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Obesity
Pre-Diabetes to
Type 2 Diabetes
Gül Bahtiyar, MD, MPH
Woodhull Medical Center
Clinical Associate Professor
NYU School of Medicine
Overview
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1/3 of U.S. population is obese
2/3 of U.S. population is overweight or obese
74% Increase over 10 year period
Costs U.S. companies $13 billion/year
Employers have important roles in addressing this
epidemic
Obesity on the Map
Obesity Has a Hefty Price Tag
 ~$117 billion in 2000 ($61 billion
direct and $56 billion indirect)
 6-10% of U.S. health care spending
 Health costs >30% higher than
normal weight individuals
Definitions of Obesity
Classification
Underweight
BMI (kg/m2)
< 18.5
Comorbidity Risk
Low*
Normal range
18.5 to 24.9
Average
Overweight
25.0 to 29.9
Increased
Obese class 1
30.0 to 34.9
Moderate
Obese class 2
35.0 to 39.9
Severe
Obese class 3
(Morbidly obese)
40.0
Very severe
*risk of other clinical problems increased
Calculate your own BMI: http://www.nhlbisupport.com/bmi/
Apples and Pears
Waist circumference is tied to cardiovascular risk
Tipping Point:
Men: >40 inches
Women: >35 inches
Obesity Major Player in
Many Diseases
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Diabetes
Coronary artery disease
Peripheral artery disease
Stroke
Hypertension
Hyperlipidemia
Arthritis
Obstructive sleep apnea
Pulmonary disease
PCOS/infertility
Dysmenorrhea
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Pregnancy complications
Gallbladder disease
GERD
Skin infections
Urinary incontinence
Depression
Eating disorders
Social stigma
Cancers: breast, endometrial,
colon, prostate, gallbladder,
kidney, esophagus…
 Increase in all causes mortality
Natural Selection?
Energy Balance
Helping Shift the
Balance of Energy
 Lifestyle modification
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Mindful eating
Exercise
Healthy self-talk
Diets
 Medication
 Surgery
An Informed Approach
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Recognize as chronic disease
Responsibility exists at many levels
Prevention as individual and society
Can make impact in workplace
Why Workplace Solutions?
 Workplace can be part of the problem
 Employees willing to pay for it
 An ideal opportunity for social reinforcement
Workplace Solutions:
A Range of Options
 Education
 Community resources
 Getting involved
 Inexpensive approaches
Education Strategies:
A Simple Way to Start
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Employee newsletter
Informational e-mails
Bulletin boards
Include:
– Calories burned from common
activities
– Mindful eating tips
– Local walking/bike trails
– Upcoming fitness activities/events
Small Changes
Each Day Add Up…
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Diet over regular soda, 1 can.......15 pounds/year
1 Candy bar/day...........................26 pounds/year
Skim milk over whole, 1cup..........7 pounds/year
1Tbs mustard instead of mayo.......9 pounds/year
2 Scoops ice cream/day................33 pounds/year
Apple juice, 8oz cup.....................12 pounds/year
Orange juice, 8oz cup...................10 pounds/year
2 Beers/day....................................31 pounds/year
Workplace Involvement
Pays Off
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Scheduling physical breaks during the day
Onsite wellness centers, exercise/walking trails
Stress management programs
Encourage walking/biking to/from work and
during breaks
 Memberships or discounts to health clubs
 Walking clubs, weight loss competitions
Inexpensive Approaches
for Better Nutrition
 Offering healthier food choices at reasonable
prices
 Provide nutritional info in cafeteria
 Provide healthier snacks at meetings and other
employee events
 Provide bottled water and healthier items in
vending machines
Create a Healthy
Work Environment
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Encourage employees to use stairways
Discourage employees from eating at their desks
Support physical activity breaks during the workday
Offer alternative work schedules
Have a weekly casual day
Provide enough time for lunch so employees can walk or
use the gym and don’t eat in a rush
Additional Strategies
 Wellness programs with onsite or online wellness
coaches are effective
 Incentives
 Ongoing reminders through newsletters, posters,
speakers
 Weight management support groups
Partner with
Community Resources
 Health fairs
 Onsite employee meetings with Overeaters
Anonymous or Weight Watchers
 Local speakers or
personal trainers
 Walk-a-thons, bike-athons
Global Projections for the Diabetes
Epidemic: 2000-2030 (in millions)
EU
17.8
25.1
41%
NA
19.7
33.9
72%
LAC
13.3
33.0
248%
Wild, S et al.: Global prevalence of diabetes:
Estimates for 2000 and projections for 2030
Diabetes Care 2004;40(5):134-141
SSA
7.1
18.6
261%
MEC
20.1
52.8
263%
China
20.8
42.3
204%
India
31.7
79.4
251%
World
2000 = 171 million
2030 = 552 million
Increase 213%
A+NZ
1.2
2.0
65%
Geographic Distribution
of Diabetes in the US
Shrestha S et al. Am J Prev Med 2011;40(4):434-39
Projected Obesity Prevalence
from 1960 to 2025
Kopelman P. Nature 2000; 404, 635-643
Intra-abdominal (Visceral) Fat
The dangerous inner fat!
