&
Supported by: Novo Nordisk, Inc.
Renal hyperfiltration promotes the development of diabetic nephropathy
and has been attributed to both hemodynamic and tubular mechanisms. Our
primary objective was to determine the impact of 8 weeks of sodium glucose
co-transport 2 inhibition with empagliflozin 25 mg QD on renal hyperfiltration
in subjects with type 1 diabetes (T1D) (NCT01392560). Inulin (GFR) and
paraaminohippurate (effective renal plasma flow [ERPF]) clearances were
used in patients stratified based on having either hyperfiltration (T1D-H,
GFR ≥ 135 ml/min/1.73m2, n=27) or normal GFR (T1D-N, n=13) at baseline
during clamped euglycemia. Blood pressure, renal function, circulating
levels of aldosterone, angiotensin II and nitric oxide (NO) were measured
under clamped euglycemic (4-6 mmol/L) and hyperglycemic (9-11 mmol/L)
conditions at baseline and again after empagliflozin. During clamped
euglycemia, hyperfiltration was attenuated with empagliflozin in T1D-H (GFR
172±23 to 139±25 ml/min/1.73 m2, p<0.0001). This effect was accompanied
by declines in plasma NO (p=0.0016), ERPF and renal blood flow and an
increase in renal vascular resistance (p<0.0001). Results were similar
under clamped hyperglycemic conditions. Systolic blood pressure declined
with empagliflozin in T1D-H during clamped euglycemia (-3.1±8 mmHg,
p=0.0495), despite a modest rise in circulating aldosterone (p=0.0189)
and angiotensin II (p=0.0439). In T1D-N, renal function, blood pressure
and NO remained unchanged. In summary, empagliflozin attenuated renal
hyperfiltration in T1D-H but did not influence renal function in T1D-N
patients. Our findings suggest for the first time that the effect of SGLT2
inhibition on tubuloglomerular feedback may play a favourable role against
the pathogenesis of renal hyperfiltration in patients with T1D.
We aimed to assess the effects of prior antidiabetic treatment on the
severity and outcome of acute ischemic stroke (IS).
We prospectively studied 378 consecutive patients (38.9% males, age
78.8±6.5 years) who were admitted for IS. Stroke severity was evaluated
with the National Institute of Health stroke scale (NIHSS) at admission and
the outcome was assessed with in-hospital mortality and with the modified
Rankin scale (RSS) at discharge. Type 2 diabetes mellitus (T2DM) was present
in 32.3% of the patients. Prior to stroke, antidiabetic treatment included
metformin, sulphonylureas (SU), insulin and dipeptidyl-peptidase IV (DPP-IV)
inhibitors, alone or in combination, in 60.0, 46.0, 24.0 and 27.0% of patients,
respectively. Stroke severity and outcome did not differ between patients
who were on monotherapy with metformin, SU or insulin. Patients who were
treated prior to stroke with DPP-IV inhibitors, alone or in combination with
other antidiabetic agents, showed a trend for less severe stroke compared
with patients who were not receiving DPP-IV inhibitors (NIHSS score at
admission 6.1±7.5 vs. 10.0±9.2, respectively; p=0.079) and had lower inhospital mortality (0.0% vs. 15.1%, respectively; p<0.05) and lower RSS at
discharge (2.1±1.9 vs. 3.2±2.1, respectively; p<0.05), even though they had a
higher prevalence of hypertension (100.0% vs. 84.9%, respectively; p<0.05).
Other cardiovascular risk factors did not differ between the two groups.
Stroke severity and outcome did not differ between patients who were
treated prior to stroke with metformin, SU or insulin, alone or in combination
with other antidiabetic agents, and patients who were not receiving the
respective antidiabetic agent. In conclusion, in patients admitted for IS,
prior treatment with DPP-IV inhibitors appears to be associated with more
favorable in-hospital outcome and with less severe stroke compared with
prior treatment with other antidiabetic agents.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1197-P
Pharmacological Prevention of Diet Induced Metabolic Dysfunction
by the SIRT1 Activator SRT3025
1195-P
VIPIN SURI, MEGHAN L. DAVIS, QING NIE, ELDEN LAINEZ, SHI LIANG, YONG QI,
JAMES L. ELLIS, GEORGE P. VLASUK, Cambridge, MA
The Effect of Androgen Therapy on Genes and Proteins Involved in
Oxidative Phosphorylation and Lipid Metabolism in Skeletal Muscle of Men With Subnormal Testosterone Levels
The NAD+-dependent protein deacetylase SIRT1 has been suggested
to be involved in the regulation of a number of metabolic pathways.
Transgenic overexpression of SIRT1 confers resistance to the metabolic
dysfunction induced by a high fat diet (HFD). We investigated the effect of
pharmacological SIRT1 activation on prevention of HFD-induced metabolic
dysfunction in mice.
We have previously shown that the small molecule SIRT1 activator
SRT3025 reverses high fat diet induced obesity, insulin resistance and
dyslipidemia. To explore the preventative effect of SRT3025, we placed 6
week old C57/BL6 mice on HFD or HFD supplemented with SRT3025 (HFD3025) for 15 weeks. Despite similar food intake, the HFD-3025 group was
completely protected from the rapid weight gain observed in the HFD group
and was indistinguishable from the chow-fed animals (Figure 1). HFD-3025
also prevented development of hyperinsulinemia (-92%), hyperglycemia
(-27%), glucose intolerance (-36% AUC, intraperitoneal glucose tolerance
test) and adiposity (-62% fat mass) compared to the HFD group. Replacement
of the HFD-3025 diet with HFD resulted in an increased rate of weight gain
similar to the HFD group.
Our data clearly demonstrates that in addition to reversing the
metabolic dysfunction induced by HFD, SRT3025 can effectively prevent
the development of metabolic dysfunction in mice fed a HFD and has the
potential to be clinically beneficial in Obesity and Type 2 Diabetes.
STINE J. PETERSSON, LOUISE FREDERIKSEN, JONAS M. KRISTENSEN, RIKKE K.
HENRIKSEN, MARIANNE ANDERSEN, KURT HØJLUND, Odense, Denmark
Recent studies have reported that low serum testosterone in men is
associated with low insulin sensitivity and reduced expression of oxidative
phosphorylation (OxPhos) genes, and that treatment with testosterone
increases lipid oxidation. Here, we aimed to investigate the effect of
testosterone therapy on genes and proteins involved in OxPhos and lipid
metabolism in skeletal muscle in vivo in men with low serum testosterone.
In 25 elderly men with subnormal serum levels of testosterone, skeletal
muscle biopsies were taken before and after treatment with either
testosterone gel (n=12) or placebo (n=13) for 6 months. Insulin sensitivity
and substrate oxidation were assessed by euglycemic hyperinsulinemic
clamps combined with indirect calorimetry. Muscle mRNA levels and
protein abundance of a selected set of enzymes involved in OxPhos and lipid
metabolism and phosphorylation of AMPK were examined by qRT-PCR and
western blotting.
Despite a placebo-controlled increase in lipid oxidation (p<0.05), testosterone therapy had no effect on insulin sensitivity or muscle transcript levels of
genes involved in OxPhos (NDUFS1, ETFA, SDHA, UQCRC1, COX5B, PPARGC1A),
lipid oxidation (ACADVL, CD36, CPT1B, HADH, PDK4) or adiponectin-AMPK
signaling (ADIPOR1, ADIPOR2, PRKAA2, PRKAG3). Moreover, we could not
&
For author disclosure information, see page 829.
A312
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ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS
into an ApoE -/- background. Diabetes was produced by streptozotocin at 3
months of age. Vitamin E or placebo was administered in the drinking water
beginning one month after the onset of DM. Plaque size and progression
were assessed repetitively in vivo using a Vevo-2100 high frequency microultrasound system (Visualsonics) in the brachiocephalic artery at multiple
time points.
We observed markedly larger plaques in Hp 2-2 DM mice at all time points
as compared to Hp 1-1 DM mice and mice without DM . Furthermore, vitamin
E completely prevented progression of plaques in Hp 2-2 DM mice.
Vitamin E can prevent plaque progression in Hp 2-2 DM mice recapitulating
the ability of vitamin E to provide cardiovascular benefit to Hp 2-2 DM
humans.
Supported by: NIH (R0IDK085226)
1200-P
OLEG TSUPRYKOV, MARKUS L. ALTER, KAROLINE VON WEBSKY, LYUBOV
CHAYKOVSKA, CHRISTOPH REICHETZEDER, VIKTORIIA ANTONENKO, JAN RAHNENFÜHRER, THOMAS KLEIN, BERTHOLD HOCHER, Potsdam, Germany, Berlin,
Germany, Zürich, Switzerland, Biberach, Germany
IRENE G. MANDERS, MICHAELA DIAMANT, KATRIN STOECKLEIN, CAROLINE
H.C. LUBACH, JUDITH BIJL-OELDRICH, PRABATH NANAYAKKARA, JAN A. RAUWERDA, MARK H.H. KRAMER, ELISABETH M.W. EEKHOFF, Amsterdam, Netherlands
DPP-4 inhibitors may have kidney-protective properties independent of
glucose control. We compared the effect of linagliptin with an angiotensin II
receptor antagonist - the current clinical gold standard - on preventing renal
disease progression in a nondiabetic rat model of chronic renal failure. Male
Wistar rats were allocated to 4 groups: sham operated; 5/6 nephrectomy
(5/6 Nx) plus placebo treatment (placebo); 5/6 Nx plus linagliptin (LIN; 0.083
mg/kg/d in chow); 5/6 Nx plus telmisartan (TEL; 5 mg/kg/d in drinking water).
Study duration was 130 days; blood pressure and albumin excretion were
assessed repeatedly. Kidneys and plasma biomarkers were analyzed at
study end. Interstitial fibrosis increased by 69% in placebo rats vs SHAM
rats (p<0.05), and decreased by 48% with LIN (p<0.05) and 24% with TEL
(p=ns) vs placebo. Glomerular size increased by 28% in placebo vs SHAM
rats (p<0.01), and decreased by 18% (p<0.001) with LIN but not significantly
with TEL vs placebo rats. The glomerulosclerosis index was significantly
increased in placebo rats vs SHAM rats. There was a trend towards
decreased glomerulosclerosis with LIN and TEL. Analysis of collagen
type I and III mRNA and protein levels confirmed histopathologic findings.
The urinary albumin/creatinine ratio increased 14-fold in placebo rats vs
SHAM rats (p<0.001), and decreased by 66% with LIN (p<0.05) and 92%
with TEL (p<0.01) vs placebo rats. Blood pressure was lowered by TEL (31
mmHg; p<0.05) and unaffected by LIN. TIMP-1, calbindin, osteopontin and
β2 microglobulin (B2M) were significantly increased in the placebo rats vs
SHAM rats. LIN decreased plasma levels of TIMP-1, calbindin, osteopontin
and B2M vs placebo rats (all p<0.05), whereas TEL significantly decreased
osteopontin and TGF-β expression. In summary, LIN is as effective as TEL
in preventing renal disease progression in rats with 5/6 nephrectomy.
Furthermore, the underlying molecular mechanisms appear to be different.
Optimal glycemic control in hospitalized patients with diabetes mellitus
in non-Intensive Care Units (non-ICU) may improve outcome and shorten
admission duration. However, achieving these targets is difficult and
development and implementation of appropriate protocols remain major
challenges. A Nurse-driven Diabetes In-hospital Treatment protocol
(N-DIABIT) was developed, i.e. a sliding-scale protocol carried out by trained
ward nurses, supervised by registered diabetes nurses. We investigated the
feasibility, safety and efficacy of the N-DIABIT in patients with diabetes
mellitus, admitted to non-ICU.
We prospectively collected data of 210 patients with diabetes admitted
in the five-month period after N-DIABIT introduction (intervention group)
and compared these to a historical control group, consisting of 200 patients
admitted in the five-month period before starting N-DIABIT. Additional
analyses were repeated in patients in whom protocol adherence was ≥ 70%
with respect to blood glucose measurements during admission (intervention
and matched control subgroup; n = 240).
Mean protocol adherence was >75%. Only the intervention- versus control
subgroups showed significant lower mean blood glucose levels (P = 0.044),
significantly less consecutive hyperglycemic episodes (≥10.0 mmol/L; P =
0.049) and a numerically shorter admission duration (mean 1.3 days shorter).
Hypoglycemia incidence (<4.0 mmol/L) was similar before and after protocol
implementation.
Implementation of the N-DIABIT by trained ward nurses in non-ICU
hospital diabetes care is feasible, effective and safe in improving glycemic
control and in case of appropriate protocol adherence, may ultimately reduce
admission duration.
Supported by: Boehringer Ingelheim Pharmaceuticals, Inc.
1201-P
Clinical Outcomes Following Discharge from a Pharmacist-Led Diabetes Intense Medical Management Clinic
1199-P
Vitamin E Arrests Atherosclerotic Plaque Progression in Haptoglobin 2-2 Diabetic Mice
CANDIS M. MORELLO, ANDREA BECHTOLD, JAN D. HIRSCH, La Jolla, CA
A collaborative pharmacist-endocrinologist Diabetes Intense Medical
Management (DIMM) Clinic (held ½ day per week) was developed at
the Veterans Affairs San Diego Healthcare System to help primary care
providers meet diabetes specific compliance measures and help patients
achieve metabolic goals. Referred type 2 diabetes patients with A1C >
9% were treated by a pharmacist-CDE who combined clinical care with
patient-specific diabetes education. Outcomes show mean A1C was reduced
significantly from 10.2% at enrollment to 8.8% at 3 months and 8.0% at 6
months (p<0.001).
Percent of patients achieving goals was significantly increased for
Triglycerides (TG) (3 and 6 months) and Fasting Plasma Glucose (FPG) (6
months) compared to baseline (p<0.05). After achieving A1C goals, patients
were discharged back to their primary care provider.
The primary objective was to compare A1C at 6 and 12 months post
discharge to A1C at discharge from the DIMM Clinic. Secondary outcomes
were also compared [i.e. mean FPG, weight, BMI, cholesterol (LDL, HDL),
TG, and blood pressure (BP)]. Thirty-one patients have been discharged from
the DIMM Clinic after meeting metabolic goals. Time to discharge for these
patients was ≤6 months (44%), ≤9 months (31%) and >9 months (25%). Follow
up data was available for 22 patients at 6 and 12 months post-discharge.
HILLA LEE VIENER, RACHEL LOTAN, ROSTIC GORBATOV, NINA S. LEVY, ANDREW
P. LEVY, Haifa, Israel
Nine independent longitudinal studies have demonstrated that individuals
with the Hp 2-2 genotype and Diabetes Mellitus (DM), which constitutes
approximately 40% of all individuals with DM, have a 2-3 fold increased
incidence of atherosclerotic cardiovascular disease (CVD) and its sequelae
as compared to DM individuals without the Hp 2-2 genotype. The mechanism
responsible for this interaction between the Hp genotype and CVD in DM
appears to be due to oxidative modification of HDL inHp 2-2 DM. Proof of
concept for this hypothesis has been that antioxidant supplementation with
vitamin E can restore HDL function in Hp 2-2 DM and vitamin E has been
shown in two trials to significantly reduce MI and CVD death in Hp 2-2 DM
individuals.
We sought to determine if there was an interaction between atherosclerotic
plaque progression and the Hp genotype that could be mitigated by vitamin
E in mice.
The Hp 2 allele, which is present only in man, is defined by the presence
of a 1.7kb in-frame duplication of exons 3 and 4 of the Hp 1 allele. We
engineered a murine Hp 2 allele and introduced it into the murine Hp locus by
homologous recombination. We backcrossed Hp 2 and wild type (Hp 1) mice
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A313
POSTERS
1198-P
Adherence to a Nurse-Driven Sliding Scale Protocol Improves Glycemic Control and Shortens Admission Duration in Hospitalized
Non-ICU Patients With Diabetes Mellitus
Clinical Diabetes/
Therapeutics
Linagliptin Is as Efficacious as Telmisartan in Preventing Renal Disease Progression in Rats With 5/6 Nephrectomy
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS
Mean age was 60±8 years. Mean duration of diabetes was 16±9 years and
100% of patients were male. A1C at 6 months post-discharge was 7.6±1.6%
compared to 7.1±0.7% at discharge (p=0.20). At 12 months post-discharge
A1C was 7.5±1.2% (p=0.34). Systolic BP was higher at 6 months (138±25
mmHg) and 12 months post-discharge (134±12 mmHg) versus 122±11 mmHg
at discharge (p=0.01). Other secondary outcomes were not significantly
different than at discharge. These results show significant A1C reductions
that had been achieved by patients attending a pharmacist-led DIMM Clinic
were maintained at 6 and 12 months after discharge back to their primary
care provider.
1202-P
Effects of Herbal Fomula AMP-1915 on Metabolic Syndrome
POSTERS
Clinical Diabetes/
Therapeutics
SHENGJIE FAN, GAIGAI LIU, LU GUO, LIGANG ZHOU, CHENG HUANG, Shanghai,
China
Supported by: Research Ministry of Romania (52164/2008)
Herbal formulae have been used in Traditional Chinese Medicine (TCM)
widely for thousands years. Huangqisan (AMP-1915), consistent of Astragalus
membranaceus (Fisch.) Bge, Cortex Mori radices and Pueraria lobata (Willd.)
Ohwi, was recorded in 1117 AD firstly for the treatment of diabetes. However,
there is no experimental evidence to support the therapeutic effects of
the formula for diabetes. Ethanol extract of AMP-1915 was prepared from
Astragalus membranaceus (Fisch.) Bge, Cortex Mori radices and Pueraria lobata
(Willd.) Ohwi and HPLC study was carried out to analyze the major chemical
components of the extract. High-fat diet-fed C57BL/6 obese (DIO) mice and
db/db mice were treated with AMP-1915 and the fasting blood glucose,
glucose tolerance test, serum lipid profile and the livers lipid contents were
analyzed. Gene expression assay was performed with a real time RT-PCR
and RNA-seq, and protein levels were determined by Western blot. Our
results showed that eight monomer components were detected in AMP1915 by HPLC assay, including Astragaloside IV, Morin, Daidzein, etc.. AMP1915 (2% and 5%) significantly reduced fasting blood glucose level, improved
glucose tolerance test and serum lipid profiles in the DIO mice. In db/db mice,
AMP-1915 lowered fasting blood glucose and serum total choleterol content.
Real time RT-PCR assay showed that AMP-1915 upregulated the expression
of PPARγ and its target genes in the DIO mouse liver. Western blot assay
revealed that AMP-1915 increased PPAR γ and phosphorylation of AMPK in
HepG2 cells. The results indicate that AMP-1915 could lower blood glucose
levels and improve serum lipid profiles both in DIO mice and db/db mice
through the enhancement of PPARγ and AMPK signaling. Our data suggest
that the herbal formulae may be used as therapeutic drug for the patients
mixed with hyperglycemia and hyperlipidemia.
1204-P
Comparative Study of Azelnidipine With Trichlormethiazide in
Japanese Type 2 Diabetic Patients With Hypertension: The COAT
Randomized Controlled Trial
MASAHIRO TAKIHATA, AKINOBU NAKAMURA, HIROSHI KAMIYAMA, YUKO
DOBASHI, TAKASHI MIYAZAKI, HARUKA TAMURA, RIKA SAKAMOTO, MINORI
MATSUURA, YOSHINOBU KONDO, SATSUKI KAWASAKI, MARI KIMURA, YASUO
TERAUCHI, Yokohama, Japan, Chigasaki, Kanagawa, Japan, Fujisawa, Japan
Few randomized trials that compare calcium antagonists with diuretics
in type 2 diabetic patients with inadequately controlled hypertension with
angiotensin II receptor blocker have been published. The aim of this study
is to compare the efficacy and safety of these two agents and the impact
on surrogate markers related to diabetic and hypertensive complications.
In a multicenter, open-label trial, 240 patients with adequately controlled
diabetes (HbA1c ≤ 6.5%) and inadequately controlled hypertension (systolic
blood pressure [sBP] ≥ 130 mmHg or diastolic blood pressure [dBP] ≥ 80
mmHg) with olmesartan were randomly assigned to a azelnidipine group
(16 mg/day) or a trichlormethiazide group (1 mg/day) and were followed up
for 48 weeks. Main outcome measure was the difference in the changes in
HbA1c level from the baseline at 48 weeks between these two groups. Of
the 240 subjects enrolled, 209 subjects (azelnidipine group: 103 patients,
trichlormethiazide group: 106 patients) completed this trial. At 0 week, mean
HbA1c level, sBP, and dBP were 6.26 ± 0.62% vs. 6.23 ± 0.60%, 142 ± 11
mmHg vs. 141 ± 11 mmHg, and 80 ± 6 mmHg vs. 79 ± 7 mmHg. At 48 weeks,
the changes in HbA1c level, sBP, dBP, estimated glomerular filtration rate, and
albumin-to-creatinine ratio from the baseline were 0.19 ± 0.52% vs. 0.19 ±
0.54% (n.s.), -10.7 ± 9.6 mmHg vs. -7.1 ± 7.7 mmHg (P < 0.001), -6.6 ± 6.6
mmHg vs. -3.3 ± 6.1 mmHg (P < 0.001), -2.6 ± 11.9 mL/min vs. -3.8 ± 9.2 mL/
min (n.s.), and -12 ± 105 mg/g Cr vs. -35 ± 94 mg/g Cr (P = 0.041). Dizziness
(12 patients, 11.7% vs. 16 patients, 15.1%), and edema (16 patients, 15.5%
vs. 7 patients, 6.6%, P = 0.047) were observed for 48 weeks. In conclusion,
azelnidipine was more effective for BP control than trichlormethiazide, and
trichlormethiazide was more effective for reduction of albuminuria than
azelnidipine. Both of them, however, similarly exacerbated glycemic control
in type 2 diabetic patients with hypertension.
1203-P
The Influence of Thiamine Hydrochloride on Kidney Disease in a
Model of Wistar Diabetic Rat
CIPRIAN CONSTANTIN, AURELIAN RANETTI, GEORGIANA CONSTANTIN, CRISTIAN SERAFINCEANU, DAN CHETA, Bucharest, Romania
Previous experiments on streptozotocined Wistar rats, including our own,
showed kidney diabetic damage even if model of type 2 diabetes is with a
good metabolic control. On the other hand, thiamine compounds are known
for its kidney protective effects. In order to quantify the kidney changes
and study the possible beneficial effect of a thiamine compound, 48 Wistar
Rats are used to obtain a model of type 2 diabetes using streptozotocin. 3
Groups were matched for sex and metabolic control. For a period of 180
days 0g/l, 1g/l, 2g/l thiamine hydrochloride solution was administered
daily to each rat in the intervention groups (A,B,C), using the water as a
support. Weight, glucosuria and glycemia were determined periodically. At
the end of the study period, rats were sacrificed. Liver, kidneys and heart
were the organs investigated using optical microscopy. The most interesting
findings were the kidney structural changes. 3rats (18.75%) in Agroup, 4rats
(25%) in Bgroup and 7rats (43,75%) in Cgroup had a normal kidney structure
(p<0.5). The rest had various degrees of structural alteration ranging from
vacuolar dystrophy to polymorphic inflammatory infiltrate. The frequency of
each finding is shown in the figure. Our data show that, even in pretty well
controlled model of type 2 diabetes, kidney disease is very frequent in initial
stages of disease. More data were collected to highlight the protective
effects of this thiamine compound has on the kidney.
&
For author disclosure information, see page 829.
A314
Guided Audio Tour poster
ADA-Funded Research
CLINICAL THERAPEUTICS/NEW TECHNOLOGY—PHARMACOLOGIC TREATMENT OF COMPLICATIONS
at baseline (8.9 vs 7.9%) and at time of insulin initiation or event in non-users
(9.0 vs 7.4%) and experienced a longer time period without complications
(40.8 vs 21.6 months).
This analysis demonstrates that despite having a higher A1C at baseline,
those initiating insulin during follow-up spent a significantly longer time
period free of microvascular complications compared to those not initiating
insulin. Approaches to facilitate early insulinization should be identified.
1205-P
Impact of Ramadan Fasting on HbA1c in Relation to Medication Use
MELANIE SIAW, NUR HIDAYAH SHAMSURI, DANIEL CHEW, RINKOO DALAN,
SHAIKH ABDUL ABDUL SHAKOOR, NOORANI OTHMAN, THERESA CHOO, SITI
NURHANNAH ABDUL KARIM, OLIVE LAI, JOYCE Y. LEE, Singapore, Singapore
Muslims worldwide observe religious fasting of Ramadan from dawn
to sunset. While the practice of fasting often affects the blood glucose of
patients with diabetes as reported in the literature, little is known about
the use of pharmacologic agents in relation to the degree of changes in
HbA1c during this period. In this prospective study, we aimed to examine
the change of HbA1c during Ramadan in relation to pharmacotherapy use by
tracking HbA1c values and medication use before, during and after Ramadan
for a total of 13 months.
A total of 136 Muslim patients were eligible for this study. The mean age
was 56.4 ± 8.9 years with 40.4% male and 59.6% female. Of these, 63.2%
were on insulin containing therapies, 34.6% were on oral hypoglycemic
agents (OHA) only and 2.2% were not on medication. During Ramadan, mean
HbA1c improved by 0.66% and 0.27% for patients who were on OHA only and
insulin containing regimen, respectively. After adjusting for demographics,
health status and baseline HbA1c, patients who were on OHA only were
5.9 times more likely to observe improvement in HbA1c during Ramadan
compared to those given insulin containing regimen (p<0.05). Furthermore,
there were no significant hypoglycemic events related to fasting during
Ramadan. Overall, the improvement in HbA1c during Ramadan appeared to
be more prominent in Muslim patients who take oral antidiabetic medications
without insulin.
Supported by: sanofi-aventis
1207-P
New Inhibitors to Preserve and Protect Islet Function in T1DM
Supported by: CDMRP (PR093521)
1208-P
Derivatives of 2-Aminoimidazole from Sea Sponges have Potent
Anti-Glycating Activity
RANDALL J. BASARABA, DAVID ACKART, BRENDAN PODELL, JESSICA HAUGEN,
ROBERTA WORTHINGTON, CHRISTIAN MELANDER, Fort Collins, CO, Raleigh, NC
Currently there are no approved drugs for humans that inhibit the
formation and accumulation of advanced glycation end products (AGEs).
AGEs accumulate as a consequence of uncontrolled diabetes, aging and
other chronic inflammatory diseases. In diabetes the combination of
high blood glucose levels combined with oxidative stress accelerates
AGE formation. This is particularly true when diabetes is combined with
infectious or noninfectious causes of myeloid cell-mediated inflammation.
We have generated a library of over 700 small molecular weight compounds
based on the 2-aminoimidazole (2-AI) subunit from the naturally occurring
sea sponge-derived metabolites oroidin and bromoageliferin, some of which
have potent anti-glycating activity in vitro. We used a high throughput in
vitro fluorescence assay to screen the 2-AI library for compounds that both
prevented the formation and interrupted covalent cross linking of serum
albumin for seven days with the potent glycating agent and glycolytic
intermediate glycolaldehyde. In the initial screen, seven compounds were
found to have significant biological activity when compared to the known
anti-glycating drugs aminoguanidine (AG) and ALT-711. One compound
designated 2C4 was found to be active at inhibiting protein glycation by
65% at less than 5 micromolar whereas AG inhibited 35% only at the 400
micromolar dose. An additional 2-AI derivative (2C8) had biological activity in
the 40 micromolar range. These data demonstrate that 2-AI derivatives have
therapeutic potential as potent anti-glycating compounds. The synthesis
of these biologically active compounds represents a focused and rational
design strategy for the discovery of new anti-glycating compounds.
1206-P
Timing of Insulin Initiation and Diabetes Complications in a Large
Health System: Developing a Profile for Secondary Prevention
JANICE C. ZGIBOR, LI CHUAN TU, SHIH CHEN KUO, WEI HSUAN LO-CIGANIC,
FRANCIS SOLANO, KRISTINE RUPPERT, Pittsburgh, PA
Diabetes and its complications contribute to significant morbidity and
mortality, however, approximately one half of patients remain above the
recommended A1C goal. Currently, there is a paucity of data from real
world settings examining longitudinal outcomes in those using various
treatment regimens. Identifying the ideal time for insulin intervention, from
a population perspective, remains elusive and could provide insight into
missed opportunities for prevention. This analysis used existing electronic
health record data from the University of Pittsburgh Medical Center, to
examine the association between timing of insulin initiation and incidence
of microvascular complications. 1279 patients seen between 1/2/200306/08/2011 with type 2 diabetes were identified using previously validated
algorithms. Average follow-up was 5.3 years. Retinopathy, nephropathy,
and neuropathy were defined by ICD-9 and CPT codes. Prevalent cases
were excluded. Follow-up started at the first available A1C (baseline)
≥ 7% and ended at the time of event or last contact. Time from baseline
to development of complications was assessed. Four hundred sixty-five
patients (36%) developed complications over the follow up period. Among
those with complications, 98 (21%) started insulin, an average of 10.9
months post-baseline. Insulin users were significantly (p<0.001) younger (53
vs 61 yrs), more likely to be African American (47 vs 29%), had a higher A1C
ADA-Funded Research
&
Supported by: NIH
For author disclosure information, see page 829.
Guided Audio Tour poster
A315
POSTERS
Curative strategies for type 1 diabetes are likely to combine beta
cell regeneration with agents to uncouple destructive autoimmunity.
Lisofylline (LSF) is a compound that disrupts autoimmune processes and
protects beta cells from inflammatory injury. As a therapy, LSF is limited
by poor bioavailability. Novel molecules from a LSF-activity screen have
been identified. Compounds exhibit enhanced drug-like properties, having
passed predictive in silico and ADME screens. Select compounds have been
characterized using in vitro efficacy assays conducted in beta cell lines (INS1, βTC3), primary mouse islets and primary human donor islets. The efficacy
of select compounds to preserve and protect beta cells from the harmful
effects of pro-inflammatory cytokines (PICs) has been assessed. Following
acute exposure to PICs, beta cells have elevated apoptosis, loss of glucosestimulated insulin secretion (GSIS) and enhanced gene expression of IL-12
ligand, MCP-1, and IFNγ. Assessment of five select compounds (DT09, DT021,
DT042, DT047, DT079) at 50µM, showed significant protection to PIC-induced
apoptosis measured by caspase-3 activation and YO-PRO1/PI fluorescent
microscopy in beta cell lines and primary (mouse/human) islets (p<0.05).
Compounds preserved GSIS in INS-1 cells exposed to PICs (p<0.05). IL-12ligand, IFNγ and MCP-1 gene expression induced by PIC-stimulation was
inhibited by select compounds (p<0.05). Compounds were well tolerated
in vivo and insulitis score in pre-diabetic NOD mice treated for six weeks
was assessed. Collectively, the activity-profile of each compound varies,
reflecting different molecular structures. Relative to LSF, DT042 and DT047
exhibited equal or greater activity to preserve and protect beta cell function
following PIC exposure. These chemotypes are candidates for proof-ofprinciple combination therapy and provide new opportunities to protect beta
cells exposed to an inflammatory environment.
Clinical Diabetes/
Therapeutics
DAVID A. TAYLOR-FISHWICK, JESSICA R. WEAVER, LINDSEY GRIER, WOJCIECH
GRZESIK, Norfolk, VA
HEALTH CARE DELIVERY—ECONOMICS
1209-P
Comparative Assessment of the Effects of Strong Statins on Residual Risk in Diabetes With Accumulated Metabolic Risk FactorsTOHO-LIP Diabetes Sub-Analysis at 96 Weeks
POSTERS
Clinical Diabetes/
Therapeutics
TERUO SHIBA, SUMIE OKAHATA, KENTARO SAKAMOTO, FUMIHIKO HARA,
SHUUJI NANJO, SHINJI HISATAKE, ATSUSHI NAMIKI, SHOHEI YAMASHINA,
KENJI WAGATSUMA, JUNICHI YAMAZAKI, GEN YOSHINO, TAKAHISA HIROSE,
YASUO IWASAKI, SHIGEO YAMAMURA, HIDEHIKO HARA, KAORU SUGI, TOSHIKI FUJIOKA, MAO TAKAHASHI, HIROFUMI NOIKE, KOHJI SHIRAI, Tokyo, Japan,
Hyogo, Japan, Chiba, Japan
A recent analysis has revealed diabetes patients still bear residual risk
after strong statin therapy. Most notably, HDL- C and non-HDL-C both seem
to be of considerable importance in diabetics with multiple metabolic risk
factors (MR). The TOHO-LIP (TOHO-Lipid Intervention Trial Using Pitavastatin)
is a direct head-to-head comparison between pitavastatin (2mg/day) (P) and
atrovastatin (10 mg/day) (A) conducted at three TOHO University hospitals
in Japan on 652 enrolled patients with high-risk hypercholesterolemia. We
conducted a diabetes sub-analysis on 414 diabetes patients to evaluate the
statin effects in lipid profiles and safety at 96 weeks of treatment. Along
with accumulation of MR, baseline HDL-C values were significantly reduced.
Baseline non HDL-C values were increased only to a statistically significant
level in the diabetics (p < 0.0001 , ANOVA). Both statin treatments brought
about significant improvements of non HDL-C (-33%,p<0.0001 (P), -36%,
p<0.0001 (A), respectively) and other atherogenic lipids at 96 weeks in the
diabetics. In patients with densely accumulated MR,HDL-C at 96 weeks
was increased significantly only in the pitavastatin-treated group (9.2%
increase; p=0.0158). No adverse effects on glucose metabolism parameters
(FPG or HbA1c) were observed in either group. The statin doses found to
affect cardiac outcome are reported to range significantly from high to
standard doses. There have few prospective studies comparing strong
statins administered at standard doses. In our comparison pitavastatin, but
not atrovastatin, improved the HDL-C level, one of the primary residual risks,
in diabetics with accumulated MR. Pitavastatin thus appears to effectively
prevent cardiovascular events. TOHO-LIP will determine the cardiovascular
outcome brought about by pitavastatin’s favorable effects on residual risk
and follow the patients for 5-7 years at maximum.
&
MAN WO TSANG, CHI SANG HUNG, SZE YUEN FUNG, YU CHO WOO, MAN-FUK
LEUNG, PHILIP TSANG, Hong Kong, China
The aims are to enhance diabetic management and reduce diabetes
related hospital admission. Phase one is to develop a web-based glucose
monitoring system based on One-Touch glucometer so that once the meter is
connected to a net- book the glucometer readings will automatically upload
to the server based at our institution. Phase two is a one year randomized,
controlled prospective study of elderly with type 2 diabetes mellitus using the
web-based computer assisted diabetes monitoring system, DMS. Patients
were randomly assigned on block to control group or study group. Written
consent was obtained.The aged home staff performed at least twice per
week blood glucose haemoglucostix for all patients. Only data from study
group were to be transmitted via a net-book to our centre. Two diabetologists
took terms in reviewing the results and recommended feedback to the care
providers at the aged home on management. The feed- back included dietary
advice, drug adjustment or early follow up as indicated. The control group
had the usual care and twice weekly glucose monitoring. 113 patients were
recruited. 13 (4 from control group and 9 from study group) died and were
excluded from this analysis. Mean age for study vs control group 83.30±5.1
vs 78.78±7.60 (P<0.001). Baseline Hba1c between study and control group
was comparable, 7.42±1.36 vs 7.6±1.64 , (P=0.57).The decrease in HbA1c, at
the end of one year study was -0.70±1.57 vs -0.46±1.37 in study and control
group respectively (p=0.041). The causes of death were due to pneumonia,
renal failure, stroke and ischaemic heart disease. The number of admission
due hypoglycemia was too low for meaningful comparison. The higher death
rate in the study group might partially accounted for by their older age. The
study suggested that compared with usual care application of web-base
diabetes monitoring system improved diabetes management among elderly
with diabetes mellitus.
HEALTH CARE DELIVERY—ECONOMICS
Guided Audio Tour: Improving Diabetes Care (Posters: 1210-P to 1217-P),
see page 15.
&
1211-P
A Web-Based Remote Tele-Monitoring System to Monitor Blood
Glucose Levels in Aged Home Residents With Type-2 Diabetes
Mellitus
1210-P
Weight Loss Outcomes Among Older and Younger Adults in an
Adapted Diabetes Prevention Program
SARAH BROKAW, DIANE ARAVE, MARCENE BUTCHER, STEVEN D. HELGERSON,
TODD S. HARWELL, Helena, MT
The purpose of this study was to evaluate if there are differences in selfmonitoring (SM) behaviors, physical activity (PA) levels, and achievement of
7% weight loss goal among older and younger adults enrolled in an adapted
diabetes prevention program (DPP). From 2008 through 2011, adults (N =
1,820) at high-risk for CVD and diabetes were enrolled in a group-based
lifestyle intervention. Multiple logistic regression (LR) analyses were used
to identify factors associated with SM of fat intake, achievement of the PA
goal, and achievement of the 7% weight loss goal. Twenty-five percent of
participants (n = 455) were 18 to 44 years of age, 60% (n = 1,097) were 45 to
64 years of age, 14% (n = 258) were 65 years of age and older. In bivariate
analyses, participants aged >65 years were significantly more likely to
achieve the weight loss goal (44%) compared to participants 45-64 years
of age (40%), and participants 18-44 years of age (28%). Using multiple LR
analyses adjusting for age, sex, baseline BMI, achievement of the PA goal,
and number of weeks SM fat intake, older participants were significantly
more likely to SM their fat intake, and to achieve the PA goal compared to
younger participants (Table). However, age was not independently associated
with achievement of the weight loss goal. Our findings indicate that older
participants in an adapted real world DPP can achieve weight loss related
behaviors and the weight loss goal as well as younger participants can.
Supported by: Johnson & Johnson; OTDMS
&
For author disclosure information, see page 829.
A316
Guided Audio Tour poster
ADA-Funded Research
HEALTH CARE DELIVERY—ECONOMICS
&
1212-P
We performed a multicenter study in insulin-injecting Spanish adults to
assess the frequency of lipohypertrophy (LH) and determine its relationships
to site rotation, needle reuse, glucose variability, hypoglycemia and
consumption of insulin. The study involved 430 outpatients, 177 with
DM1 and 253 with DM2. Multiple injection parameters were assessed by
questionnaire; then each subject was examined by a study nurse for the
presence of LH and for correct site rotation technique. Subjects were roughly
half male, half female with ages ranging from 5 to 76 years (mean 49 ±23
[SD] years, 41 in DM1 and 55 in DM 2). Median number of injections/day was
4 for DM1 and 2 for DM2. 2/3 of patients (64.4%) had LH, more commonly in
DM 1 (72.3%) than DM2 (53.4%). There was a strong relationship between
the presence of LH and non-rotation of sites (p=0.01), with correct rotation
technique having the strongest protective value (p=0.001). Of the patients
without LH, 94% were observed to rotate injection sites correctly. Of
patients with LH, 95% were observed to not rotate or to rotate incorrectly.
Of those with LH 39.1% had unexplained hypoglycemia; for those without
it was 5.9% (p=0.03). Of those with LH 49.1% had glycemic variability; for
those without it was 6.5% (p=0.02). LH was also related to needle reuse,
with risk rising significantly when use was more than 5 times (p=0.008).
Longer duration of insulin therapy (p=0.02) and higher number of injections
per day (p=0.01) were also risk factors for LH. Subjects with LH consumed
on average 56 IU/day while those without consumed 41 IU/day (p<0.001).
This 15IU difference multiplied over the number of daily injections into LH
and assuming a cost of 0.0243 euros/IU equates to total annual cost to the
Spanish health care system of over 122 million euros. In conclusion, correct
injection site rotation is the critical factor in preventing LH. Avoidance of
LH is associated with reduced glucose variability, hypoglycemia, insulin
consumption and health care costs.
Many diabetes patients fail to attain glycemic targets. We investigated
factors influencing the setting and attainment of A1c targets in a sample of
patients with type 1 diabetes (T1D). We recruited 1,893 adults (>18 years)
from the T1D Exchange registry to complete a web-based survey on diabetes
management, self-reported glycemic targets, and hypoglycemia. Responses
were linked with registry data, including A1c laboratory results.
We tested for differences between respondents with and without A1c
targets, and across respondents with aggressive (<6.5%), normal (6.5 to 7%),
and less aggressive (>7%) targets. We estimated logistic models to identify
correlates of setting a less aggressive target than physician due to fear of
hypoglycemia and correlates of target attainment. Standard errors were
clustered to account for within clinic treatment patterns and propensity
weighting was used to adjust for non-response bias.
Respondents who reported having an A1c target (n=1771) were more
likely to be married, have a graduate degree, and hold private insurance
than those without targets (all p<0.05). Approximately half (54%) set targets
below 6.5%. Respondents with depression (odds ratio=1.48), anxiety (1.76),
and more frequent hypoglycemic events in the past month (1.03) or a major
event in the past year (1.28) were more likely to have less ambitious targets
than physician due to fear of hypoglycemia; those with a graduate degree
(0.79) and married (0.74) were less likely (all p<0.05). Respondents with a
bachelor (1.31) or graduate (1.44) degree, married (1.36), reporting more
frequent testing of blood sugar (1.13), or using a continuous glucose monitor
(1.40) came closer to attaining A1c targets; those with fear of fainting (0.54)
and depression (0.68) were further from targets (all p<0.05).
Our findings suggest that glycemic targeting may partially explain
socioeconomic gradients in diabetes outcomes. Interventions identifying
and alleviating symptoms of hypoglycemia early may improve A1c targeting
and attainment.
Supported by: Institute for Health Technology Studies
1213-P
Now or Later? Real-World Study of Impact of Timing of Insulin Initiation on Outcomes Among Elderly Medicare Patients With Type 2
Diabetes Mellitus (T2DM)
&
USHA SAMBAMOORTHI, WENHUI WEI, STEVE ZHOU, RITUPARNA BHATTACHARYA, JOHN LING, MAYANK AJMERA, Morgantown, WV, Bridgewater, NJ
PHILIP C. MCEWAN, MARK LAMOTTE, DAVID GRANT, JAMES PALMER, ADAM
LLOYD, VOLKER FOOS, Cardiff, United Kingdom, Vilvoorde, Belgium, London, United
Kingdom, Basel, Switzerland
Initiation of insulin after failing oral antidiabetic drugs (OADs) has been
suggested to be beneficial for patients with T2DM, but real-world data on
the impact of timing of insulin initiation on clinical and economic outcomes
among the elderly (≥65 y) is limited.