Front
Visceral AT
Subcutaneous AT
Back
Waist Circumference Correlates Closely
with Intra-abdominal Adiposity (IAA)
300
Front
r = 0.80
IAA (cm2)
Visceral AT
200
100
Subcutaneous AT
AT: adipose tissue
Back
0
60
80
100
120
Waist circumference (cm)
To assess IAA, the simplest anthropometric index is the measurement of waist
circumference, which is strongly correlated with direct measurement of IAA by CT scan or
MRI, considered to be the gold standard
Pouliot et al. Am J Cardiol. 1994;73:460-8.
Després et al. 2001 BMJ. 2001;322:716-20
Insulin Resistance is a Root Cause of
Diabetes
Genetic factors
• Family history
• Ethnicity
> 80% of
diabetics
are
insulin
resistant
Environmental
factors
• Obesity
• Age
• Diet
• Lack of exercise
Haffner SM et al. Diabetes Care 1999; 22: 562–568
Bloomgarden ZT. Clin Ther 1998; 20: 216–231
Diabetes: Lifetime Risk
Narayan
JAMA 2003;290:1884-1890
Roger VL et al. Published
onlineetinal.Circulation
Dec. 15, 2010 .
Criteria for Testing for Diabetes in
Asymptomatic Adult Individuals
1. Testing should be considered in all adults who are
overweight (BMI ≥25 kg/m2*) and have additional risk factors:
• Physical inactivity
• First-degree relative with diabetes
• High-risk race/ethnicity (e.g.,
African American, Latino, Native
American, Asian American, Pacific
Islander)
• Women who delivered a baby
weighing >9 lb or were diagnosed
with GDM
• Hypertension (≥140/90 mmHg or
on therapy for hypertension)
• HDL cholesterol level
<35 mg/dL (0.90 mmol/L) and/or a
triglyceride level >250 mg/dL (2.82
mmol/L)
• Women with polycystic ovary
syndrome (PCOS)
• A1C ≥5.7%, IGT, or IFG on
previous testing
• Other clinical conditions associated
with insulin resistance (e.g., severe
obesity, acanthosis nigricans)
• History of CVD
ADA. II. Diabetes Care 2013;36(suppl 1):S14
Criteria for Testing for Diabetes in
Asymptomatic Adult Individuals
2. In the absence of criteria (risk factors on previous
slide), testing for diabetes should begin at age 45 years
3. If results are normal, testing should be repeated at
least at 3-year intervals, with consideration of more
frequent testing depending on initial results (e.g., those
with prediabetes should be tested yearly), and risk status
ADA. II. Diabetes Care 2013;36(suppl 1):S14
Natural History of Diabetes
Disease Progression
Natural History of Diabetes
Relative -cell
Function (%)
Glucose
(mg/dL)
Obesity
IFG*
Diabetes
350
300
250
200
150
100
50
Uncontrolled Hyperglycemia
Post-meal Glucose
Fasting Glucose
250
200
150
Insulin Resistance
Insulin Level
100
50
0
-cell failure
-10
-5
0
5
10
15
20
25
30
Diagnosis of Diabetes
Years of Diabetes
*IFG
= impaired fasting glucose.
Adapted from: International Diabetes Center (IDC), Minneapolis, Minnesota .
Insulin Resistance and -cell Dysfunction are
Core Defects of Diabetes
Genetic susceptibility, obesity, Western lifestyle
Glucagon
Incretins
Insulin
Resistance

IR
β-Cell
Dysfucntion
TypeDiabetes
2 diabetes
Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13
Diagnostic Criteria for
Glycemic Abnormalities
Fasting Plasma
Glucose
Hemoglobin A1C
Diabetes
126 mg/dL
Diabetes
7.0 mmol/L
6.5%
Prediabetes
100 mg/dL
Diabetes
200 mg/dL
Prediabetes
5.6 mmol/L 5.7%
Normal
2 hour Plasma Glucose
on OGTT
140 mg/dL
Normal
11.1 mmol/L
Impaired Glucose
Tolerance
7.8 mmol/L
Normal
WHO position statement 2011: HbA1c > 6.5 diagnostic for DM, levels below do not exclude
diagnosis using glucose tests, no formal recommendation to interprete levels < 6.5 %
To convert mg/dL to mmol/L multiply mg/dl by 0.055
The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2001;24:S5-S20
The Expert Committee
on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2001;24:S5-S20
American Diabetes Association. Diabetes Care 2010;33:S11-61
American Diabetes Association. Diabetes Care 2010;33:S11-61
-cell Mass in Diabetes
3.5
 -Cell volume (%)
3.0
-50%
2.5
2.0
-63%
1.5
1.0
0.5
0.0
ND
IFG
T2DM
ND
Obese
T2DM
Lean
ND=non-diabetic; IFG=impaired fasting glucose; T2DM=Type 2 diabetes mellitus
Butler et al. Diabetes. Diabetes. 2003;52:102-110
What actually is Insulin
Resistance?