Using the Humana Medicare claims database, this retrospective study
analyzed elderly T2DM patients initiating basal insulin between 2007 and
2011. The number of baseline OADs was used as a proxy for the timing of
insulin initiation. One-year follow-up outcome measures were treatment
persistence, A1C, hypoglycemia rates, health care utilization, and costs.
Of the 14,669 elderly patients included (mean age 74 y, female 49%,
A1C 8.60% [where available]), 32% (n=4702) initiated insulin after 1 OAD,
48% (n=6980) after 2 OADs, and 20% (n=2987) after 3+ OADs. At baseline,
compared with 2 or 3+ OAD patients, 1 OAD patients were similar in A1C
(8.5%), but were sicker and had higher health care utilizations and costs.
During 1-year follow-up, despite the 1 OAD group showing a lower insulin
treatment persistence rate compared to the 2 and 3+ OAD groups (58.3%
vs 64.6% and 70.2%; both P<0.0001), they had the highest reduction in
A1C values (−0.88 vs −0.72 and −0.52; both P<0.05). Hypoglycemia rates
increased, but decreased during the second half year. Significant reduction
from baseline in annualized health care costs was observed in the 1 and 2
OAD groups (−$4913 and −$1599, respectively; both P<0.001) during 1-year
follow-up, mainly due to decreased inpatient costs offsetting increasing
drug costs. Health care costs stayed the same in the 3+ OAD group.
Among elderly Medicare T2DM patients, significant improvements were
observed after insulin initiation, not only in clinical but also economic
outcomes, particularly among the 1 OAD group. A limitation of this study
is that the duration of T2DM of each group is not known. Further study is
needed to explore the heterogeneity of this population.
Accurate estimation of baseline cardiovascular (CV) risk and relative risk
reduction (RRR) is crucial to ensure that economic evaluations of new health
technologies for the treatment of type 2 diabetes (T2DM) are robust.
Many economic models (such as the CORE Diabetes Model) use risk
equations (RE) derived from UKPDS and concerns persist regarding their
validity; particularly as new equations are published. The objective of this
study was to compare the consistency of predicted CV risk using RE derived
from various T2DM populations.
All CV equations identified from a recent systematic review, derived from
populations with T2DM, were coded and validated. Equations from Australia
(Fremantle), New Zealand (DCS), Sweden (Cederholm), China (Yang), Scotland
(DARTS), USA (ARIC) and UK (UKPDS) were included. Predicted 5-year CV risk was
obtained using baseline cohort characteristics taken from ACCORD. Relative risk
reductions (RRR) were obtained by applying a 10% relative reduction in HbA1c,
total cholesterol and SBP both individually and in combination.
Mean 5-year predicted risk of CVD was 11.0% (SE 1.9%); minimum of 3.4%
(ARIC) and maximum 20.7% (DARTS). A 10% reduction in HbA1c, TC and
SBP resulted in a mean RRR of 6.4%(SE 0.7%), 6.8% (SE 1.5%)and 9.8% (SE
2.3%) respectively. The DCS equation (New Zealand) predicted the lowest
RRR for HbA1c, TC and SBP reduction (4.3%, 1.0% and 3.5% respectively).
The highest RRR for HbA1c change was Cederholm (8.3%) and the DARTS
equation for TC and SBP, 10.3% and 18.9%, respectively.
The difference in absolute risk across these equations does not appear
dependent on geographical location or study recruitment period. Generally,
the UKPDS equations produced consistent absolute CV risk and RRR estimates
close to the group averages; this is of reassurance given their widespread use.
Healthcare policy decisions that rely on CV risk estimation should perform
sensitivity analysis across multiple equations where practicable.
Supported by: Sanofi U.S., Inc.
ADA-Funded Research
&
1215-P
Assessing the Consistency of Absolute Cardiovascular Risk Prediction and Relative Risk Reduction in Type 2 Diabetes Mellitus
For author disclosure information, see page 829.
Guided Audio Tour poster
A317
POSTERS
PETER HUCKFELDT, TARA K. KNIGHT, YAWEN JIANG, ROY BECK, KELLEE M.
MILLER, ANNE L. PETERS, DANA GOLDMAN, Santa Monica, CA, Los Angeles, CA,
Tampa, FL
KENNETH STRAUSS, MARTA BLANCO, M. TERESA HERNÁNDEZ, MARISA AMAYA, Erembodegem, Belgium, Barcelona, Spain, Algeciras, Spain
&
1214-P
Patient Factors Associated With Setting and Attaining A1c Targets
Clinical Diabetes/
Therapeutics
&
Prevalence, Risk Factors and Estimated Costs of Lipohypertrophy in
Insulin-Injecting Patients With Diabetes
HEALTH CARE DELIVERY—ECONOMICS
&
Guided Audio Tour: Moving Towards Better Diabetes Health Care Delivery
(Posters: 1218-P to 1225-P), see page 15.
Actionable Data to Improve Quality Diabetes Care
1216-P
&
POSTERS
Clinical Diabetes/
Therapeutics
SARAH G. IMERSHEIN, RICHARD A. JACKSON, Boston, MA
Current clinical DM guidelines are important guideposts for clinicians
to inform treatment decisions, but do not take into account individuals’
DM complexity or the results of recent clinical trials such as ACCORD and
EDIC. To address this, we developed an algorithm that stratifies patient
populations using medication regimen as a proxy for disease complexity.
This algorithm places people with DM into 5 different groups of glycemic
complexity, depending on their current medication regimen, assigning
different A1C targets for each group.
This algorithm was used with a large national network of affiliated
diabetes centers. Stratified reports were delivered to each center. For 5
providers whose A1C score was < 70%, we provided individual reports and
a brief discussion of their results by the individual groupings for glycemic
complexity.
To date 3874 charts have been assessed at 28 centers. Of these, 2191
(57%) are at 11 centers that have completed both a baseline and followup assessment. The network average for glycemic control in centers that
have completed follow-up improved from 63.1% to 68.9%, p=0.002. More
importantly, the 5 providers given reports followed by a brief discussion
showed greater improvement than those who did not participate in brief
discussions (Table 1).
ROZALINA G. MCCOY, JIAQUAN FAN, STEVEN A. SMITH, JAMES R. DEMING,
JEANETTE Y. ZIEGENFUSS, NILAY D. SHAH, Rochester, MN, Tomah, WI, Minneapolis, MN
Quality metrics are used to measure the quality of diabetes-related care
and guide quality improvement efforts. The D5 measures (HbA1c <8%,
blood pressure <130/80 mmHg, LDL cholesterol <100 mg/dL, non-smoking,
aspirin therapy), are approved by the National Quality Forum and are used
by the majority of healthcare providers and payers, including the Centers
for Medicare and Medicaid Services. Recent focus on patient-centered
care led to the introduction of a patient-reported metric of chronic disease
management: the Patient Assessment of Chronic Illness Care (PACIC).
We sought to establish whether the PACIC correlates with traditional
intermediate clinical outcome metrics, such as the D5. A postal survey
was mailed to 4796 patients randomly selected from a diabetes registry
maintained by 34 clinics in a Midwest practice-based research network
in November 2009. The survey included the 20-item PACIC survey and
questions on patient health, diabetes control, and demography. D5 metrics
were obtained from electronic health records as of 2009. Logistic regression
models were used to evaluate the association of outcomes with the PACIC
score, adjusting for age, gender, diabetes duration, marital status, education
level, and ethnicity. The survey response rate was 42.8% (2055 of 4796).
Respondents were predominantly married (69.2%) and insured (61.9%
public, 36.8% private); mean age was 65 years, 50.4% were male, and 93.4%
had type 2 diabetes. Only 21.6% of patients (443 of 2055) met all five D5
quality metrics. PACIC scores were positively and significantly associated
with confidence in diabetes self-management (p<0.001) and self-rating of
health (p=0.02). However, there was no association between PACIC and
the D5 (p=0.3). The PACIC may serve as an important tool to measure and
improve the quality of patient-centered diabetes care that is distinct from
and complementary to the currently available quality measures.
Table 1. Percent of patients achieving A1C targets among providers with
lower A1C scores, with and without additional discussion of results vs. the
Network Average
Lower Provider
Network Average
Scores (<70%)
Discussed Did NOT
Results discuss results
(n=5)
(n=6)
At A1C Target Baseline
53.9%
57.6%
63.1%
At A1C Target Follow-up
66.5%
62.2%
68.9%
Difference
+12.6%*
+4.6%*
+5.8%
* Weighted average difference of difference, p<0.001
&
Providing actionable data directly to providers, plus a brief discussion, may
improve the number of patients achieving appropriate A1C targets.
&
1218-P
Patient Assessment of Diabetes Care Reflects Patient-Centered
Outcomes But Not Traditional Outcome Quality Metrics
1219-P
Comparing Apples With Apples: Diabetes Care by Endocrinologists
vs. Internists
LAWRENCE S. PHILLIPS, ARUN V. MOHAN, MARJAN KHOSRAVANIPOUR, ANNE
TOMOLO, WENQIONG XUE, QI LONG, DIANA BARB, SANDRA L. JACKSON,
DARIN E. OLSON, MARY K. RHEE, SONYA HAW, PHYLLIS WATSON-WILLIAMS,
Atlanta, GA, Decatur, GA
1217-P
Transitional Care Clinic for Patients With Diabetes May Prevent ReHospitalizations
CECILIA C. LOW WANG, STACEY SEGGELKE, MATTHEW HAWKINS, ELIZABETH
COHLMIA, JOANNA GIBBS, NEDA RASOULI, BORIS DRAZNIN, Aurora, CO
Patients, insurers, and other stakeholders need to be able to assess diabetes
care by healthcare institutions and providers, but we lack a good metric. As
a common and costly disorder, diabetes is a model problem for evaluation of
quality and value. However, simple performance measures may not take into
account the time needed to improve glycemic control, and the complexities of
care in patients who need insulin. To determine the need for such granularity,
we used the Emory Healthcare data warehouse to compare the most recent A1c
levels in patients seen by 8 endocrinologists (ENDOs) and 8 internists (GIMs).
In all 5880 patients with use of the diabetes ICD-9 code 250.xx over 24 mo,
the proportion with A1c >7% was higher for ENDOs vs. GIMs (51% vs. 38%,
p<0.001). We then restricted analysis to the 3735 patients seen >3 times over
24 mo, and >1 time over 12 mo, and categorized as using only oral agents ±
incretins (n=1880), also using basal insulin (n=324), and also using mealtime
insulin (n=1531). Insulin-using patients were less well controlled: A1c was >7%
in 66% of those using mealtime insulin and 55% of those using basal insulin,
vs. 21% of those without insulin (p<0.0001 for trend). Moreover, ENDOs had
more insulin-using patients than GIMs: 53% vs. 22% using mealtime insulin
(p<0.0001), 10% vs. 7% using basal insulin (p=0.02), and 37% vs. 71% without
insulin (p<0.0001), respectively. However, within each group, control was
comparable or better for ENDO vs. GIM patients; A1c >7% was 18.8% vs. 23.4%
without insulin (p=0.01), 53.7% vs. 57.1% with basal insulin (p=0.6), and 65.6%
vs. 65.4% with mealtime insulin (p=0.9), respectively. Conclusion: Assessing
performance in diabetes management on the basis of recent A1c levels in all
patients may be misleading and inaccurate. Since patients seen by ENDOs are
more complex than those seen by GIMs, assessments need to take into account
the time needed to improve glycemic control and the difficulties of treatment
with insulin. Our approach may be a useful model for evaluating care.
Transitioning from the inpatient to the outpatient setting is often a
problematic aspect of diabetes care. Different factors during hospitalization
may adversely affect glycemic control.
Patients are frequently discharged on regimens that differ markedly from
pre-hospitalization outpatient regimens. Moreover, these regimens may
have not been tested adequately during a relatively short length of stay,
posing a significant threat to patient safety. We hypothesized that seeing
patients with diabetes shortly after discharge would reduce readmissions.
In our Transitional Care Clinic (TCC), patients with diabetes are seen within
2-5 days of discharge.
We evaluated the effectiveness of TCC in preventing hospital readmissions
within 90 days. One hundred indigent patients with diabetes discharged
from the hospital were randomized to intervention group (INT, n=50) and
seen in the TCC, vs. control group (CON, n=50). Since these patients lacked
health insurance, timely follow-up for CON was often not available. The INT
patients were seen by a diabetes specialist for a single 30 minute visit to
adjust medications. All patients were contacted 90 days after discharge to
collect information about re-admissions. Fourteen CON (28%) and 10 INT
patients (20%) were re-admitted during follow-up (p=NS). Among patients
originally admitted for diabetes-related issues (14 CON and 16 INT), 6 in CON
(42.8%) and 2 (12.5%) in INT were re-admitted during the follow-up period (p<
0.05). In conclusion, TCC was effective for prevention of re-hospitalizations
in indigent patients admitted for diabetes-related problems. However, the
diabetes-specific TCC was not effective for patients originally admitted for
other medical problems.
Supported by: University of Colorado Hospital
Supported by: U.S. Dept. of Veterans Affairs
&
For author disclosure information, see page 829.
A318
Guided Audio Tour poster
ADA-Funded Research
HEALTH CARE DELIVERY—ECONOMICS
&
1220-P
Improving Health Outcomes in Emerging Adults With Diabetes
Supported by: CDC
&
ERIN S. LEBLANC, ANA G. ROSALES, SUMESH KACHROO, JAYANTI MUKHERJEE, KRISTINE L. FUNK, GREGORY A. NICHOLS, Portland, OR, Wallingford, CT
Diabetes patients often exceed desired A1C levels for months prior
to medication adjustments. To better understand this clinical inertia, we
examined patient and provider characteristics associated with optimal
and poor glycemic control.149 primary care providers at Kaiser Permanente
Northwest (KPNW) were identified as the primary provider for at least 10
diabetes patients. Using hierarchical linear modeling, we assessed both
patient (n=14,430) and provider characteristics to determine predictors of
optimal glycemic control (all A1C values <7%) as well as poor control (at
least 1 A1C >9%).
Of 14,430 patients, 5,823 (40.4%) were in optimal control and 2,446
(17.0%) were in poor control. Patient characteristics associated with optimal
control included older age, lower baseline A1C, shorter diabetes duration, not
using insulin, and fewer primary care visits (p<0.001 for all). The inverse of
these variables also predicted poor control. Higher comorbidity burden and
more visits to specialists, including endocrinologists, were not associated
with optimal glycemic control. Males and patients who had more visits to
specialists other than endocrinology were more likely to have poor control.
No provider characteristics [age, gender, time with KPNW, mean comorbidity
burden of patients, percentage of patients with diabetes, specialty (internal
medicine vs family practice), degree (MD vs NP/PA) or clinic] were associated
with optimal glycemic control. Only 1 provider characteristic, diabetes
patients as a percent of total patients, was associated with poor control
(p=0.03); each additional percentage point increased the odds of an A1C
being ≥ 9% by 4%.
More patient than provider characteristics predicted glycemic control.
To better understand clinical inertia, future research should focus on
understanding how provider decision making in response to poor glycemic
control is influenced by individual patient characteristics, needs, beliefs and
attitudes.
Supported by: CDC
&
1222-P
Understanding Clinical Inertia: Are Patient or Provider Characteristics Predictive of Glycemic Control?
1221-P
Does Group Size Impact Weight Loss Outcomes among Participants
in an Adapted Diabetes Prevention Program?
SARAH M. BROKAW, DIANE ARAVE, DEREK N. EMERSON, MARCENE K. BUTCHER, STEVEN D. HELGERSON, TODD S. HARWELL, Helena, MT
The purpose of this study was to assess if group size is associated with
weight loss goal among participants in an adapted diabetes prevention
program (DPP). Adults at high-risk (N = 841) for CVD and diabetes were
enrolled in the lifestyle intervention in 2011. The median group size was
16 (range 8-38). Multiple logistic regression (LR) analyses were used to
determine if group size (smaller group <16 participants; larger group >16
participants) was independently associated with weight loss goal among
participants. The mean age of participants was 53.4, and 82% were
female. The mean number of core sessions attended was 13.0, and 36%
of participants achieved the 7% weight loss goal. In the bivariate analyses,
compared to participants in the larger groups those in smaller groups were
more likely to have a higher BMI at baseline, attended fewer intervention
sessions, were less likely to self-monitor their fat intake for >14 weeks,
and lost less weight during the intervention. However, using multiple LR
analyses adjusting for age, sex, baseline BMI, achievement of the physical
activity goal, number of weeks self-monitoring fat intake, and group size,
only two factors were independently associated with achievement of the
weight loss goal: frequency of self-monitoring of fat intake and achievement
of the physical activity goal (Table). Our findings indicate that group size is
not associated with achievement of weight loss goal in an adapted DPP.
Supported by: Bristol-Myers Squibb/AstraZeneca
&
1223-P
Visit-Based EMR Reminders With Exception Reporting Improve
Diabetes Outcomes
MICHAEL E. BOWEN, JASON FISH, DEEPA BHAT, BRETT MORAN, TEMPLE HOWELL-STAMPLEY, LYNNE KIRK, KIM BATCHELOR, ETHAN HALM, Dallas, TX
Although best practice alerts (BPAs) may improve care via just-in-time
reminders, the impact of provider engagement by exception reporting is
poorly understood. This project examines the impact of BPAs with exception
reporting on nationally recognized diabetes quality metrics.
BPAs were developed and implemented in an internal medicine clinic.
Established patients with diabetes were identified according to NCQA
definitions. Providers voluntarily reported exceptions to BPA adherence.
We describe the nature and frequency of BPA exceptions and assess the
impact of BPAs on quality metrics using time series linear regression models.
Patients with exceptions indicating the absence of diabetes, medical, or
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A319
POSTERS
Studies of emerging adults (ages 18-24; EA) with diabetes often focus on risk
factors for poor disease outcomes. Features of positive health outcomes [high
health satisfaction (HS) and good glycemic control] are less defined. In particular,
the role of buffering factors [anticipatory guidance of adult screening guidelines,
diabetes related social support, frequency of physical activity and quality of life
(QoL)] is unknown. We tested the hypothesis that higher HS survey ratings were
associated with higher amounts of buffering factors and lower A1c.
The study population consisted of participants in the SEARCH for Diabetes
in Youth Study (prevalent diabetes in 2001) who completed the Quality of
Care and Pediatric Quality of Life Generic Core Young Adult measures in
2008. Respondents (n= 342) had a mean age and diabetes duration of 21.9 +
2.4 and 11.7 + 3.7 yrs., respectively. The sample included: 71.9% type 1
diabetes, 79.8% minority status, 56.1% female, 77.6% continuously insured
for the past 12 months. HS score was defined as a composite of overall
health satisfaction and ratings of health care in the preceding 12 months,
(range 2-10). Four buffering factors (described above), were also derived
from the survey. Associations between HS and both the 4 buffering factors
and self-reported A1c were assessed using Pearson correlations.
HS scores were positively correlated with the levels of the 4 buffering
factors: anticipatory guidance (r= 0.26, p=<0.0001), social supports (r=
0.16, p= 0.003), physical activity (r= 0.14, p=0.01), QoL total score (r=0.45,
p=<0.0001); while HS was inversely related to A1c (r=-0.31, p=<.0001). There
was no significant difference in the relationship between buffering factors
and HS across diabetes type.
These data demonstrate that higher HS scores are associated with higher
levels of buffering factors and lower A1c in a diverse cohort of EA with
longstanding diabetes. Further study of buffering factors in EA may identify
interventions for improving health outcomes in this vulnerable population.
Clinical Diabetes/
Therapeutics
SARAH D. CORATHERS, JESSICA C. KICHLER, DANIEL P. BEAVERS, DANA DABELEA, JEAN M. LAWRENCE, ANGELA D. LIESE, JENNIFER RAYMOND, SHARON H.
SAYDAH, MICHAEL SEID, JOYCE YI-FRAZIER, LAWRENCE M. DOLAN, SEARCH
FOR DIABETES IN YOUTH STUDY GROUP, Cincinnati, OH, Winston-Salem, NC, Aurora, CO, Pasadena, CA, Columbia, SC, Atlanta, GA, Seattle, WA
HEALTH CARE DELIVERY—ECONOMICS
patient BPA exceptions were excluded from the denominator in outcome
calculations.
Between July 2011 and June 2012, 1761 established patients age 1875 with diabetes completed 5180 encounters with 37 providers after BPA
implementation. At least one diabetes BPA was triggered in 2923 encounters
for a total of 4794 BPAs. Of the 230 exceptions reported, 13% did not have
diabetes, 37% had medical exceptions, 26% had patient exceptions, and
24% received services outside the health system. BPAs improved rates of
glycemic control, LDL measurement, and LDL control after controlling for
secular trends. Rates of A1C measurement were high at baseline and did not
change post-intervention. (Table 1)
BPAs engaging providers in exception reporting improved performance on
A1C and LDL metrics.
POSTERS
Clinical Diabetes/
Therapeutics
Supported by: Eli Lilly and Company
&
Supported by: University of Texas Health System
1225-P
&
Japan Diabetes Outcome Intervention Trial-1 (J-DOIT1): A Cluster
Randomized Controlled Trial of Type 2 Diabetes (T2DM) Prevention
by Telephone-Delivered Lifestyle Support for High-Risk Subjects
NAOKI SAKANE, KENTARO OKAZAKI, KAZUHIKO KOTANI, KAORU TAKAHASHI,
YOSHIKO SANO, KOKORO TSUZAKI, JUICHI SATO, SADAO SUZUKI, SATOSHI
MORITA, YOSHITAKE OSHIMA, KAZUO IZUMI, MASAYUKI KATO, NAOKI ISHIZUKA, MITSUHIKO NODA, HIDESHI KUZUYA, Kyoto, Japan, Nagoya, Japan, Yokohama, Japan, Kobe, Japan, Tokyo, Japan
1224-P
Is the Current Standard of Care Leading to Cost-Effective Outcomes
for Patients With Type 2 Diabetes Requiring Insulin in the UK?
To contain the growing T2DM population, it is critical to clarify effective
and efficient modalities for intervention delivery with a wide population
reach. The J-DOIT 1 was designed to test an effectiveness of goal-focused
lifestyle support delivered by telephone for subjects with impaired fasting
glucose (IFG) detected at health checkups. Forty-three groups (clusters),
formed from 17 health checkup divisions in communities and worksites
across the country, were randomly assigned to an intervention or a control
arm. Study candidates, aged 20-65 years with fasting plasma glucose (FPG)
of 5.6-6.9 mmol/l, were identified in each group using health checkup data
in 2006. A total of 2840 subjects, 1336 from the intervention and 1504 from
the control arm, were enrolled. The intervention was delivered by healthcare
providers over a one year period, followed by 3 years’ follow-up period by
annual health checkups. Primary outcome is the development of diabetes
defined as FPG≥7.0 mmol/l. After one-year intervention, proportions of those
who achieved the goals in terms of weight control, vegetable intake, and
restriction on alcohol intake were modestly but significantly increased in
the intervention arm. In spite of these favorable changes, overall, we could
not find an improvement in the 5 years’ cumulative incidence of diabetes,
with the hazard ratio (HR) in intervention group being 0.97 (95% confidence
interval (CI), 0.75-1.25). In the sub-analyses with obese subjects (Body
Mass Index≥25), no difference was found between the arms. However, the
intervention significantly reduced the HR to 0.36 (95% CI, 0.15-0.83) among
subjects with nonalcoholic fatty liver disease (NAFLD). Thus the effects
of intervention by telephone appear limited in a real-world primary care
setting. NAFLD subjects with IFG may be promising target populations for
preventing T2DM.
WILLIAM VALENTINE, BRADLEY H. CURTIS, RICHARD POLLOCK, KRISTINA S.
BOYE, KATE VAN BRUNT, DAVID M. KENDALL, MICHAEL BRANDLE, Basel, Switzerland, Indianapolis, IN, Windlesham, Surrey, United Kingdom, St. Gallen, Switzerland
To investigate whether insulin intensification, based on use of intensive
insulin regimens recommended by the current standard of care in clinical
practice would be cost-effective for patients with type 2 diabetes (T2DM)
in the UK.
Data were derived from a retrospective analysis of 3,185 patients with
T2DM on basal insulin in The Health Improvement Network general practice
database. Of those who changed therapy, 48% (614 patients) intensified
insulin therapy, defined as adding bolus or premix insulin to a basal regimen.
Projection of clinical outcome and cost (2011 GBP) over patient lifetime was
made using a recently validated model of T2DM.
Insulin intensification was associated with improvements in life
expectancy, quality-adjusted life expectancy and time to onset of
complications versus no intensification or delaying intensification by 2, 4, 6,
or 8 years. Direct costs were higher with the insulin intensification strategy
(due to the acquisition costs of insulin). Incremental cost-effectiveness
ratios for insulin intensification were GBP 32,560, GBP 35,187, GBP 40,006,
GBP 48,187 and GBP 55,431 per QALY gained versus delaying intensification
2, 4, 6 and 8 years, and no intensification, respectively.
Although associated with improved clinical outcomes, insulin intensification as currently practiced in the UK has a relatively high cost per QALY
and may not lead to cost-effective outcomes in the UK for patients with
type 2 diabetes.
Supported by: Health and Labour Sciences
&
For author disclosure information, see page 829.
A320
Guided Audio Tour poster
ADA-Funded Research
1228-P
Improving Community Diabetes Care Through a Novel, Educational
Outreach Visit Program
BELINDA A. BROOKS, FRANZISKA H. LIMACHER, LYNDA MOLYNEAUX, MARIA
CONSTANTINO, DENNIS K. YUE, Camperdown, Australia, Sydney, Australia
JILL E. VOLLBRECHT, Traverse City, MI
In recent years, increased emphasis has been placed on tracking
outcomes of evidenced-based care of chronic disease. It is therefore
essential that community leaders explore new methods of educating
medical providers that result in sustained outcome improvements. In this
program, an endocrinologist designed a curriculum based on ADA guidelines
for management of diabetes, and reviewed it with each of nine primary care
physicians (PCP). The endocrinologist and PCP then evaluated four diabetic
patients together, and together formulated a treatment plan for each. The
effect of this site visit was analyzed on previously-controlled diabetic patients
(HbA1c <7%, n = 291; LDL <100 mg/dL, n=186; urine microalbumin:creatinine
(ACR) <30 µg/mg, n=170) and uncontrolled patients (HbA1c >7%, n =216; LDL
>100, n=148; ACR >30 µg/mg, n=42). Nine months following the education,
statistically significant reductions in median LDL (123 to 106 mg/dL, p=0.008)
and ACR (64 to 24.8 µg/mg, p=0.003) were demonstrated in previouslyuncontrolled patients. A trend toward improvement in median A1c was
noted (7.9 to 7.7%, p=0.26). Eighteen months after the education, the effect
was sustained (median LDL 80 mg/dL, p=0.001; median ACR 8 µg/mg,
p=0.032; median HbA1c 7.8%, p=0.5). No improvements were noted in any
outcome measures on analysis of data from previously-controlled patients.
Total diabetic education referrals from the participants increased 23%
following the site visit (142 to 175). The number of diabetic patients referred
to endocrinology for diabetic management remained stable at 4% of the
total diabetic population of the participants. PCP satisfaction was assessed
using pre- and post-visit surveys; PCP’s reported a subjective increase in
knowledge of and confidence in treating diabetes. The results indicate that
a half-day educational session with an experienced diabetologist can lead
to sustained, improved glycemic and lipid control in previously-uncontrolled
diabetic patients.
Ideally, clinical trial participants (CTP) should be representative of
patients in clinical practice but rarely has this been tested in diabetes. We
examined clinical parameters and individual case fatality data (matched
with the Australian National Registry) of our CTP (n = 444). Overall, more
males took part in clinical trials (68% vs 56%, p<0.0001). We matched CTP
1:5 with non clinical trial participants (NCTP) (n = 2220) for age, gender, type
and duration of diabetes according to the year the trial was conducted. CTP
were more likely to be anglo-celtic, less likely to smoke, have lower case
fatality and die at an older age (Table 1). To overcome the possibility that
CTP had less severe diabetes, we further matched a subgroup of CTP with
comprehensive clinical data (n = 247) with NCTP (n = 1720) for glycaemic
control, microvascular and macrovascular complications. Whilst case fatality
rates were not significantly different (10.1 vs 14.3%; p = 0.07), CTP lived
longer (73.4 vs 68.3 yrs; p = 0.01). CTP were also on less blood pressure and
lipid lowering treatment despite having similar blood pressure and higher
cholesterol than NCTP. Our findings indicate that the applicability of clinical
trial results to the diabetic population at large could be altered if the efficacy
of the treatment modality being tested is affected by gender, ethnicity or
smoking status. These subtle differences in CTP may distort the calculation
of the cost benefit ratio for the general diabetes community.
Matched 1:5
Age (years)
Males (%)
Duration of Diabetes (years)
Case Fatality (%)
Age at Death (years)
Duration of Diabetes at Death
(years)
Current Smoker (%)
CTP n = 444
NCTP n = 2220 Statistic
54.0 ± 13.2
54.0 ± 13.3 p = 1.0
68
68
p = 1.0
8.3 [2.6 - 15.3] 8.3 [2.8 - 15.1] p = 0.5
11.7
16.5
p = 0.01
72.2 ± 11.1
68.5 ± 10.3 p = 0.02
19.2 [12.9 - 28.3] 14.8 [9.4 - 21.4] p = 0.001
9.5
24.1
Supported by: Michigan Dept. of Community Health
1229-P
p = 0.001
WITHDRAWN
1227-P
Association of ≥5% Weight Loss and Self-Reported Adherence With
6-Month Glycemic Control in Type 2 Diabetes Mellitus (T2DM): the
DELTA Study
CARRIE MCADAM-MARX, BRANDON K. BELLOWS, GAIL D. WYGANT, JAYANTI
MUKHERJEE, SUDHIR UNNI, XIANGYANG YE, JOSHUA LIBERMAN, UCHENNA
H. ILOEJE, DIANA BRIXNER, Salt Lake City, UT, Princeton, NJ, Wallingford, CT, Sacramento, CA
The association between weight loss, adherence and glycemic control in
patients with uncontrolled T2DM remains largely uncharacterized. T2DM
patients ≥18 years were identified in a US integrated health system (1/1/2009
to 10/31/2011). Those prescribed a new class of anti-diabetic therapy (AD)
on index date not previously used and with baseline HbA1c ≥7.0% were
included. Outcomes of HbA1c goal attainment (<7.0%) and weight loss of ≥5%
were defined at 6 months. Outcomes were evaluated by literature defined
weight-effect properties of prescribed AD (weight loss - Metformin, GLP-1
agonists) or no weight loss (sulfonylureas, thiazolidinediones, insulin, DPP-4
inhibitors, and others) and by patient-reported medication compliance per
the Medication Adherence Reporting Scale. Structural equation modeling
described simultaneous associations between adherence, weight loss, and
glycemic control. A total of 477 patients met inclusion criteria; mean (SD)
age was 59.1 (11.6) years; 50.9% were women; and 30.4% were treatment
naïve. Mean baseline HbA1c was 8.6% (1.6) and weight was 102.0 kg (23.0).
A majority of patients (67.9%) reported being adherent to the index AD. At 6
months 15.9% had weight loss of ≥5% and 42.8% attained HbA1c goal. Mean
weight change was -1.3 (5.1) kg, (p=0.39); mean HbA1c reduction was -1.2%
(1.8) (p<0.001). Patients prescribed an AD with weight loss properties (OR
2.62; p=0.001) were more likely to experience weight loss ≥5% relative to
those prescribed an AD not associated with weight loss. Weight loss of ≥5%
(OR 6.40; p<.001) and being adherent with AD therapy (OR 1.85; p=0.005)
were associated with HbA1c goal attainment. Though weight loss ≥5% and
adherence were associated with glycemic control in T2DM, weight loss was
a stronger predictor of HbA1c goal attainment than medication adherence in
this study population. It is important to consider weight-effect properties, in
addition to adherence counseling, when prescribing ADs.
1230-P
Flexible Insulin Dosing Improves Health-Related Quality of Life
(HRQoL) in a Basal Only Treatment Regimen: A Time Trade-Off
Survey
MARC EVANS, HENRIK H. JENSEN, METTE BØGELUND, JENS GUNDGAARD,
BARRIE CHUBB, KAMLESH KHUNTI, Cardiff, United Kingdom, Holte, Denmark,
Søborg, Denmark, Crawley, United Kingdom, Leicester, United Kingdom
Rigidity of insulin regimens may negatively impact HRQoL and therapy
adherence, with the requirement for basal insulin dosing at the same time
every day being a significant contributing factor. We examined the HRQoL
impact of both flexible dose timing and the number of basal insulin injections
in a basal-only regimen using time trade-off (TTO) methods.
HRQoL was quantified via an online TTO survey in the UK, Canada and
Sweden with separate analyses of 1,121 respondents from the general
population and 192 people with type 2 diabetes (T2D). HRQoL was measured
on a utility scale: 0 (dead), 1 (perfect health). Respondents traded-off length of
life for improving HRQoL in described health states. Respondents evaluated
health states with diabetes and once-daily injections with flexible timing,
once-daily fixed time injections, and twice-daily fixed time injections.
In the general population, time flexible once-daily injection was associated
with 0.016 (95% CI 0.011; 0.022) higher utility vs. a fixed time of injection as
shown in table 1. The people with diabetes confirmed these results with
a utility benefit of 0.015 (95% CI 0.004; 0.027). Once-daily injections had
significantly higher utility compared to twice-daily.
Flexible dosing and fewer injections have a positive HRQoL impact, which
may enhance therapy adherence and potentially contribute to improved
long-term outcomes in people treated with basal only insulin regimens.
Supported by: Bristol-Myers Squibb
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A321
POSTERS
1226-P
Diabetic Clinical Trial Participants Have Less Cardiovascular Risk
Factors and Lower Case Fatality
Clinical Diabetes/
Therapeutics
HEALTH CARE DELIVERY—ECONOMICS
HEALTH CARE DELIVERY—ECONOMICS
Table 1. Utility differences from the time trade-off survey
N Utility CI95
CI95
Lower Upper
General population
1 Flex vs. 1 Fixed
1121 0.016 0.011 0.022
1 Fixed vs. 2 Fixed
1121 0.039 0.032 0.046
1 Flex vs. 2 Fixed
1121 0.055 0.048 0.063
Patients with T2D
1 Flex vs. 1 Fixed
192 0.015 0.004 0.027
1 Fixed vs. 2 Fixed
192 0.042 0.025 0.061
1 Flex vs. 2 Fixed
192 0.057 0.040 0.076
SE
when HbA1c exceeded 8.0%, first by adding sulfonylurea (SU), then by
discontinuing SU and adding basal insulin, and then by adding prandial
insulin. Alternative scenarios were run using metformin as the first rescue
therapy. Health utilities and costs associated with microvascular and
macrovascular events were obtained from established sources. Sensitivity
analyses were performed.
Both algorithms with CANA 100 and 300 mg were estimated to reduce
diabetes complications vs LMA: macrovascular events between 5% to 17%
and microvascular events up to 36%. The CANA algorithms postponed the
start of SU and insulin vs LMA. Within 1 year, 20% and 13% of the CANA
100 or 300 mg groups, respectively, vs 43% of the LMA group required
SU. By year 10, only 27% and 19% of the CANA 100 and 300 mg groups,
respectively, vs 66% of the LMA group were estimated to require insulin. In
base case and sensitivity analyses, improvements in outcomes associated
with the CANA algorithms led to lower costs and improved quality of life vs
LMA over 30 years.
p-value
0.003 <0.0001
0.003 <0.0001
0.004 <0.0001
0.006 0.0095
0.009 <0.0001
0.009 <0.0001
Supported by: Novo Nordisk, Inc.
1231-P
POSTERS
Clinical Diabetes/
Therapeutics
Limited Effectiveness of Collaborative Primary Care Model for Diabetes and Depression: An Implementation Trial
1233-P
Community One-Stop Diabetes Care Center in Cooperation With
HMO Can Provide Effective Management for Diabetics in a Specific
Ethnic Group
JEFFREY A. JOHNSON, FATIMA AL SAYAH, LISA WOZNIAK, SANDRA REES, ALLISON SOPROVICH, WEIYU QUI, CONSTANCE CHIK, PIERRE CHUE, PETER FLORENCE, JENNIFER JACQUIER, PAULINE LYSAK, ANDREA OPGENORTH, WAYNE J.
KATON, SUMIT R. MAJUMDAR, Edmonton, AB, Canada, Seattle, WA
GEORGE LIU, VIVIEN HUI, TA-MIN CHANG, New York, NY
Diabetes mellitus is the 7th leading cause of death in the US, affecting
8.3% of US population in 2011. Increasing cases of diabetes have occurred
in Chinese Americans, affecting 15% of Chinese community population
in New York City including 48% of patients at age of 65 years or older.
Poor medication and diet compliance, lack of diabetic education, cost
of medications, language/cultural differences, and depression are main
obstacles for management of diabetes in Chinese American community. The
Asian Diabetic Center (ADC) is established with a grant supported by United
Health Group Inc. to promote the health of local Asian American community
in New York City by providing accessible and high-quality medical care
including consultations in Endocrinology, Nutrition, Podiatry, Nephrology,
Vascular, Ophthalmology, and diabetes education. The purpose of this
study is to determine the efficiency of one-stop health care management
of 350 diabetic patients at ADC from March 17, 2011 to December 31, 2011.
Significant first year improvement in various clinical parameters (mean ± SE,
P<0.0001) were observed between first visit and after ADC consultation.
Significant changes were: body mass index (from 26.21 ± 0.45 to 25.56 ±
0.41; 48.8% of patients had weight loss of 5.07±0.51 lb), HbA1C (from 7.87 ±
0.14 to 7.12 ± 0.11 %; the number of patients with ≤7% HbA1C increased from
38.1% to 59.2% and patients with ≥9% HbA1C decreased from 22.2% to
6.4%), LDL (from 83.65 ± 3.09 to 72.37 ± 2.66 mg/dl; the number of patients
with ≤100 mg/dl increased from 70.8% to 82.9%), non-HDL (122.05 ± 3.46 to
107.62 ± 3.27 mg/dl; ≤130 mg/dl patients increased from 59.4% to 72.7%),
and blood pressures (number of patients with ≤130/80 increased from 74.8%
to 90.8%; ≤140/90, from 86.3% to 96.2%; >140/90, decreased from 13.7% to
3.8%). These observations indicate our one-stop care of diabetic patients is
highly effective for the Asian American community.
Depression is common in those with diabetes; when the two co-exist
it worsens outcomes and increases health care costs. We evaluated the
implementation of a nurse case-manager based collaborative team model
to improve depressive symptoms and diabetes management in primary care
in Alberta, Canada.
We conducted a controlled implementation trial in 4 non-metro primary
care networks. Eligible patients had type 2 diabetes and screened positive
for depression, based on Patient Health Questionnaire (PHQ-9) scores >10.
Patients were allocated using an “Intervention-On or -Off” monthly timeseries. Intervention consisted of case-managers working 1:1 with patients
and their physicians, using motivational interviewing, evidence-based
treatment algorithms, and specialist consultations as needed to deliver
individualized care that prioritized depression, then cardio-metabolic
treatment. The main outcome was improvement in PHQ-9 scores at
12-months; secondary endpoints included improvements in A1c, systolic
pressure and LDL. We compared outcomes using random effects models,
with intent-to-treat analyses.
Of 1924 patients screened, 476 (25%) had PHQ >10. Of these, 95 were
allocated to intervention and 62 to control. There were no baseline
differences between groups: mean age 57.8 (SD 9.8) years, 55% women,
53% had BMI>35, mean PHQ-9 score 14.5 (SD 3.7), A1c 7.6% (SD 1.8),
systolic pressure 125.2 mmHg (SD 16.0), and LDL was 2.2 mmol/L (SD
0.8). Preliminary analyses showed that intervention and control patients
had similar 12-month improvements in PHQ-9 (6.4 [SD 5.7] vs 5.1 [SD 5.7]
for controls; difference 1.1 [95%CI -2.8, 0.5]; p=0.18) and similar rates of
depression remission (61% vs 58% of controls, p=0.71). No differences were
observed in secondary outcomes.
In patients with type 2 diabetes who screened positive for depression, a
case-manager collaborative care model did not lead to improved outcomes
compared to enhanced usual care in a Canadian primary care setting.
Supported by: United Health Group
1234-P
A Provider Satisfaction Inventory for Prediabetes Management
Supported by: Alberta Health; CIHR (OTG-88588)
JORDAN SILL, JEANINE ALBU, NANCY SOHLER, BRENDA MATTI, EDWIN
YOUNG, GARY BURKE, New York, NY
1232-P
Training of both providers and care teams is essential in the context of
patient-centered medical home; assessing and measuring their satisfaction
with management of type 2 diabetes (DM) has been reported but such
methodology is not described for DM prevention. We administered a Provider
Satisfaction Inventory (PSI) before and immediately after 1 hour training
sessions we had designed for teaching the principles of systematic DM
screening and prediabetes management. The PSI was a previously published
scale (Montori et al Endocr Pract 2002) used to evaluate satisfaction with
DM care on 4 categories: Chronic Disease Management, Collaborative Team
Practice, Outcomes and Supportive Environment. The PSI was adapted
to determine satisfaction with pre-diabetes care for this study. Forty
providers (primary care physicians and extenders), 135 Internal Medicine
residents (years 1-3), and 54 ancillary personnel (office coordinators,
medical assistants, licensed practical nurses) from an inner city primary
care network participated. Our baseline data shows the adapted instrument
with adequate reliability, similar to the original version: correlations of each
item to total PSI score with that item removed ranged from 0.49 to 0.74,
and the Cronbach alpha for each scale ranged from 0.81 to 0.90 (0.94 for
the PSI). Our training was successful: mean scores improved significantly
A Health Economic Analysis of the Long-Term Benefi ts and Associated Cost Offsets of Canagliflozin Monotherapy in the U.S.
CHERYL NESLUSAN, PIERRE JOHANSEN, MICHAEL WILLIS, SILAS MARTIN, Raritan, NJ, Lund, Sweden
Canagliflozin (CANA) is a novel inhibitor of the sodium glucose cotransporter 2 in development for treating type 2 diabetes mellitus (T2DM). In
a previously reported 26-week, randomized, double-blind, placebo-controlled
Phase 3 study of 584 subjects inadequately controlled with diet and
exercise, CANA 100 and 300 mg significantly decreased HbA1c vs placebo
by 0.91% and 1.16%, respectively. We simulated how the observed changes
in biomarkers (HbA1c, body weight, systolic blood pressure, cholesterol) may
affect future outcomes and costs.
We compared treatment algorithms beginning with lifestyle management
and CANA 100 or 300 mg as monotherapy with one beginning with lifestyle
management alone (LMA) using a validated micro-simulation model, the
Economic and Health Outcomes Model (ECHO)-T2DM. Baseline patient
demographics, baseline biomarker data, and treatment effects were
sourced from the trial. In the base case, simulated treatment was intensified
&
For author disclosure information, see page 829.
A322
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HEALTH CARE DELIVERY—ECONOMICS
insulin after 1 OAD, 48% (n=6980) after 2 OADs, and 20% (n=2987) after 3+
OADs. Multivariate analysis showed that those with older age (≥75 y), baseline
hospitalization, diabetes complications, and discordant comorbidities were
less likely to delay insulin initiation. Patients with more office visits, higher
A1C levels, and polypharmacy at baseline were more likely to delay.
These results suggest that current diabetes medical practice of insulin
use is focusing on the sicker patients for earlier treatment, possibly because
they may encounter urgent situations where they have to take insulin.
However, the broader diabetes population needing insulin treatment by
treatment guidelines is more likely to delay. Polypharmacy, which is common
in the elderly, is another major obstacle. Our study highlights the importance
of a patient-centered approach when evaluating timing of insulin initiation
among the heterogeneous elderly population.
after the training for each of the four scales and all provider groups (p<0.05),
with the exception of two scales for which the ancillary personnel group
had relatively high ratings at baseline. Though our training was successful,
differences in satisfaction across the groups indicate a need for targeted
training for specific personnel. For example ancillary personnel reported
significantly lower satisfaction on Chronic Disease Management at both
time periods than both providers and residents. Our results underscore
the importance of satisfaction evaluations as part of the chronic disease
prevention and management system for DM.
Supported by: CDC (5U58DP002717)
1235-P
Burden of Type 2 Diabetes and Out-of-Pocket Expenditures in Argentina
Supported by: Sanofi U.S., Inc.
JORGE ELGART, LORENA GONZÁLEZ, SANTIAGO ASTEAZARÁN, JOAQUÍN E.
CAPORALE, J. DE LA FUENTE, CECILIA CAMILLUCCI, JUAN J. GAGLIARDINO, La
Plata, Argentina, Córdoba, Argentina
1237-P
DEBORAH J. WEXLER, STEPHANIE EISENSTAT, ELIZABETH GEAGAN, GIANNA
WILKINS, LINDA DELAHANTY, MARCY BERGERON, ANNE THORNDIKE, MIRA
KAUTZKY, BARBARA CHASE, MELANIE PEARSALL, ADRIAN ZAI, Boston, MA
The patient centered medical home (PCMH) model offers novel opportunities
for integrated, collaborative type 2 diabetes care, especially for complex
care processes such as insulin initiation, which can be delayed between 2-7
years in primary care. Our objective was to reengineer the available clinical
care team in the primary care practice to improve the quality and efficiency
of insulin initiation. The team included a practice-based nurse diabetes care
manager (not necessarily CDE-certified but called a Diabetes Champion)
with a PCMH-based dietitian trained in diabetes medical nutrition therapy
to coordinate care with the PCP. Three primary care practices were trained
in protocols for insulin initiation, medical nutrition therapy, and behavioral
assessment and motivational interviewing. The Diabetes Champions at
each site used a patient registry to identify patients in the practice in need
of insulin initiation using HbA1c and medication criteria. Over a 4 month
intervention period, 42 patients were eligible and participated in the pilot.
Mean age was 59 (SD 13) years (56% White, 31% Black, 10% Hispanic, 3%
Other). The pre-intervention HbA1c for all participants was 8.8% (SD 2.2).
Post-intervention, HbA1c was 7.7% (SD 1.6), weight decreased 0.04 (SD 5.6)
kg, and there was a 5% rate of mild hypoglycemia. Fourteen patients had
dietitian visits. Among the subgroup that started insulin, the pre-intervention
HbA1c was 10.1% (SD 2.20). Post-intervention, HbA1c decreased to 7.3% (SD
1.2), a mean HbA1c reduction of 2.5% (SD 3.1); weight increased 0.1 (SD
1.05) kg; and there was an 8% rate of mild hypoglycemia. The usual rate
of HbA1c decline in our population is 0.4% (95% CI 0.08-0.8) over 4 months.
On average, the process required 1.2 nurse visits and 6.3 phone calls per
patient. This model, teaming a Diabetes Champion nurse care manager with
a dietitian based within the PCMH, improved the quality and efficiency of
diabetes care. The next phase is to apply the model more broadly to other
diabetes-related processes in the PCMH.
Quarterly direct medical (MC) and Non Medical (NMC) costs (median
[interquartile ratio] (number of cases)
MC
C
Physician office visit
24 [12-48] (190)
Laboratory test
114 [77-176] (86)
Drugs
217 [61-473] (77)
Practices
200 [90-481] (116)
Hospitalizations
1,456 [674-4,388] (15)
Subtotal
251 [72-666] (204)
NMC
10 [0-34] (414)
T2DM
T2DM-C
48 [24-72] (201)
60 [24-96] (208)
159 [104-214] (154)
172 [120-247] (166)
676 [174-791] (155)
676 [296-1,414] (181)
159 [82-409] (125)
226 [130-583] (150)
453 [344-1,435] (11) 3,265 [1,473-6,569] (22)
573 [243-1,207] (215) 1138 [575-2,341] (213)
10 [0-40] (265)
20 [0-60] (277)
P<0.05 compared to # ”C and *T2DM.
Supported by: Novo Nordisk, Inc.
1238-P
Trends in Insulin Initiation and Treatment Intensification Among Patients With Type 2 Diabetes
1236-P
AMANDA R. PATRICK, MICHAEL A. FISCHER, NITEESH K. CHOUDHRY, WILLIAM
H. SHRANK, JOHN D. SEEGER, JUN LIU, JERRY AVORN, JENNIFER M. POLINSKI,
Boston, MA
Real-World Study of Delayed Initiation of Insulin and Associated
Factors Among Elderly Patients With Type 2 Diabetes Mellitus
(T2DM)
Many patients with type 2 diabetes eventually receive insulin, yet little
is known about the patterns and quality of pharmacologic care following
insulin initiation. Guidelines from the American Diabetes Association and
the European Association for the Study of Diabetes recommend that insulin
secretagogues such as sulfonylureas and meglitinides be discontinued
at insulin initiation to reduce the risk of hypoglycemia. Our objective was
to describe pharmacologic treatment patterns over time among adults
initiating insulin.
We identified a large commercially-insured population of adult patients
without recorded type 1 diabetes who initiated insulin. We evaluated
changes in non-insulin antidiabetic medication use during the 60 days
immediately following insulin initiation, increases in insulin dose and/or
dosing frequency during the 270 days following an insulin initiation period of
90 days, and rates of insulin discontinuation.
7,932 patients initiated insulin during 2003-2008, with the majority (61%)
initiating basal insulin only. Metformin (55%), sulfonylureas (39%), glitazones
(30%), and meglitinides (9%) were commonly used prior to insulin initiation.
Basal or pre-mixed insulin dose and/or dosing frequency increased among
RITUPARNA BHATTACHARYA, STEVE ZHOU, WENHUI WEI, MAYANK AJMERA,
JOHN LING, USHA SAMBAMOORTHI, Morgantown, WV, Bridgewater, NJ
Timely initiation of insulin in elderly patients with T2DM is a challenging
and critical task in diabetes care, which requires evidence to help understand
the patterns, limitations, and issues of current practice. Few real-world
studies have investigated this topic, mainly due to the difficulties of defining
“timely initiation of insulin” and limited access to treatment data on elderly
patients with T2DM.
Using the Humana Medicare claims database, this retrospective study
analyzed elderly (≥65 y) patients with T2DM who initiated basal insulin
between 2007 and 2011. The number of baseline oral antidiabetic drugs
(OADs) was used as a proxy for the delay in insulin initiation. Multinomial
logistic regression was used to assess the independent contributions of
patients’ sociodemographic, clinical, and elderly-specific complexities to
delayed insulin initiation.
Included were 14,669 elderly patients (female 49%, white 71%, baseline
mean age 74 y, A1C 8.60% [where available]), with 32% (n=4702) initiating
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A323
POSTERS
We performed a case-control study to a) assess the impact of diabetes on
different social and economic variables in Argentina, and b) compare them
with those recorded in non diabetic people (C). We compared cases with
Type 2 diabetes with (T2DM-C, n=387) or without chronic complications
(T2DM, n=387) and C (n=774) paired by age, gender and social context. Data
were obtained by structured telephone interviews (March-April 2011) and
from clinical records. Statistical analysis was done using ANOVA/KruskalWallis and Chi-square (in proportions) tests. All subjects provided oral
informed consent. In each group 54.8% were female. Diabetes duration
in T2DM-C was significantly higher than in T2DM (8.1±8.4 vs. 10.8±9.0).
T2DM-C had significantly lower salaries, higher monthly expenditures (with
lower expenditure/income ratio), lower percentage of people with university
degree, and higher hospitalization rate and resource consumption; they also
lost more working days compared to T2DM or C. T2DM-C had significantly
higher direct medical and indirect costs. The data show the heavy burden of
diabetes and its complications for the patient, his/her family, health systems
and society overall in Argentina. They also act as a warning to health
authorities to strengthen the implementation of prevention strategies to
reduce this burden.
Clinical Diabetes/
Therapeutics
Diabetes Home: A New Team-Care Model for Insulin Initiation in the
PCMH
HEALTH CARE DELIVERY—ECONOMICS
with reductions in the no-show rate from 42.7% to 38.2% and the mean A1C
from 10.4% to 9.8%. The top barriers addressed by navigators were related
to transportation, finances, check-in processes, insurance, and housing.
Although the study is ongoing, current data indicates PNPs in diabetes
have promise for improving attendance and clinical outcomes in a inner-city
patient population with healthcare disparities.
21% of patients, mealtime dose increased for 18%. Insulin was discontinued
by 27% of patients. Among patients continuing insulin, metformin was
continued by 62% of patients following insulin initiation, and nearly as often
sulfonylureas (56%) and meglitinides (53%).
We found evidence of substantial departures from guideline-recommended
diabetes pharmacotherapy. Insulin secretagogues were frequently coprescribed with insulin. The majority of patients had no evidence of treatment
intensification after insulin initiation, although this finding is difficult to
interpret without HbA1c values. Addressing divergence from treatment
guidelines following insulin initiation may improve patient outcomes.
Supported by: William Randolph Hearst Foundation
1241-P
WITHDRAWN
Supported by: Eli Lilly and Company (F3Z-MC-B010)
1239-P
Cost Predictors in Type 2 Diabetes Mellitus: A Retrospective Claims
Database Analysis
POSTERS
Clinical Diabetes/
Therapeutics
MORGAN BRON, ANNIE GUÉRIN, DOMINICK LATREMOUILLE-VIAU, RALUCA
IONESCU-ITTU, JENNIFER SAMP, ERIC WU, Deerfield, IL, Boston, MA
This study aimed to identify cost predictors in type 2 diabetes mellitus
(T2DM) patients using oral antidiabetic therapies (OADs).
Adult patients with T2DM using OADs were identified in the Truven
Health Analytics MarketScan® databases (2004-2010). Patients with ≥4
HbA1c tests within 1 year were classified into cohorts based on quartiles
(Q) of the distribution of total 12-month diabetes-related costs following a
randomly selected OAD prescription date (i.e., index date). Diabetes-related
costs were defined as the sum of costs for medical services with a diagnosis
for diabetes and antidiabetic (AD) medications. Patient demographics,
comorbidity profile, AD use, HbA1c level, and resource use were measured
over the 12-month pre-index period and compared between cohorts with
the highest costs (i.e., Q4) and lower costs (i.e., Q1-Q3). Multivariate logistic
regression was used to identify predictors of the highest diabetes-related
costs.
Among the 3,921 selected patients with HbA1c tests (i.e., 5% of the
eligible T2DM patients using OADs), the average 12-month diabetes-related
cost was $12,623 for the highest cost cohort (N=981) and $1,871 for the
lower cost cohort (N=2,940). Compared to the lower cost cohort, during the
pre-index period, fewer patients in the highest cost cohort were female and
achieved the glycemic goal (HbA1c ≤7%), more patients used insulin, and
patients had a higher comorbidity burden, in particular microvascular diabetic
complications, hypertension, and lipid disorders (all p<0.01). The main
predictors (by greatest ORs) of the highest diabetes-related costs include
insulin use (OR=3.08), coronary artery disease (OR=2.27), endocrinologist
visit (OR=1.69), number of AD classes used (OR=1.56), diabetic retinopathy
(OR=1.53), neuropathy (OR=1.44), and lipid disorder (OR=1.43) (all p<0.05).
In a sample of T2DM patients receiving OADs, the main predictors for high
diabetes-related costs included factors suggesting greater T2DM severity
and diabetic complications.
Supported by: Takeda Pharmaceuticals International, Inc.
1240-P
1242-P
Navigation Program for Patients With Diabetes at an Inner-City
Hospital Reduces A1C and Improves Clinic Attendance
Evaluating the Patient Experience in the Asian Treat to Target Lantus Study (ATLAS): A 24-Week Randomized, Multinational Study
WILJEANA J. GLOVER, VASSILIKI PRAVODELOV, ROBERTA CAPELSON, MELISSA
NORGAISSE, DANIEL O’SHEA, VARSHA G. VIMALANANDA, JAMES L. ROSENZWEIG, Boston, MA
NICK FREEMANTLE, KARIM ADMANE, SATISH K. GARG, ATLAS STUDY GROUP,
London, United Kingdom, Paris, France, Aurora, CO
Patients who keep their appointments manage their diabetes better
than those who do not; patient navigation programs (PNPs) have been
implemented to overcome barriers that may limit appointment attendance,
as well as provide health education and psychosocial support. Navigators
are used extensively in cancer care, but to a limited extent in diabetes care.
We performed a pilot study to determine if the use of patient navigators
would be associated with a decline in no-show rates and improved clinical
outcomes.
After nine months (1/30/2012-11/11/2012) of the PNP in Diabetes Services
at the Boston Medical Center (BMC) using two patient navigators, 625
patients were accepted into the program based on the criteria of having
an A1C > 8.5 and more than two no-shows or being recommended for the
program by a provider [mean age 54 +/- 14; Black/Afr Am 52%, Hisp. 24%,
White 12%, Other 12%; English 73%; Spanish 17%, Other 10%; Unemployed
39%, Full-time employed 12%, Part-time employed 4%, Other 45%]. Of these,
128 patients (20.5%) had participated in the program for >= 180 days, had
>= 1 interaction with a navigator, and had been patients at BMC prior to
1/30/2012.
We find a statistically significant difference in the no-show rate and A1c
for these 128 participants. Specifically, PNP participation was associated
The ATLAS study was designed to evaluate titration of insulin glargine in
uncontrolled insulin-naïve patients on 2 OADs in Asia. A total of 552 patients
were randomized: 275 patient-led and 277 physician-led. Insulin dose was
adjusted using the same algorithm to achieve a target FBG of 110 mg/dL.
ATLAS demonstrated noninferiority of patient-led compared to physician-led
insulin titration. The overall scores for the Diabetes Treatment Satisfaction
Questionnaire status (DTSQs) and change (DTSQc) were similar in the 2
groups. At week 24, DTSQs and DTSQc improved significantly for both
groups (p<0.001); between-group difference was not significant. There were
no differences in any DTSQc item. Health utility elicited with the EuroQol
EQ-5D was high at baseline despite the need for insulin initiation. Baseline
mean utility was 0.86 (95% CI 0.83 - 0.88) and 0.88 (95% CI 0.85 - 0.90)
for each group respectively. Baseline EQ-5D was similar between countryrandomized groups but different between countries. Russian patients had
the lowest health utility - mean 0.73 (95% CI 0.68 - 0.78) while Japanese
patients had the highest - mean 0.94 (95% CI 0.91 - 0.96). No systematic
differences between country randomized groups existed in the end of study
utility. The ATLAS results confirm that Asian patients initiating basal insulin
with a self-titration plan may do so without compromising health related
quality of life or treatment satisfaction.
&
For author disclosure information, see page 829.
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HEALTH CARE DELIVERY—ECONOMICS
($50,000–$100,000 per QALY or LYG), or not cost-effective (>$100,000 per
QALY or LYG) and whether evidence was strong or supportive. Costs were
in 2012 U.S. dollars.
A total of 16 studies were included in the review (table).Sixteen studies
met our inclusion criteria and were included in the review. Overwhelming
evidence has shown that both lifestyle and metformin for preventing
type 2 diabetes are efficient uses of heath care resources and should be
implemented in a large scale in the US and the world (table).
Table. Summary of the Cost-effectiveness Studies on Diabetes Primary
Prevention
1243-P
Type 2 Diabetes Mellitus Patients Who Are Trying to Lose Weight:
Satisfaction With Oral Antihyperglycemic Agents (AHA)
Lifestyle
Standard High-risk
counseling in
care
patients
primary care
setting
CommunityNo
Overweight
supported
campaign
adults
media campaign
Intensive life- Standard Women with
style modificare
history of
cation
GDM,NGT or
IGT
ROBERT BAILEY, JANICE LOPEZ, KATHY ANNUNZIATA, LIEN VO, SILAS MARTIN,
Raritan, NJ, Princeton, NJ
Weight loss is recommended for overweight or obese individuals with type
2 diabetes mellitus (T2DM); however, excess weight and obesity continue to
be a challenge to effective T2DM management. Some AHAs are associated
with weight gain. An understanding of the relationship between weight
gain and a patient’s satisfaction with medication may help inform treatment
decisions under the recent ADA recommendation for the individualization of
T2DM treatment.
The study aim was to provide an assessment of T2DM patients’ satisfaction level with their current oral AHA.
Results were taken from the 2011 US National Health and Wellness Survey,
an online self-administered survey of a nationally representative sample of
n = 75,000 adults aged ≥18 y. Medication satisfaction for all current AHAs
was measured on a scale from 1 (“extremely dissatisfied”) to 7 (“extremely
satisfied”); values of 6-7 = “satisfied”. Respondents were asked if they are
currently taking steps to lose weight (TSLW) and were asked whether they
gained weight, lost weight, or stayed the same over a 6-month period.
The analysis focused on 7,828 T2DM patients (44% female; mean age =
58.5 y). About two-thirds of T2DM patients were TSLW. Their overall oral
medication satisfaction was similar to those not TSLW (63% vs 62%).
However, among those TSLW, those who lost weight were the most satisfied
(67%) with their medication compared with those who gained weight (56%)
or stayed the same (61%). Patients TSLW with HbA1c ≥7% had the most
weight gain and the lowest satisfaction scores (21% gained and 55%
satisfied) vs those TSLW with HbA1c <7% (18% gained and 70% satisfied).
Weight loss is an important therapeutic objective along with AHA for
T2DM. These data suggest that patients TSLW who failed to lose weight
report lower levels of satisfaction with their AHA than those who lost
or gained weight. Further study on the impact of specific AHAs in obese
patients TSLW and satisfaction is warranted.
2
2 European countries
1
Australia
CS
2
Australia,
Israel, and
India
CS
CS
CS-$2700/LYG
1245-P
Physician Specialty and Glycemic Control of Insulin Treated Patients in the U.S.
MICHAEL GRABNER, SCOTT ABBOTT, MATT NGUYEN, YONG CHEN, RALPH
QUIMBO, Wilmington, DE, Bridgewater, NJ
Many patients [pts] on insulin do not reach the ADA-recommended level
for A1C (<7%). Treatment decisions and A1C targets may vary by physician
specialty, but there is little real-world evidence on this issue. This study
compared the therapeutic management of insulin-treated pts between those
with ≥1 prescription from an endocrinologist [Endo pts] and those without.
Pts aged ≥18 years, with ≥1 insulin fill and health plan enrollment in
2011 were selected from the HealthCore Integrated Research DatabaseSM
(representing a national health insurer with ~700,000 diabetes pts).
Demographic and clinical characteristics were assessed.
We identified 74,950 qualifying pts, of whom 28,154 (37.6%) were treated
by 1,644 endocrinologists. A1C results were available for 16.4% of all pts.
Compared to non-Endo pts, Endo pts were younger (54.1 vs. 58.3 yrs), more
likely to be female (47.8% vs. 45.5%), have type 1 diabetes (15.3% vs. 7.1%),
and have advanced disease (e.g. neuropathy, 22.7% vs. 16.7%). They were
less likely to receive OADs (41.2% vs. 55.3%) but were more likely to receive
basal-bolus insulin (48.5% vs. 37.9%). Average A1C was lower among Endo
pts (8.36% vs. 8.62%) and they were less likely to have A1C ≥9% (Figure).
We observed significant differences in patient profiles and treatment
patterns across Endo and non-Endo pts. Regardless of specialty, nearly 80%
of pts receiving insulin had an A1C ≥7%. These results highlight the unmet
need for improved glycemic control among insulin treated pts.
1244-P
RUI LI, PING ZHANG, Atlanta, GA
Both lifestyle and metformin are effective in preventing type 2 diabetes
and their cost-effectiveness (CE) has been evaluated in different delivery
settings. We conducted a systematic review on all CE studies on diabetes
primary prevention published between January 1985 and December 2012
using the procedure defined in the Cochrane Reviewers Handbook. Seven
electronic bibliographic databases were searched to identify relevant
studies. Quality of the study was assessed and studies that did not meet
the criteria were excluded. Interventions were classified according to costeffectiveness ratios as cost saving, cost-effective (0–$50,000 per qualityadjusted life-year [QALY] or life year gained [LYG]), marginally cost-effective
&
Saving $5.7 billion nationwide
or $1.8-$7.3 billion for Medicare in 10-25
years
$750/QALY $250-$2700
CS: cost-saving; GDM: gestational diabetes; NGT: normal glucose tolerance;
IGT: impaired glucose tolerance
Cost-Effectiveness of Primary Prevention of Type 2 Diabetes: An
Update of Systemetic Review
ADA-Funded Research
CS-$82,000/
QALY
For author disclosure information, see page 829.
Guided Audio Tour poster
A325
POSTERS
Supported by: Sanofi
Range of the
cost-effectiveness ratios
CS-$91,500/
QALY
Clinical Diabetes/
Therapeutics
Intervention Comparison Intervention Number Country Median of the
Population of stud- Settings cost-effectiveies
ness ratios
Intensive life- Standard
IGT
11 US and 7 $1,400/QALY
style modifi- lifestyle
European
cation
recommencountries
dation or no
intervention
Metformin
Placebo IGT, Obese
8 US and 6
CS
European
countries
A nationwide No this US popula2 US
CS
community- program tion at high
based DPP
risk for diatranslational
betes
program
HEALTH CARE DELIVERY—ECONOMICS
Supported by: Valeritas, Inc.
POSTERS
Clinical Diabetes/
Therapeutics
quality indicators. The performance of foot examination was uniformly low.
That of albuminuria test had a wide variation across doctors. HbA1c levels
increased with the number of patients per one clinic. Although there were
variations in their performances, they were within 3 SDs. In conclusion, we
did not find an abnormal variation. However, unfavorable quality of the foot
examination rate was reported. HbA1c levels increased with the number of
patients per one clinic, suggesting a busy practice could lead to diminished
quality of care.
1246-P
Use of Insulin in the VA Is Improving
DIANA BARB, WENQIONG XUE, CHRISTINE JASIEN, DARIN E. OLSON, JEEHEA
S. HAW, MARY RHEE, ARUN V. MOHAN, ANNE TOMOLO, SANDRA L. JACKSON,
QI LONG, LAWRENCE S. PHILLIPS, Decatur, GA, Atlanta, GA
Most diabetes patients eventually come to need insulin, but primary care
physicians (PCPs) - who manage most patients - often have difficulty using
insulin, and a recent European study found that A1c was high at the time of
insulin initiation and did not improve from 2005 to 2010 (EASD 2011). We
asked if use of insulin is improving in the VA, where A1c levels are a “quality
indicator” for PCP performance, and can impact PCP pay. We used a database
of veterans from SC, GA, and AL, and identified nine type 2 diabetes cohorts
with initiation of basal insulin 2001 through 2009. Metrics included A1c
when insulin was initiated, A1c 12 months after initiation, nadir A1c within 3
years after initiation, and time to reach nadir A1c. 1583 veterans had mean
age 67.7 years and BMI 32.6, and were 96.5% male and 38% black. From
2001 through 2005, there was no improvement in A1c at initiation, A1c at 12
months, or nadir A1c (all p=ns for linear trend). In contrast, from 2005-2009,
there were highly significant trends for improvement: A1c at initiation fell
0.27 per year (p<.0001), A1c at 12 months fell 0.11 per year (p=.005), and nadir
A1c was similar but the time to achieve nadir A1c was 7.7 weeks earlier per
year (p<.0001). In 2005 vs. 2009, median A1c at initiation was 9.70 vs. 8.40
(p<.0001), A1c at 12 months was 8.10 vs. 7.70 (p=.09), and time to nadir was
111 vs. 61 weeks (p<.0001), respectively. Moreover, in 2005 vs. 2009, the
proportion with A1c ≥8.0% at initiation decreased from 85% to 61%, and
the proportion with A1c <8.0% at 12 months increased from 48% to 59%
(both p<.05) - but those with A1c <7.0% at 12 months did not change (22%
vs. 26%, p=ns). Conclusion: Although use of insulin in the VA changed little
from 2001 through 2005, it improved 2005-2009, with significant decreases
in A1c at initiation, A1c after 12 months, and time to reach nadir A1c. While
further research is required to determine the impact of these improvements
on patient outcomes and the VA, the VA’s use of A1c levels as a performance
“quality indicator” which can affect pay may be a useful model for improving
diabetes management in the US.
1248-P
Assessing the Economic Impact of a Podiatrist: Analysis of Clinic
Activity after Temporary Loss of 50% of the Podiatrists from a Tertiary Specialist Foot Clinic
CATHERINE GOODAY, RACHEL MURCHISON, KETAN K. DHATARIYA, Norwich,
United Kingdom
Podiatrists form an integral part of the multidisciplinary foot team,
however, their importance is often overlooked by purchasers of specialist
services. A set of unforeseen circumstances within our specialist diabetes
foot service meant that we lost 50% of our podiatry team within a few days
for 6 months. Some of this time was filled by non-specialist community
podiatrists. We wanted to assess the economic impact of this loss by
examining data for the 5 years prior to this 6 month interruption, & for the 2
years after ‘normal service’ was resumed
The results are shown in the table.
Clinic
No of
Activity Admissions
1247-P
Introduction of Statistical Process Control into Diabetes Care
2005
2006
2007
2008
2009
2010
2835
2921
3325
4197
4799
4058
30
43
39
50
58
72
% of
Total
Activity
1
1.5
1.1
1.2
1.2
1.8
2011
2012
4294
5270
41
45
0.95
0.89
Total
Bed
Days
515
775
570
919
867
1194
838
733
Mean Length
of Hospital
Stay (±SD)
17.2 (9.2)
17.2 (19.2)
14.6 (11.3)
18.4 (16.8)
14.7 (11.3)
16.5 (12.3) Year of
interruption
20.4 (16.6)
16.2 (15.1)
Our data shows that the loss of the podiatrists led to a significant rise in
the numbers of admissions into hospital. At our institution a single bed day
cost is $363. In the first month after the cut in service, we had 8 extra admissions, accounting for a total of 132 extra bed days. This equates to $47965.
During the 12 months the extra costs increased by a total of $147333. Had
the community help not been available, & admission rates stayed the same
for the year, estimated costs would have risen to $547255
Our data does not look at the costs saved from avoiding surgery (currently set
at $15270 for major amputations). Thus the actual costs incurred are likely to
be higher.
The annual salary of a senior podiatrist in the UK is set at $56394, thus
they more than pay for themselves.
MAKI KAWASAKI, YUSUKE KABEYA, MARI OKISUGI, MASUOMI TOMITA, TAKESHI KATSUKI, YOICHI OIKAWA, KIYOE KATO, YOSHIHITO ATSUMI, AKIRA SHIMADA, Tokyo, Japan
Quality of diabetes care has been addressed recently. However, a universal
method to control the quality has not been established. The aim of the study
was to introduce a method derived from statistical process control (SPC),
which is often used in manufacturing lines to control the quality of products,
into diabetes care. Our hospital has a diabetes department, where 16 doctors
provide diabetes care to approximately 8,000 patients. We sampled 1,105
regular visitors who attended the department from 23rd July to 4th August
2012. We calculated the overall and doctor-specific performances of quality
indicators. Then, control charts were described. The measured values were
plotted on the axis of each doctor’s average number of patients per one outpatient clinic. We tried to detect an abnormal variation in the performance
from random variations. As a general rule of SPC,a value exceeding 3 SDs
from the mean was defined as abnormal. Figure shows control charts of the
&
For author disclosure information, see page 829.
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HEALTH CARE DELIVERY—ECONOMICS
1249-P
Diabetes Care for Emerging Young Adults With Type 1 Diabetes: A
National Survey of Adult Endocrinologists in the United States
KATHARINE C. GARVEY, JONATHAN A. FINKELSTEIN, PETER FORBES, LORI M.
LAFFEL, Boston, MA
Previous work has addressed challenges reported by pediatric providers
caring for older teens and young adults (YA) with type 1 diabetes (T1D),
yet little is known about the barriers faced by adult endocrinologists (AEs)
accepting T1D patients in this vulnerable developmental stage. To assess
AE experiences, resources and barriers in caring for this population, we
fielded a web-based survey to AEs in the AMA Masterfile. We received
responses from 536 of 4214 AEs (13% response rate) representing 47 states.
Respondents were 57% male and 79% Caucasian; 64% had practiced >10
years and 42% worked at an academic center. Most AEs (72%) felt that
reviewing pediatric records of transitioning YA with T1D prior to the first
visit was important/very important for patient care, but only 36% often/
always had the opportunity to do so. While most AEs reported access to
diabetes educators (94%) and dietitians (95%), less than half (42%) reported
easy access to mental health care (MH) and 54% desired more access to
MH for YA patients. Access to MH for YA with T1D was more likely to be
reported by AEs in academic settings (p = 0.0006). In a series of patient
scenarios, controlling for academic setting and years in practice, AEs without
easy access to MH were 2 to 6 times more likely to report barriers to T1D
management for YA with depression, eating disorders, substance abuse, and
developmental disability (all p<0.0001). In contrast, AEs reported minimal
barriers to YA management for glucose sensor use, obesity, recurrent DKA,
elite athletics, and fear of hypoglycemia. To improve care, AEs endorsed
support groups for YA with T1D (82%), improved reimbursement (76%), and
continuing medical education (CME) about YA behaviors (57%). Our findings
underscore the importance of enhanced information transfer between
pediatric and adult providers and increased MH access for YA with T1D,
particularly in non-academic settings. Provider CME modules should focus
on behavioral issues specific to YA with T1D.
KALPITA MAJUMDAR, MARIA BARNARD, London, United Kingdom
Secondary care diabetes specialists in the United Kingdom take many
referrals from primary care, and provide expertise in complex cases. We
studied referrals into our diabetes clinic to assess our care objectively, and
to study specialist interventions offered to these patients.
In a retrospective survey, we studied the source and reason for referrals
to secondary care over 12 months. Each patient was followed over 18
months. Data was collected on documentation of 9 care processes and
changes in three measurable targets (blood pressure, cholesterol, glycated
haemoglobin) as set out in the UK National Diabetes Audit 2010-11, and
referrals to allied diabetes professionals or other experts.
A total of 355 patients were referred over the study period, excluding
patients who can only be managed in specialist settings. 71% patients were
referred by their primary care physician. Reasons for referrals were for a
combination of poor glycemic control (201), type 1 diabetes (99), significant
or worsening complications (105), and associated co-morbidities (91). We
evaluated clinical care on 289 patients, excluding non-attenders. Data was
collected for age, gender, type of diabetes. After analysing 100 cases, 79%
patients had 9 care processes documented. A positive impact on at least
one of three measurable targets was noted in 69% patients. Medications
were started/altered in 86%, and 78% were seen by at least one other
allied professional in the diabetes team. Referrals for other specialist
opinion, structured education and/or psychological input were made for
45% patients.
In times of economic austerity, with burgeoning numbers of diabetes
patients, models of diabetes care are under greater scrutiny to assess their
impact. Our study proves that patients are being referred for multiple and
complex needs that cannot be comprehensively met in primary care. These
patients require high quality diabetes expertise and multiple reviews, along
with appropriate contributions from allied and expert specialists to optimise
their metabolic milieu.
Supported by: William Randolph Hearst Foundation
1250-P
Effects of Insulin Adherence and Delivery Device on Real World
Outcomes Among Patients With Type 2 Diabetes Mellitus (T2DM)
RAJEEV AYYAGARI, WENHUI WEI, DAVID CHENG, CHUNSHEN PAN, ERIC Q. WU,
Boston, MA, Bridgewater, NJ, Boca Raton, FL
Treatment adherence affects real world insulin effectiveness and may
itself be impacted by the delivery device (pen or vial/syringe). This study
aims to understand the combined effects of insulin adherence and device on
real world health outcomes.
A national managed care administrative database was used to identify
T2DM adults initiating insulin, who had continuous health plan insurance
≥6 months prior to initiation (baseline) and ≥1 y after. Outcomes included
1 y follow-up A1C reduction, hospitalization rate, total health care costs,
and pharmacy costs. To account for the time-varying relationship between
adherence (ie, all days covered in each calendar quarter) and outcomes,
marginal structural generalized linear models were used to estimate joint
causal effect of adherence and device. Mean outcomes were predicted for
different combinations of adherence and device.
Among the 13,428 patients (mean age 54 y, 46% female, baseline A1C
9.3%), adherent pen users had greater A1C and hospitalization rate reductions
and higher pharmacy costs vs non-adherent vial users. Pen use and adherent
vial use decreased hospitalization rate and increased pharmacy but not total
costs (Figure).
Our study suggests that adherence and pen use both have beneficial
effects on patients’ real world outcomes, with the most favorable effects
attributed to adherent pen use. Naturalistic studies of insulin therapy are
needed to inform optimization of therapy for T2DM.
ADA-Funded Research
&
Supported by: Whittington Hospital
1252-P
Utilization of Electronic Health Records (EHRs) to Evaluate Prediabetes and Diabetes Screening Guidelines
VANITA R. ARODA, SAMEER DESALE, CHRIS ST CLAIR, JOHN JANAS, DANIEL
MERENSTEIN, PETER BASCH, ROBERT E. RATNER, NAWAR SHARA, Hyattsville,
MD, Concord, NH, Washington DC, Columbia, MD, Alexandria, VA
Many guidelines advocate early screening of individuals at risk of type
2 diabetes. Guidelines from the United States Preventive Services Task
Force (USPSTF) and the ADA, however, differ in the recommended screening
populations. The objective of this analysis was to evaluate the extent to
which these two guidelines have been translated into practice, and the yield
of this screening. We examined EHR data from 46,779 adult patients seen
from 5/1/11-5/1/12 across 70 adult primary care practices within MedStar
Health, a large healthcare system in the Maryland-DC region. Based on data
within the EHR, an estimated 7.8% of this adult cohort aged 20 years or older
carried a diagnosis consistent with prediabetes.
Of the 46,779 patients, USPSTF guidelines identified 11768 (25%) with
an indication for diabetes screening, of whom 4720 (40%) had evidence
of screening by fasting glucose, HbA1c, or 2-h OGTT. When screened, the
diagnostic yield, i.e. lab results consistent with prediabetes or diabetes, was
For author disclosure information, see page 829.
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1251-P
Secondary Care for Diabetes: Are We Worth It?
Clinical Diabetes/
Therapeutics
Supported by: Sanofi U.S., Inc.
HEALTH CARE DELIVERY—ECONOMICS
evident in 45% and 35%, respectively. 42% of those with labs consistent
with prediabetes had prediabetes listed in the active problem list within
the EHR.
By contrast, 30,646 (66%) of our cohort met ADA guideline indications for
screening, of which 11,530 (38% of these) had evidence of screening, with
diagnostic yields of 47% for prediabetes and 33% for diabetes, identifying
> 2.5 fold as many patients with prediabetes as captured by USPSTF
guidelines (5339 versus 2073). Still, only 39% of those with labs consistent
with prediabetes had prediabetes listed in the active problem list within
the EHR.
In sum, significant gaps in diabetes screening and prevention are in
determining which individuals are at risk (USPSTF vs ADA), screening these
individuals identified as at risk, and then consistently using the screening
data to make an appropriate diagnosis of prediabetes. These findings can
inform further efforts to improve earlier diagnosis and treatment of patients
with prediabetes and diabetes.
Medication Classes
POSTERS
Patients without DM** p-Value
n (%)
Mean MPR
(Median)
Oral antidiabetic
MPR at 1 yr
11,452 (50.7)
0.74 (0.86)
MPR at 3 yrs
4,873 (53.2)
0.65 (0.75)
Insulin
MPR at 1 yr
5,111 (22.6)
0.56 (0.59)
MPR at 3 yrs
1,929 (21.1)
0.50 (0.53)
Antihypertensives
< 0.0001
MPR at 1 yr
16,059 (71.1)
0.82 (0.93) 31,260 (64.7) 0.78 (0.91) < 0.0001
MPR at 3 yrs
6,614 (72.2)
0.73 (0.86) 12,807 (64.8) 0.68 (0.80)
Statins
0.0386
MPR at 1 yr
11,735 (52.0)
0.70 (0.81) 24,289 (50.2) 0.71 (0.83) 0.8759
MPR at 3 yrs
4,712 (51.4)
0.59 (0.66) 9,863 (50.0) 0.60 (0.68)
Antiplatelets
< 0.0001
MPR at 1 yr
9,263 (41.0)
0.70 (0.85) 19,332 (39.9) 0.73 (0.89) 0.2977
MPR at 3 yrs
3,891 (42.5)
0.55 (0.61) 8,039 (40.7) 0.56 (0.61)
Anticoagulants
0.0096
MPR at 1 yr
2,259 (10.0)
0.55 (0.59) 3,704 (7.7)
0.53 (0.56) 0.1740
MPR at 3 yrs
888 (9.7)
0.42 (0.38) 1,507 (7.7)
0.40 (0.33)
* Patients with T2DM are defined as having a) two or more claims of T2DM
at least 30 days apart; and/or b) ≥ 1 claim of T2DM and ≥ 1 claim of oral or
injectable antidiabetics; and/or c) ≥ 2 prescriptions of oral antidiabetics or
GLP-1 agonist medications during the study period.
** Patients without DM are defined as not meeting criteria for T2DM and
having no claim for type 1 DM during the study period.
1253-P
Clinical Diabetes/
Therapeutics
Patients with T2DM*
n (%)
Mean MPR
(Median)
Sub-Optimal Medication Initiation and Adherence Following Acute
Coronary Syndrome in Real-World Patients With and Without Diabetes Mellitus: 2006–2011
VANESSA S. REDDY, RAKESH LUTHRA, YAPING XU, KENNETH WILHELM, THOMAS P. POWER, MAXINE D. FISHER, MARK J. CZIRAKY, San Francisco, CA, Wilmington, DE, Deerfield, IL
Medication adherence is critical for optimal management of chronic
disorders such as type 2 diabetes mellitus (T2DM) and coronary artery
disease. This study assessed mean drug initiation and medication possession
ratios (MPRs) for guideline-recommended acute coronary syndrome (ACS)
and antidiabetic treatments 1 and 3 years following hospitalization for
ACS, by presence or absence of T2DM. ACS patients hospitalized from Jan
2006 to Sept 2011 were identified from the HealthCore Integrated Research
Database using pharmacy claims data. Of 120,398 ACS patients identified,
32% had T2DM. Patients with T2DM were on average older and had more
baseline comorbidities than patients without DM (Table). Following the
index ACS event, only 51% of patients with T2DM filled a prescription for
an oral antidiabetic, 23% insulin, 52% statin, 71% antihypertensive (antiHTN) and 10% anticoagulant medications (Table). After 3 years of followup, patients with T2DM were most adherent to anti-HTN (MPR = 0.73) and
least adherent to anticoagulants (MPR = 0.42) (Table). Overall, patients with
and without T2DM had comparable MPRs across assessed drug classes;
however, adherence continued to decline at 3 years in both cohorts. This
analysis identifies critical areas for improving both initiation and long-term
adherence to guideline-recommended treatments following an ACS event.
1254-P
Vulvovaginal Candidiasis (VVC) and Urinary Tract Infection (UTI) in
Women With and Without Type 2 Diabetes Mellitus (T2DM)
ROBERT STELLHORN, WING CHOW, SILAS MARTIN, MANEESHA MEHRA, Raritan, NJ
Women with T2DM have an increased risk of VVC and UTI. This analysis
compared the occurrence of VVC and UTI and the associated treatment
costs between women with T2DM and women without T2DM using the
Pharmetrics commercial claims database. Data were examined for a 2-year
period from 1/1/2010 to 12/31/2011 using a 10% sample. A cohort of women
aged ≥25 years with a diagnosis of T2DM and/or use of antihyperglycemic
agents before 1/1/2010 (N = 44,371) and a matched control cohort (N =
42,471) were identified. Diagnosis for VVC (ICD-9 codes: 112.1, 616.10, 616.11,
627.3) and UTI (ICD-9 codes: 590.10, 590.11, 590.80, 590.81, 595.0, 595.9,
599.0) and prescriptions for antifungal or antibiotic drugs in these cohorts
were assessed over the 2-year period.
In the T2DM and control cohorts, 9.7% and 9.1% of women, respectively,
were diagnosed with VVC. Among these women, 36.4% (1,559/4,287)
used prescription antifungals in the T2DM cohort compared with 36.3%
(1,402/3,863) in the control cohort. For women diagnosed with VVC, median
prescription antifungal treatment cost per person over the 2-year period was
$10.00 for the T2DM cohort and $8.02 for the control cohort. Similar trends
were observed between the T2DM and control cohorts when the occurrence
of VVC and antifungal cost were assessed in women who had either a VVC
diagnosis or an antifungal drug prescription.
A diagnosis of UTI was made for 18.7% and 12.3% of women in the T2DM
and control cohorts, respectively. Among women with a UTI diagnosis,
antibiotics were used by 48.4% (4,009/8,276) of those in the T2DM cohort
compared with 50.3% (2,629/5,224) in the control cohort. Median antibiotic
treatment cost per person over 2 years was $8.00 for the T2DM cohort and
$7.30 for the control cohort. In summary, similar occurrences of diagnosed
VVC and higher occurrences of diagnosed UTI were observed in women with
T2DM compared with women without T2DM, with minimal antifungal or
antibiotic treatment costs that were comparable among the cohorts.
Table: Medication Possession Ratios by Diabetes Status, 1 and 3 Years
Patients with T2DM*
Patients without DM** p-Value
Baseline
Mean or %
Median
Mean or %
Median
Characteristics
Age, years
68.2
69.0
65.6
64.0
< 0.0001
Male
58.9%
58.7%
0.5337
Follow-Up Rate, years
1.8
1.4
1.8
1.4
0.9679
Hypertension
74.7%
52.5%
< 0.0001
Dyslipidemia
57.5%
40.7%
< 0.0001
Heart Failure
24.3%
11.5%
< 0.0001
Renal Failure
16.5%
4.8%
< 0.0001
&
For author disclosure information, see page 829.
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1255-P
1257-P
Medication Costs for Patients With Type 2 Diabetes Mellitus:
How They Vary With Body Mass Index Status, Age, Gender and
Co-Morbidity
Analysis of a Large Payer Claims Database Suggests Elderly Patients With Diabetes are Under-Treated
This retrospective cross-sectional study utilized medical, pharmacy and
laboratory claims from a large Medicare Advantage with Prescription Drug
Coverage (MAPD) payer. MAPD members (mean age 72 years) diagnosed
with T2DM between 2009 and 2011 were eligible for inclusion. A 12-month
baseline period before the first A1c value (the index date) was evaluated for
demographic and clinical differences. Antidiabetic therapy was evaluated
during a 6-month post-index period. The study population was stratified
into three cohorts based on index A1c value: controlled (≤7%), uncontrolled
(>7% and ≤9%), and severely uncontrolled (>9%). Despite elevated A1c
values (>7%) 7-12% of patients were not on antidiabetic therapy during the
post-index period. Metformin and sulfonylureas were the oral antidiabetics
(OADs) most frequently used as monotherapy. In cohorts with A1c >7%,
insulin use was higher while biguanide and sulfonylurea use was lower.
Of those on combination therapy, the majority were on 2 or more OADs
and higher injectable use was observed in the severely uncontrolled
cohort. Metformin was included in 62% of the combination regimens with
‘Metformin + sulfonylurea’ being the most common. This study suggests
suboptimal treatment of those not in control (A1c >7%). Many patients
classified as uncontrolled based on A1c received only monotherapy postindex. Opportunities exist for treatment modification within this population
to achieve tighter glycemic control.
Proportion of Elderly Patients Treated with Various Levels of Antidiabetic
Therapy
Therapy
A1c ≤7%
A1c >7%
A1c >9%
P-value
and ≤9%
N=100,023
N=34,766
N=8,551
No antidiabetic prescription 48,072 48.1% 4,327 12.4% 631 7.4% <0.01
claims
Monotherapy
36,602 36.6% 14,179 40.8% 3,031 35.4% <0.01
Biguanide
23,410 23.4% 7,200 20.7% 1,187 13.9%
Sulfonylurea
10,279 10.3% 5,597 16.1% 1,051 12.3%
Insulin
2,026 2.0% 2,981 8.6% 1,657 19.4%
Combination Therapy
15,349 15.3% 16,260 46.8% 4,889 57.2% <0.01
Supported by: National University of Ireland
1256-P
The Burden of Hospitalizations due to Hypoglycemia in Belgium
MARK LAMOTTE, PIERRE CHEVALIER, TOM VANDEBROUCK, Vilvoorde, Belgium,
Brussels, Belgium
Strict control of glycemia in diabetic patients is impeded by the risk of
hypoglycemia, especially when insulin is used. However, not all insulins have
the same risk of hypoglycemia. The aim of this study was to study the cost of
hypoglycemia requiring hospitalization (at least one overnight stay) in type 1
and 2 diabetes in Belgium.
A retrospective database study was conducted using the longitudinal
IMS Hospital Disease Database (HDD 2009), covering 34.3% of Belgian
hospital beds. In this database hypoglycemic events can be identified based
on ICD-9 codes (Diabetes hypoglycemic coma/insulin coma: 250.3; Diabetic
hypoglycemia/hypoglycemic shock: 250.8; Anti-diabetic agent poisoning and
adverse events: E932.3, 962.3). Number of stays for hypoglycemia, average
length of stay (LOS) and on intensive care (ICU), in hospital mortality, rehospitalizations for hypoglycemia and costs were estimated using SAS
software.
The number of patients with diabetes in Belgium was estimated to be
600,000. In the HDD 3,674 patients were hospitalized for hypoglycemia. In
2009, each patient had on average 1.16 hospitalizations. Extrapolated to
Belgium this means 10,806 patients hospitalized for hypoglycemia. Eightythree percent of those stays were in patients older than 55. The average
LOS was 17.32 days (with 0.21 days on ICU) strongly driven by stays in
the population >55 years (12 vs. 18 days; p<0.0001). Mortality during
hospitalization was 5.83% driven by the age group older than 65 (2.89%
vs. 7.60%; p<0.0001). The average cost of a hospitalization was €9,283
[€9,037-9,529].
Hospitalizations for hypoglycemia are expensive and result in an important
in hospital mortality. Especially in the older age (>55), the costs for the health
care payer are high due to extensive LOS. Interventions that can help reduce
the risk of hypoglycemia, and as a consequence the burden on hospitals and
society, without compromising glycemic control will help further improve
diabetes management.
Supported by: Novo Nordisk, Inc.; Humana, Inc.
1258-P
Treatment Intensification after Early Failure of Metformin or Sulfonylurea among VA Patients With Type 2 Diabetes
LI WANG, WENHUI WEI, MEHUL DALAL, ONUR BASER, Dallas, TX, Bridgewater,
NJ, Ann Arbor, MI
Randomized trials have documented the long-term cardiovascular (CV)
benefits of treatment intensification in patients with type 2 diabetes
mellitus (T2DM). However, there is little real world data on the factors
affecting intensification choices among patients failing metformin (MET) or
sulfonylurea (SU) soon after initiation.
Using Veterans Health Administration (VHA) health care claims data
from October 2005 to September 2011, a retrospective cohort study was
conducted among T2DM patients with early treatment failure of MET or SU
(defined as having A1C ≥ 9.0% or ≥ 2 A1C ≥ 7.0% dated > 90 days apart
within 1 y of initiation). Factors associated with the time from treatment
failure to intensification, and choices of intensification (OAD or insulin) were
identified.
A total of 27,556 patients were included (68.3% MET and 31.7% SU;
95.8% male; 55.4% white; mean age 61 y; A1C 9.0%; BMI 34.9 kg/m2; median
follow-up 29 months). After treatment failure, 64.4% (n=17,742) intensified
their treatment during follow-up (median time: 4 months; 79.2% with a 2nd
OAD, 9.9% basal insulin, and 9.2% basal-bolus/premix insulin), with 36.9%
(n=10,174) intensifying within 1 y. Independent factors associated with
intensification included: white race; younger age; later index year; higher
A1C; higher BMI; SU use; shorter time from initiation to failure; diabetes
education; comorbid neuropathy, retinopathy, or mental illness; and absence
of chronic kidney disease (CKD) (all P < 0.05). Patients intensifying with
insulin within 1 y (n=1,865) were more likely to have initiated with SU, and
were associated with a higher comorbidity burden, CV disease, CKD, and
baseline hypoglycemic events (all P < 0.01).
This study showed that among VA patients who failed MET or SU early,
only 1/3 intensified their treatment within a year, and significant differences
Supported by: Novo Nordisk A/S
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A329
POSTERS
While type 2 diabetes is characterised by insulin resistance and relative
beta cell failure, there is heterogeneity in the degree to which excess
adiposity contributes to the individual diabetes phenotype, reflected in
different treatment modalities for different patients. We sought to determine
whether the degree of overweight or obesity, measured with body mass index
(BMI), influences the cost of drug therapy for type 2 diabetes patients.
We identified a subgroup of 185 adult type 2 diabetes patients attending
our university hospital-based diabetes clinic, for whom detailed information
about drug therapy and comorbidities (obesity, hypertension, dyslipidaemia)
was available. Data relating to the cost of medications from the Medical
Information Management System (MIMS) Ireland and the Health Service
Executive Primary care Reimbursement Service (PCRS) were used to
generate a Net Present Value (NPV) of the drug cost, discounting the annual
cost over the average life expectancy of the patient group.
There was a positive association between BMI and medication costs in
linear regression analyses. Mean estimated annual costs were €615 higher
in patients with a BMI greater than 35 kg m-2 compared to those with BMI
less than 30 kg m-2 (p less than 0.01). Of note, the peak cost occurred in
the BMI range 35-40 kg m-2 with an unanticipated decline in costs in those
with BMI greater than 40 kg m-2. Overall, diabetic patients with obesity,
hypertension and dyslipidaemia had an estimated annual medication
cost that was €418 higher than those diabetic patients without any such
comorbidity (p less than 0.05).
These findings suggest that the substantial health economic costs
associated with the rising prevalence of type 2 diabetes are differential with
respect to the BMI status of affected individuals. In considering the risks
and benefits of interventions such as bariatric surgery in this patient group,
these additional medication costs need to be borne in mind.
Clinical Diabetes/
Therapeutics
S. LANE SLABAUGH, YIHUA XU, JANE STACY, NICK PATEL, YUNUS A. MEAH,
JEAN C. BALTZ, JONATHAN BOUCHARD, Louisville, KY, Princeton, NJ
MICHELLE QUEALLY, CIARAN O’NEILL, FRANCIS M. FINUCANE, Galway, Ireland
HEALTH CARE DELIVERY—ECONOMICS
existed between those who intensified with OAD vs insulin. This needs to be
carefully evaluated when conducting outcomes studies in this population.
1261-P
Successful Implementation of a T2D Prevention Program in a Community Health Center Setting
Supported by: Sanofi U.S., Inc.
ANNE CAMP, WILLIAM V. TAMBORLANE, GRACE KIM, ELIZABETH MAGENHEIMER, ABMARIDEL MONTOSA, New Haven, CT
1259-P
The Diabetes Prevention Program (DPP) showed that an intensive
lifestyle intervention (ILI) reduces the development of T2DM in adults with
prediabetes. However these results have not been widely translated into
practice, especially in Community Health Centers (CHCs) that care for poor
minority populations at high risk for T2D. This study evaluated a DPP lifestyle
intervention adapted for a CHC in an inner-city Hispanic neighborhood in
which 68% of women are obese.
We randomly assigned 109 women (92% Hispanic, age 42.2 ± 10.5 yr) with
prediabetes determined by OGTT to a 14 week group-based ILI or to usual
care control group at Fair Haven CHC. Primary outcome was the difference
in changes in body weight after 1 year. Eighty-nine subjects (82%) completed
1 year follow-up.
Age, weight, BMI, lipids, blood pressure and OGTT were matched in the
2 groups at the start of the study. After 1 year, the ILI group experienced
significantly greater decreases in body weight compared with controls (-4.3
vs +0.2 kg; P<0.0001), % body weight (-5.1% vs +0.1% ; P<0.0001), BMI (-1.77
vs -0.02 kg/m2; P<0.0001) and triglycerides (-21 vs +35 mg/dL; P=0.036).
Changes in secondary outcomes are shown in the Table.
Despite limited resources, a DPP-style ILI can be effectively delivered in a
CHC setting that serves poor minority patients at high risk for T2D. CHCs are
a promising health care delivery system to disseminate diabetes prevention
programs among disadvantaged groups.
Correlation between Hypoglycemia and Adherence With Oral Antihyperglycemic Agents in Patients With Type 2 Diabetes
POSTERS
Clinical Diabetes/
Therapeutics
JANICE LOPEZ, ROBERT BAILEY, KATHY ANNUNZIATA, SILAS MARTIN, Raritan,
NJ, Princeton, NJ
Patients with type 2 diabetes mellitus (T2DM) on oral antihyperglycemic
agents (AHAs) continue to be impacted by hypoglycemia (HG), a known
adverse event of medications used to control blood glucose.
In this study, we explore the association between HG and medication
adherence as adherence is important for maintaining glucose control,
avoiding complications, and improving long-term outcomes.
The 2011 US National Health and Wellness Survey recruited a nationally
representative sample of 75,000 adults (aged ≥18 y) using a self-administered
survey. Participants reported their experiences with HG (occurring ever and/
or in the past 3 months) and answered questions on the Morisky Medication
Adherence Scale, which was used to determine adherence to diabetes
medications. Some patients also reported recent HbA1c results.
A total of 4,516 participants reported a diagnosis of T2DM and use of oral
AHAs only (no insulin, no GLP-1 agonists). The mean age was 59.8 ± 13.2 y
and 57% were male. Overall, 47.1% ever experienced HG and 23.5% reported
recent HG (past 3 months). Of the T2DM patients who reported HG (ever or
in the past 3 months), 58.8% were adherent versus patients with no HG
who reported 69.1% adherence. 24.8% of T2DM patients with HbA1c <7%
experienced HG in the past 3 months, compared to 29.3% of T2DM patients
with HbA1c ≥7%. Of those with HbA1c <7%, those who had not experienced
HG reported better medication adherence than those with HG (those with
HbA1c ≥7% had similar adherence for both HG and no HG).
Despite newer AHA treatment options, a large proportion of T2DM
patients report experiencing HG. Those who reported a HG episode were
more likely to report poorer medication adherence than those who did not
experience HG. Further investigation is warranted on the types of AHA used
and the relationship of HG and adherence.
Outcome
Weight (kg)
% Weight Change
BMI (kg/m2)
Intervention Gp
Control Gp
Treatment
(n=44)
(n=45)
Effect
-4.3 (-5.4,-3.1)
+0.2 (-0.7,1.0)
-4.5 (-6.0,-2.8)
-5.1(-6.3,-3.6)
+0.1(-1.0, 1.2)
-5.2(-6.8,-3.3)
-1.77 (-2.25, -1.29) -0.02 (-0.36, 0.33) -1.75 (-2.34,-1.16)
Fasting glucose (mg/dL) -4.4(-7.6,-1.2)
-4.1(-7.8,0.5)
2 hr glucose (mg/dL)
-19 (-30,-7)
-11 (-25,3)
Triglycerides (mg/dL)
-21 (-37,-6)
35 (-16,85)
Data are means (95% Confidence Intervals)
1260-P
Resource Use of Type 2 Diabetes Mellitus Patients Following Initiation With Saxagliptin or Sitagliptin
JASMINA IVANOVA, ANNA KALTENBOECK, KELLY BELL, NINA THOMAS, FRANCES SCHWIEP, YANA YUSHKINA, HOWARD BIRNBAUM, New York, NY, Boston,
MA, Menlo Park, CA
P-value
<0.0001
<0.0001
<0.0001
-0.3 (-4.8,4.9)
0.88
-7 (-28,13)
-56 (-105,-6)
0.40
0.036
Supported by: Donaghue Foundation
1262-P
This analysis compared healthcare resource use by type 2 diabetes mellitus
(T2DM) patients treated with saxagliptin or sitagliptin in the 6 months
following treatment initiation. Patients with T2DM treated with saxagliptin
(N=13,929) or sitagliptin (N=36,813) in 2010 or later were identified in
the Truven MarketScan database of commercially insured beneficiaries.
Patients were required to have no saxagliptin or sitagliptin claims in the
6 months pre-initiation, at least 6 months of continuous eligibility pre &
post initiation and be 18 or older. Demographics and comorbidities were
evaluated in the baseline period. All-cause & diabetes-related resource use
was evaluated in the study period. Chi-squared tests assessed differences
in resource use. Logistic regression assessed treatment effects on study
period hospitalization, adjusting for baseline patient characteristics &
hospitalization.
Saxagliptin patients compared with sitagliptin patients were younger
(58 vs. 60 yrs; p<0.001) with similar gender distribution (47.0% vs. 47.1%
female; p=0.852). Saxagliptin patients had a lower mean CCI (Charlson
Comorbidity Index) (0.48 vs. 0.65; p<0.001), but higher rates of dyslipidemia
& hypertension (44.8% vs. 41.9%, & 51.8% vs. 49.8%). During the study
period, they experienced lower rates of all-cause hospitalization, ED visits, &
other medical visits (7.2% vs. 10.6%, 14.1% vs. 17.5%, and 67.0% vs. 70.4%;
p<0.001). Saxagliptin patients were also less likely to have diabetes-related
hospitalizations (4.0% vs. 6.6%; p<0.001). Odds of all-cause or diabetes
related hospitalizations were lower for saxagliptin patients after adjusting
for baseline characteristics. (OR 0.80 & 0.74, respectively, p<0.001).
Saxagliptin patients had less evidence of acute comorbidities, higher
rates of cardiometabolic risk factors & following treatment initiation were
less likely to experience hospitalizations.
What Is the Delay in Insulin Therapy Initiation in Patients With
T2DM Not Responding to Oral Glucose Lowering Agents?
RUTH MAST, DANIELLE JANSEN, AMBER AWA VAN DER HEIJDEN, JACQUELINE
M. DEKKER, JACQUELINE G. HUGTENBURG, ROBERT J. HEINE, GIEL NIJPELS,
Amsterdam, Netherlands, Indianapolis, IN
What is the delay in insulin therapy initiation in patients with T2DM not
responding to oral glucose lowering agents?
Available data suggest that insulin therapy is initiated late in patients
failing to respond adequately to oral glucose lowering agents (OGA).
Determinants of this delay are unknown.
The aim of this study was to assess the time to insulin initiation and
HbA1c value in T2DM patients inadequately controlled with OGA. Also, the
influence of BMI, diabetes duration, and general practitioner (GP) practice on
timing of insulin initiation was investigated.
All 3772 T2DM patients who entered a regional diabetes care system
(DCS) in the Netherlands between 1998 and 2011, aged 40 years and over,
with a follow-up of a minimum of 2 years, with at least once a HbA1c ≥ 58
mmol/mol (7,5%) whilst on OGA. The time to insulin initiation was calculated
(delay time). GP practices were categorized in three types; having a practice
nurse (PN) and initiating insulin; or with PN but initiating insulin by DCS; or
without PN and initiating insulin by DCS. A Cox proportional hazard model
was used to determine the influence of BMI, diabetes duration, and GP
practice on insulin initiation. The influence of BMI, diabetes duration, and
GP practice on the delay time were analyzed with regression analyses. All
adjusted for age and gender.
The median time to insulin initiation was 5.5 yr (range 1- 14.2 yr). The mean
HbA1c level preceding initiation of insulin was 66 mmol/mol (8.2%). Only
diabetes duration showed a significant association with insulin initiation.
With a diabetes duration of 0-2 yr as reference category, the hazard ratios
were respectively for 2-5 years 1.24 (95 % CI 1.05-1.5) and for 5-10 years 1.27
(95% CI 1.058-1.529) at insulin initiation.
Supported by: Bristol-Myers Squibb
&
For author disclosure information, see page 829.
A330
Guided Audio Tour poster
ADA-Funded Research
HEALTH CARE DELIVERY—ECONOMICS
In conclusion, despite current guidelines that advice insulin therapy
in patients not responding adequately to OGA the mean time to insulin
initiation was 5.5 years. Only diabetes duration showed a weak association
with the timing of insulin initiation.
1263-P
Determination of Normal Inpatient Glucose Values in the National
VA Population
Supported by: Health Workforce (New Zealand)
1265-P
Medical Costs Attributed to Arthritis among Persons With Diabetes
RUI LI, MIRIAM CISTERNAS, SUNDAR SHRESTHA, JUSTIN TROGDON, LOUISE
MURPHY, Atlanta, GA, San Diego, CA, Research Triangle Park, NC
Nearly half of US population 18 years and older with diabetes also
have arthritis. Unlike other common comorbidities of diabetes, such as
cardiovascular disease, little is known about the economic impact of
arthritis among people with diabetes. We estimated arthritis-attributable
medical cost among US adults with diabetes using 2009 and 2010 Medical
Expenditure Panel Survey data (MEPS); MEPS represents the US community
(non-institutionalized civilian) population. Mean medical costs (total and
by service [inpatient care, outpatient care, prescription drugs, and other
services]) attributable to arthritis among persons with diabetes were
estimated using regressions that controlled for demographic characteristics,
socioeconomic status, insurance status, and eight common comorbidities of
diabetes. All costs are in 2010 US dollars. In the MEPS population, costs
attributable to treating arthritis accounted for 16.0% of total medical cost
among persons with diabetes. Mean costs among people with both diabetes
and arthritis were consistently greater than among those with diabetes
only: excess total medical was $2,897 (22.8% more); inpatient care was
$620 (17.1% more); outpatient care was $1025 (43.0% more), prescription
drugs were $849 (32.1% more), and other services were $446 (38.7% more).
Considering the high prevalence of arthritis among people with diabetes and
substantial excess arthritis-attributable medical costs among persons with
diabetes, diabetes control programs should consider addressing arthritis
as an integral component of control strategies; meeting physical activity
recommendations and participating in chronic disease self-management
education courses are evidence-based strategies for managing both
conditions.
Supported by: U.S. Dept. of Veterans Affairs
1264-P
Diabetes Nurse Specialist Prescribing: The New Zealand Experience
HELEN J. SNELL, TIMOTHY F. CUNDY, PAUL L. DRURY, CLAIRE BUDGE, Palmerston
North, New Zealand, Auckland, New Zealand, Nelson, New Zealand
In New Zealand (NZ) prescribing has resided with medical or nurse
practitioners. In 2011 a new regulation in the Medicines Act enabled
Diabetes Nurse Specialists (DNS) to prescribe under supervision. The NZ
Society for the Study of Diabetes (NZSSD) tested safety and effectiveness
over 6 months in 4 demonstration sites. Twelve DNSs made 3396 prescribing
decisions for 1274 patients from a range of diabetes and cardiovascular
medicines. Safety and effectiveness was determined via a previously
presented external evaluation. In 2012 NZSSD undertook a follow-up study
to examine continuing safety and efficacy.
Clinical data was analysed for a subgroup of patients from the 2011
project using SPSS v19. The data was added to that collected during the
2011 project to enable a comparison over 3 time points; 2011 project baseline
and endpoint and 2012 follow up.
Data was collected on 205 patients, 49% male, mean age 57 years, 58%
NZ European, 31.2% Maori and Pacific people, 11% other. Most (74%) had
Type 2 diabetes. HbA1c improved from 81.8 to 72.8 mmol/mol and systolic
blood pressure improved from 132.1 to 123.5 mmHg. Table 1 provides a
summary of the clinical data for all 205 patients at the three time points .
This study demonstrated that DNS prescribing continues to be both safe
and effective in the long term with clinical parameters remaining stable or
improved. The incomplete nature of the data limited a direct longitudinal
comparison but findings for this small set of patients were reassuring.
ADA-Funded Research
&
1266-P
Cost-Effectiveness of “Team of 4” versus Standard of Care in Diabetes
SWARMA VARMA, TONY AMOS, NICOLE T. ANSANI, Pittsburgh, PA
ABC goal attainment (A1C <7%, blood pressure <130/80mm/Hg, and
cholesterol (LDL) <100mg/dL) is difficult to achieve and complications are
costly. We analyzed the economic impact of utilizing a “team of 4” approach
in patients with diabetes.
An outcomes evaluation analyzed the incidence of ABC goal attainment
and cardiovascular outcomes (CVD) in a “team of 4” approach (defined
as involvement & accountability of physician, staff, patient, and family
member). These data were compared to standard of care (NHANES
population statistics for patients with diabetes). 22% of “team of 4” patients
achieved ABC goals vs 7% in standard of care (SOC); CVD was seen in 18%
and 24%, respectively. Two decision tree analyses, using TreeAge software,
were used to determine the cost-effectiveness relative to ABC goals or CVD
from a managed care perspective over a 10 year period. Clinical inputs came
from the outcomes evaluation for the “team of 4” and NHANES data for
SOC. Costs were from the literature and discounted to 2012 U.S. dollars.
Sensitivity analyses were performed for all inputs. Key assumptions are:
outcome probabilities and costs from the literature represent practice; costs
of administering care to “team of 4” is equal to SOC; and a 500,000 member
health plan will have 50,000 patients with diabetes.
For author disclosure information, see page 829.
Guided Audio Tour poster
A331
POSTERS
Inpatient hyperglycemia is associated with poor outcomes, but the range
of normal hospital glucose is not known. Since identifying a normal range
could help determine targets for inpatient management, we evaluated
hospital glucose levels in 23,019 veterans using the VA Informatics and
Computing Infrastructure (VINCI) database - hospitalized between 2000 and
2009 for ≥3 days on medical/surgical services, with ≥1 primary care visit
within 2 years before and annually for 3 years afterwards. 7,556 patients
without use of the ICD-9 code 250.xx or a diabetes drug throughout this
period were defined as normal (NL), and their glucose values were compared
with those in 12,131 patients with diabetes throughout (DM PRIOR), 366
initially diagnosed during hospitalization (DM HOSP), and those diagnosed
after discharge - 719 DM 1y, 568 DM 2y, 550 DM 3y, and 1,129 DM 4-5y.
Patients had mean age 59.4 yr and BMI 35.8, and were 92% male, 74%
white, 22% black, 4% other/unknown. Using three glucose values per patient
(minimum, maximum, median) to offset variability in sample numbers, mean
(sd) glucose values were: NL 114 mg/dl (40 mg/dl), DM PRIOR 169 (99), DM
HOSP 265 (247), DM 1y 140 (59), DM 2y 125 (43), DM 3y 122 (41) and DM 4-5y
119 (44). NL group glucose values were significantly lower than those in the
other groups (all p<0.05), but were higher when compared to random glucose
levels (mean 93 mg/dl, sd 16, p<0.0001) in 979 outpatient adult volunteers
with normal OGTTs. NL group 25th, 50th, 75th, 90th, and 95th percentile
hospital glucoses were 94, 106, 125, 150, and 169 mg/dl, respectively.
Conclusions: Patients not diagnosed with diabetes before, during, or within
3 years after hospitalization (“normal”) have inpatient glucose levels lower
than those in patients who are diagnosed during that time period. Since
the 95th percentile of “normal” hospital glucose is 169 mg/dl, screening
for diabetes could be considered in patients with glucose values above this
level, and keeping inpatient glucose below this level might be a reasonable
goal.
Clinical Diabetes/
Therapeutics
MARY K. RHEE, SANDRA L. JACKSON, WENQIONG XUE, DARIN E. OLSON, DIANA BARB, J. SONYA HAW, ANNE TOMOLO, ARUN V. MOHAN, QI LONG, PHYLLIS WATSON-WILLIAMS, LAWRENCE S. PHILLIPS, Atlanta, GA, Decatur, GA
HEALTH CARE DELIVERY—ECONOMICS
SH was reported as primary or secondary diagnosis, respectively. The LoS
was 5 days (interquartile range 2.5-10; Mean±SD: 7.79±8.70) in T1 diabetes
and 7 days (interquartile range 4-11; Mean±SD: 9.13±8.94) in T2 diabetes.
The costs increased with greater LoS (quartiles): from € 1,894 for LoS <5
days to € 4,393 for LoS >11 days.
If the estimates referred to Region Puglia were applied to Italy (3,000,000
of patients with diabetes), we can estimate 15,000 hospitalizations/year for
SH and a total expenditure of € 45,000,000/year.
Results showed “team of 4” approach relative to ABC goals and CVD was
~ $180 and $480 less costly/patient vs SOC. Overall costs of “team of 4” vs
SOC were $9213 and $9394, for ABC attainment and $7556 and $8037 for
CVD, respectively. These data extrapolated (500,000 member plan) show a
potential cost avoidance of the “team of 4” approach is $189,943 for ABC
control and $24,044,500 for CVD costs over 10 years. Sensitivity analyses of
outcome probabilities and costs showed minimal impact on each model.
Adopting the “team of 4” approach can lead to significant cost savings
while increasing ABC goal attainment and decreasing CVD. This data may
serve as rationale for the development of education and adoption of systems
to improve patient care processes.
1269-P
Type I Diabetes in Medicare: Use of Services & Program Expenditures in 2010
1267-P
CLAUDIA GRAHAM, DAN WALDO, San Diego, CA, Annandale, VA
On-Demand On-Line Specialist Assistance from Hospital to General
Practice: Telemedical Treatment of Diabetic Foot Ulcers
Differences in utilization and program expenditures between controlled
and uncontrolled Type 1 (T1) Medicare enrollees were analyzed.
Analysis was done using the 2007-2010 Medicare Limited Data Set (LDS)
Five-Percent Standard Analytic Files (5% SAFs). The 5% SAFs are comprised
of fee-for-service claims for a sample of Medicare enrollees; sample
inclusion is determined by the last 2 digits of the Health Insurance Claim
Number, ensuring a random draw from the population. Count regressions
and generalized linear model regressions were used to explore relationships
between diabetes diagnosis and use of services or program expenditures.
SAS and Stata software were used for analysis.
Based on the LDS 5% SAF, in 2010 there were more than 500,000 persons
with T1 in the Medicare population. Of those identified as T1, 229,300 (25%)
had claims indicating that diabetes was uncontrolled. Diabetes identification
and the state of control were determined from claims data, using ICD 9 code
250.XX.
On average, enrollees with uncontrolled T1 have 5% higher expected
medical costs per capita than those with controlled T1. This is based on
a regression of the logarithm of enrollees’ hierarchical condition category
(HCC) risk scores, controlling for age, sex, original reason for Medicare
entitlement (age, disability, or end-stage renal disease), and dual eligibility
for Medicaid.
In terms of service use, enrollees with uncontrolled TI had a greater number
of emergency department (ED) visits per capita than did enrollees with
controlled TI , and almost twice the rate of ED visits for hypoglycemia (ICD9
code 250.8x). Overall, they had slightly more inpatient days of care and rates
of inpatient admission, but relatively higher rates of admission corresponding
with more hospital days per capita for hypoglycemia. Results suggest further
characterization of hypoglycemia events in Medicare T1 is needed.
POSTERS
Clinical Diabetes/
Therapeutics
BENJAMIN S. RASMUSSEN, JEANETT BRAENDSTRUP, MICHAEL VAEGGEMOSE,
LARS D. MADSEN, KNUD YDERSTRAEDE, NIELS EJSKJAER, Odense, Denmark,
Aarhus, Denmark, Holstebro, Denmark
Objective: To assess the effects of implementation of on-demand on-line
telemedical specialist assistance from hospitals to general practice in order
to optimise the course of treatment of diabetic foot ulcers. Method: A priori
conventional (historic) treatment courses for 30 individual patients were
registered with regard to 1) time lines for diagnosis and treatment, 2) delay
in first contact to foot ulcer specialist, 3) delay in first screening for diabetes
late complications and contact to a diabetologist. After implementation of
telemedicine all patients with diabetic foot ulcers in 6 general practices
were consecutively recruited and clinical data and pictures documented in
the internet-based communication system thereby time-stamping all events
to be compared with the “historic” data. All parties (patients, relatives,
staff in general practices and hospitals) are subjected to focus group
interviews and questionnares describing satisfaction/dissatisfaction and
advantages/disadvantage with the current treatment and treatment in this
study. More than 40 patients will have been included from January 1st 2011
to 31st December 2012. Result: Preliminary results reveal 1) great patient/
relative satisfaction sparing the patient transport to hospital and allowing
treatment in more comfortable and well known surroundings 2) satisfaction
in general practice with on-demand assistance, but reluctance with regard
to implementing the communication system 3) satisfaction among hospital
staff as patients are stratified according to severity 4) overall diminished
delays in diagnosis, treatment and first contact to specialists. Conclusion:
On-demand on-line specialist assistance from hospitals to general
practices is feasible. In our study treatment was optimized and patients
and relatives were overall satisfied as was hospital staff. Barriers include
reimbursement issues and apprehension towards yet another technology to
be implemented.
1270-P
An Intensive Discharge Intervention for Patients With Diabetes
JEFFREY L. SCHNIPPER, JORGE CHIQUIE BORGES, NYRYAN V. NOLIDO, CHERLIE
MAGNY-NORMILUS, STEPHANIE LABONVILLE, JUDY CHENG, BETH A. HIRNING,
IWONA E. RYBAK, HEATHER DELL’ORFANO, MARGO HUDSON, MAUREEN MCQUEENEY, Boston, MA
1268-P
Costs Related to Hospitalization for Hypoglycemic Episodes in Italy
Patients with diabetes and comorbid cardiovascular disease may be at
particularly high risk for post-discharge medication non-adherence and
adverse outcomes.
We randomly assigned inpatients on medicine and cardiology services
with type 2 diabetes and comorbid cardiac disease, likely to be discharged
home on insulin, to an intensive transitional intervention or to usual care.
The intervention includes: 1) a nurse practitioner (NP) to coordinate care and
patient education; 2) an inpatient pharmacist to perform intensive medication
reconciliation and patient counseling; 3) standardized visiting nurse visits;
4) a post-discharge clinic visit staffed by the NP and a pharmacist; and 5)
telemonitoring of point-of-care glucose readings. The primary end point is
adherence to insulin 90 days after discharge based on pharmacy prescription
refill data.
To date, we have enrolled 125 of a planned 200 patients, including 37
with complete 90-day post-discharge pharmacy refill data. The mean
medication possession ratio for all insulin types was 85.9% (SD 26.5)
among intervention patients and 79.0% (SD 22.2) among usual care patients
(difference 6.9%, 95% CI -10.4 to 24.2, p=0.23). Intervention patients had
a 1.02 decrease in their 90-day A1c levels compared with a 0.83 decrease
with usual care (p=0.61). No significant differences have been found to date
in 30-day emergency department or readmission rates or rates of hypo- or
severe hyperglycemia per monitored patient-day, although there was a
trend towards increased self-reported hypoglycemia in the intervention arm
(48.1% vs. 25% of patients with at least one episode, p=0.10).
To date, the intervention is associated with a non-significant but promising
trend towards increased adherence to insulin in the 90 days after discharge.
MONICA FRANCIOSI, GIORGIA DE BERARDIS, FABIO PELLEGRINI, ANTONIO
D’ETTORRE, LUCIA BISCEGLIA, FRANCESCO GIORGINO, VITO LEPORE, GIUSEPPE
LUCISANO, FABIO ROBUSTO, ANTONIO NICOLUCCI, Santa Maria Imbaro, Italy,
Bari, Italy
The aim of the study was to evaluate the incidence and cost of
hospitalization for severe hypoglycemia (SH) using the Administrative
Databases related to 12 local Health Authorities of Region Puglia. We
conducted a population-based cohort study using a record-linkage analysis
of hospital discharge records, prescription databases, and civil registry,
including data on 4.1 million citizens during the period 2002-2010. All
subjects with pharmacologically treated diabetes were eligible regardless
of gender, age and hypoglycemic treatment; 385,527 subjects (92% with T2
diabetes) were included.
We identified 10,362 hospitalizations relative to 9,021 subjects. SH
was reported as primary and secondary diagnosis in 40.46% and 59.54%
of hospitalizations, respectively. Overall, in the period 2002-2010 the total
cost related to hospitalization for SH was € 31,256,985. The average cost of
hospitalization was of € 3,016. Despite a decrease in the number of events,
the costs rose after 2006 and remained stable in the following years (up to
€ 3,374 in 2010). The average cost of hospitalization was € 2,326 if SH was
reported as primary diagnosis and € 3,489 if SH was reported as secondary
diagnosis. The greatest cost increase was observed in patients with T2
diabetes in Basal Oral Therapy (+56%).
The median length of stay (LoS) for SH was 7 days (interquartile range
4-11 days; Mean±SD: 9.03±7.9): 6 days (interquartile range 3-10; Mean±SD:
7.53±7.35) and 8 days (interquartile range 4-13; Mean±SD: 10.13±9.99) when
&
For author disclosure information, see page 829.
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HEALTH CARE DELIVERY—ECONOMICS
The study demonstrates the feasibility of implementing a multi-disciplinary
transitional intervention in medically complex patients with diabetes, and
in the use of a promising method of determining insulin adherence using
pharmacy refill data.
Conclusions: Taking into account the costs of managing overt disease in
Catalonia this primary care-led intensive lifestyle intervention was not only
effective but also efficient in delaying progression to type2 diabetes
1271-P
Effectiveness of an Inpatient Insulin Order Set Using Human Insulin
in an Indian Health Service Hospital
1273-P
Group Diabetes Visits to Support Self-Management Goals: A Model
for Care in an Urban, Resource-Poor Community
Supported by: Merck Company Foundation
1272-P
Efficiency of a Primary Care-Led Lifestyle Intervention in Delaying
Progression to Type 2 Diabetes Among High-Risk MediterraneanSpanish Individuals
XAVIER COS, BERNARDO COSTA, JOAN J. CABRE, ORIOL SOLA-MORALES, RAMON SAGARRA, BERTA SUNYER, FRANCISCO BARRIO, JAAKKO TUOMILEHTO,
THE DE-PLAN-CAT/PREDICE RESEARCH GROUP, Barcelona, Spain, Reus-Tarragona, Spain, Helsinki, Finland
Objective: Transferring the findings of diabetes prevention research
into primary healthcare was the objective of the Diabetes in Europe_
Prevention using Lifestyle, Physical Activity and Nutritional intervention
project, developed in Catalonia (DE-PLAN-CAT). We report the 4-year costeffectiveness assessment of the intervention.
Research Design and Methods: Incidence of diabetes, resource utilization,
cost and quality of life (15D questionnaire) were collected alongside a reallife prospective cohort study conducted in 18 primary care centres. WhiteEuropean without diabetes aged 45-75 years (n=2,054) were screened using
the FINDRISC and a 2-h OGTT. Where feasible, high-risk identified individuals
who agreed to participate (n=552) were allocated sequentially to standard
care (n=219), a group-based (n=230) or an individual level (n=103) intensive
lifestyle DE-PLAN intervention. Analyses after 4.2-year median follow-up
were performed based on the intention-to-treat principle.
Results: The incidences of diabetes were 7.2 and 4.6 cases per 100
person-years in the standard care group and the intensive intervention
group_4 and 3.6 cases in the group-based and the individual-based
intensive intervention which represented 36.5% relative risk reduction
(p<0.005) reaching to 49.3% in the individual intensive intervention group.
The corresponding incremental cost-effectiveness ratios were 108€ (group)
and 746€ (individual) per averted case of diabetes compared to standard
care group. At study close quality of life was higher in the intensive lifestyle
intervention group (0.93/0.91, p<0.01) being the incremental cost-utility ratio
3,243€ (4,250 USD) per quality-adjusted life-years gained.
ADA-Funded Research
&
1274-P
A Randomized, Controlled, Open-Label Study to Evaluate the Effi cacy of Smart Phone Application Based Diabetes Self-Management
Program in Patients With Type 2 Diabetes
JONG DAI KIM, SEUNG HYUN YOO, YU MI HA, SUNG AH MIN, JIN SUN CHOI,
YOO MI BAE, KYONG PIL MIN, SE EUN PARK, EUN JUNG RHEE, CHEOL YOUNG
PARK, WON YOUNG LEE, KI WON OH, SUNG WOO PARK, Seoul, Republic of Korea,
Sungnam, Republic of Korea
The aim of this study is to evaluate the efficacy of smart phone application
based diabetes self-management program (DSMP) for diabetic patients.
A total 35 type 2 diabetic patients were enrolled (control group n=12 and
intervention group n=23). And patients were followed during 6 months.
The smart phone application based DSMP is interactive program based on
analyzing data between self-monitoring of blood glucose, blood pressure,
weight and life style pattern (meal, exercise, etc.). This program also
provides alarm system and specific recommendation related to diet and
exercise according to the results for improving self-management.
For author disclosure information, see page 829.
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Basal-bolus-correctional (BBC) insulin therapy is superior to “sliding
scale” insulin alone in controlling hyperglycemia and improving outcomes
in inpatients. An insulin order set for BBC using primarily analog insulins
has been most studied for use outside the ICU. The Gallup Indian Medical
Center recently made available a BBC order set, using human insulins
due to resource constraints. This study assessed the effectiveness of the
availability of this order set.
Admissions to non-ICU services of adults with type 2 diabetes were
reviewed for 4-month periods in 2011 (N=274) before and in 2012 (N=302)
after availability of the order set and physician training. Comparing the
cohorts, use of BBC therapy increased from 11% to 28% (p<.001) and use of
any basal insulin increased from 50% to 63% (p<.001). The estimated mean
blood glucose (by random regression adjusting for age, sex, initial glucose,
A1C, service, and correlation of observations within individuals) for the first
9 days after admission showed that after day 2 the blood glucose levels in
the 2012 cohort were lower than the 2011 cohort (Figure), with a difference
for days 3-9 of -14.4 mg/dl (SE 6.2; p=.020). The incidence of hypoglycemia
did not change.
In conclusion, availability of a BBC human insulin order set in this rural
community hospital was associated with improved physician ordering
practices and improved control of hyperglycemia.
A program of group diabetes visits (GDVs) in an urban, resource-poor
community (Camden, NJ) was initiated to provide a team approach to
ongoing patient-centered diabetes (DM) care and offer a model for sustaining
behavioral change after diabetes self-management education (DSME).
Patients who complete 6.5 hrs of DSME are offered a quarterly GDV with
their primary care provider (PCP) and a certified diabetes educator (CDE). The
CDE and a program assistant review charts prior to class to develop a DM
Care Plan based on history, lab results and goals. The PCP and CDE discuss
the patient’s clinical measure and behavior goals in advance of the GDV.
Each two-hour program is divided into three components: DSME, clinical
care, and an interactive Q&A. At the visit, the PCP completes the care plan
for each patient. An endocrinologist attends the GDV for the first 6 months
to model clinical decision making. After the program the CDE and PCP review
the medical decisions, behavior goals and plan follow up care. Patient’s
demographics, clinical measures (HbA1C, BP and lipids) are measured at
baseline and every three months in the initial six months of the program.
Thirty patients with previous DSME participated in the GDV. Complete
pre and post A1c data was able to be collected for 16 patients (72% African
American, 11% Hispanic, and 17% White; 50% male and 50% female;
average age of 53.6 SD 12.4; average A1c of 9.10 SD 2.17). 14 GDV were held
over a 2-year period.
Attendance: 63% attended 2+ visits, and 36% attended 3+ visits.
Change in HbA1c: Pre HbA1c 9.10 SD 2.17; Post HbA1c 7.98 SD 1.78
(p=.085).
GDVs were investigated as a novel method for delivering DM care in an
urban, resource-poor community. GDV allow for medical care, peer-to-peer
support and continued emphasis on behavior change. Although the decrease
in HbA1c was not statistically significant many patients had a reduction
in their HbA1c. Combining education and medical components of a visit
improves glycemic control in an underserved patient population.
Clinical Diabetes/
Therapeutics
JOSHUA VALGARDSON, MARICRUZ MERINO, JAMIE REDGRAVE, JAMES I.
HUDSON, MARGO S. HUDSON, Gallup, NM, Boston, MA, Belmont, MA
STEVEN KAUFMAN, FRANCINE GRABOWSKI, NADIA ALI, ANDREW KATZ, Cherry
Hill, NJ, Camden, NJ
HEALTH CARE DELIVERY—ECONOMICS
SMBG requires effective patient-provider communication and patient
education.
Baseline characteristics of two groups were not different in age, sex,
body mass index (BMI), and other metabolic parameters. At baseline,
mean A1c of control group vs test group were 7.6± 0.5 vs 7.4±0.9%. After 6
months intervention using smart phone application based DSMP, there were
increasing trend in control group (from 7.6±0.5 to 7.6±0.7%) and decreasing
trend in intervention group (from 7.4±0.9 to 7.2±1.0%) for A1C. But it was
not statistically different. Target A1C (below 7.0%) achievement were
significantly different between two group (9.1% in control group vs 47.8% in
intervention group, P<0.027). We divided the intervention group into good or
poor user. The A1c level was significantly improved in good user-intervention
group than poor user-intervention and control group. (-0.59±0.26, +0.10±0.13
and +0.07±0.18%, P<0.028). Smart phone application based DSMP was
resulted in significant reduction of A1c during 6 months intervention,
especially in the good user of this system.
Supported by: R01DK-081796, R01DK-080726, R01DK-065664, R01HD-46113,
P3DK092924, P30DK09
1277-P
Do Food Costs Increase for Participants in a Diabetes Prevention
Program?
GERALD L. SCHAFER, THOMAS J. SONGER, M. KAYE KRAMER, VINCENT C.
ARENA, RACHEL G. MILLER, KARL K. VANDERWOOD, ANDREA M. KRISKA, Pittsburgh, PA
Given the high number of individuals at risk of developing type 2 diabetes, it
is imperative that perceived obstacles to successful participation in diabetes
prevention programs be thoroughly investigated. One perception is that
food expenses increase for individuals making the healthy lifestyle changes
recommended in these intervention efforts, i.e. it costs more to eat healthfully.
This project assessed household food expenses over the course of a year in
overweight adults (BMI ≥ 24kg/m2) with pre diabetes and/or the metabolic
syndrome, participating in the Group Lifestyle Balance ™ Program, a diabetes
prevention intervention adapted from the Diabetes Prevention Program.
Data were obtained from 28 participants (a subgroup of a larger study) who
completed baseline expense surveys, with 22 and 21 surveys completed at
6 and 12 months, respectively. Compared to baseline, significant decreases
were found at 6 months in mean weight (-11.6 lbs, -5.4%, p<0.001), median
triglycerides (-27.5 mg/dl, p=0.02), and mean diastolic (-6.8 mmHg, p<0.001),
and systolic (-7.6 mmHg, p<0.0001) blood pressure. Weight loss, diastolic, and
systolic blood pressure remained significantly lower at 12 months. The median
of reported monthly food expenses at grocery and other food stores was
unchanged from baseline ($450) to 6 months ($450, p=0.42), and baseline to 12
months ($463, p=0.37). This finding of no change held true for the median of total
reported food expenses (spending at grocery and other stores, take-out food,
and restaurant purchases) from baseline ($728) to 6 months ($735, p=0.85), and
baseline to 12 months ($741, p=0.81). These results demonstrate that healthy
lifestyle changes can take place without a significant increase in household
food expenses. Such a finding may help dispel perceptions that prevent some
individuals from participating in type 2 diabetes prevention programs.
1275-P
GANG CHEN, PEIYING HUANG, MINGZHU LIN, JUNPING WEN, HUIBIN HUANG,
XUEJUN LI, SHUYU YANG, Fuzhou, China, Xiamen, China
POSTERS
Clinical Diabetes/
Therapeutics
Correlation of Peri-Operative Blood Glucose Level With Post-Operative Complications, Hospital Costs, and Length of Hospital Stay in
Patients With Gastrointestinal Malignancies
Objective: To investigate the effect of peri-operative hyperglycemia on
post-operative complications, hospital costs, and length of hospital stay in
non-diabetic patients with gastrointestinal malignancies.
Methods: A total of 1015 non-diabetic patients with gastrointestinal
malignancies who had complete clinical information and underwent surgical
intervention in our hospital between January 2010 and December 2010 were
retrospectively evaluated. Records on fasting plasma glucose (FPG), liver
function, and kidney function were collected before and 1 d after surgery.
The correlation of peri-operative blood glucose level with post-operative
complications, hospital costs, and length of hospital stay was further
assessed in non-diabetic patients with gastrointestinal malignancies.
Results: One day after surgery, a blood glucose >6.1 mmol/L and > 7.0
mmol/L existed in 79.0% and 60.4% of the patients, respectively, which
was significantly higher than before surgery. A blood glucose >9.13 mmol/L
significantly increased the length of hospital stay, hospital costs, and the
incidence of post-operative complications.
Conclusion: Non-diabetic patients with gastrointestinal malignancies
should be monitored when the blood glucose is > 9.13 mmol/L 1 d after
surgery. Glucose-lowering measures should be carried out if necessary to
reduce the incidence of post-operative complications, length of hospital
stay, and medical costs.
Supported by: NIH
1278-P
Real-World Retrospective Study of Treatment Intensification After
Failing 2 Oral Antidiabetic Drugs (OADs) Among Elderly With Type 2
Diabetes Mellitus (T2DM)
MAYANK AJMERA, WENHUI WEI, STEVE ZHOU, RITUPARNA BHATTACHARYA,
CHUNSHEN PAN, USHA SAMBAMOORTHI, Morgantown, WV, Bridgewater, NJ,
Boca Raton, FL
1276-P
Self-Monitoring Blood Glucose Without Using the Results: Findings
from the Diabetes & Aging Study
Among elderly patients, the management of T2DM is complicated by
population heterogeneity and elderly-specific complexities. Few studies
have been done to understand treatment intensification among elderly
patients failing multiple OADs.
Using the Humana database, this retrospective cohort study analyzed
elderly (≥65 y) Medicare patients with T2DM and previously treated with 2
OADs, but having poor glycemic control (A1C ≥8%). Treatment intensification
was defined as addition of a third OAD, a glucagon-like peptide-1 (GLP-1)
receptor agonist, or insulin during the observation period. Factors associated
with time to treatment intensification and the choice of intensification were
identified.
Of the 16,802 included patients (female 48.6%, white 69.6%, mean age
73.2 y, baseline A1C [where available] 8.9%, mean follow-up 22 months),
49.1% (n=8,252) intensified treatment during the follow-up period, with
median time to intensification of 18 months using product-limit estimates.
Of those patients who intensified treatment, 57.6 % used a third OAD, 40.6%
used insulin, and 1.8% used a GLP-1 receptor agonist, and 76.0% received
these within 1 y after the index date. Independent factors associated with
higher likelihood of intensification were: polypharmacy (adjusted hazard ratio
[aHR] 1.10; 95% CI: 1.05-1.15); 3 or more office visits (aHR 1.09; 95% CI: 1.031.15); baseline A1C >9% (aHR 1.51; 95% CI: 1.44-1.58); and higher diabetes
complication burden (aHR 1.09; 95% CI: 1.01-1.16). The aHR was lower for
patients of African-American race; of higher age; living in the South; with
HMO coverage; and before/after a Medicare coverage gap.
Among elderly T2DM patients failing multiple OADs, only half received
treatment intensification, and patient complexities play a significant role in
its timing, which should be a critical component when designing effective
intervention programs.
RICHARD W. GRANT, ELBERT HUANG, DEBORAH J. WEXLER, NEDA LAITEERAPONG, MARGARET WARTON, HOWARD H. MOFFET, ANDREW J. KARTER, Oakland, CA, Chicago, IL, Boston, MA
We investigated the prevalence, predictors, and costs associated with
unused results from self-monitored blood glucose (SMBG) in type 2 diabetes.
We studied 7320 patients not prescribed insulin enrolled in the Diabetes
Study of Northern California (DISTANCE) survey cohort. Patients were 58.7
(9.9) years old and had 8.3 (7.1) years diabetes duration. Patients reported
whether they used SMBG results to make adjustments to diet, exercise
or medicines; and whether their doctor reviewed their SMBG results. We
categorized SMBG results as “used” (by patient or provider) or “unused” (not
used by either patient or provider).
SMBG results were unused by patient and provider in 15.2% of
patients. Patients with unused results had lower HbA1c (7.1 ± 1.5% vs.
7.3 ± 1.4%, p < 0.001) than patients who used results. In separate models
adjusted for demographic and clinical differences, major predictors of
unused results included: patient report that diabetes was not a high
priority (RR 1.81; 95% CI: 1.58-2.07), that his/her PCP did not engage
in shared decision making (RR 1.66; 1.46-1.90), and that no health care
provider had taught them to adjust their diet or medicines based on
SMBG results in the past year (RR 2.27; 2.00-2.57). Patients with unused
results were dispensed 171 ± 191 test strips/year in the prior two years
at an estimated cost of $168 per year.
The nearly 1 in 6 non-insulin treated patients practicing SMBG without
either the patient or provider using the results represents a wasteful
and ineffective practice for patients and health systems alike. Our
results suggest that the decision to initiate and continue SMBG must
be made in concert with the patient’s own priorities, and, if prescribed,
Supported by: Sanofi U.S., Inc.
&
For author disclosure information, see page 829.
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YOSHIKO ONDA, AYA MORIMOTO, RIMEI NISHIMURA, HIRONARI SANO, KAZUNORI UTSUNOMIYA, NAOKO TAJIMA, Tokyo, Japan
Background and aims: We previously reported that about 1 out of 10
patients with childhood-onset type 1 diabetes was still presenting to
pediatricians, even after the age of 30 years or older. The objective of this
study is to investigate the factors determining the behavior of these adult
patients still presenting to pediatricians.
Materials and methods: Of the 1,385 patients diagnosed as having type 1
diabetes at < 18 years of age between 1965 and 1979 from two nationwide
surveys, the current study included a total of 857 patients for whom information
on their attending physicians was available as of January 1, 2000. We sent these
physicians a questionnaire to investigate the size of their practice (hospital/
clinic-based), their office locations, the population size of their city (≥ 500,000
or < 500,000 or government-designated cities [GDC] or non-governmentdesignated cities [NGDC]), and their board certification status (BCS).
Results: 52.8% of their physicians’ offices were located in GDC, with the
47.2% located in NGDC. 72.5% of the pediatricians and 76.6% of the internists
were found to have BCS with no difference seen in the rate of specialist
visits between those presenting to pediatricians and those presenting to
internists (p = 0.32; chi-square test). Logistic regression analysis showed
that the younger the age at diagnosis and the more the physicians’ offices
tended to be in GDC, the significantly more likely that they still presented to
pediatricians, but that their physicians’ BCS had no correlation with the rate
of their visits to pediatricians (p = 0.003/0.002/0.271).
Conclusion: Not physician BCS but physician office location was the factor
determining the behavior of adult patients still presenting to pediatricians.
1282-P
Metabolic Control in Adults With Type 2 Diabetes (T2D) in the General Population and a Diabetes Center
1280-P
SANJEEV N. MEHTA, ALLISON B. GOLDFINE, MARTIN J. ABRAHAMSON, LORI
M. LAFFEL, Boston, MA
A Cross-National Comparison of Safety and Efficacy Information in
Insulin Glargine Drug Labels
In the US, <20% of T2D adults achieve control of A1c, BP, and cholesterol
(ABC). Effectively managing the T2D epidemic may require timely referral
of suboptimally controlled patients to diabetes specialty providers. We
assessed ABC control from 2005-10 in T2D adults (age ≥20 yrs) in the general
population (3 2-year NHANES cycles) and in T2D patients newly referred to
an outpatient diabetes center and after 1 year of specialty care. We used
2005 ABC goals: A1c<7%, BP<130/80, LDL<100 mg/dL. At baseline, referrals
(n=3298, 57% male) were younger (58.0 vs. 61.4, p<.001) and had shorter T2D
duration (7.6 vs. 7.9 yrs, p<.001) than NHANES adults (n=1569, 50% male).
At baseline, referrals were less likely to be at target for A1c (referrals vs.
NHANES: 33 vs. 56%, 22 vs. 53%, 22 vs. 51%, p<.001 for all) or BP (37 vs.
43%, 37 vs. 51%, 38 vs. 54%, p<.001 for all) compared to NHANES adults;
those at LDL goal differed only in 2009-10 (50 vs. 51%, p=.9; 52 vs. 56%,
p=.2; 61 vs. 52%, p=.009). After 1 year, more referrals were at goal for A1c
(43%, 38%, 41%, p<.001 compared to baseline), BP (46%, 42%, 45%, p<.001
compared to baseline), and LDL (61%, p=.01; 69%; p<.001; 69%, p.08 (trend)
compared to baseline). Within 1 year, the proportion of referrals achieving
ABC control increased 240% (Figure). By 2009-10, 1 in 15 T2D adults
presenting to the diabetes center had ABC control, compared to 1 in 4 in the
general population, suggesting appropriate referral of sicker T2D adults and
measurable benefit for this group.
JENNIFER M. POLINSKI, AARON S. KESSELHEIM, JOHN D. SEEGER, JOHN G.
CONNOLLY, NITEESH K. CHOUDHRY, WILLIAM H. SHRANK, Boston, MA
Type 2 diabetes mellitus (T2DM) has reached epidemic proportions
worldwide. Many patients with T2DM will require insulin, and the evidencebased use of insulin is described in the prescription label. However, labels in
different settings may provide inconsistent or contradictory information.
We examined label content for insulin glargine across 17 settings with
high T2DM prevalence: Abu Dhabi, Argentina, Brazil, Canada, China,
Germany, Israel, Italy, Japan, Mexico, Russia, Saudi Arabia, South Korea,
Spain, Turkey, United Kingdom, and the US. We assessed heterogeneity
across 7 label sections pertinent to effective and safe use: indications
and usage, contraindications, dosage and administration, warnings and
precautions, adverse drug reactions (ADRs), use in specific populations, and
overdose. We compared label characteristics in settings where drug labels
were governed by a local regulatory authority, versus settings where labels
were administered by a regional body or adopted from another locale.
All 17 labels cautioned that providers should consider age, illness, diet,
and exercise when prescribing. Only 2 (12%) described care of the fasting
patient. Caution was urged for patients with renal or hepatic impairment
in 16 (94%) labels. Four (24%) did not describe responses to missed doses
and 5 (29%) failed to recommend that patients be counseled about the
risk of hypoglycemia. ADR counts ranged from 4 (Brazil) to 41 (Argentina).
Labels emerging from regional or adopted regulatory bodies reported fewer
patients in efficacy studies than did labels from settings with their own drug
regulatory agencies (365±0 patients vs. 3,560±2,938, p=0.04).
There is substantial variation in the content of drug labels for glargine.
Information describing the risks or prevention of hypoglycemia was often
missing. Settings with local regulatory agencies based labels on the
experiences of a larger number of patients. Such variation may lead to
international inconsistency in T2DM quality of care.
Supported by: Eli Lilly and Company
1281-P
The Effect of Comorbidity on the Costs of Recent-Onset Type 2 Diabetes Mellitus in Veterans
MANGALA RAJAN, ANUSHUA SINHA, HEATHER FRANKLIN, LEONARD POGACH,
East Orange, NJ
Recent epidemiological studies suggest that the cardiovascular benefit of
tighter control in recent onset diabetes (DM) may be limited to individuals
with a lower illness burden. The goal of this study is to compare total costs
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A335
POSTERS
of treating a Veteran with recent-onset DM with and without comorbidities
in the Veterans Health Administration (VHA).
VHA data for FY2004 from the Health Economic Resource Center were
used to assess costs. Chronic comorbidity was categorized as either
dominant (limited life expectancy and extensive medical treatment likely
to minimize attention to diabetes), discordant (not related to diabetes in
terms of pathophysiology, treatment plans, or self-management strategies),
or concordant (related to diabetes with synergies in treatment plans and
management) based on ICD-9 and CPT codes, using a validated protocol.
There were 53,513 veterans with recent-onset DM, of whom 7%
had microvascular illnesses, 25% had macrovascular disease, 32% had
discordant illness and 7% dominant illnesses. There were 3,816,487 veterans
with no DM who were used as the comparison group with a slightly lower
comorbidity burden.
The inpatient and outpatient costs associated with treating patients with
no comorbidities and DM was $2,416 [CI $2,088 - $2,203]; an incremental
cost of $743 compared to equivalent patients with no DM. For veterans with
discordant disease (such as mental illness), this cost was $6,867 [CI $6,645
- $7,087]with an incremental cost of $2,361. For veterans with concordant
disease the cost was $5,338 [CI $5,070 - $5,605] with an incremental cost of
$2,508. For those veterans with dominant disease the cost was $19,907[CI
$18,810- $21,000]; an incremental cost of $11,181.
Chronic comorbidity is associated with higher incremental costs for DM.
These results can be used to project long-term costs of Veterans with DM
and co-morbid conditions. These results support the recent ADA guidelines
on individualizing goals for patients with DM and comorbidity from the
perspective of costs.
1279-P
What Are the Factors Determining the Behavior of Adult Patients
With Childhood-Onset Type 1 Diabetes Still Presenting to Pediatricians? Results from the DERI Mortality Study
Clinical Diabetes/
Therapeutics
HEALTH CARE DELIVERY—ECONOMICS
HEALTH CARE DELIVERY—ECONOMICS
6.5%, and no dementia. Prior to a physician encounter, intervention patients
interacted with the tool and generated a summary for their physician that
included individual patient’s LE estimates, geriatric screening results
and treatment preferences. Control patients received an A1C pamphlet.
Physicians and patients were surveyed before and after the encounter.
Results: Intervention (N=68) and control patients (N=25) were similar
by gender (77% female), age (mean 74 years), ethnicity/race (89% black)
and duration of diabetes (mean 16 years). Intervention patients were more
likely to have their physician report an A1C discussion versus controls (90%
vs. 76%, p=0.20). Intervention patients were slightly more likely to report
an A1C goal (53% vs. 44%, p=0.44) and have a goal that matched their
physician’s goal (35% vs. 28%, p=0.51). Decisional conflict scores tended to
decline more for intervention (53.8→24.7) than control patients (51.6→36.6)
(p=0.09). Intervention patients with LE estimates ≤ 5 years had a shift
towards higher A1C goals, 7.1-8.0% (55%→65%) (p<0.01). Patients with LE
estimates > 5 years had a shift towards lower A1C goals, ≤7.0% (49%→60%)
(p<0.01). Control patients did not have A1C goal shifts of the same size and/
or direction.
Conclusion: A personalized decision support tool incorporating prognostic
information and patient preferences encouraged active discussion regarding
A1C goal selection, decreased patients’ decisional conflict regarding A1C goal
choice, and increased personalization of A1C goals based on LE estimates.
1283-P
Patient Reported Perspectives on Diabetes Disease, Comorbidities,
Glucose Control, and Adherence
POSTERS
Clinical Diabetes/
Therapeutics
JANICE LOPEZ, ROBERT A. BAILEY, KATHY ANNUNZIATA, MARCIA F.T. RUPNOW,
SILAS MARTIN, Raritan, NJ, Princeton, NJ
The ADA/EASD guidelines suggest the management and treatment of
type 2 diabetes mellitus (T2DM) can be impacted by many factors such
as age, comorbidities, risk of hypoglycemia, and treatment adherence.
Understanding the burden of these important factors from a patient
perspective is important in determining treatment approaches.
Using the 2011 US National Health and Wellness Survey (NHWS) data,
we characterized the T2DM population as a whole, with added focus on
the elderly. NHWS results were stratified by age and gender, then weighted
and projected to reflect the demographic composition of the total adult
population (based on Census data).
Of 75,000 US adults aged ≥18 y who responded to the survey, 7,828
reported a diagnosis of T2DM (mean age, 58.5 ± 13.6 y; 56% male). Of this
population, 3,241 (34.5%) were ≥65 y and 636 (14.8%) were ≥75 y (54% and
49% were male, respectively). These respondents represent the projected
US population ≥65 y and ≥75 y of 7.6 M and 3.2 M, respectively. In the
≥65 y and ≥75 y subgroups, the most common comorbidities were high
cholesterol (69%, 66%), hypertension (69%, 70%), and arthritis (53%, 57%).
In both subgroups ≥65 y and ≥75 y, nearly 56% used statins; 49% and 47%,
respectively, reported ever experiencing hypoglycemia. 63% of participants
reported being adherent to treatment.
These data show that compared to the overall population, older adults
have a greater burden of comorbidities, but a trend of better glucose control
based on reported HbA1c.
Supported by: Retirement Research Foundation (2007-250); NIDDK
(P30DK092949-01)
1285-P
Factors Associated With Adherence to Oral Antihyperglycemic
Monotherapy in Patients With Type 2 Diabetes
KAAN TUNCELI, CHANGGENG ZHAO, MICHAEL J. DAVIES, KIMBERLY G. BRODOVICZ, CHARLES M. ALEXANDER, LARRY RADICAN, Whitehouse Station, NJ
Medication adherence in type 2 diabetes (T2DM) is low, leading to
suboptimal outcomes. This study focused on factors associated with
adherence in patients (pts) with T2DM on oral antihyperglycemic monotherapy (OAM). This retrospective cohort analysis used a US claims database
(MarketScan). The index period was 01/01/07 to 03/31/10 and the index date
was the date of first OAM prescription (Rx) in this period. Eligible pts with
T2DM were ≥18 yrs old at T2DM diagnosis, were continuously enrolled in
the database for 1 yr before and after the index date, and had an OAM
Rx. Adherence was assessed using the proportion of days covered (PDC).
Logistic regression was used to assess factors (age, gender, OAM status
[new to or previously on OAM], OAM dosing regimen [once- or twice-daily],
average daily drug cost, and number of concomitant Rxs) associated with
adherence (PDC ≥80%). Eligible pts (N=133,449; 51% men) had a mean age
of 61 yrs (35% ≥65 yrs), 39% were on a once-daily OAM, and 49% on ≥3
concomitant Rxs. Overall, 59% of pts were considered adherent to OAM.
Table shows results from the logistic regression analysis examining factors
associated with adherence to OAM. In conclusion, adherence to OAM is
multifactorial and is influenced by pt characteristics, treatment regimens,
and drug cost.
Table. Odds Ratios (OR) for adherence to OAM (PDC ≥80%)*
Parameter**
OR***
95% CI
Male
1.14
1.11, 1.17
Age <45 years
0.35
0.33, 0.36
Age 45 and <65 years
0.60
0.58, 0.61
New to OAM treatment
0.83
0.81, 0.85
Twice-daily dose for OAM
0.82
0.80, 0.84
Average Daily Cost/Copay for OAM
0.72
0.69, 0.75
No other concomitant Rxs
0.42
0.41, 0.44
1 concomitant Rxs
0.67
0.65, 0.70
2 concomitant Rxs
0.87
0.84, 0.89
* Adjusted for baseline characteristics and comorbid conditions.
** Reference categories: female, age ≥65 years, previously on OAM treatment, once-daily dose for OAM, and ≥3 concomitant Rxs.
*** An OR >1 indicates a positive association with adherence and an OR <1
indicated a negative association with adherence.
1284-P
A Pilot RCT of Personalized Decision Support for Older Patients
With Diabetes
ELBERT S. HUANG, AVIVA G. NATHAN, JENNIFER COOPER, PRIYA M. JOHN, WILLIAM DALE, NANANDA COL, DAVID O. MELTZER, MARSHALL H. CHIN, Chicago,
IL, Biddeford, ME
Background: Geriatric diabetes care guidelines encourage individualized
glycemic targets (i.e., A1C goal) for older patients based on patient life
expectancy (LE) and preferences. We pilot tested a web-based decision
support tool which provides individualized prognostic information and elicits
patient preferences.
Methods: We randomized physicians and their patients to the decision
support tool, with 3:1 recruitment. Patients were > 65 years, had A1C ≥
Supported by: Merck, Sharp & Dohme
&
For author disclosure information, see page 829.
A336
Guided Audio Tour poster
ADA-Funded Research
PEDIATRICS—OBESITY AND TYPE 2 DIABETES
5TT) and were pair-matched for age, gender, BMI, and whole body insulin
sensitivity index (WBISI). Within all subjects, fasting %DNL was associated
positively with BMI (r=0.62; P=0.05) and negatively with WBISI (r = -0.66;
P=0.03). Interestingly, when the two genotypes were compared, the TT
subjects showed a lower %DNL peak (P=0.01) and a lower delta increase of
%DNL (P=0.05), compared to CC after the drink. By contrast, AbsDNL tended
to be higher in TT subjects at fasting (P=0.16) and was significantly higher
after the drink (P=0.05). These are the first data of de novo lipogenesis in
children and show that the rs1260326 variant in the GCKR gene modulates
the lipogenic pathway and leads to metabolic inflexibility. Also, these data
suggest that higher fasting lipogenic rates, that are inappropriately resistant
to stimulation by consumption of sugars, are associated with the higher
triglycerides levels and hepatic fat accumulation.
1286-P
Quality of Care for Type 2 Diabetes Mellitus Patients in Dubai: A Retrospective Cohort Study
KATHERINE M. OSENENKO, BONNIE M. KORENBLAT DONATO, SHELAGH M.
SZABO, ELLEN E. KOROL, LARA QATAMI, FATHEYA AL AWADI, JABER AL ANSARI, ROSS MACLEAN, ADRIAN R. LEVY, ABDULRAZZAQ A. AL MADANI, Vancouver, BC, Canada, Wallingford, CT, Dubai, United Arab Emirates, Princeton, NJ
Despite the high prevalence (25%) of type 2 diabetes mellitus (T2DM) in
the United Arab Emirates (UAE), few data are available on the types and
quality of care administered. The objective was to assess quality of T2DM
care in Dubai, UAE.
T2DM patients were systematically sampled from the Diabetes Clinic
database at a large hospital in Dubai. Inclusion criteria were: visit between
October 2009 and March 2010 (accrual period), age ≥18 years and UAE
nationality. Patient and disease characteristics and care patterns were
synthesized. Quality of care was assessed for the 12 months after the
accrual period, based on the United States (US) Healthcare Effectiveness
Data and Information Set (HEDIS) Comprehensive Diabetes Care measures,
including: glycosylated hemoglobin (HbA1c) screening, control (<8%) and
poor control (>9%); low-density lipoprotein (LDL) screening and control
(<100 mg/dL); blood pressure (BP) control (<140/90 mmHg); and screening for
retinopathy or nephropathy.
Of 250 eligible patients, mean age at enrolment was 58 years (standard
deviation (SD): 12 years), 33% were male, and mean T2DM duration was 14
years (SD: 8 years). Quality of care measures are presented in Table 1.
Although guideline monitoring of clinical measures was conducted for
most, higher rates of screening for complications and meeting clinical targets
would reduce the burden of T2DM in the UAE. These measures would be
useful for informal comparison to other local, or US, HEDIS estimates.
Supported by: AHA (11CRP5620013)
&
Supported by: Bristol-Myers Squibb
PEDIATRICS—OBESITY AND TYPE 2 DIABETES
&
Guided Audio Tour: Pediatric Obesity and Type 2 Diabetes—Insights and
Outcomes (Posters: 1287-P to 1293-P), see page 19.
CHERIL L. CLARSON, HILARY BROWN, STEPHANIE DEJESUS, MICHELLE JACKMAN, FARID H. MAHMUD, HARRY PRAPAVESSIS, KEVIN J. SHOEMAKER, JUSTINE WILSON, DAVID J. HILL, London, ON, Canada, Toronto, ON, Canada
1287-P
Hepatic De Novo Lipogenesis in Youth: Role of the GCKR rs1260326
Variant
The REACH study (ClinicalTrials.gov #NCT00934570) assessed a structured
lifestyle intervention with metformin extended release (MXR) or placebo
on BMI, metabolic risk factors, and adipokines in obese adolescents in a
2-year trial. Sixty-nine obese adolescents (10-16 years, BMI >95th centile)
were randomized to MXR or placebo, and subsequently to moderate or
vigorous intensity exercise for 12 weeks. Group exercise continued weekly
and nutritional and behavioral counseling monthly. Sixty-one subjects (88%)
completed 6 months, 47 (68%) 12 months, and 29 (42%) 24 months. Mixed
factor ANOVA with an interaction term between treatment condition and
time was used to compare the patterns of change over time, depending on
treatment condition. The medication (ignoring exercise) time interaction was
significant for BMI z score (p=.01) and % body fat (p=.03). In the MXR group,
there were significant differences in BMI z score at baseline (2.22±037)
and 6 months (2.08±0.48, p<.001), 12 months (2.05±0.49, p=.002) and
24 months (2.10±0.46, p=.04); The % body fat also decreased in the MXR
group between baseline (45.81±5.03) and 6 months (42.65±7.13, p<.001),
12 months (43.47±06.17, p=.0002), and 24 months (44.90±07.19, p=.03). No
significant improvements were seen in placebo assigned subjects. The
NICOLA SANTORO, ELIZABETH PARKS, BRIDGET PIERPONT, SONIA CAPRIO, New
Haven, CT, Dallas, TX
The rs1260326 single nucleotide polymorphism (SNP) in the glucokinase
regulatory protein (GCKR) gene variant has been recently associated with an
increased hepatic fat content, elevated concentrations of plasma large VLDL
and triglycerides (TG) in obese children and adolescents. The rs1260326 is a
functionally-relevant SNP consisting of a C (common allele) to T (risk allele)
substitution coding for a proline to leucine substitution at the position 446
(P446L). Recent studies have suggested that the mechanism underlying
increased HHF% may be an increased hepatic de novo lipogenesis (%DNL).
To test this hypothesis, 10 adolescents (mean age of 15.8±2.3, mean BMI
of 35.8±7.57) underwent the assessment of lipogenic stimulation, an oral
glucose tolerance test (OGTT), and fast-MRI to assess hepatic fat content
(HFF%). Lipogenesis was assessed by measuring D2O incorporation into
VLDL-TG palmitate after consumption of glucose (75g) and fructose (25g).
Absolute lipogenesis (AbsDNL) was calculated as %DNL x large VLDLTG content. Subjects were selected according to the genotype (5CC and
ADA-Funded Research
&
1289-P
Structured Lifestyle Intervention With Metformin Extended Release
or Placebo in Obese Adolescents
For author disclosure information, see page 829.
Guided Audio Tour poster
A337
POSTERS
Hyperinsulinemia is commonly associated with obesity in cross section
studies. However, it is debated if hyperinsulinemia predicts weight gain in
adults and children. Aim of the present study was to investigate the effect of
fasting insulin on longitudinal changes in body weight and the development
of cardiovascular disease risk factors in early childhood.
424 Children (211 boys and 213 girls) from Da Qing city, China, were recruited
at 5 years old and followed-up for 5 years. Blood pressure, anthropometric
measurements, fasting plasma insulin, glucose and triglycerides (TG) levels
were measured at baseline and follow up, while birth weight and television
(TV) viewing time only at baseline. The relationships among these parameters
were investigated in boys and girls. Multivariate regression analysis was
used to test if the fasting insulin predicts weight change (ΔWeight) during
the 5-years follow-up.
Compared with children in the lowest quartile of fasting insulin at 5 years
old, the children in the top quartile had significant higher ΔWeight 5 years
later in both boys (18.39±0.86 vs. 13.08±0.73 kg, p<0.01) and girls (15.80±0.60
vs. 12.03±0.71 kg, p<0.01).Similar trend was found in body mass index (BMI).
Fasting insulin at entry significantly associated with ΔWeight over the
5years follow-up period after the adjustment of gender, birth weight, TV
viewing time and body weight at 5 years old (p<0.0001). In addition, Systolic
blood pressures, fasting plasma glucose, TG and the HOMA_IR at 10 years
old were also significantly higher in those children who had higher fasting
insulin 5 years before. Of note, body weight at baseline did not significantly
associated with change of fasting insulin during the follow-up period
(p>0.05).
Fasting insulin predicts weight gain and the increase of cardiovascular risk
factors in Chinese children of early childhood, but the body weight dose not
predict increasing of fasting insulin over 5 year follow-up.
Clinical Diabetes/
Therapeutics
YANYAN CHEN, JINPING WANG, YAYUN JIANG, HUI LI, YINGHUA HU, GUANGWEI LI, Beijing, China, Daqing, China
Table 1. Quality of care assessment among T2DM patients in Dubai, April 1,
2010 to March 31, 2011
T2DM Patients
(N=250)
Diabetes Care Measure
n
(%)
HbA1c screening
245
(98.0)
HbA1c poor control (>9.0%)
65
(26.0)
HbA1c control (<8.0%)
135
(54.0)
LDL screening
225
(90.0)
LDL control (<100 mg/dL)
160
(64.0)
BP control (<140/90 mmHg)
108
(43.2)
Retinopathy attention/screening
80
(32.0)
Nephropathy attention/screening
39
(15.6)
&
1288-P
Fasting Insulin Predicts Weight Gain and Cardiovascular Risk Factors in Early Childhood over a 5-Year Period: The Da Qing Children
Cohort Study
PEDIATRICS—OBESITY AND TYPE 2 DIABETES
at least 1 major event, and by 2.4 (95% CI 1.4-4.3) for those with at least
4 major events. The odds for clinically elevated depressive symptoms or
impaired QOL were associated with a 2-fold increase among those reporting
at least 1 major event (95% CIs 1.1-4.7 and 1.1-3.6) and with a 4-fold
increase among those with at least 4 major events (95% CIs 2.1-10.2 and
1.9-7.9). Assessing exposure to stressful events among youth with T2D and
identifying supportive interventions may be important in mitigating risk of
diminished self-management and psychosocial dysfunction.
following changes were significant but did not differ by medication group:
insulin resistance (HOMA) (p=.03) and fasting glucose (p<.001) decreased
at 6 months; leptin decreased at 6 (p=.003) and 12 months (p=.02); The
following changes were significant but did not differ by intensity of exercise
at 6 months: BMI z score (p=.0004), % body fat (p=.001), HOMA (p=.007),
fasting glucose (p<.001), and leptin (p=.005) decreased at 6 months, while
the adiponectin to leptin ratio (p=.01) increased. A structured lifestyle
intervention was successful in arresting the rise in BMI z score and % body
fat in obese adolescents and the addition of MXR to lifestyle intervention
led to a decline in BMI z score and % body fat.
Supported by: NIDDK/NIH (U01-DK61212)
&
Supported by: Children’s Health Foundation; CIHR
&
1290-P
SILVA A. ARSLANIAN, LAURA PYLE, NEIL H. WHITE, FIDA BACHA, SONIA CAPRIO,
MOREY W. HAYMOND, LYNNE LEVITSKY, ROBIN S. GOLAND, STEVEN M. WILLI,
Pittsburgh, PA, Rockville, MD, St. Louis, MO, Houston, TX, New Haven, CT, Boston,
MA, New York, NY, Philadelphia, PA
Effects of Sex and Race on the Change in Total and Abdominal
Adipose Tissue and Intrahepatic Lipid in Response to Exercise in
Obese Adolescents
The TODAY trial enrolled 699 obese youth (10-17 years) with type 2
diabetes (T2D) of < 2 years, and found that, regardless of random assignment
to 1 of 3 treatments (metformin alone, metformin + rosiglitazone, or
metformin + lifestyle), glycemic failure rates (HbA1c ≥8% for 6 months or
sustained metabolic decompensation) were higher in non-Hispanic blacks
(NHB, 52.8%) vs. whites (NHW, 36.6%) and Hispanics (H, 45.0%). We
investigated whether differences in insulin sensitivity (IS, 1/fasting insulin
[1/IF]), insulinogenic index (IGI, ΔI30/ΔG30), or β-cell function (βCF) relative to
IS (oral disposition index [oDI], 1/IF x ΔI30/ΔG30) explained the racial disparity
in response to treatment. The table shows baseline characteristics in NHB,
H and NHW.
ANTHONY R. DELDIN, JENNIFER L. KUK, FIDA BACHA, INGRID LIBMAN, TAMARA S. HANNON, CHRIS BOESCH, SOJUNG LEE, Pittsburgh, PA, Toronto, ON,
Canada, Houston, TX, Indianapolis, IN, Bern, Switzerland
POSTERS
Clinical Diabetes/
Therapeutics
1292-P
Racial Disparity in Maintenance of Glycemic Control in the TODAY
Trial: Does Insulin Sensitivity, β-Cell Function, or Both Play a Role?
We examined the influence of sex and race on the change in total (TAT),
abdominal subcutaneous (ASAT) and visceral adipose tissue (VAT) and
ectopic fat in the liver and skeletal muscle in response to aerobic (AE)
versus resistance exercise (RE) training without calorie restriction in obese
youth. Fifty-nine obese adolescent boys and girls (BMI>95th, 12-18 yrs) were
randomized to 3-months of AE (n=29) or RE (n =30). Total and regional AT
were measured by whole-body MRI and intrahepatic lipid by proton magnetic
resonance spectroscopy. Mid-thigh skeletal muscle density was measured
by computed tomography. Independent of sex, body weight did not change
(P>0.1) in response to AE and RE training. In both exercise groups, there
were no ethnic differences in changes in skeletal muscle density, TAT or
ASAT. There were also no sex differences in skeletal muscle density. With
respect to intrahepatic lipid, white girls had greater (P<0.05) reductions in
intrahepatic lipid than black girls and white boys with RE, but the differences
were diminished with increasing intrahepatic lipid loss. For TAT and ASAT,
girls had significantly greater decreases in TAT with AE than boys, wherein
the differences diminished with increasing fat loss. For VAT, there were sex
and race main effects in that girls and blacks lost more VAT in response to the
same RE training (P<0.05), after adjusting for baseline differences in VAT. In
terms of the fitness measures, boys gained 25.5% more strength with RE and
28% more aerobic fitness with AE than girls (P<0.05). Our findings suggest
that in response to aerobic or resistance training, there are sex and race
differences in adiposity and fitness changes in obese adolescent boys and
girls. In general, there are more sex differences than racial differences and
that females have greater improvements in adiposity, but boys have greater
improvements in fitness.
NHB had higher BMI, HbA1c, IGI, and oDI, and lower IS compared with H
and NHW. Within each race, the trends were similar between those who
failed vs. those who did not fail to maintain glycemic control on assigned
treatment; baseline HbA1c was higher and βCF (IGI and oDI) was lower in
those who failed vs. those who did not; BMI and IS were the same (data
not shown).
These results indicate that, regardless of race, impaired βCF at baseline
but not IS, was associated with failure of glycemic control over time. The
higher failure rate in NHB was not associated with greater impairment in
βCF. Other factors, e.g. behavioral/psychosocial, may underlie the racial
disparity in response to treatment in TODAY.
Supported by: NIDDK
&
Supported by: NIDDK
1291-P
Correlates of Exposure to Stressful Life Events in Youth With Type 2
Diabetes (T2D) in the TODAY Clinical Trial
&
NATALIE WALDERS-ABRAMSON, ELIZABETH M. VENDITTI, BARBARA J. ANDERSON, LAURE EL GHORMLI, MITCHELL GEFFNER, JOAN KAPLAN, MICHAELA
KOONTZ, CAROLYN LANDIS, MARISA PAYAN, RONALD SALETSKY, PATRICE
YASUDA, Aurora, CO, Pittsburgh, PA, Houston, TX, Rockville, MD, Los Angeles, CA,
Philadelphia, PA, Cleveland, OH, Syracuse, NY
1293-P
Minimum Prevalence of Persistent Albuminuria in Youth <18 Years
of Age With Type 2 Diabetes Mellitus: A Canadian Paediatric Surveillance Program Study
ELIZABETH A.C. SELLERS, STASIA HADJIYANNAKIS, SHAZHAN AMED, ALLISON DART, ROLAND DYCK, JILL HAMILTON, VALERIE LANGLOIS, CONSTADINA
PANAGIOTOPOULOS, ANNE-MARIE UGNAT, HEATHER J. DEAN, Winnipeg, MB,
Canada, Ottawa, ON, Canada, Vancouver, BC, Canada, Saskatoon, SK, Canada, Toronto, ON, Canada
The NIDDK-sponsored TODAY clinical trial of youth-onset T2D provided
the opportunity to examine relationships between stressful life events,
physiological measures (BMI, metabolic control, hypertension, triglycerides),
medication adherence, and psychosocial factors (depression, quality of life
[QOL]). During the final TODAY visit, participants completed the Yeaworth
(1980) Adolescent Life Change Event Scale. Respondents indicated whether or
not 33 events had occurred over the past year and, if so, rated the associated
level of distress (0=not at all upsetting to 4=extremely upsetting). Data were
available from 497 participants at mean age 18.4 years and 66% female,
31% Black non-Hispanic, 40% Hispanic, and 22% White non-Hispanic. Total
number of events, number of major stressful events (considering only those
events that were somewhat, very, or extremely upsetting), and sum of
distress levels were calculated for each respondent. Participants reported
an average 5.2 events (SD 2.9, range 0-14), 1.9 major events (SD 2.1, range
0-13), and 11.7 cumulative event distress (SD 9.1, range 0-61). Major stressful
events were not related to physiological measures. Relationships between
stress exposure and psychosocial factors were found. The odds of nonadherence to medication increased by 1.6 (95% CI 1.0-2.3) for those with
The natural history of type 2 diabetes diagnosed in childhood is still
largely unknown. Evidence suggests that microvascular complications
occur at an earlier age with a shorter duration of diabetes in youth-onset
compared to adult-onset disease. The prevalence of albuminuria, the first
sign of nephropathy, is not known in this population.
This observational study used data from the Canadian Pediatric
Surveillance Program (CPSP) that reported cases of persistent albuminuria
in youth (< 18 years of age) with type 2 diabetes. Case reporting occurred
during a 24 month period from March 2010-2012. Type 2 diabetes was defined
using national guidelines. Persistent albuminuria was defined as a positive
albumin-to-creatinine ratio in a minimum of 2 out of 3 urine samples over a
minimum of 3-6 months and confirmed with at least one first morning sample.
Descriptive statistics were used to illustrate demographic and clinical
features of the population. Data from a previous national surveillance study
&
For author disclosure information, see page 829.
A338
Guided Audio Tour poster
ADA-Funded Research
PEDIATRICS—OBESITY AND TYPE 2 DIABETES
Methylation of CpG loci at 5-7y showed temporal stability, and predicted
future adiposity. Thus, longitudinal tracking co-efficients (p< 0.001 for all
loci) were such that methylation at 5-7y predicted 77-88% of the variation
in methylation at 14y, and for each unit of methylation at 5-7y, adiposity (%
fat) differed by 1.25 (95% CI: 0.47-2.03) at CpG locus -841; 0.75 (0.26-1.24)
at CpG -816; 0.63 (0.09-1.17) at CpG -78 and 0.70 (0.01-1.40) at CpG -521
(all p≤0.03). Whilst there were also associations between methylation and
insulin resistance, these were attenuated by the inclusion of adiposity in
the models.
PCG1α is central to energy homeostasis through regulation of mitochondrial function, pancreatic β-cell function and adipogenesis. These
findings are novel, and suggest a functional role for early methylation of
PCG1α in the later development of obesity and such epigenetic marks in
childhood may have predictive value.
for type 2 diabetes in youth was used to calculate the minimum prevalence
of persistent albuminuria.
50 cases were reported over the 24 month study period. Mean age at
diagnosis of diabetes was 12.3 years (SD 2.1). Mean duration of diabetes
at diagnosis of albuminuria was 0.76 years (SD 1.36). 64% were female.
80% were of Canadian First Nation heritage, 10% Caucasian and 10% other
ethnicities. 38/50 (76%) were from Manitoba, 10/50 (20%) from Ontario and
one each from Alberta (2%) and Nova Scotia (2%). 65% were exposed to
either gestational or pre-gestational diabetes in utero. Minimum prevalence
of persistent albuminuria in youth with type 2 diabetes was 7.4%.
In conclusion, persistent albuminuria occurs in youth with type 2 diabetes
in the first year after diagnosis, demonstrates regional variation and is
associated with First Nation heritage and exposure to maternal diabetes
in pregnancy.
Supported by: Public Health Agency of Canada
1296-P
MING LI, JINHUA YIN, LU XU, BCAMS GROUP, XINHUA XIAO, Beijing, China
CLAUDIA TOLEDO-CORRAL, BRIDGETTE BLEBU, PRAJAKTA PARAB, PRASANNA
MOHANTY, LAUREN GYLLENHAMMER, TING LIU, MICHAEL I. GORAN, MARC J.
WEIGENSBERG, Los Angeles, CA
Abnormal intrauterine growth resulting in a birth weight (BW) lower or
greater was an independent risk factor for future metabolic disorders. The
aim of this study was to clarify the association of BW with insulin resistance
(IR), adverse adipokine profile and abnormal metabolism in a population of
Chinese children and adolescence. This is a retrospective study including
3091 children and adolescents aged 6 to 18 in the Beijing area from the
Beijing Child and Adolescent Metabolic Syndrome (BCAMS) study. The
subjects were evaluated with respect to anthropometric measurements,
pubertal development, blood pressure, glucose, insulin, lipid profiles,
and adipokines including leptin, adiponectin, RBP-4 and resistin. When
compared with normal birth weight (NBW) peers, low birth weight (LBW)
was a strong determinant for children’s IR (OR=1.79, P=0.006), but high
birth weight (HBW) predicted current central obesity (OR=1.712,P=0.002) in
our study population of Chinese children and adolescents. BW negatively
correlated with children’s serum leptin level (P=0.008), leptin/adiponectin
ratio (P<0.001) and RBP-4(P=0.005), but positively correlated with serum
adiponectin level (P=0.006) after adjusting for age, gender, Tanner stage,
parental DM history, current body mass index (BMI), family annual income,
parental education and children’s physical activity. BW negatively correlated
with current HOMA-IR (P<0.001) and MetS components including systolic
blood pressure (P<0.001), diastolic blood pressure (P=0.007), triglycerides
(P=0.003) and fasting plasma glucose (p=0.014) after adjustment for above
covariates.
In conclusions, a lower BW was a strong predictor for future glucose and
lipid metabolic disorder including adipokine changes early in childhood,
whereas higher BW predicted childhood central obesity.
This study extends previous findings showing associations between
elevated serum cortisol and metabolic syndrome (MS) in Latino children ages
8-13 yrs, by examining associations between salivary cortisol patterns and
MS, visceral adipose tissue (VAT), and insulin sensitivity (Si) in older OLAs.
107 healthy OLAs (51M/46F; age 15.8±1.2y; BMI-z: 2.0±0.4) were admitted to
hospital overnight to measure nocturnal cortisol rise (NCR=salivary cortisol
rise from 2200hrs to awakening at 0530hrs), cortisol awakening response
(CAR=salivary cortisol from awakening to 30 min later); blood pressure
(BP), fasting serum cortisol, glucose, insulin, and lipids; % body fat by DXA;
VAT using 1.5T MRI. Si was determined by FSIVGTT and minimal modeling.
Children with MS had higher CAR vs children without MS (1.10±0.09 vs.
0.82±0.08 µg/dl, p=0.02), after adjusting for age, sex, %body fat. Serum
cortisol and NCR were not associated with MS (p>0.05). Among individual
features of MS, children with either a high systolic or diastolic BP had a
lower NCR than those with normal BP (0.57±0.08 vs 0.81±0.06 µg/dl, p=0.02)
when adjusted for age, sex and total %body fat. Waist circumference,
triglycerides, and HDL were not associated with any cortisol measures (all
p>0.05). Fasting serum cortisol, but not CAR or NCR, was associated with
VAT (r=0.20, p=0.04). Si was negatively correlated to CAR and serum cortisol
(r=-0.23 & -0.22, p<0.05) and marginally associated with NCR (r=0.18,
p=0.06) after adjusting for age, sex and %body fat. Adjusting for VAT did
not alter the association between CAR and MS (p=0.04). However adjusting
for Si did weaken this relationship (p=0.18). In OLAs, multiple markers of
hypothalamic-pituitary-adrenal axis activity (HPA) were associated with
cardio-metabolic risk factors. The specific link between MS and altered HPA
axis activity may be at least partly mediated by Si, but is independent of VAT
or total body fat.
Supported by: Beijing Municipal Science Technology Commission
1297-P
Supported by: NCMHD (P60MD00254); NCRR (M01RR00043-46)
Lower Soluble Receptor for Advanced Glycation End Products Independently Predicts Metabolic Syndrome in Youth
1295-P
SARAH R. BRICKEY, JUSTIN RYDER, DONALD R. MCCLELLAN, GABRIEL Q. SHAIBI,
Phoenix, AZ
Methylation of PGC1α at 5-7y Predicts Adiposity Throughout Childhood: A Longitudinal Study
The soluble receptor for advanced glycation end products (sRAGE) has
antiatherogenic properties in adults. Despite the increasing prevalence of
obesity, metabolic syndrome and type 2 diabetes in youth, little is known
about the relationship between sRAGE and cardiometabolic disease risk in
the pediatric population. Therefore, the purpose of this investigation is to
examine the relationship between sRAGE and cardiometabolic risk factors
in Latino youth. Data from 133 Latino youth (58% female; age 15.3±3.3 years)
enrolled in the Arizona Insulin Resistance Registry were analyzed. Metabolic
syndrome was determined using a continuous risk score calculated from the
individual components normalized to the population adjusting for age and
gender. Components included waist circumference, high-density lipoprotein
cholesterol (HDL-c), triglycerides, mean arterial pressure (MAP), and HOMAIR. sRAGE levels were determined from fasting serum using an enzymelinked immunosorbent assay. In univariate analysis, sRAGE was inversely
associated with waist circumference (r=-0.22, p= 0.01), MAP (r=-0.15, p= 0.09),
and HOMA-IR (r=-0.29, p<0.01) and positively associated with HDL-c (r=0.19,
p<0.05). In multiple regression analysis that included age, gender, and BMI,
as covariates, sRAGE was an independent protective predictor of metabolic
syndrome risk score (p=0.03). This model accounted for approximately
55% of the total variance in metabolic syndrome (total R2=0.55, p<0.001).
JOANNE HOSKING, REBECCA CLARKE-HARRIS, TERENCE J. WILKIN, ALISON
N. JEFFERY, BRAD S. METCALF, JONATHAN PINKNEY, KAREN A. LILLYCROP,
GRAHAM C. BURDGE, Plymouth, United Kingdom, Southampton, United Kingdom,
Exeter, United Kingdom
Obesity is considered the most important cause of the increase in type
2 diabetes in childhood. Early environmental exposures modify the risk
of obesity, but epigenetic association has so far been based on single
measurements at time points that are disparate from either the health
outcome, or the environmental exposure. Crucial evidence from longitudinal
studies linking events over time is lacking.
We undertook longitudinal analysis of DNA methylation in the peroxisomal
proliferator-γ-co-activator-1α promoter (PCG1α) in blood taken from 40
children (20 boys) annually over nine years. Seven CpG loci were sequenced
which have been shown previously to be hypermethylated and associated
with decreased PGC1α expression in overweight subjects. The association
between methylation of PGC1α at 5-7y, adiposity (DEXA % fat) and insulin
resistance (HOMA2-IR) between 9-14y was modelled using generalised
estimating equations, taking into account gender, pubertal timing, and
physical activity.
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A339
POSTERS
Associations between Salivary Cortisol Patterns and Cardio-Metabolic Risk Factors in Overweight Latino Adolescents (OLAs)
Clinical Diabetes/
Therapeutics
Birth Weight Predicts Adverse Adipokine Profile, Insulin Resistance and Abnormal Metabolism in Chinese Children and Adolescents: Results from BACMS Study
1294-P
PEDIATRICS—OBESITY AND TYPE 2 DIABETES
These data suggest that sRAGE may be an early independent biomarker of
cardiometabolic disease risk in youth. Prospective studies are needed to
establish the predictive utility of sRAGE for long-term disease outcomes.
Distinct HDL Subspecies are Associated With Increased Arterial
Stiffness in Youth With Type 2 Diabetes
1298-P
AMY S. SHAH, SCOTT M. GORDON, L. JASON LU, LAWRENCE M. DOLAN, ELAINE
M. URBINA, W. SEAN DAVIDSON, Cincinnati, OH
1300-P
Human epidemiological studies demonstrate that increased HDL
cholesterol (HDL-C) concentrations are associated with a decrease risk in
cardiovascular disease. However, recent drug therapies designed to raise
plasma HDL-C concentrations have failed to reduce cardiovascular events.
These findings suggest that the cardio-protective effects of HDL may lie
in specific HDL subspecies and not in the HDL-C number. Thus, we sought
to define the composition of HDL in adolescents with T2D and determine
whether specific HDL subspecies are associated with early markers of
arterial disease.
Youth with T2D (n=10) and two control groups lean (n=9) and obese (n=11)
adolescents were recruited in a cross sectional study. Plasma was separated
into 18 fractions using gel filtration chromatography. Lipid associated
proteins were then isolated and identified using mass spectrometry.
Concurrently, arterial thickness and stiffness measures including common/
bulb/internal carotid intima media thickness (IMT) and pulse wave velocity
(PWV) were measured.
Compared to lean and obese controls, youth with T2D exhibited decreased
phospholipid content in fractions containing large HDL subspecies that was
inversely associated with pulse wave velocity (p<0.001). No association
between HDL-C and pulse wave velocity was seen. Proteomic analysis of the
HDL sized fractions demonstrated decreases in 17 of 45 identified proteins in
the T2D group compared to lean youth. The most striking protein decreases
occurred in apolipoprotein (apo) A-1, apoC-I, apoE and paraoxonase-1
(p<0.05) in fractions associated with large HDL particles.
Our data demonstrate early changes in the lipid and protein compositions
of specific HDL subspecies in adolescents with T2D that are related to
early markers of arterial disease. These findings suggest that analyzing
the composition of HDL, rather than HDL-C, may be useful in assessing
cardiovascular risk in this population.
Overweight/Obese Girls With Type 1 Diabetes (T1D) at High Risk for
Adverse Behavioral Health Outcomes
POSTERS
Clinical Diabetes/
Therapeutics
KARL E. MINGES, ROBIN WHITTEMORE, ARIANA CHAO, KATHRYN M. MURPHY,
MARGARET GREY, New Haven, CT, Philadelphia, PA
Overweight/obese youth and youth with T1D report more health-related
concerns relative to their normal weight peers and youth without T1D.
However, the relationship between weight status and behavioral health
outcomes in youth with T1D is not known.
A secondary analysis of baseline data from a multi-site trial of an internet
behavioral program was undertaken to examine differences of normal
weight (BMI ≥ 5th and < 85th percentile) and overweight/obese (BMI ≥ 85th
percentile) boys and girls with T1D in clinical (HbA1c, duration), psychosocial,
self-management, quality of life, and family factors. Youth (n=318, mean
age=12.3 ± 1.1 years, 55% female, 62.7% white) completed validated
self-report measures of perceived stress, self-worth, social relationships,
depression, self-management (activities, adherence to treatment), quality
of life, and family conflict and support. Parents reported socioeconomic
factors, and HbA1c was determined by DCA2000. T-tests and chi-square
analyses were used.
Overall, overweight/obesity was prevalent (39.0%) and was high in girls
(42.6%) and boys (33.1%). Overweight/obese youth had a significantly higher
HbA1c (8.6 ± 1.6) relative to normal weight youth (8.2 ± 1.4) (p=0.03), but
this was attenuated when stratified by gender. Overweight/obese girls had
parents with lower education (p<0.01), but not lower income (p=0.09), and
had longer diabetes duration (p=0.02) compared to normal weight girls.
Further, overweight/obese girls exhibited significantly lower psychosocial
functioning (p=0.001-0.04), self-management (p=0.01-0.02), quality of life
(p=0.01) and family functioning (p=0.01-0.04) compared to normal weight
girls. No significant differences were exhibited between normal weight and
overweight/obese boys. Thus, overweight/obesity is prevalent among youth
with T1D and overweight/obese girls with T1D comprise a group at high risk
of adverse health outcomes. Greater attention to weight status in youth
with T1D is warranted.
1301-P
The Relationship between A1c, 2hr Plasma Glucose, and Continuous Glucose Monitoring-Determined Glycemic Patterns in Obese
Adolescents
Supported by: NIH/NINR (2R01NR04009); NIH/NIDDK (1T32DK097718)
CHRISTINE L. CHAN, KIM MCFANN, KRISTEN J. NADEAU, LINDSEY NEWNES,
PHILIP S. ZEITLER, MEGAN M. KELSEY, Aurora, CO
1299-P
Studies comparing A1c in diagnosing diabetes to the “screening gold
standard” 2hr plasma glucose after 75 gram glucose load (2hr PG) or fasting
plasma glucose (FPG) have reported discrepancy of the A1c vs. 2hr PG. To better
understand these discrepancies, continuous glucose monitoring (CGM) was
utilized to directly study free-living glycemic patterns in obese adolescents.
Relationships among A1c, FPG, 2hr PG and CGM variables were examined.
111 adolescents ages 10-18 yrs, BMI ≥85th%ile, A1c ≤7.5% and not on
pharmacologic diabetes treatment participated. Linear regression was
used to examine the association of A1c, 2hr PG, and FPG with the following
outcomes from 24 hours of CGM data: % time spent ≥120, ≥140, and ≥200
mg/dl; day area under the curve (AUC), night AUC, and total AUC.
Subjects average age was 13.9 ± 2.2 yrs, A1c 5.7 ± 0.4%, 2hrPG 134 ±
34 mg/dL, BMI 97.9 ± 2.6%.; 37% male, 59% Hispanic, 23% white, 17%
black. While OGTT and A1c each correlated significantly with multiple CGM
outcomes, r2 did not differ significantly between A1c and OGTT on any CGM
outcome (Table 1). FPG failed to predict any CGM outcome.
This is the first study to compare A1c and 2hr PG to direct measures of
glycemia with CGM in overweight/obese adolescents. 2hr PG did not
outperform A1c in predicting CGM outcomes. Thus, under free-living
circumstances, 2hr PG and A1c may be equally valid in predicting glycemia.
Predicting Progression to Prediabetes in Obese Latino Youth
JOON YOUNG KIM, MICHAEL I. GORAN, CLAUDIA M. TOLEDO-CORRAL, MARC
J. WEIGENSBERG, MYUNGHAN CHOI, GABRIEL Q. SHAIBI, Phoenix, AZ, Los Angeles, CA
We have previously shown that 1-hr glucose concentration during an Oral
Glucose Tolerance Test (OGTT) independently predicts the development of
prediabetes and β-cell dysfunction among obese Latino youth. However,
whether 1-hr glucose is a more powerful predictor than other glycemic
indicators is unknown. Therefore, the purpose of this study was to compare
the predictive power of 1-hr glucose to HbA1c, fasting, and 2-hr glucose
for identifying future prediabetes in youth. Obese normoglycemic Latino
youth with a family history of type 2 diabetes (67 M / 49 F; 11.5 ± 1.9
yrs) were assessed at baseline for HbA1c, fasting, 1-hr, and 2-hr glucose
during an OGTT and were subsequently followed for up to 8 years. Receiver
operating characteristic (ROC) curves were used to estimate the predictive
power of each glycemic indicator at baseline for identifying progression to
prediabetes (impaired fasting glucose and/or impaired glucose tolerance). In
addition, a multivariable prediction model combining all glycemic indicators
was assessed for predictive power. During follow-up, 52.9% of participants
developed prediabetes. The area under the 1-hr glucose ROC curve was
significantly greater than the area under the HbA1c ROC curve (73.4% vs.
58.1%; p<0.05). When compared to fasting and 2-hr glucose, predictive power
of 1-hr glucose was modestly but not significantly greater than that of either
fasting (66.9%; p=0.35) or 2-hr glucose (63.6%; p=0.12). The multivariable
model that included HbA1c, fasting, 1-hr, and 2-hr, glucose was the most
powerful model and was more predictive than the model that did not include
1-hr glucose (77.4% and 70.7%, respectively; p=0.07). These results provide
support for the clinical utility of 1-hr glucose during a standard OGTT as a
prospective marker of diabetes risk. Specifically, combining 1-hr glucose
concentrations with traditional glycemic indicators may help to identify
normoglycemic youth at highest risk for progressing to prediabetes.
Table 1. R2, P-value for LnA1c and Ln2hrPG
LnA1c
Ln2hrPG
FPG
R-square p-value R-square p-value R-square p-value
%≥120mg/dl
0.18
<0.0001 0.21
<0.0001
0.04
0.02
%≥140mg/dl
0.13
0.0004 0.26
<0.0001
0.03
0.04
%≥200mg/dl
0.11
0.10
0.08
0.09
0.03
0.06
Day AUC
0.18
<0.0001 0.25
<0.0001
0.06
0.01
Night AUC
0.20
0.0002 0.13
0.0002
0.03
0.10
24hr AUC
0.21
<0.0001 0.25
<0.0001
0.06
0.02
Supported by: NIH (R01DK59211)
Supported by: NIH/NCATS (UL1TR000154); Genentech, Inc. (1210-F05); Medtronic
Diabetes
&
For author disclosure information, see page 829.
A340
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ADA-Funded Research
PEDIATRICS—OBESITY AND TYPE 2 DIABETES
1302-P
DOSE
DIFFERENCE (95% CI) OF LEAST-SQUARE MEAN
FROM PLACEBO
Obstructive Sleep Apnea in Obese Adolescents: Associations With
Cardiometabolic Risk Markers
SARA WATSON, ZHUOKAI LI, WANZHU TU, HASNAA JALOU, JAMIE BRUBAKER,
SANDEEP GUPTA, JORDAN HUBER, AARON CARROLL, TAMARA S. HANNON,
Indianapolis, IN
2-hr blood glucose
(mg/dL)
Pediatric studies examining the association between obstructive sleep
apnea (OSA) and insulin sensitivity/cardiometabolic risk are limited and
conflicting. We examined cardiometabolic risk markers among obese youth
with OSA and their obese peers without OSA.
We performed a retrospective analysis of 162 patients (age 13.5±2.4 y) who
underwent polysomnography for suspected obesity-related OSA. Fasting
lipids, glucose, insulin, and glycosylated hemoglobin (HbA1c) were performed
as part of clinical evaluation. Patients were categorized into three groups by
degree of OSA as measured by the apnea hypopnea index (AHI): none or mild
(AHI <5), moderate (AHI 5-9.9), and severe (AHI >9.9).
Despite similar degrees of obesity, patients with moderate or severe OSA
had higher fasting insulin (p = 0.0031) and non-HDL cholesterol (p = 0.0061),
as compared with those without OSA. After controlling for body mass index
(BMI), there was a positive association between the AHI and log HOMAIR (homeostasis model assessment-insulin resistance) (p = 0.002). The
association of AHI with HOMA-IR was greatest among Hispanic patients
(p= 0.018).
Obese youth with OSA show evidence of worse cardiometabolic profiles
(including higher fasting insulin, HOMA-IR, and non-HDL cholesterol)
compared with their equally obese peers who do not have clinically
significant OSA. A novel finding is that fasting insulin and HOMA-IR are more
strongly linked with OSA among male Hispanic adolescents.
OGTT
MTT
OGTT
-15.7
-53.5
1.05
(-79.7, 48.3) (-133.0, 26.0) (-13.3, 15.4)
OGTT
75.2
(-49.2, 199.7)
OGTT
2.0
(-1.4, 5.5)
OGTT MTT
2.8
2.8
(1.7, 4.5) (1.9, 4.1)
100
-48.2
-78.01
( -112.2, 15.8) (-157.5, 1.5)
-11.5
(-25.8, 2.9)
26.4
(-101.4, 152.2)
1.2
(-2.4, 4.7)
3.4
2.6
(2.1, 5.4) (1.8, 3.8)
200
-42.5
-71.39
-18.3
(-108.3, 23.4) (-153.2,10.4) (-33.1, -3.6)
47.0
(-90.4, 184.4)
1.4
(-2.4, 5.2)
2.8
2.8
(1.7, 4.6) (1.9, 4.1)
mean ratio; bweighted average
EIRIN CAROLAN, DECLAN CODY, JEAN O’CONNELL, ANDREW HOGAN, DONAL
O’SHEA, Dublin, Ireland
Childhood obesity is an epidemic that threatens the health of future
generations.The development of insulin resistance and Type 2 Diabetes
Mellitus in children is a major concern. We investigated the inflammation
and immune profile in obese versus lean children. In total 49 subjects were
recruited from a pediatric tertiary center, categorized as obese (n=29)
and non-obese (n=20). The obese cohort had a mean BMI z score of 3.40;
lean cohort had a score of 0.18. Albeit none of the study participants had
developed Type 2 Diabetes Mellitus, there is a significant level of insulin
resistance in the obese cohort, with a mean HOMA-IR of 4.8 and mean
fasting insulin of 149 pmol/L.
A pro-inflammatory environment was found in the obese cohort with
significantly increased levels of circulating TNF-alpha, leptin and soluble
CD 163 (mean 105ng/ml in non obese vs 150ng/ml in obese cohort). This
is an important marker linking the pro-inflammatory “M1” macrophage
function to insulin resistance. On a cellular level TLR-4 stimulation of obese
peripheral blood mononuclear cell (PBMC) resulted in high levels of IL-1beta
(mean 1500pg/ml in non obese vs 2100 pg/ml in obese cohort), a cytokine
well described as pathogenic in metabolic disease. Micro RNA 33a, 33b
and 107 have been associated with metabolic disease in murine models
and adults, these small sequences post-transcriptional modify the target
gene expression. We measured circulating PBMC microRNA and found a
significantly increased expression of micro RNA 33a and 33b in the obese
cohort.
The significant alterations in the immune profile of the children from our
study population clearly depict the need for action in both preventing and
reversing childhood obesity from a young age.
1303-P
Metabolic Effects and Safety of Single Rising-Dose Sitagliptin in
Adolescents With Type 2 Diabetes
LARRY A. FOX, IAIN P. FRASER, NAOMI NEUFIELD, MARK S. KIPNES, TRACIE
L. MILLER, PHILLIP S. ZEITLER, HENRY RODRIGUEZ, JOCELYN GILMARTIN, SUSI
LEE, JACLYN K. PATTERSON, XIUJIANG LI, LATA MAGANTI, WEN-LIN LUO, DANIEL TATOSIAN, EDWARD A. O’NEILL, S. AUBREY STOCH, Jacksonville, FL, Whitehouse Station, NJ, West Hollywood, CA, San Antonio, TX, Miami, FL, Aurora, CO,
Indianapolis, IN
Supported by: National Children's Research Centre (Ireland)
The incidence of type 2 diabetes (T2DM) in adolescents is rising, but
limited antihyperglycemic treatments are available to them. In a double-blind
study, 35 patients (10 to 17 yrs old) were randomized to single oral doses of
sitagliptin (SITA) or placebo (PBO) in a 3:1 ratio. SITA doses (50, 100, or 200 mg)
were tested in ascending order in up to 12 patients/dose. Pharmacodynamic
parameters were measured during an oral glucose tolerance test (OGTT) and
a meal tolerance test (MTT). Glucose concentrations 2 hours after OGTT or
MTT were reduced in patients receiving SITA compared to those receiving
PBO, but changes did not reach statistical significance. The 100 and 200 mg
doses demonstrated similar effects, but were larger compared to the 50 mg
dose. The ratio of active to total GLP-1 was significantly increased for all
SITA doses in both tests. Glucagon concentrations were numerically lower
for the 100 and 200 mg doses relative to PBO, and insulin and C-peptide
levels were greater for all three doses of SITA during the OGTT. Trends
toward changes observed in these parameters are consistent with known
mechanistic effects of SITA. A total of 18 adverse experiences, 13 with SITA,
5 with PBO, were reported by 8 patients. With the exception of 1 report of IV
site pain of moderate intensity, all were considered mild in intensity by the
investigator. In conclusion, a 100 mg/day dose of SITA is an appropriate dose
for further evaluation in adolescent patients with T2DM.
1305-P
Natural History of Elevated Alanine Aminotransferase (ALT) Levels
in Youth With Type 2 Diabetes (T2D)
NORMA VAN WALLEGHEM, HEATHER J. DEAN, ELIZABETH SELLERS, DIABETES
EDUCATION RESOURCE FOR CHILDREN, Winnipeg, MB, Canada
Non-alcoholic fatty liver disease (NAFLD) is the most common cause of
liver disease among children, paralleling the rise of obesity. Unexplained ALT
elevation is a frequently used surrogate marker for NAFLD in children and
adults. At the Diabetes Education Resource for Children and Adolescents
(DER-CA) in Winnipeg, Canada, ALT levels are done at diagnosis of T2D
and annually if ALT <30 IU/L. If ALT >30 IU/L, levels are repeated at every
subsequent clinic visit (every 3 to 4 months). We target ALT >100 IU/L for
further evaluation for NAFLD; these children are tested for hepatitis B and
C and undergo liver ultrasound to confirm steatosis. The aim of this clinic
audit was to assess the frequency of NAFLD identified by elevated ALT
in our clinical population and describe the natural history of elevated ALT
over 5 years. Between 2007 and 2011, 69/395 youth with T2D (30 males,
39 females) have had an ALT >100 IU/L on one or more occasions. NAFLD
was confirmed by ultrasound in >85% of youth. During this 5 year period
For author disclosure information, see page 829.
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1304-P
The Development of Metabolic Disease in Obese Children: The Role
of Immune Cell Dysregulation via Increased Micro-RNA 33a and
33b, Soluble CD163 and IL-1beta
Clinical Diabetes/
Therapeutics
Supported by: Merck, Sharp & Dohme
Supported by: T32DK065549-08 (to S.W.); NIH (R03HD057532 to T.S.H.); IUPUI
(to T.S.H., W.T., A.C.)
&
50
aweighted
Demographic and clinical characteristics associated with
HOMA-IR
Regression Coefficient
95% CI
p-value
AHI
0.008
0.003 – 0.012
0.002
Female sex
0.104
-0.089 – 0.296
0.289
Black race
0.153
-0.039 – 0.345
0.117
Hispanic Race
0.502
0.141 – 0.863
0.007
Other Race
0.401
-0.177 – 0.980
0.173
Age
-0.069
-0.113 – -0.024
0.003
BMI
0.032
0.019 – 0.044
<0.001
*log HOMA-IR was used to accommodate the skewness in the HOMA-IR
ADA-Funded Research
GEOMETRIC MEAN
RATIO
(SITAGLIPTIN/
PLACEBO)
2-hr glucagon 2-hr insulin 2-hr C-peptide
GLP-1a
(pg/mL) (microIU/mL) (ng/mL) 2-hr Activeb/Totalb
PEDIATRICS—OBESITY AND TYPE 2 DIABETES
the prevalence of elevated ALT has ranged from 10-15% of our clinical
population. Three year data shows persistence of ALT >100 IU/L in <25%
of youth. Four year data shows normalization of liver enzymes in all youth,
despite no significant improvement in A1c or BMI z-score. All youth are of
Canadian First Nations heritage. The majority (71%) presented with elevated
ALT at diagnosis of T2D. The mean age at first ALT elevation >100 IU/L was
12.2 years (median 12 years; range 8-17 years). In these youth, the mean ALT
was 126 IU/L, mean A1c was 9.6%, and mean BMI z-score was 2.2. Of the 29
youth who had genotyping for the G319S polymorphism of the HNF-1alpha
gene, 69% (20/29) have one or two copies of the S allelle. In summary, many
youth with T2D have resolution of the biochemical signs of NAFLD overtime
suggesting no need for invasive testing or repeat imaging.
diabetes were compared to a group of youth with type 2 diabetes without
albuminuria reported in a previous CPSP Study conducted from 2006-2008.
Compared to youth with type 2 diabetes and no albuminuria, those with
albuminuria were younger at diagnosis of diabetes (12.2 vs. 13.6 years;
p<0.001); more likely to be of Canadian First Nation heritage (80 vs. 47%);
p<0.001), more likely to have been exposed to maternal pre-gestational
diabetes (39 vs. 21 %, p=0.03) and more likely to be hypertensive (56 vs.
24%, p<0.001) at the time of diagnosis of diabetes. Gender distribution,
BMI z-score, exposure to gestational diabetes, symptomatic presentation,
and presence of dyslipidemia or elevated liver transaminases did not differ
significantly between the 2 groups at diagnosis of type 2 diabetes.
In conclusion, in youth with type 2 diabetes of First Nation heritage, those
exposed to maternal pre-gestational diabetes and those with hypertension
at diagnosis of diabetes are at increased risk for the development of
persistent albuminuria.
1306-P
Racial Differences in Intima Media Thickness (IMT) in Obese Adolescents: No Relationship to Insulin Sensitivity
Supported by: Public Health Agency of Canada
POSTERS
Clinical Diabetes/
Therapeutics
FIDA BACHA, KIM SUTTON-TYRRELL, SOJUNG LEE, HALA TFAYLI, SILVA A. ARSLANIAN, Houston, TX, Pittsburgh, PA, Beirut, Lebanon
1308-P
African Americans (AA) men and women have twice the age adjusted rate
of fatal coronary heart disease (CHD) compared with whites. Carotid IMT is
a marker of subclinical atherosclerosis (ScA) and is predictive of the risk of
CHD and stroke. We investigated whether racial differences in ScA, IMT and
pulse wave velocity (PWV), are present in high-risk obese adolescents, and
examined its determinants.
85 adolescents, 35 with normal glucose tolerance (NGT), 26 impaired
glucose regulation (IGR), and 24 type 2 diabetes (T2DM) underwent carotid
ultrasound (IMT and PWV), DEXA, BP, and lipids. A subset (27AA, 36AW)
underwent a 3-h hyperinsulinemic (80 mu/min/m2)-euglycemic clamp to
assess the relationship of insulin sensitivity to ScA.
Age (years)
BMI (kg/m2)
Visceral adipose tissue (VAT) (cm2)
Intima media thickness (mm)
Pulse Wave Velocity (cm/msec)
Insulin sensitivity adjusted for VAT
(mg/kg/min per µu/mL)
HbA1c (%)
SBP (mmHg)
AA
(13 male, 27 female; 16
NGT, 10 IGR, 14 T2DM)
14.8 ± 0.3
34.8 ± 0.8
61.4 ± 5.1
0.54±0.007
674.5± 49.2
1.9±0.3
6.0±0.2
125.6±2.3
Mobile Health (mHealth) Intervention Called BodiMojo Using Text
Messaging Aimed at Healthy Lifestyles for Youth With Diabetes
(DM): A Pilot Randomized Controlled Trial (RCT)
ALAN T. SCHULTZ, JESSICA T. MARKOWITZ, TARA M. COUSINEAU, DEBRA L.
FRANKO, LORI M. LAFFEL, Boston, MA
Teens and young adults with type 1 and type 2 diabetes (T1D/T2D) are
frequently overweight or obese, increasing their risk for comorbidities.
mHealth modalities provide opportunities for lifestyle interventions in such
populations that almost universally use mobile technologies. We compared
an mHealth lifestyle intervention, BodiMojo, with a pamphlet about healthy
lifestyle activities in a 1-month pilot RCT in 90 youth with DM. Participants
set physical activity and nutrition goals following randomization to either
the mHealth or pamphlet group. We measured self-efficacy and A1c at
baseline and after 1 month and also assessed satisfaction with the mHealth
intervention. The mHealth group received daily text messages with general
health tips plus check-in text messages inquiring about goals 3x/week and
logistical check-ins 2x/month (total of 14 texts that were programmed for
text responses from mHealth participants). Eligibility required a cell phone
with texting capacity; 79% had a smartphone. Participants (47% male, 87%
white, 91% T1D) were 18.7±1.6 years old with DM duration of 10.0±4.6 years;
A1c of 8.5±1.7%. Of the 45 in the mHealth group, 40 (89%) responded to ≥1
text; range of responses 0-13. Of the 40 who responded, mean response
rate was 10.3±3.5; median 12. There were no differences in self-efficacy
or A1c between groups at baseline or follow-up. Of those in the mHealth
group, 82% believed BodiMojo helped them achieve health goals and 58%
would recommend BodiMojo to others. Although self-efficacy and A1c were
unchanged, it is encouraging that 89% of mHealth participants responded
to texts and ~75% (33/45) responded to ≥50% of the texts. More intensive
or longer duration mHealth interventions can likely offer greater opportunity
to engage young persons with DM in healthy lifestyle activities as well as
initiatives aimed at improving A1c in order to preserve health and prevent
complications.
AW
P
(12 male, 33 female; 19
NGT, 16 IGR, 10 T2DM)
15.3 ± 0.3
ns
35.3 ± 0.8
ns
85.6 ± 5.1
0.001
0.50±0.007
0.001
704.7 ± 42.7
ns
2.4±0.2
0.02
5.6±0.1
126.2±1.8
0.07
ns
Triglycerides were lower (95.9±9.2 vs. 125.6±8.8 mg/dl) and HDL higher
(41.9±1.6 vs. 37.5±1.4 mg/dl), p<0.05 in AA vs. AW with no differences in
cholesterol, BP or hs-CRP. In a multiple regression analysis, race independently
contributed to the variance in IMT (β= -0.41, p<0.001) besides age (β= 0.30,
p=0.009), SBP (β= 0.26, p=0.016) and HbA1c (β= 0.28, p=0.013), while sex,
insulin sensitivity and BMI did not (R2= 0.35, p<0.001). Racial difference in
IMT persisted when the NGT and dysglycemia groups were analyzed separately.
The racial disparity in ScA is present in high risk youth, is not explained by
traditional CVD risk factors, insulin resistance or CRP. It remains to be determined what factors are driving these racial differences.
Supported by: NIH/NIDDK (1R43DK85748-1A1)
1309-P
Uric Acid: Is There a Link With Cardiovascular Risk Factors also in
Youth?
MARCELE SCHETTINI, LORENA VENEZA, JAQUELINE CAIRES, PAULA PERAZZO,
ATILA OLIVEIRA, ANA LUISA OLIVEIRA, ANA MAYRA OLIVEIRA, Salvador, Brazil,
Feira de Santana, Brazil, Campinas, Brazil
1307-P
Clinical Factors Associated With Persistent Albuminuria in YouthOnset Type 2 Diabetes Mellitus: A Canadian Paediatric Surveillance
Program Study
There are evidences that recognize uric acid (UA) as cardiovascular risk
factor and link it with insulin resistance (IR) in adults but comprehensive
studies on this issue are sparse in youth. We aimed to evaluate the
frequency and characteristics of hyperuricemia in a sample of 543 Brazilian
youth (251 boys; 11.1±3.2y; BMI_zs 2.3±2.1). The measurements included:
anthropometry, blood pressure, uric acid, insulin, lipid profile, standard oral
glucose tolerance test. IR was defined by Homeostasis model assessment
of IR (HOMA-IR), excessive weight by body mass index z-score (BMI zs),
abdominal obesity by waist circumference (WC) and metabolic syndrome
by International Diabetes Federation criteria. Hyperuricemia was defined
as the values over the median value for each age and the subjects were
classified as with hyperuricemgia (Group 1) and normal uricemia (Group 2).
Hyperuricemia was seen in 348 (46.4%) individuals. The number of subjects
with hyperuricemia was higher in males than in females (p=0.001). There
were significant association between Group 1 and BMIzs, abdominal
obesity, high systolic and diastolic blood pressure, total cholesterol,
ELIZABETH A.C. SELLERS, STASIA HADJIYANNAKIS, HEATHER J. DEAN, ALLISON DART, ROLAND DYCK, JILL K. HAMILTON, VALERIE LANGLOIS, CONSTADINA PANAGIOTOPOULOS, ANNE-MARIE UGNAT, SHAZHAN AMED, Winnipeg,
MB, Canada, Ottawa, ON, Canada, Saskatoon, SK, Canada, Toronto, ON, Canada,
Vancouver, BC, Canada
Evidence is compelling that microvascular complications of type 2
diabetes occur at an earlier age with a shorter duration of diabetes in youthonset type 2 diabetes mellitus compared to adult-onset disease. The aim
of this study was to identify the clinical features at the time of diagnosis
of diabetes associated with persistent albuminuria in youth with type 2
diabetes (<18 years of age).
This observational case-control study used data from the Canadian
Pediatric Surveillance Program (CPSP) that reported cases of persistent
albuminuria in youth with type 2 diabetes. Clinical features at diagnosis of
&
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ADA-Funded Research
PEDIATRICS—OBESITY AND TYPE 2 DIABETES
group. In contrast, mean HDL-C (37 vs 44 mg/dL) and vitamin D levels (12.4
vs 14.5 IU/L) significantly decreased in the control group. Separate linear
regression models, adjusted for sex, age and z-BMI, showed that children
post-vitamin D intake had a 2 mg/dL higher HDL-C (p=0.02); a 6 mg/dL lower
LDL-C ( p<0.001); a 5 mg/dL lower glucose ( p<0.001); and a 3.2 IU/L higher
vitamin D level (p<0.001) than at baseline. In contrast, children who did not
receive vitamin D had a 6 mg/dL lower HDL-C (p<0.01), and a 1.8 IU/L lower
vitamin D level (p<0.01) than at baseline. These results suggest that vitamin
D supplementation among Indian children with inadequate vitamin D levels
could improve lipid and glucose levels.
triglyceride, fasting insulin, HOMA-IR, number of metabolic syndrome (MS)
components, C-protein reactive (CRP) (p<0.001 for all) and HDL-c (p=0.018)
and LDL-c (p=0.011). After adjustment for age and sex, BMI zs (OR, 3.1; CI,
1.8 to 5.5; p=0.000), arterial hypertension (OR, 2.1; CI, 1.2 to 3.9; p=0.007),
HOMA-IR (OR, 2.0; CI, 1.3 to 3.1; p=0.000) and dyslipidemia (OR, 2.3; CI, 1.5
to 3.7; p=0.001) were independently associated with hyperuricemia. These
observations suggest that AU in youth is associated with abdominal obesity,
IR and CRP, a marker of inflammation, supporting the hypothesis that AU
is probably a real risk factor for cardiometabolic disease even in early
stages of life. However the significance of this factor in trigger or accelerate
atherosclerosis process ask for follow-up studies.
Supported by: FAPESB
1312-P
Effect of a Resistance Training Program on Body Composition and
Metabolic Profile in Obese Non-Diabetic Adolescents
1310-P
Effects of a Short-Term Resistance Training Program on Blood Pressure and on Emerging Cardiovascular Risk Factors in Obese NonDiabetic Adolescents
Aerobic exercise is considered an effective tool in the improvement of body
composition and metabolic profile thus able to preventing cardiovascular
diseases. However the effects of an isolated resistance training (RT) program
have not been well established. We aimed to evaluate the effects of an
isolated RT program on body composition and metabolic profile in obese nondiabetic adolescents. The intervention was performed three times/week
solely with resistance exercises during three months, including 24 sedentary
obese non-diabetic adolescents (17 girls/7 boys; 14.1±1.0 y; 87.8±11.3 Kg;
32.1±3.6 kg/m2; Z-IMC 2.6±0.3). Body fat, lean and fat mass were measured
by dual-energy X-ray absorptiometry. Fasting (FPG) and 2-h post-load PG (2hPG) after 75 g glucose anhydrous, insulin, HOMA-IR, leptin, adiponectin and
non-esterified fatty acids (NEFA), triglycerides (TG), total (TC), high-density
(HDL-c) and low-density lipopotrein (LDL-c) cholesterol were analyzed. After
written informed consent all volunteers were evaluated before and after
RT. After the intervention period of an isolated and regular RT program, we
noticed a significant reduction on percent body fat (44.6±4.3 vs. 44.0±4.1 %,
P<0.01), while body mass (87.8±11.3 vs. 87.2±11.5 Kg, NS), lean (46.849±7.344
vs. 46.666±7.98 g, NS) and fat mass (37.427±6.426 vs. 36.921±6.700 g, NS)
were kept unchanged. Instead of it, insulin (28.5±13.6 vs. 23.3±10.2 mU/
ml, P<0.01) and HOMA-IR (6.0±3.2 vs. 4.9±2.2, P<0.05) were significantly
reduced after intervention while no differences on FPG, 2-hPG, TC, HDL-c,
LDL-c, TG, leptin, adiponectin and NEFA levels were observed. Our results
suggest that a 3-month program solely of RT was able to reduce body fat,
insulin levels and HOMA-IR, independently of weight loss in obese nondiabetic adolescents.
The effects of isolated resistance training exercises (RT) on blood pressure
(BP), endothelial function and low-grade inflammation are still unclear in
obese adolescents. We aimed to evaluate the effects of RT on BP, endothelial
function, and inflammatory markers in obese non-diabetic adolescents. RT
was performed three times/week solely with resistance exercises during
three months, including 24 obese non-diabetic adolescents (17 girls/7 boys;
14.1±1.0y; 87.8±11.3Kg; 32.1±3.6kg/m2; Z-IMC 2.6±0.3). BP was measured by
casual and 24h ambulatory method. Microvascular reactivity was performed
at skin using laser-Doppler flowmetry and vasomotion analyses was
assessed by fast-fourier transform analysis to determine the contribution
of the five frequency components (i.e., endothelial, 0.01-0.02Hz; neurogenic,
0.02-0.06Hz; myogenic, 0.06-0.15Hz; respiratory, 0.15-0.40Hz; and cardiac,
0.40-1.60Hz) on the variability of the signal. Endothelial-dependent and
-independent vasodilation was tested respectively after acetylcholine
and sodium nitroprusside iontophoresis. Endothelin-1 (ET-1), C-reactive
protein (CRP), fibrinogen, interleukin-6 (IL-6) and tumor necrosis factor-α
(TNF-α) were measured. All volunteers were evaluated before and after
RT. No change in body mass (32.1±3.6 vs. 31.7±3.7kg/m2; P>0.05) was
observed after the RT program, but we noted a reduction in casual and 24h
ambulatory systolic (P<0.01), diastolic (P<0.01) and mean BPs (P<0.01). RT led
to significant reductions on fibrinogen (P<0.05) and ET-1 (P<0.05) levels while
TNF-α and CRP were kept unchanged. We observed increments on cardiac
component of the vasomotion (P<0.05) and on endothelium-dependent
response (P<0.05) after RT. An isolated RT program reduced casual and 24h
ambulatory BPs and also some of the emerging cardiovascular risk factors
studied, independently of weight loss in obese non-diabetic adolescents.
Supported by: FAPERJ
1313-P
Glucose Screening and Identification of Pre-Diabetes in Children
and Adolescents 2007–2011
Supported by: FAPERJ
PATRICK J. O’CONNOR, NICOLE TROWER, ALAN SINAIKO, KAREN L. MARGOLIS,
ELYSE KHARBANDA, EMILY PARKER, NANCY SHERWOOD, KENNETH ADAMS,
JOAN LO, LOUISE C. GREENSPAN, DAVID MAGID, MATTHEW DALEY, Minneapolis, MN, Oakland, CA, Denver, CO
1311-P
Improvement in Cardiovascular Risk in Argentine Indian School
Children after Vitamin D Supplementation
This cohort study quantifies glucose screening rates in children and
adolescents in defined age, gender, BMI, and race strata. Subjects were
68,322 individuals ages 3-17 at cohort entry followed for a median of 37
months from 1/1/2007 to 12/31/2010, and with at least one clinic visit.
Subjects’ laboratory data were examined for date and results of any
outpatient fasting or random glucose, glycated hemoglobin (A1c), or oral
glucose tolerance tests (oGTT). We report descriptive statistics on glucose
testing rates and results indicating pre-diabetes by age, gender, BMI, race/
ethnicity, and year. Prediabetes was defined as fasting plasma glucose
of 100-125 mg/dL, 2-hour oGTT glucose of 140-199 mg/dL, or glycated
hemoglobin (A1c) of 5.7%-6.4% without a diabetes diagnosis.
Overall, the rate of glucose screening was 10.7% (7,278/68,322). It was
similar in males and females but higher in those with older age, obesity,
minority race, or Hispanic ethnicity. The screening rate increased from 3.9%
(1,132/28,948) per year in 2007 to 7.2% (2,301/32,167) in 2010. Glucose
screening was most often done with fasting or random glucose, but 7.7%
(560/7,278) of tests were A1c. About 13.9% (1,013/7,278) of tests indicated
pre-diabetes. Of 1,013 subjects with pre-diabetes, 79.1% (801/1,013) were
age 12 or older, 60.0% (608/1,013) had minority race or Hispanic ethnicity,
and 30.9% (313/1,013) were obese. A diabetes diagnosis (250.xx) was
present in 2.2% (161/7,278) of subjects with one or more glucose/A1c tests.
We concluded that glucose screening rates in children and adolescents are
VALERIA HIRSCHLER, GUSTAVO MACCALLINI, MILVA SANCHEZ, CLAUDIO
ARANDA, MARIANA HIDALGO, LUIS CASTANO, CLAUDIA MOLINARI, Buenos
Aires, Argentina, Barakaldo, Argentina
Low vitamin D levels correlate with measures of cardiovascular risk.
The objective was to determine whether vitamin D supplementation
reduces cardiovascular risk among Argentine Indian school children. In a
prospective one-year study, 215 (98M) children aged 10.1±2.6 years, were
evaluated in November 2011 (spring season) at baseline. A treated cohort
of 194 (106 M) children aged 10.9±2.3 years who received 5000 units of
vitamin D weekly during 8 weeks; and a control group of 21 (7M) children
aged 10.8±1.6 years who did not receive vitamin D were evaluated 1 y later
(November, 2012). Anthropometry, lipids, glucose, and vitamin D levels
([25(OH)D]) were measured at baseline and one year. The prevalence of
overweight and obesity was 26/215 (12.1%) at baseline; 16/194(8.2%) in the
treated; and 2/21 (9.5%) in the control . 31(14.4%) at baseline, 2 (1%) in the
treated, and 7 (33.3%) in the control had severe vitamin D deficiency ( <10
IU/L); 165 (77.1%) at baseline, 147(76.6%) in the treated, and 14 (66.7%) in
the control had deficiency (10- <20 IU/L); 18 (8.4%) at baseline, 43 (22.2%) in
the treated, and none in the control had insufficiency (20- <30 IU/L). Mean
values of glucose (73 vs 78 mg/dL), LDL ( 83 vs 89 mg/dL), HDL-C (46 vs 44
mg/dL), and vitamin D (17.7 vs14.5 IU/L) significantly improved in the treated
ADA-Funded Research
&
For author disclosure information, see page 829.
Guided Audio Tour poster
A343
POSTERS
INGRID BARBARA FERREIRA DIAS, PAULO DE TARSO VERAS FARINATTI, MARIA
DAS GRAÇAS C. SOUZA, DIOGO G. PANAZZOLO, DIOGO P. MANHANINI, ERICK
BALTHAZAR, DIEGO M. DANTAS, PRISCILA A. MARANHÃO, EDUARDO H.A.
PINTO, ELIETE BOUSKELA, LUIZ GUILHERME KRAEMER-AGUIAR, Rio de Janeiro,
Brazil
Clinical Diabetes/
Therapeutics
INGRID B.F. DIAS, PAULO DE TARSO VERAS FARINATTI, MARIA DAS GRAÇAS
C. SOUZA, ERICK BALTHAZAR, DIOGO G. PANAZZOLO, DIOGO P. MANHANINI,
DIEGO M. DANTAS, PRISCILA A. MARANHÃO, ELIETE BOUSKELA, LUIZ GUILHERME KRAEMER-AGUIAR, Rio de Janeiro, Brazil
PEDIATRICS—TYPE 1 DIABETES
low but increasing, and the proportion of those screened who meet criteria
for pre-diabetes is nearly 14%. Opportunistic screening rates are higher in
demographic subgroups with the highest risk of pre-diabetes. Little is known
about the overall health status, comorbidities, care, or subsequent metabolic
status of children and adolescents who meet criteria for pre-diabetes.
Parameter*
Sitagliptin 50 mg Sitagliptin 100 mg Sitagliptin 200 mg
(n=9)
(n=9)
(n=8)
3438 (2881, 4103) 5869 (4918, 7003) 12965 (10749, 15638)
AUC0-∞ (nM·hr)
Cmax (nM)
366 (288, 464)
666 (526, 845)
1876 (1458, 2413)
C24hr (nM)
32 (25, 41)
43 (34, 55)
78 (60, 101)
Tmax (hr)
3.0 (1.5, 5.0)
3.0 (2.0, 4.5)
2.5 (1.0, 3.1)
Apparent t1/2 (hr)
12.1 (1.7)
11.2 (2.1)
11.7 (1.8)
Between Population Comparisons
Parameter#
Adolescent
Adult
GMR (90% CI)
AUC0-∞ (nM·hr)
6424 (5740, 7190)‡ 7851 (6360, 9691)§ 0.82 (0.66, 1.01)
Cmax (nM)
1876 (1435, 2453)¥ 1803 (1354, 2401)† 1.04 (0.75, 1.44)
C24hr (nM)
78 (54, 112) ¥
106 (72, 156)†
0.74 (0.48, 1.14)
*Values shown for AUC and Cmax and C24hr are back-transformed geometric
least square mean (95% CI) from ANOVA model performed on natural logtransformed values; for Tmax the median (min, max) and for apparent terminal
t½ the harmonic mean with jack-knife standard deviation are shown.
#Between population comparison was made for dose-adjusted (to 100 mg)
sitagliptin AUC across all available doses in adolescent and adult patients
with T2DM; between population comparison for sitagliptin Cmax and C24hr
were made at 200 mg dose in adolescent and adult patients. Population values shown are back-transformed geometric least-squares means (95% CI)
from linear mixed effect model (for AUC0-∞) or ANOVA model (for Cmax and
C24hr) performed on natural log-transformed values.
Herman et al, JCEM 91:4612 (2006); ‡N = 25; §N=14 observations from 7 subjects; ¥N = 8; †N = 7.
Abbreviations: GMR, geometric least square mean ratio for Adolescent /
Adult; CI, confidence interval.
1314-P
Longitudinal Correlates of Youth Health Risk Behaviors among Children and Adolescents With Type 2 Diabetes in the TODAY Study
POSTERS
Clinical Diabetes/
Therapeutics
CAROLYN E. IEVERS-LANDIS, PATRICE YASUDA, NATALIE WALDERS-ABRAMSON, NANCY AMODEI, KIMBERLY L. DREWS, JOAN KAPLAN, LORRAINE KATZ,
SYLVIA LAVIETES, RON SALETSKY, DANIEL SEIDMAN, Cleveland, OH, Los Angeles, CA, Aurora, CO, San Antonio, TX, Washington, DC, Philadelphia, PA, New Haven,
CT, Syracuse, NY, New York, NY
The purpose is to report predictors of health risk behaviors (cigarette
and alcohol use) among children and adolescents with type 2 diabetes
(T2D) enrolled in the Treatment Options for type 2 Diabetes in Adolescents
and Youth (TODAY) clinical trial. Hypothesized predictors included
key demographics, child psychological and health factors (depressive
symptomatology, academic achievement, BMI z-scores, HbA1c), and parent/
family and environmental factors (stressors, neighborhood safety). Data
were obtained from TODAY participants at baseline (N=599), 6- (N=569)
and 24-month (N=507) assessments. At baseline, participants were on
average 14.2 years old (SD=2.1), 22.0% were Non-Hispanic White, 43.0%
Hispanic, and 34.9% Non-Hispanic Black. Mean BMI-for-age percentile was
97.7 (SD=3.3). A notable percentage was from a disadvantaged background
with 26.7% of parents having less than a high school degree. At baseline
10.0% had tried smoking cigarettes and drinking alcohol (4.0% smoking only;
18.0% drinking only), at 6 months 13.4% smoked/drank (4.0% smoking only;
21.4% drinking only), and at 24 months 17.8% smoked/drank (3.6% smoking
only; 26.4% drinking only). Optimal multivariate linear regressions at each
assessment generally indicated that older White males with worse grades
and higher levels of depression and stress were more likely to report engaging
in health risk behaviors, similar to findings with youth without diabetes. A
demographic variable (SES), environmental factor (neighborhood safety), and
both biological measures (BMIz and HbA1c) were not significant correlates
at any assessment. These findings may assist health care providers in
identifying youth with T2D who are at greatest risk for engagement in these
health risk behaviors.
Supported by: Merck, Sharp & Dohme
PEDIATRICS—TYPE 1 DIABETES
Guided Audio Tour: Pediatric Type 1 Diabetes—Highlights from Multicenter
Studies (Posters: 1316-P to 1322-P), see page 19.
Supported by: NIDDK/NIH (U01-DK61212), (U01-DK61230), (U01-DK61239), (U01DK61242), (U01-DK61254)
A Potential New Diagnostic Index for Type 1 Diabetes
&
1316-P
JAY M. SOSENKO, JAY S. SKYLER, LINDA A. DIMEGLIO, JEFFREY P. KRISCHER,
CRAIG A. BEAM, LISA RAFKIN, DELLA MATHESON, JERRY P. PALMER, DIABETES
PREVENTION TRIAL-TYPE 1 AND TRIALNET, Miami, FL, Indianapolis, IN, Tampa,
FL, Seattle, WA
1315-P
Pharmacokinetics and Pharmacodynamics of Sitagliptin in Adolescents With Type 2 Diabetes
We assessed the use of a 60-minute index (Index60) for diagnosing
type 1 diabetes (T1D) among those who underwent serial 2-hr OGTTs for
diagnostic surveillance in the Diabetes Prevention Trial-Type 1 (DPT-1).
Index60 is derived from a proportional hazards model that includes the
fasting C-peptide, 60-minute glucose, and 60-minute C-peptide of baseline
OGTTs in DPT-1. Since repeat testing is needed for the standard 2-hr glucose
value ≥200 mg/dl (2-hr≥200) in the absence of symptoms or unequivocal
hyperglycemia (ADA guideline), we particularly examined confirmation at the
next OGTT (at or before the 6-month visit). When an Index60 value ≥2.30
(Index60≥2.30) was first exceeded, the frequency of diagnosis of T1D was
comparable to the frequency of diagnosis when 2-hr≥200 was first exceeded
[153/170 (90%) for Index60≥2.30 vs. 166/188 (88%) for 2-hr≥200]. Of 61 with
Index60≥2.30 and a 2-hr glucose value <200 mg/dl on the same OGTT, 47
(77%) were diagnosed. Of 64 with 2-hr≥200 and an Index60 value <2.30 on
the same OGTT, 45 (70%) were diagnosed. A higher proportion was confirmed
for Index60≥2.30 (80/124; 65%) than for 2-hr≥200 (74/148; 50%). Of the 80
confirmed with Index60≥2.30, 32 could not also be confirmed with 2-hr≥200
on the same OGTTs. All 32 (confirmed solely with Index60≥2.30) were later
diagnosed by standard criteria. If Index60≥2.30 had been used as a criterion
in those 32, the diagnosis would have been made1.0±0.2 years (mean±SEM;
p<0.001) earlier. The use of Index60≥2.30 and 2-hr≥200 together as criteria
(whichever was first exceeded) instead of 2-hr≥200 alone, would have
resulted in more confirmed (92 vs. 74; 24% increase). In summary, a diagnosis
of T1D was at least as likely for Index60≥2.30 as for 2-hr≥200. Moreover,
the confirmation rate was higher for Index60≥2.30 than for 2-hr≥200, and
confirmation with Index60≥2.30 often preceded the standard diagnosis of
T1D. Index60≥2.30 and 2-hr≥200 used together resulted in a higher number
confirmed. As an adjunct to the 2-hr glucose, Index60 should contribute to
the earlier diagnosis of T1D.
IAIN P. FRASER, NAOMI NEUFELD, LARRY A. FOX, MARK S. KIPNES, TRACIE L.
MILLER, PHILLIP S. ZEITLER, HENRY RODRIGUEZ, JOCELYN GILMARTIN, SUZI
LEE, JACLYN K. PATTERSON, XIUJIANG LI, LATA MAGANTI, WEN-LIN LUO, DANIEL TATOSIAN, EDWARD A. O’NEILL, S. AUBREY STOCH, Whitehouse Station,
NJ, West Hollywood, CA, Jacksonville, FL, San Antonio, TX, Miami, FL, Aurora, CO,
Indianapolis, IN
The increase in obesity has led to an increased incidence of type 2 diabetes
(T2DM) in adolescents. There are limited antihyperglycemic treatment
options in this population. This study evaluated the pharmacokinetic (PK)
and pharmacodynamic (PD) properties of sitagliptin (SITA), a DPP-4 inhibitor,
in adolescents with T2DM. In a double-blind study, 35 patients (10 to 17 yrs
old) were randomized to single oral doses of SITA or placebo (PBO) in a 3:1
ratio. SITA doses (50, 100, or 200 mg) were tested in ascending order in up
to 12 patients/dose. SITA AUC0-∞ increased in a dose-proportional manner,
whereas SITA Cmax increased in a modestly greater than dose-proportional
manner and C24hr increased in a modestly less than dose proportional
manner (Table). Pooled across available doses, adolescents had an ~18%
lower AUC0-∞ as compared to adults with T2DM, but this difference was
contained within the prespecified bounds (0.50, 2.00) for similarity between
adolescents and adults. Mean weighted average inhibitions (WAI) of
plasma DPP-4 activity over 24 hours were significantly different between
SITA and PBO (PBO-adjusted DPP-4 WAI = 67.2% for 50 mg, 73.8% for 100
mg, and 81.2% for 200 mg). The PK/PD relationship between plasma SITA
concentration and DPP-4 inhibition was similar between adolescents (IC50
value = ~25.4 nM) and adults (25.7 nM). Given the observed PK and PK/PD
data in this study, SITA 100 mg q.d. is an appropriate dose for further clinical
evaluation in adolescents with T2DM.
Supported by: NIDDK
&
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PEDIATRICS—TYPE 1 DIABETES
~2 Weeks ~6 Months~12
Months
N=561
N=490
N=547
A1c mean ± SD(%)
11.5
7.3 ±
7.8
± 2.3
1.3
± 1.4
Injections
NA
7.3
8.0
± 1.3
± 1.5
Pump
7.3
7.4
± 1.3
± 1.1
IDAA1c
50%
26%
≤ 9.0%
Pump Use
<1%
14%
33%
1317-P
Treatment Patterns in Asymptomatic Patients With Type 1 Diabetes
Diagnosed by Research Screening
RACHELLE GANDICA, MARY PAT GALLAGHER, ELLEN GREENBERG, SARAH
POLLAK, STEVEN COOK, ELIZABETH LEVINE, ROBIN GOLAND, TYPE 1 DIABETES
TRIALNET STUDY GROUP, New York, NY
We present the 2 year clinical follow up of subjects with asymptomatic type
1 diabetes (T1D) diagnosed by research screening, a unique population since
new-onset T1D is generally diagnosed with symptoms of hyperglycemia. Fifteen
subjects with asymptomatic new-onset T1D were referred to the Berrie Center
for routine clinical care because of an abnormal oral glucose tolerance test done
in the NIH TrialNet study. Subjects were followed for at least 24 months.
Subjects’ mean age at T1D diagnosis was 12 ± 3 years (range 1-42): 8
males and 7 females. At T1D diagnosis, A1C was < 6% in 13 subjects; 14
had normal fasting blood sugars, and mean A1C was 5.7 ± 0.1% (range 4.9
to 6.6%). Insulin treatment was not recommended at T1D diagnosis in 9
subjects because self-monitored blood sugars and A1C were in the normal
range. Insulin was initiated at a mean of 11 months after diagnosis (range
1-20 months) in this group for elevated self-monitored blood sugars. Six
subjects were started on insulin immediately at T1D diagnosis because of
elevated self-monitored blood sugars. (Table 1). No subject had DKA or was
hospitalized for hyperglycemia.
Clinical management of asymptomatic new-onset T1D is variable. Initiation
of insulin at biochemical T1D diagnosis occurred in only 6 of 15 subjects. The
clinical outcome based on A1C after 2 years appears similar regardless of
timing of insulin start but more information is needed. A randomized trial
should be done to guide therapy of asymptomatic new-onset T1D.
Age
Age range
Time from diagnosis to insulin start
Time from diagnosis to A1c > 6%
A1C at 0 months
A1C at 12 months
A1C at 24 months
BMI Z score at 0 months
BMI Z score at 24 months
44%
&
1319-P
Hypoglycemia is one of the most important barriers to the achievement
of the metabolic target in young patients. We evaluated the incidence of
severe hypoglycemia (SH) in children and adolescents with T1DM cared
for by 29 Italian diabetes Centers, and identified the main risk factors
related to the patients and their parents. Information on clinical and sociodemographic patient characteristics and their family was collected during a
routine visit. Overall, 2025 consecutive patients were evaluated (mean age
12.4±3.8 years; 53% males; mean diabetes duration 5.6±3.5 years; 21.1%
treated with CSII; mean Hba1c levels 7.9±1.1). During 12 months 102 (5.0%)
patients experienced one or more SH episodes (incidence of 7.7 events/100
patients-years). At multivariate Poisson regression analysis the risk of SH
was 44% higher in male children (OR 1.44; 95%CI 1.04-1.99), 2 times higher
when the patient used short acting insulin analogues (OR 2.11; 95%CI 1.173.79) compared to regular insulin and 54% lower for patients treated with
insulin glargine (OR 0.46; 95%CI 0.22-0.95) compared with NPH insulin.
Mother’s age was inversely associated with the risk of SH (OR 0.95; 95%CI
0.92-0.97). After adjusting for clustering (center effect) the magnitude of
the risk associated with short acting insulin analogues was decreased and
no longer statistically significant (OR 1.61; 95%CI 0.87-2.97). Similarly, the
protective effect of insulin glargine as compared with NPH insulin was no
longer significant, although a lower risk associated with insulin glargine was
still present (OR 0.51; 95%CI 0.19-1.44). In conclusion, SH still represents an
important problem in children and adolescents with T1DM. The experience of
the specialist in managing insulin therapy can play an important role, and the
incidence of SH could be reduced through better use of existing therapeutic
options and better education to individuals with diabetes and their families.
1318-P
EDA CENGIZ, CRYSTAL CONNOR, KATRINA RUEDY, WILLIAM V. TAMBORLANE,
CRAIG KOLLMAN, ROY BECK, JOYCE M. LEE, GEORGEANNA KLINGENSMITH,
MARIA J. REDONDO, JANET SILVERSTEIN, PEDIATRIC DIABETES CONSORTIUM,
New Haven, CT, Tampa, FL, Ann Arbor, MI, Aurora, CO, Houston, TX, Gainesville, FL
&
1320-P
SWEET: Securing Appropriate Services and Infrastructure for Pediatric and Adolescent Diabetes in Europe
The PDC T1D NeOn study was designed to assess the natural history and
clinical outcomes in children with T1D. Clinical measures were analyzed for
590 participants with an A1c result 18-27 mos after diagnosis (mean age
9.1 yrs, 51% female, 67% non-Hispanic White). A1c levels rose substantially
6-12 mos after T1D onset in association with waning of residual endogenous
insulin secretion, as estimated by the % of participants with Insulin Dose
Adjusted A1C (IDAA1c) values <9.0%(Table). A modest rise in A1c levels was
observed from 12-24 mos, despite a further reduction in the % of participants
with IDAA1c values <9.0%. The proportion of participants who switched from
injection to pump therapy increased steadily and A1c levels were lower in
pump vs injection therapy participants during the 2 years (Table). Moreover,
a repeated measures regression model adjusting for clinical site, socioeconomic factors, race and age group showed that switching to a pump was
associated with a mean 0.41% decrease in subsequent A1c levels (p<0.001).
The substantial loss of residual endogenous insulin during the 2nd yr of T1D
suggests that future β-cell preservation studies should target differences
in c-peptide responsiveness between experimental and control groups in
the 2nd rather than the 1st yr of T1D. The metabolic consequences of waning
of the honeymoon period may have been blunted, in part, by a concomitant
increase in use of insulin pump therapy.
MICHAEL WITSCH, OLGA KORDONOURI, BAERBEL ASCHEMEIER, THOMAS
DANNE, SWEET GROUP, Luxembourg City, Luxembourg, Hannover, Germany
“SWEET” is an acronym derived from “Better control in Pediatric and
Adolescent diabeteS : Working to CrEat CEnTers of Reference” and is based
on a partnership of established national and European diabetes organizations (www.sweet-project.eu) led by the International Society for Pediatric
and Adolescent Diabetes (ISPAD) with valuable contributions of IDF Europe,
FEND, and PCDE. Peer audited Centers of Reference (COR´s) with a continuous
electronic documentation of at least 150 pediatric patients with diabetes
treated by a multidisciplinary team based on the ISPAD Clinical Practice
recommendations have been created in 12 European countries. Although
these clinics should not be regarded as representative for the whole country,
the acknowledgement as COR includes a common objective of targets and
guidelines as well as recognition of expertise in treatment and education at
the center. In a first step, the SWEET Online platform allows twelve countries
in eleven languages to connect to one unified diabetes database. Aggregate
data is de-identified and exported for longitudinal health and economic data
analysis and includes now more than 92,000 patient visits. In 2012, data was
documented of 5,766 youth with type 1 diabetes, 58 with type 2 and 110
For author disclosure information, see page 829.
Guided Audio Tour poster
A345
POSTERS
VALENTINO CHERUBINI, RICCARDO BONFANTI, DONATELLA LO PRESTI, GIUSEPPE LUCISANO, CLAUDIO MAFFEIS, CARLAMARIA MONCIOTTI, IPPOLITA P.
PATERA, FABIO PELLEGRINI, BASILIO PINTAUDI, IVANA RABBONE, MARIA CHIARA ROSSI, STEFANO ZUCCHINI, ANTONIO NICOLUCCI, SHIP-D STUDY GROUP,
Ancona, Italy, Milan, Italy, Catania, Italy, Santa Maria Imbaro, Italy, Verona, Italy,
Padova, Italy, Passoscuro, Italy, Turin, Italy, Bologna, Italy
Clinical Outcomes in Youth Within the 2nd Year of Type 1 Diabetes:
Results of the Pediatric Diabetes Consortium (PDC) T1D New Onset
(NeOn) Study
&
39%
Severe Hypoglycemia in Italian Pediatric Population With Type 1 Diabetes Mellitus: A Multicenter Retrospective Observational Study
Supported by: NIH; TrialNet
ADA-Funded Research
~24
Months
N=508
8.1
± 1.5
8.4
± 1.7
7.7
± 1.0
10%
Supported by: Novo Nordisk, Inc.; DK020572
Insulin Treatment Insulin Treatment
Not Recommended Initiated at T1D
at T1D Diagnosis
Diagnosis
N=9
N=6
17 ± 4 years
5 ± 1 years
3 to 42 years
1 to 7 years
11 ± 7 months
0 months
8 ± 1 months
0 months
5.5 ± 0.1%
6.1 ± 0.1%
6.2 ± 0.4%
6.3 ± 0.2%
7.1 ± 0.3%
6.9 ± 0.2%
0.2
0.6
0.0
0.9
&
~18
Months
N=566
8.0
± 1.5
8.2
± 1.6
7.6
± 1.1
16%
Clinical Diabetes/
Therapeutics
&
PEDIATRICS—TYPE 1 DIABETES
with other diabetes forms. The median age was 14.04 years and diabetes
duration was 5.07 years. Among centers notable differences in the average
HbA1c was present ranging between 7.5 and 9.4%, respectively. This
benchmarking data will now be used in quality control circles to exchange
best practices. Through their network, the COR´s wish to obtain political
power on a national and international level and to facilitate dissemination
of new approaches and techniques. The SWEET Group hopes to extend from
the initial group of centers within countries, throughout Europe and beyond.
OB, respectively (p=0.59). Frequency of HTN, dyslipidemia and/or MA was
relatively low (Fig. 1). By multivariate analysis, OB youth were more likely
to have HTN (p<0.001) and dyslipidemia (p<0.001), but slightly less likely
to have MA (p=0.05), than NW youth. In OW youth, frequency of HTN and
MA were intermediate but not statistically different from NW youth, while
dyslipidemia was significantly higher in OW than NW youth (p=0.006).
In conclusion, OB youth with T1D are more likely to have concomitant HTN
and dyslipidemia than NW youth, which may increase their cardiovascular
disease risk. The slightly lower rate of MA in the OB group merits further
investigation.
Supported by: Bayer; DexCom, Inc.; Eli Lilly and Company; Medtronic, Inc.; Novo
Nordisk, Inc.; sanofi-aventis
&
1321-P
Polyunsaturated Fatty Acids (PUFA) and Cardiovascular Risk Factors in Youth With Type 1 Diabetes (T1D): SEARCH Nutrition Ancillary Study
POSTERS
Clinical Diabetes/
Therapeutics
SARAH C. COUCH, JAMIE L. CRANDELL, ABIGAIL PEAIRS, ANGELA D. LIESE,
AMY S. SHAH, LAWRENCE M. DOLAN, JANET TOOZE, TESSA L. CRUME, IRENA
B. KING, ELIZABETH MAYER-DAVIS, Cincinnati, OH, Chapel Hill, NC, Columbia, SC,
Winston-Salem, NC, Aurora, CO, Albuquerque, NM
Individual plasma n-3 and n-6 PUFAs and estimates of fatty acid desaturase
activity may influence plasma lipids and thereby cardiovascular disease
(CVD) risk. In youth with T1D, altered PUFA synthesis has been reported, but
associations with CVD risk factors have not been ascertained. We investigated
whether individual plasma phospholipid (PL) n-6 and n-3 PUFAs and delta-5
desaturase (D5D) and delta-6 desaturase (D6D) activities were associated with
fasting triglycerides (TG), total cholesterol (TC), low-density lipoprotein (LDL)-C
and high-density lipoprotein (HDL)-C in 881 youth with T1D. In multivariate
analyses adjusted for demographics (age, race, gender, parental education,
and clinical site), disease factors (disease duration, insulin regimen and dose,
HbA1c), and body mass index (BMI) the following associations (expressed as
beta coefficients, * =p<.05; **p<.01) were observed:
Supported by: Leona M. and Harry B. Helmsley Charitable Trust
Guided Audio Tour: Pediatric Type 1 Diabetes—Adolescence and Beyond
(Posters: 1323-P to 1329-P), see page 19.
Plasma PL n-6 PUFA Plasma PL n-3 PUFA Desaturase
activitya
1
2
3
4
5
6
Independent LA DGLA AA
ALA EPA DHA D5D D6D
outcomes
Log-TG
0.00 0.04 -0.04* 0.44* 0.01 -0.02 -0.24* 0.07
TC
0.01 1.46 -1.26* 27.19 7.96** -0.25 -8.84* 3.58
LDL-C
0.12 -0.36 -0.09 12.57 3.28** -2.47 -0.10 -0.73
HDL-C
-0.15 1.54 -0.60 6.59 4.57* 2.38 -5.93 4.03
a Estimated D5D activity = AA/DGLA; Estimate D6D activity = DGLA/LA; 1LA =
Linoleic Acid; 2DGLA = Dihomo-γ-linolenic acid; 3AA = Arachidonic acid; 4ALA
= Alpha linolenic acid; 5EPA = Eicosapentaenoic acid; 6DHA = Docosahexaenoic acid
&
ARIANA M. CHAO, ROBIN WHITTEMORE, KARL E. MINGES, KATHRYN M. MURPHY, MARGARET GREY, New Haven, CT, Philadelphia, PA
Though it is recognized that duration of type 1 diabetes impacts HbA1c,
psychosocial adjustment, and family functioning, few studies have explored
these relationships among young adolescents. Further, the impact of
developmental stage at diagnosis is not well established. The purpose of
this study was to explore differences in HbA1c, psychosocial adjustment,
and family functioning in young adolescents by duration of diabetes and
developmental stage at diagnosis.
We used baseline data from 320 participants (11-14 years; 55% female;
37% minority) enrolled in a multi-site clinical trial of a coping skills training
program. Data on participant and clinical characteristics were obtained by
self-report. Duration of diabetes was categorized into 5 years. Developmental
stage at diagnosis was categorized into infant/toddler/preschool (diagnosed
between 1-5 years), school age (diagnosed between 5-10 years), and early
adolescence (diagnosed after 10 years). HbA1c was determined by DCA2000.
Scales were used to measure self-management, perceived stress, response
to stress, self-efficacy for diabetes, depression, quality of life, diabetesspecific family support, and diabetes-related family conflict.
One-way ANOVA with Tukey’s post-hoc comparisons revealed that
youth diagnosed for <2 years had lower HbA1c (p<.01) as well as higher
self-management diabetes care activities and self-management diabetes
communication (p=.02, .03). There were no significant differences by
developmental stage except for HbA1c, where youth diagnosed in early
adolescence had lower HbA1c (p<.01). Although psychosocial adjustment and
family functioning did not differ by developmental stage at diagnosis, selfmanagement was higher among adolescents diagnosed for a shorter time.
This suggests that young adolescents with longer diabetes duration need
additional self-management support during the transition to adolescence to
optimize metabolic control.
In this sample, n-6 PUFAs and D5D activity were related to beneficial effects
on plasma lipids, whereas findings were mixed relative to n-3 PUFAs. Further
research is needed to determine whether associations observed are related
to long-term health implications in individuals with T1D. Studies of genetic
variants of desaturase enzymes in T1D and associations with PUFA status
may help to understand the link between dietary fatty acids and blood lipids
and the impact of PUFA metabolism on health.
Supported by: NIH/NIDDK
&
1323-P
Developmental Stage at Diagnosis and Duration of Diabetes: Implications for Young Adolescents With Type 1 Diabetes
1322-P
Prevalence of Cardiovascular Risk Factors in Obese Youth With
Type 1 Diabetes (T1D)
MARIA J. REDONDO, DONGYUAN XING, INGRID M. LIBMAN, SANJEEV MEHTA,
JOANNE HATHWAY, KATHLEEN BETHIN, BRANDON NATHAN, MICHELLE ECKER,
AVNI SHAH, KELLEE M. MILLER, VINCE CHEN, WILLIAM V. TAMBORLANE, JENISE WONG, ROY BECK, Houston, TX, Tampa, FL, Pittsburgh, PA, Boston, MA, Buffalo, NY, Minneapolis, MN, Stanford, CA, New Haven, CT, San Francisco, CA
We studied the relationship between body mass index (BMI) and coexistence
of hypertension (HTN), dyslipidemia and micro-/macroalbuminuria (MA) in
youth <18 yrs with T1D≥1 yr enrolled in the T1D Exchange clinic registry.
Analysis included 11,285 participants (median age 12.8 yrs, median
duration 4.0 yrs, 49% female, 78% non-Hispanic white, 56% pump users)
from 59 centers, classified as obese (OB, BMI ≥95th percentile), overweight
(OW, 85-<95th) or normal weight (NW, 5-<85th). Underweight (<5th) were
excluded. Current diagnoses of HTN, dyslipidemia and MA were collected
from medical charts. The three groups were compared in logistic regression
models for complications and linear regression model for A1c.
We found that 64% of youth were NW, 22% OW and 14% OB. Mean
HbA1c at enrollment was 8.5±1.5%, 8.6±1.4% and 8.6±1.4% in NW, OW and
Supported by: NIH/NINR (2R01NR04009); Jonas Center for Nursing Excellence
&
For author disclosure information, see page 829.
A346
Guided Audio Tour poster
ADA-Funded Research
PEDIATRICS—TYPE 1 DIABETES
Table. Change between Baseline and 2-year follow-up within T1D and non-DM
T1D
Non-DM
Baseline 2-YR F/U Change Baseline 2-YR F/U Change
Breakfast#
3.3±1.2 3.8±1.6 0.5±1.7** 3.5±1.0 3.7±1.8 0.2±1.7
Vegetables#
2.8±1.2* 3.6±1.4 0.9±1.5** 3.1±1.2* 3.8±1.3 0.7±1.3**
Fruit#
2.9±1.2 3.8±1.3 0.9±1.4** 2.9±1.3 3.8±1.5 -0.9±1.6**
PA d/wk
5.0±1.8 4.8±1.7 -0.3±2.2
4.9±1.7 4.5±1.9 -0.4±2.3
PA hrs/d
1.8±1.2* 2.2±1.4 0.4±1.6** 1.5±0.8* 1.9±1.3 0.4±1.2**
PA level†
1.9±0.6 2.0±0.5 0.1±0.7
2.0±0.5 2.1±0.6 0.1±0.7
#Times per week
†PA level: 1=mild, 2=moderate, 3=strenuous
*p<0.05 comparing T1D and non-DM at baseline
**p<0.05 comparing change between baseline and 2-year follow-up within
T1D and non-DM
1324-P
KELLY K. ZINN, BARBARA VELSOR-FRIEDRICH, SUE PENCKOFER, MEG GULANICK, Huntsville, TX, Chicago, IL
The purpose of this study was to explore diabetes self-care practices
among older adolescents, 15 to 18 years old, with type 1 diabetes (T1DM)
and determine if there was a difference in self-care practices between
adolescents who reported good (HbA1c < 9%) versus poor (HbA1c > 9%)
glycemic control (GC).
Six focus groups were conducted (3 good GC, 3 poor GC) by the same
moderators. Sessions were digitally recorded and transcripts were analyzed
using an inductive approach. Thirteen adolescents with good GC (mean age =
16.2 yrs, mean HbA1c = 7.7%, mean duration = 5.8 yrs) and 8 adolescents
with poor GC (mean age = 16.5 yrs, mean HbA1c = 11.4%, mean duration =
7.8 yrs) participated. Fifty-two percent of the sample was female and 85%
were White.
Themes generated directly from the focus group data were categorized
as 1) life as a teen with T1DM, 2) diabetes self-care, or 3) interactions with
the healthcare team. Teens with good GC described life with T1DM as a
struggle, but that they were stronger than the disease. In contrast, teens
with poor GC felt that diabetes interfered with their life and that diabetes
self-care was a burden for which they had to adjust their lifestyle. Teens
with good GC have integrated diabetes self-care into their identity and are
able to adjust diabetes self-care to fit their lifestyle. Teens with good GC felt
physicians were impersonal where those with poor GC described physicians
as condescending. Teens with good and poor GC felt nurses treated them
like a person.
Adolescents with T1DM struggle with the complex treatment regimen
but those with good GC demonstrated acceptance of the disease as part
of who they were as a person thus diabetes self-care was part of their
routine. The findings suggest that healthcare professionals must develop a
trusting relationship with older adolescents with T1DM and include them
in treatment decisions. By treating teens with respect and as a valuable
partner, healthcare professionals can facilitate acceptance of the disease
and its treatment regimen.
&
&
RACHEL LIEBERMAN, R. PAUL WADWA, FRANZISKA K. BISHOP, JANET K. SNELLBERGEON, CHRISTINA REINICK, DAVID MAAHS, St. Louis, MO, Aurora, CO
Vitamin D deficiency is common and associated with increased cardiovascular disease (CVD) risk. Pulse wave velocity (PWV) is a marker of
vascular stiffness associated with CVD. We hypothesized that Vitamin D
(25(OH)D) levels would be inversely associated with PWV.
Comparisons were made between adolescents with T1D (n= 178; age= 17.6 +
2.2 y; duration= 10.9 + 3.1 y; A1c= 9.1 + 1.7%) and non-DM controls (n= 46;
age= 16.8 + 1.6 y). Vitamin D was categorized (deficiency < 20; insufficiency
21-29; and sufficiency > 30 ng/ml) and PWV measured in the carotid-femoral
segment (Sphygmocor Vx,AtCor Medical, Lisle, IL).
Vitamin D was slightly higher in adolescents with T1D v. controls (29.0 +
0.8 v. 25.5 + 1.6 ng/ml; p = 0.052). Vitamin D was significantly associated
with PWV after adjusting for age, sex, quarter of the year, and ethnicity in
adolescents with T1D (beta = -0.01 + 0.004, p = 0.02) but not in the non-DM
adolescents (beta = -0.01 + 0.008, p = 0.17). Vitamin D remained significantly
associated with PWV after additionally adjusting for hs-CRP in adolescents
with T1D (-0.01 + 0.004, p = 0.009). After adjusting for BMI z-score, lipids,
and BP, the relationship of Vitamin D with PWV was not significant (Table).
Low Vitamin D levels are significantly associated with increased PWV
in adolescents with T1D, but not independent of BMI, lipids, or BP. Further
research is needed to determine if Vitamin D supplementation would be
beneficial to lower CVD risk in adolescents with T1D.
1325-P
Changes in Diet and Physical Activity in Adolescents With and
Without Type 1 Diabetes Over 2 Years
FRANZISKA K. BISHOP, R. PAUL WADWA, JANET K. SNELL-BERGEON, NHUNG
NGUYEN, JENNA REYNOLDS, DAVID MAAHS, Aurora, CO
Diet and physical activity (PA) are fundamental aspects of care in type 1
diabetes (T1D), but scant data exist on diet and PA behaviors of T1D adolescents
over time, especially compared to non-diabetic (non-DM) controls.
Data in 210 T1D (baseline age=15.4±2.1 yrs, T1D duration=8.8±3.0 yrs,
A1c=9.0±1.6%, 52% male) and 67 non-DM (age=15.4±2.1 yrs, 51% male)
adolescents were collected at baseline and again at 2-year follow-up
(mean follow up=2.2±0.4 yrs). Diet data (meals/day, snacks/day, and weekly
consumption of breakfast, fruit, and vegetables), and PA were collected
using interviewer administered questionnaires. T-tests and chi-squared
tests were used for comparisons.
Both T1D and non-DM adolescents reported increased vegetable and fruit
intake and increased PA (hrs/d on PA days) from the baseline to the 2-year
follow-up and these changes were significant (Table). T1D adolescents
reported eating breakfast more often from baseline to the 2-year follow-up
while meals and snacks per day remained unchanged for both groups.
Over 2 years, T1D and non-DM adolescents had a healthier diet with
increased fruit and vegetable intake and increased PA. However, both
groups are far from meeting the guidelines of daily fruit and vegetables
intake Overall, T1D and non-DM adolescents have similarly poor dietary
patterns despite T1D adolescents receiving dietary education and support
through their diabetes care. Late adolescence could be an age range to
target diet interventions.
ADA-Funded Research
&
1326-P
The Association Between Vitamin D and Pulse Wave Velocity in
Adolescents With and Without Type 1 Diabetes
Supported by: NIDDK; JDRF
&
1327-P
The Impact of a Multidisciplinary Program using Motivational Interviewing to Improve Glycemic Control in Adolescents With Diabetes
AMANDA G. PERKINS, LINDA GRAHAM, ANNA L. CASS, ELAINE C. MORELAND,
JOYCE W. ADAMS, BRYCE A. NELSON, Greenville, SC, Columbia, SC
Adolescents in the Diabetes Control and Complications Trial had
significantly higher hemoglobin A1cs (A1c) than adults. They have poorer
treatment compliance compared to other pediatric populations and thus
have increased risk for long term complications. This retrospective study
evaluates the efficacy of a behavior change program, “Get Real About
Diabetes” (GRAD), in improving A1c in adolescents with type 1 diabetes.
GRAD was developed at our pediatric endocrinology practice and is ongoing.
It combines traditional medical/educational visits with a Pediatric Nurse
Practitioner with motivational interviewing sessions with a Licensed Clinical
Social Worker.
Data from ninety-four patients with type 1 diabetes were analyzed.
Median age was 13 years and median duration of participation was 13
For author disclosure information, see page 829.
Guided Audio Tour poster
A347
POSTERS
Supported by: JDRF (11-2007-694); NIDDK (DK075630); CTSI (UL1RR025780)
Clinical Diabetes/
Therapeutics
&
A Comparison of Type 1 Diabetes Self-Care Among Older Adolescents With Good and Poor Glycemic Control
PEDIATRICS—TYPE 1 DIABETES
months. Patients entered GRAD with a median A1c of 9.75%. This value
was rising in the 6 visits prior to participation with a median increase of
0.4% (p<0.01). By the 10 th GRAD visit, median A1c decrease was 0.7%. Upon
completion of GRAD participants had a median A1c increase of 0.1% from the
A1c at program entry. Median A1c changes were not statistically significant
for the overall population during GRAD participation. Subgroup analysis
showed that patients with the highest baseline A1cs (4th quartile, median
A1c 11.9%) saw the largest initial improvement with a median A1c decrease
of 2.4% (p=0.02) by the 10 th GRAD visit. Further, patients demonstrated
A1c stabilization for 6 visits after completing the program (median time 50
weeks).
To our knowledge, this is the largest population studied using motivational
interviewing in youth with diabetes. We concluded that participation in
GRAD prevented deterioration in glycemic control in a population in which
glycemic control was declining. While more research is needed in this area,
this study emphasizes the feasibility of incorporating this unique approach
in routine clinic care.
1328-P
Development of a Parent Proxy Diabetes-Specific Transition Readiness Questionnaire
POSTERS
Clinical Diabetes/
Therapeutics
&
At baseline, LCs reported lapses in care of 11.6 ± 9.7 months. Compared
to CCs, LCs at baseline had higher A1C levels (%) (10.86 vs. 9.43; p = 0.009),
a greater incidence of severe hypoglycemia in the past 3 months (29% vs.
10%; p = 0.031), and more ED visits in the past 6 months (0.63 vs. 0.12; p =
0.02). They were older than CCs (21.0 vs 19.6 yrs; p = 0.000) and less likely to
have health insurance (p = 0.000) or live with family (p = 0.007).
At 12 months, 78% of CCs and 54% of LCs completed the program. The
most common reasons for loss to follow-up included being unreachable,
finding care elsewhere, and scheduling conflicts.
Among completers at 12 months, both LCs and CCs had lower A1C levels
(change in %) compared to baseline (LC -0.87 ± 1.14, p = 0.029; CC -0.37 ±
1.14, p = 0.055). Between-group differences were no longer significant for
A1C levels (p = 0.136), hypoglycemia (no cases; cannot calculate p-value), and
ED visits (p = 0.296). LCs and CCs did not differ on number of clinic visits in
the study period (LC 2.72 ± 1.46, CC 3.04 ± 1.12, p = 0.341).
Our study suggests that, for those who complete it, a transition program
is effective in reducing A1C, hypoglycemia, and ED use among YAs with a
history of lapsed diabetes care to levels comparable to those in continuous
care. Loss to follow-up remains a major challenge in this population. Results
of this pilot study need validation in a larger population due to the importance
of reconnecting these vulnerable YA to medical care.
JESSICA T. MARKOWITZ, LISA K. VOLKENING, LORI M. LAFFEL, Boston, MA
1330-P
The Transition Readiness Assessment Questionnaire (TRAQ) is a patient
self-report of preparation to transfer from pediatric to adult care for pediatric
chronic disease. The TRAQ, modeled in stages of change theory, examines
acquisition of self-care skills in 16-26 year olds with special healthcare needs.
We adapted the 29-item TRAQ to a diabetes (DM)-specific parent report of
youth’s self-care skills and assessed it in 187 parents (82% mothers; 92%
white) of youth aged 5-21 yrs with DM (99% T1D). The DM-specific survey
has 30 items with 5 response options, scored by averaging items for a total
score of 1-5 (higher score = greater readiness). The revised survey had good
internal consistency (Cronbach’s α=0.93) and demonstrated the TRAQ’s 2
factor structure (Self-Management α=0.86; Self-Advocacy α=0.88). Scores
were normally distributed and increased with youth age (Figure). At all
ages, self-advocacy scores were higher than self-management scores. In
21/30 questions, response variability was low, ≥50% of responses were
identical. In 16/21 in which parents responded child does not do task, youth
were younger than when parents chose other responses (12.7 vs 16.5 yrs;
p<0.03). In 5/21 in which parents responded child always does task, youth
were older (14.8 vs 10.5 yrs; p<0.0001). Acquisition of self-advocacy skills
develops earlier than self-management skills; thus, one should focus on DM
self-management to prepare youth for optimal transition.
Early Elevation of AER Associated With Poor Gluten Free Diet Adherence in Young People With Diabetes and Coeliac Disease
ANNA PHAM-SHORT, KIM C. DONAGHUE, GEOFFREY R. AMBLER, ALBERT K.
CHAN, STEPHEN HING, JANINE CUSUMANO, MARIA E. CRAIG, Sydney, Australia
Consensus guidelines from the ADA and ISPAD recommend screening
for coeliac disease (CD) in type 1 diabetes (T1D), however there are limited
data demonstrating adverse effects of untreated CD or non-adherence to
the gluten free diet (GFD). In particular, it is unclear whether the risk of
microvascular complications is different in people with both T1D and CD.
We therefore examined (i) the complication rates in youth aged < 20
yrs with T1D, stratified by biopsy confirmed CD (CD+, n=129, 43% M) or
not (CD-, n=2510, 48% M) and (ii) the association between GFD adherence
and complications. Outcomes examined were retinopathy, early elevation
of albumin excretion rate (AER, > 7.5µg/min) and peripheral/autonomic
neuropathy. Explanatory variables included HbA1c, diabetes duration and
GFD adherence (defined as normal TTG titres (n=69) or elevated (n=60).
Early elevation of AER was associated with GFD non-adherence vs
adherence (40% vs 23%, p=0.04). In multivariate logistic regression, early
elevation of AER was associated with GFD non-adherence (odds ratio
2.4, 95% CI 1.0-5.4, P=0.04) and diabetes duration (1.1, 1.0-1.3, P=0.03).
HbA1c was not significant in the model (1.2, 1.0-1.6, P=0.10). There was no
association between GFD adherence and neuropathy or retinopathy.
Since early elevation of AER is a recognised predictor of diabetic
nephropathy, our data support the importance of GFD adherence in CD.
Characteristics at most recent visit
CDCD+
p-value
(n=2510)
(n=129)
Current age
16.5 [14.8 - 17.9] 16.1 [14.3 - 17.8] 0.13
GFD adherent GFD non-adherent p- value
(n=69)
(n=60)
15.8 [14.1 - 17.8] 16.4 [14.3 - 17.9] 0.43
Diabetes duration (yrs)
9.3 [6.3-12.2] < 0.001
9.2 [6.6 - 12.2] 9.4 [6.3 - 12.3]
0.81
6.6 [3.0 - 10.3]
6.2 [3.1 - 9.6]
6.7 [2.8 - 11.5]
0.54
7.2 [4.9 - 10.4]
Coeliac disease duration (yrs)
&
1329-P
Outcomes of a 12-Month Transition Program (LEAP: Let’s Empower
and Prepare) among Young Adults (YA) With T1D and a History of
Continuous (CC) versus Lapsed (LC) Care
HbA1c (%)
8.6 [7.7 - 9.6]
0.04
8.2 [7.6 - 9.0]
8.7 [7.8-10.0]
0.003
Elevated AER (> 7.5 µg/min)
600/2118 (28%) 36/117 (31%) 0.60
15/65 (23%)
21/52 (40%)
0.04
Peripheral nerve abnormality
627/2425 (26%) 36/128 (28%) 0.61
17/68 (25%)
19/60 (32%)
0.40
Retinopathy
556/2381 (23%) 27/125 (22%) 0.75
12/67 (18%)
15/58 (26%)
0.38
8.3 [7.6 - 9.3]
ELIZABETH PYATAK, ANNE L. PETERS, PAOLA A. SEQUEIRA, JAMIE R. WOOD,
LUCY MONTOYA, MARC J. WEIGENSBERG, Los Angeles, CA
Individuals with T1D are often lost to care during transition from pediatric
to adult care. In this study we attempted to identify and treat YA who
had been lost to medical care. The LC group was given the one-year LEAP
program given to those in their last year of pediatric care (the CC group).
CC (n = 51) and LC (n = 24) participants in LEAP completed demographic,
psychosocial, and A1C measures at baseline and 12 months. LCs were
interviewed at baseline regarding their life circumstances and diabetes care.
&
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PEDIATRICS—TYPE 1 DIABETES
1331-P
1333-P
Circulating Biomarkers of Adiposity and Inflammation in Obese and
Lean Children With New Onset Autoimmune Type 1 Diabetes
Skin Advanced Glycation Endproducts (AGEs) are Increased at Onset in Children With Type 1 Diabetes (T1D)
MARIA J. REDONDO, LUISA M. RODRIGUEZ, DINAKAR IYER, MOREY W. HAYMOND, CHRISTIANE S. HAMPE, ASHOK BALASUBRAMANYAM, SRIDEVI DEVARAJ, Houston, TX, Seattle, WA
EILEEN BAEZ, SHREEPAL SHAH, DANIA FELIPE, JOHN D. MAYNARD, JAMES
HEMPE, STUART CHALEW, New Orleans, LA, Albuquerque, NM
No DM
108
10.6±4.8
2.08±0.44
(2.17)
1.53±0.34
(1.60)
New Onset T1D
30
9.3±4.4
0.007±0.002
2.24±0.44
(2.44)
1.65±0.35
(1.80)
Established T1D
126
13.8±3.8
6.1±3.6
2.60±0.77
(2.50)
1.96±0.60
(1.87)
Adjusted SIFs for 405 [kx0.5, km0.5] (p=0.018) and 420 [kx0.5, km0.5]
(p=0.030) were higher in children with new onset T1D compared to those
without diabetes. There was no difference between new onset and nondiabetics for SIF at 375nm or corrections using (kx=1.0, km=0).
Measurement of SIF at 405 and 420 nm with (kx=0.5, km=0.5) correction
suggest that skin AGEs may already be increased at onset of T1D in youth.
Further study will be needed to determine whether these changes are associated with later development of diabetes complications.
Supported by: Texas Children's Hospital
1332-P
“Let’s Empower and Prepare (LEAP)”: Efficacy of a Young Adult (YA)
Type 1 Diabetes (T1D) Transition Program
PAOLA SEQUEIRA, MARC J. WEIGENSBERG, JAMIE R. WOOD, SUSAN CLARK,
LUCY MONTOYA, HEATHER SPEER, MARISA COHEN, VALERIE RUELAS, ELIZABETH A. PYATAK, ANNE L. PETERS, Los Angeles, CA, Orange, CA
1334-P
Social Networking for Care Improvement and Panel Management
ELISSA R. WEITZMAN, SKYLER KELEMEN, KATHARINE C. GARVEY, Boston, MA
YA with T1D transitioning from pediatric to adult care are often lost to
follow-up and have deterioration in glycemic control. This study was done
to evaluate the efficacy of a transition program (LEAP) which consisted of
structured education, transition coordinator, and a designated YA clinic in
an urban public hospital led by a med-peds endocrinologist. Reported here
are findings from a 1-yr prospective pilot study of 19-25 yr olds with T1D in
their last year of pediatric care before leaving to adult care. We recruited: 1)
Intervention group (IG, n=51), receiving routine diabetes care at 2 pediatric
diabetes clinics plus access to the LEAP program and transfer to the YA T1D
Clinic at age 21; and 2) Control Group (CG, n=30), receiving routine care at a
3rd pediatric diabetes clinic. Demographics, surveys, number of clinic visits,
and A1C were obtained at baseline and 12mo.
At baseline, groups had same A1C (9.4% vs 9.2%, p=0.58), but differed by
ethnicity, gender, socioeconomic status (SES), and % with private insurance
(IG 2% vs CG 60%, p=0.000).
75% in IG and 83% in CG completed the study. More completers who
transitioned out of pediatric care in IG successfully achieved adult care
follow-up compared to CG (88% vs 33%, p=0.000). At 12mo, IG had a lower
3 mo incidence of severe hypoglycemia (0% vs 16%, p=0.021), improved in
Global Well Being (p=0.008) and Perceived Stress (p=0.023) compared to
CG. A1C was significantly reduced across the year intervention in IG vs CG
(-0.36% vs +0.49%, p=0.012), adjusting for SES, ethnicity, baseline A1C.
Our results demonstrate that a structured comprehensive diabetes
transition program with accessible adult care increases adult follow-up
care and lowers A1C levels in lower SES patients even when compared to a
higher SES group. Developing and studying similar transition programs may
be useful in transitioning YA in a planned manner and maintaining diabetes
control. More research is needed to investigate long term outcomes for this
critical period for YA with T1D.
Detailed self-care and behavioral health information about adolescents with
Type 1 diabetes (T1D) is scarce in clinical settings but vital to healthcare quality.
Using a social networking application (app) we collected structured reports
from youth receiving care for T1D in an ambulatory clinic, aiming to: 1) validate
patient-reported data from the app against the electronic medical record (EMR);
2) measure information gain on health risk behaviors; and 3) test acceptability
of returning aggregated app data to clinicians for panel management.
Of 88 enrolled patients ages 13-25 years, 51% were female; mean age was
18 years. Mean HbA1c% was higher in the general clinic population (8.4%)
than among participants; groups did not differ by age or gender. App data
were current with EMR data (Table 1); 84% were entered within 30 days of the
referent visit. Nearly twice as many severe hypoglycemic events were identified
using the app than EMR. App data substantially enhanced EMR reports of
health risk behaviors. Of 32 patients reporting alcohol use via the app, 27 (84%)
had no mention or a negative report of alcohol use at the concurrent visit.
Similar results were seen for tobacco (4/5 reporting use in the app had no EMR
mention) and marijuana (10/11 reporting use had no EMR mention). Clinicians
reported no workflow interruptions and high utility of app data.
Table 1. Concordance of patient-reported app and EMR data
Disease Factors
Patient App Report N (%) EMR N (%) Concordance*
Insulin pump use
66 (75.9)
67 (76.1)
96.6%
Continuous Glucose Monitor (CGM) use
9 (10.2)
4 (4.6)
93.2%
Any past-year severe hypoglycemia
13 (14.8)
7 (8.0)
88.6%
HbA1c% (average, SD)
7.7 (0.9)
7.8 (1.1)
74.0%
Age at diabetes diagnosis (average, SD)
10.4 (4.8)
10.3 (4.7)
85.2%
* Calculated as the percentage of participants with an exact match between
app report and EMR
Complementary patient-centered data sources can inform diabetes care
in a model that yields valid and novel data without burdening clinicians or
workflows.
Supported by: CIMIT (220376); Harvard Catalyst (027343.386541.05230); CDC
(PO1HK000088-01)
ADA-Funded Research
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Group
n
Age (yrs)
Duration (yrs)
SIF405[kx0.5,km0.5]
(LSM)
SIF420[kx0.5,km0.5]
(LSM)
Clinical Diabetes/
Therapeutics
AGEs mediate complications of aging and diabetes. Skin AGEs can be
estimated from skin intrinsic fluorescence (SIF) which corrects for melanin,
hemoglobin and light scattering. We previously reported that SIF is higher in
children with established diabetes compared to nondiabetics. However there
have been no prior studies evaluating SIF of children with new onset T1D.
Children without T1D and patients with new onset and established T1D
were evaluated. New onset patients were studied within 1 week of diagnosis.
Skin fluorescence (440 - 655 nm) was excited by LEDs at 375, 405 and 420
nm using a Scout DS (VeraLight, Albuquerque, NM). SIFs were generated
by correcting for excitation and white LED reflectance using (kx=1.0, km=0)
or (kx=0.5, km=0.5). SIFs between groups were compared by least squares
means (LSM) adjusted for the effects of age, gender, and race using PROC
GLM of SAS. Results reported as unadjusted mean±1SD.
Inflammation plays a pivotal role in the development of type 1 diabetes
(T1D) and its complications. However, the contribution of obesity-induced
inflammation to pediatric T1D is poorly understood. We aimed to study
biomarkers of adiposity and inflammation in children with new onset
autoimmune T1D.
We prospectively studied 32 lean (BMI<85th percentile) and 18 obese
(BMI≥95th percentile) children with newly diagnosed autoimmune T1D (age
range 2-18 yrs) for up to 2 yrs after diagnosis. Serum adipokines (leptin, total
and high molecular weight [HMW] adiponectin, omentin, resistin, chemerin,
visfatin) and cytokines (interferon [IFN]-gamma, interleukin [IL]-10, IL-12, IL-6,
IL-8 and tumor necrosis factor [TNF]) were measured 7 wks (median) (range
3-16 wks) after diagnosis.
Lean children were 71.9% non-Hispanic White, 21.9% Hispanic and 6.3%
African-American, compared with 27.8%, 55.6% and 16.7%, respectively,
among obese children (p=0.01). Obese T1D children, compared with lean T1D
children, had higher serum levels of leptin (p=0.0001), visfatin (p=0.0001),
chemerin (p=0.001) and TNF (p=0.002), and lower total adiponectin (p=0.04)
and omentin (p=0.003), after adjustment for race/ethnicity and Tanner
pubertal stage. Among children with follow-up ≥1 yr, higher leptin levels
at 7 wks of diagnosis predicted higher HbA1c 1.5 yrs later (range 1-2 yrs)
independently of race/ethnicity and diabetes duration (p=0.0006, r2=0.41,
n=41). Higher TNF was associated with obesity and female gender, after
adjusting for race/ethnicity (p=0.0003).
In conclusion, obese children with autoimmune T1D have a circulating
pro-inflammatory adipokine and cytokine profile that may contribute to
pathogenesis and thus represent a therapeutic target in this population.
PEDIATRICS—TYPE 1 DIABETES
1335-P
1337-P
Moderate Income as a Risk Factor for Youth With Type 1 Diabetes
Vascular Function Is Not Significantly Impaired in Physically Fit
Type 1 Diabetic Youth Compared With Healthy Peers
POSTERS
Clinical Diabetes/
Therapeutics
SARAH JASER, KAITLYN RECHENBERG, ROBIN WHITTEMORE, SANGCHOON
JEON, MARGARET GREY, Nashville, TN, New Haven, CT
BRENT J. LOGAN, LINDA A. JAHN, ARTHUR L. WELTMAN, EUGENE J. BARRETT,
Charlottesville, VA
Low income has been established as a risk factor for poorer outcomes in
youth with type 1 diabetes, but the effect of moderate income has not been
studied. The purpose of this secondary analysis of data from a multi-site
study was to compare glycemic control, self-management, and psychosocial
outcomes (depression, stress, and quality of life) at different income levels
in a diverse sample of early adolescents with type 1 diabetes. Youth (n =
320, mean age = 12.3 + 1.1, 45% male, 62% white, mean A1C = 8.3 + 1.4)
completed established measures of self-management and psychosocial
outcomes. A1C levels were collected from medical records, and caregivers
reported on annual family income, which was categorized as high (> $80K),
moderate ($40-80K) or low (< $40K). Youth from high-income families had
significantly lower A1C values (mean = 7.9) than those from the moderateincome group (mean A1C = 8.9, p<.01) or the low-income group (mean A1C =
8.6, p<.01). Youth from the high-income group also reported significantly
greater diabetes problem-solving and more self-management goals than
those from the moderate- or low- income groups (both p <.01). In terms
of psychosocial outcomes, youth from the high-income group reported
significantly fewer symptoms of depression, lower levels of perceived stress,
and better quality of life than those in the moderate- or low-income groups
(all p < .05). After controlling for race/ethnicity and parental education in
multivariate analysis, youth from the high-income group had lower A1C
and reported better diabetes problem-solving, less depressive symptoms,
and less perceived stress than those from the low- and moderate-income
groups (all p<.05). While previous interventions have targeted youth from
low-income families as being most vulnerable, results suggest that early
adolescents from moderate-income families are also at risk for poorer
outcomes and require greater attention.
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in
Type 1 Diabetes (DM1). In their third to fifth decades risk ratios for CVD related
deaths in DM1 are 8-20 fold higher than the general population. Current data
also indicate that DM 1 youth may be less physically fit compared to agegender matched peers. Decreased fitness has been associated with vascular
dysfunction, though data is limited.
We evaluated DM1 (n=11) and non-DM1 (n=9) adolescents for fitness
(measured by VO2max), body composition, and multiple measures of
vascular function. The latter include tonometry to evaluate arterial stiffness,
by augmentation index (AI) and pulse wave velocity (PWV), and ultrasound
to assess flow-mediated dilation nitric oxide dependent vascular reactivity
(FMD) and contrast-enhanced ultrasound of forearm muscle microvasculature
(CEU).
We found no differences in VO2max (40±3 vs 39.6±3 mL/min/kg). Our
subjects were similar in age, BMI, and percent body fat. HgbA1C (5.4 vs
8.7%) and fasting glucose (88 vs 131 mg/dL) on the day of study were both
lower in the controls (p=<0.01, each). FMD was slightly, but not significantly,
lower in DM1 (10.9±2.2 vs 8.1±1.2%). Vascular stiffness was comparable
(PWV = 4.9±0.2 vs 5.3±0.3 m/s. AI = 1.1±4 vs 0.2±5%, in controls and DM1,
respectively) and muscle microvascular volume by CEU was similar at
baseline and increased in response to insulin similarly in both groups.
Our data suggest that when compared to age and fitness matched controls,
adolescents with DM1 of > 1yr duration have similar vascular stiffness
and exhibit normal microvascular responses to insulin despite inadequate
glucose control. Nitric oxide mediated FMD may be modestly decreased.
These findings suggest that adolescents with DM 1 who maintain fitness
may be at a lower risk of developing early findings of vascular dysfunction.
Supported by: NIH/NINR (2R01NR04009)
Supported by: University of Virginia
1336-P
1338-P
Cyclical Variation in HbA1c Values During the Year—Clinical and
Research Implications
Data Mining Methodologies for Detecting Insulin Omission Eating
Disorder in Girls With Type 1 Diabetes
NATHAN R. HILL, CATHERINE J. PETERS, REBECCA J. THOMPSON, DAVID R.
MATTHEWS, PETER C. HINDMARSH, Oxford, United Kingdom, London, United
Kingdom
URI HAMIEL, YUVAL GREENFIELD, VALENTINA BOYKO, CHANA GRAPH-BAREL,
LIAT LERNER-GEVA, BRIAN REICHMAN, ORIT PINHAS-HAMIEL, Ramat Gan,
Israel
Glycosylated haemoglobin (HbA1c) is a key process and outcome measure
in diabetes. Reporting of this indicator varies Some schemes use single
measures in the year and others an average of several taken during the year.
Single measure reporting may be influenced by seasonal variation as may
intervention studies in clinical trials.
To quantify variation in HbA1c we subjected 5140 paediatric HbA1c
measurements obtained from 1999-2012 to Time Series Analysis. Fourier
Transform analysis described a waveform of maximal power/amplitude at
a periodicity of 6 months that indicated a greater than random tendency
for peaks and troughs in the time series to recur at this frequency and
indicated a distinct rhythm and the decimal precision was determined
using Autocorrelation analysis. This revealed regular oscillations within
the dataset occurring every 6.9 months so that on average HbA1c values
were 0.3% lower during the summer quarter compared to the winter quarter.
Median clinic HbA1c for 2012 was 7.9% with 41% of children attaining a
HbA1c < 7.5%. Children had a lower median HbA1c (7.7%) than adolescents
(8.4%). Insulin pump therapy was associated with a lower median HbA1c
(7.7%) than multiple daily injections (8.5%).
These data demonstrate regular cyclicity in HbA1c values during the
year. Submission of data to quality improvement schemes should be based
on the average for the individual over the whole year. Clinical trial design
should include estimates of HbA1c seasonal variation to avoid Type 1 and
2 statistical errors.
Insulin omission is a specific eating disorder that occurs in patients with
type 1 diabetes mellitus (T1DM), mostly in females, who omit or restrict
their required insulin doses in order to lose weight. Diagnosis of this specific
eating disorder is difficult. We aimed to use multiple clinical criteria to create
an algorithm for the detection of insulin omission eating disorder.
Data from 287 (181 females and 165 males) patients with T1DM and 26
patients with T1DM and eating disorders were used. The Weka (Waikato
Environment for Knowledge Analysis) machine learning software, decision
tree classifier based on the J48 algorithm with 10 fold cross validation was
used to developed prediction models. Model performance was assessed by
cross-validation in a further 43 patients.
The insulin omission eating disorder and non-eating disorder populations
were discriminated by: female sex, HbA1c>9.2%, more than 20% of HbA1c
measurement above the 90th percentile, the mean of 3 highest delta HbA1c
z-score >1.28, current age and age at diagnosis. The models developed
showed good discrimination (sensitivity and specificity 0.88 and 0.74,
respectively). The external test dataset revealed good performance of
the model with a sensitivity and specificity of 1.00 and 0.97, respectively.
In summary, using data mining methods we developed a clinical prediction
model to determine an individual’s probability of having eating disorders.
This model provides a decision support system for the detection of insulin
omission eating disorders in adolescent females with T1DM.
&
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PEDIATRICS—TYPE
CATEGORY
1 DIABETES
1339-P
1341-P
A Novel Mutation in GATA6 Causes Pancreatic Agenesis
Excess Weight Gain during Insulin Pump Therapy Is Associated
With Higher Total Daily and Basal Insulin Doses
DIANA E. STANESCU, NKECHA HUGHES, PUJA PATEL, DIVA D. DE LEON, Philadelphia, PA
1340-P
Transitioning from Pediatric to Adult T1D Care: Knowledge Alone
Is Insufficient
ANIA M. JASTREBOFF, DARRYLL CAPPIELLO, JODIE M. AMBROSINO, SYLVIA LAVIETES, PAULINA ROSE, MELINDA ZGORSKI, PATRICIA GATCOMB, WILLIAM V.
TAMBORLANE, STUART WEINZIMER, KATE WEYMAN, New Haven, CT
The transition from pediatric to adult diabetes care is a critical step in
maintaining long-term health in patients with type 1 diabetes (T1D) but there
is a paucity of data regarding the challenges that emerging young adult
patients face in making the transition. In establishing the Yale T1D Bridge
Clinic, we developed a 20 item quiz to assess diabetes knowledge and enable
targeted education for our transitioning patients. The quiz encompassed
basic diabetes pathophysiology and case-scenario management-based
questions specific to treatment modality. The first 19 patients (11 female)
who completed the quiz on enrollment in the clinic were aged 16-24 yrs
with mean A1c 7.7% (range 6.7-10.5%). As shown in the figure, knowledge
quiz score did not correlate with A1c (r=-0.26, p=0.3); patients with quiz
scores of >85% were just as likely to have A1c levels >7.5% as they were
to have values <7.0%. Thus, although many patients transitioning to adult
care may have the knowledge necessary for successful diabetes self-care,
this knowledge alone is insufficient to achieve glycemic control during the
transition process. These data underscore the need for clinicians to carefully
assess other factors that may impede glycemic control during the transition
process, such as diabetes distress/burden of care, fear of hypoglycemia,
depression, and disordered eating, and to develop better motivational
strategies for patients with T1D during the transition process.
1342-P
Carotid Intima-Media Thickness Is Increased in Youth With Type 1
Diabetes
RACHEL M. SIPPL, FRANZISKA BISHOP, DAVID MAAHS, PAUL WADWA, JANET
K. SNELL-BERGEON, Aurora, CO
Cardiovascular disease (CVD) is increased in type 1 diabetes (T1D), but it
is unknown how early in life these risks begin. This study examined carotid
intima-media thickness (cIMT) as a surrogate CVD risk marker among
adolescents with T1D and without diabetes (non-DM).
Study participants were 29 T1D youths (age 18 ± 3 yrs, duration 11 ±
3 yrs) and 27 non-DM youths (age 17 ± 2 yrs) from the Determinants of
Macrovascular Disease in Adolescents with Type 1 Diabetes. cIMT was
measured in the common carotid artery using the Panasonic CardioHealth ®
Station bilaterally, and the mean cIMT from the largest side was used. CVD
risk factors examined included gender, age, body mass index (BMI), blood
pressure and fasting lipids. Two sample t-tests and multivariable linear
regression were used to examine the relationship between diabetes status
and cIMT.
Youths with T1D had increased cIMT when compared to non-DM youths
(mean±SD=0.54±0.10 vs 0.48±0.05 mm, p = 0.01). Gender, age, body mass
index (BMI), and SBP were associated with cIMT, and so were included in
linear regression models (Table). cIMT remained significantly higher in youth
with T1D when adjusting for age and gender, and when further adjusted for
BMI and SBP.
Youths with T1D have increased cIMT when compared to non-DM youth
of the same age and gender, indicating that the higher risk for subclinical
atherosclerosis in type 1 diabetes is present as early as adolescence and is
independent of obesity and hypertension.
cIMT Least Square Means and 95% Confidence Intervals
Model covariates
T1D (n=29)
Non-DM (n=27) P-value
Age, Diabetes, Gender
0.53 (0.51-0.56) 0.48 (0.45-0.52) 0.03
Age, Diabetes, Gender, BMI
0.53 (0.50-0.56) 0.49 (0.46-0.52) 0.048
Age, Diabetes, Gender, SBP
0.53 (0.50-0.56) 0.49 (0.46-0.52) 0.04
Age, Diabetes, Gender, BMI, SBP 0.53 (0.51-0.56) 0.48 (0.46-0.51) 0.02
Supported by: K12DK094714
ADA-Funded Research
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Supported by: JDRF (11-2007-694); NIDDK; Panasonic
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While higher total daily dose (TDD) of insulin has been associated with
excess weight gain on insulin pump therapy, the role of higher total basal
dose (TBD) of insulin on weight gain has not been studied. Therefore,
we evaluated the impact of higher TBD on weight gain in relationship to
glycosylated hemoglobin (HbA1c), hypoglycemic episodes, and change in
body mass index (BMI) z score in a group of children and adolescents with
type 1 diabetes mellitus (T1DM).
One-year data from 91 (54 female and 37 male) patients (2.3 - 17.8 years of
age), transitioned from multiple daily insulin regimen (glargine and premeal
rapid acting insulin) to insulin pump therapy were reviewed retrospectively.
The patients were divided into two groups based on change in BMI z score
from baseline: Group 1 (no change or decrease) and Group 2 (increase).
There were 33 patients (60.6% female) in Group 1 and 58 patients (58.6%
female) in Group 2. Patients in Group 1 were younger than Group 2 (10.7 +
4.2 vs. 12.5 + 3.6 years; p<0.025) but had similar duration of diabetes (4.9 +
2.6 vs. 4.0 + 3.8 years; p=0.92) and pubertal status (2.5 + 1.7 vs. 3.1 + 1.4;
p=0.09). Group 2 had a significantly higher TDD (0.79 + 0.23 vs. 0.89 + 0.19 U/
kg/day; p<0.025) and TBD (0.38 + 0.1 U/kg vs. 0.28 +0.1 U/kg; p<0.025) than
Group 1. Indeed, Group 1 had higher bolus: basal insulin ratio (1.82 + 0.6 vs.
1.46 + 0.6, p<0.01) than Group 2. Groups 1 and 2 had similar HbA1c values
(7.67 + 0.71 vs. 7.70 + 0.64%; p=0.79), hypoglycemic episodes (1.01 + 0.4 vs.
1.5 + 0.9 episodes/patient/year; p=0.28) and activity levels (2.3 + 0.5 vs. 2.1
+ 0.7; p=0.15).
Excess weight gain was associated with not only higher TDD but also
higher TBD during insulin pump therapy independent of glycemic control,
frequency of hypoglycemic episodes and activity level. Therefore, frequent
evaluations of bolus and basal insulin doses during insulin pump therapy is
warranted in order to avoid excess weight gain.
Clinical Diabetes/
Therapeutics
CLAUDIA C. BOUCHER-BERRY, ELAINE PARTON, RAMIN ALEMZADEH, Chicago,
IL, Milwaukee, WI
Haploinsufficiency of GATA6 has been recently linked to pancreatic agenesis and cardiac malformations. Our aim is to describe a novel mutation in
GATA6 in a female infant diagnosed shortly after birth with truncus arteriosus,
absent gallbladder, unilateral hydronephrosis and hydroureter, and neonatal
diabetes. The child developed hyperglycemia in the first 24 hrs of life and
required insulin therapy. An abdominal CT at 1 month of life showed the
pancreas was reduced to a small portion of the pancreatic head, consistent
with pancreatic agenesis. The child expired at 3 months of age after cardiorespiratory failure due to her severe cardiac malformation. Analysis of the
child’s genomic DNA reveled a novel duplication causing a frameshift at amino
acid position 204 resulting in stop codon downstream (pHis204ValfsX97). The
truncated protein is predicted to lack DNA binding because of the absent zinc
finger domains. Plasmids containing wild type and mutated GATA6 were
transfected into HEK 293T cells and Western Blotting of cell extracts confirmed the small molecular weight of the mutant protein. Mutations in GATA6
have been demonstrated to be the most common cause of pancreatic agenesis, and have been found even in cases of diabetes, diagnosed outside the
neonatal period. The mutation described in this case expands the list of GATA6
mutations causing pancreatic agenesis and cardiac malformations. The severe
phenotype in this case underlines the importance of GATA6 on the development of multiple organs.
PEDIATRICS—TYPE 1 DIABETES
systems (one blinded, and the other display) on either abdomen and/or upper
buttocks for seven days home use. The OneTouch® Verio IQ meter (SMBG)
was used for CGM calibrations, diabetes management and served as the
comparative reference glucose values.
All subject completed the study. 17 subjects were male; 29 subjects were
white. The mean age of subjects was 12 ± 4; 3 subjects were under age 6.
Duration of diabetes was 4 ± 3 yrs. 24 subjects used CSII for insulin therapy;
6 subjects were on MDI therapy. The baseline HbA1C was 8.6 ± 1.3%.
There were no serious adverse events, sensor fractures, or infection
complications. Except for 2 (3%) infrequent mild skin irritations at the sensor
adhesive site, no other device related adverse events were reported. A total
of 1882 comparative paired CGM and SMBG values were evaluated. CGM
readings were within 20% (or 20 mg/dL for SMBG value ≤ 80 mg/dL) of the
SMBG values 77% of the time (95% CI: 75% to 79%). The Mean Absolute
Relative Difference (MARD) vs. SMBG was 15%. The clinically accurate
CEG A zone was 76%, and the combined A+B zones was 98%. The system
performed consistently between day (6 AM to 6 PM) 76% (N=1260, 95%
CI: 74% to 79%), and night 79% (N=622, 95% CI: 75% to 82%), at different
sensor wear locations, abdomen 78% (N=821, 95% CI: 76% to 81%), and
buttocks 76% (N=1061, 95% CI: 74% to 79%), all p values >0.10. The duration
of diabetes, age, sex, BMI and baseline A1C showed no significant impacts
on the performance. The system provided glucose readings on average 92%
of time with 81% of the sensors lasting to day 7, with an average 6% CV of
the concurrently worn sensors.
This is the first report of the new G4 PLATINUM CGM used in youths.
The system was safe to use and performed similarly in abdomen and upper
buttocks, and at different time of the day. The clinical accuracy, on-time
and sensor life of the system all compared favorably to the CGM system
currently approved for pediatric use.
1343-P
An Independent Inverse Association between Soluble CD25 and
Beta-Cell Function in Young People With Type 1 Diabetes
POSTERS
Clinical Diabetes/
Therapeutics
LOREDANA MARCOVECCHIO, KATE DOWNES, PAMELA CLARKE, JASON COOPER, JOHN TODD, DAVID DUNGER, Cambridge, United Kingdom
To assess the potential association between a marker of the immune
function (soluble CD25 (sCD25)) and circulating levels of C-peptide in young
people with childhood-onset type 1 diabetes (T1D) and a variable diabetes
duration.
C-peptide and sCD25 levels were measured in non-fasting serum samples
collected from 231 young people (136 males; median age (interquartile
range): 14.5 [12.9-16.3] years, T1D duration: 5.0 [2.3-7.0] years, age at T1D
onset: 10.4 [8.2-12.4] years) followed in the Nephropathy Family Study.
Median C-peptide levels were 24.7 [9.6-67.7] pmol/l and median sCD25
levels were 3179.2 [2536.5-3936.1] pg/ml. C-peptide levels (log transformed)
were positively associated with age at T1D onset (β=0.346, p<0.001),
whereas a negative association was found with T1D duration (β=-0.390,
p<0.001), log HbA1c levels (β=-0.158, p=0.021), and log sCD25 levels (β=0.223, p=0.001). In a multiple regression model, the association between
log C-peptide and log sCD25 persisted after adjusting for age at T1D onset,
duration and HbA1c levels (β=-0.158, p=0.018).
In 195 subjects, where C-peptide and sCD25 were re-assessed in a second
sample collected after a median interval of 1.2 [range: 0.8-3.6] years from the
first one, an inverse association between changes in C-peptide and sCD25
was found (β=-0.176; p=0.014), after adjusting for the effect of duration of
diabetes.
In this study sCD25 was significantly and inversely associated with
C-peptide levels, even in subjects with long-duration T1D, likely reflecting
the effect of the immune system on beta-cells. These preliminary findings
need to be confirmed in larger studies, including a better assessment of
beta-cell function.
1346-P
T-Cell Auto Reactivity and C-Peptide at Onset of Pediatric Type 1
Diabetes (T1D)
1344-P
MELISSA A. BURYK, H-MICHAEL DOSCH, INGRID LIBMAN, ROY K. CHEUNG, VINCENT C. ARENA, YIHE HUANG, MASSIMO PIETROPAOLO, DOROTHY J. BECKER,
Pittsburgh, PA, Toronto, ON, Canada, Ann Arbor, MI
Low Vitamin D Levels Observed in Over Half the Children and Adolescents in San Diego at Diagnosis of Type 1 Diabetes
HIBA AL-ZUBEIDI, LUCERO LEON-CHI, RON S. NEWFIELD, San Diego, CA
We previously reported that residual c-peptide at onset and during
remission of T1D is associated with BMI z-score, age and HbA1c, but not
islet autoantibody number. A relationship between islet T-cell autoimmunity
and low c-peptide levels has been reported in adults with phenotyp