Insulin is a Powerful Anabolic Hormone
Insulin
Liver
Adipose
tissue
Muscle
 Triglyceride synthesis
 Glycogen synthesis
 Gluconeogenesis
 Glycogen synthesis
 Triglyceride deposition
 Protein synthesis
Capillary
Mitochondria
Endothelial NO synthesis
 Glucose oxidation
 Peripheral vasodilatation
 ATP production
 Regional blood flow
 Glucose delivery and uptake
DeFronzo et al. Diabtes Metab Res rev 2006;22:423-436
Insulin Receptor and Signaling
Reduce Response to Circulating Insulin
Insulin Resistance
Liver
Adipose
tissue
Muscle
 Lipolysis
 Glycogen synthesis
 Gluconeogenesis
 Glycogen synthesis
 Proteolysis
Capillary
 Glucose uptake
 Circulation FFA
 Glucose uptake
Mitochondria
 Endothelial NO synthesis
 FFA oxidation
 Peripheral vasodilatation
 ATP production
 Regional blood flow
 Small dense LDL
 Glucose delivery and uptake
DeFronzo et al. Diabtes Metab Res rev 2006;22:423-436
Insulin Receptor and Signaling
Acanthosis Nigricans
Acanthosis Nigricans
Mechanisms by which Pre-diabetes leads to
Coronary Heart Disease
Insulin Resistance
Hyperglycemia
Inflammation
Infection
 IL-6
 CRP
 SAA
 Defense
mechanisms
 Pathogen burden
 AGE
 Oxidative
stress
HTN
Endothelial
dysfunction
Dyslipidemia
 LDL
 TG
 HDL
Subclinical Atherosclerosis
Thrombosis
 PAI-1
 TF
 tPA
Disease Progression
Atherosclerotic Clinical Events
AGE=Advanced glycation end products, CRP=C-reactive protein, HDL=High-density lipoprotein,,
IL-6 =Interleukin-6, LDL=Low-density lipoprotein, PAI-1=Plasminogen activator inhibitor-1,
SAA=Serum amyloid A protein, TF=Tissue factor, TG=Triglycerides, tPA=Tissue plasminogen activator
Biondi-Zoccai GGL et al. JACC 2003;41:1071-1077
Most Cardiovascular Patients Have
Abnormal Glucose Metabolism
GAMI
n = 164
31%
35%
34%
Normoglycemia
EHS
n = 1920
37%
CHS
n = 2263
18%
37%
36%
45%
Prediabetes
27%
Type 2 Diabetes
GAMI = Glucose Tolerance in Patients with Acute Myocardial Infarction study
EHS = Euro Heart Survey
CHS = China Heart Survey
Anselmino M, et al. Rev Cardiovasc Med. 2008;9:29-38
Marked Increase in the Risk of
Myocardial Infarction in Diabetes
7 years follow-up
7-year incidence of
cardiovascular events (%)
50
45%
40
30
20
10
19%
20%
History of MI
No history of MI
4%
0
No history of MI
History of MI
Non-diabetic (n = 1,373)
Diabetes (n = 1,059)
Haffner SM et al. N Engl J Med 1998; 339: 229–234
Survival Following a Myocardial Infarction
Minnesota Heart Survey
MEN
100
WOMEN
No diabetes
80
No diabetes
Survival (%)
n=1628
n=568
60
Diabetes
40
Diabetes
n=228
0
n=156
Months Post-MI
0
20
40
60
Months Post-MI
80
0
20
40
60
80
Sprafka JM et al. Diabetes Care 1991;14:537-543
Diabetes and Cardiovascular Disease
50% of patients with diabetes have preexisting coronary
artery disease
CVD is 2 to 4 fold higher among people with diabetes
35-45% of patients presenting with myocardial infarction
have undiagnosed diabetes
Atherosclerotic complications responsible for 80% of
mortality among patients with diabetes
Lewis GF. Can J Cardiol. 1995;11(suppl C):24C-28C
Norhammar A, et.al. Lancet 2002;359;2140-2144
Lewis GF. Can J Cardiol. 1995;11(suppl C):24C-28C
8% of people with pre-diabetes
have retinopathy
DPP Retinopathy Sub-study
DPP Research Group. Diabetic Medicine 2007; 24 (2); 137-144
79 million U.S. adults
ages 20 and older have
pre-diabetes
IFG, IGT or an A1C of 5.7% - 6.4%
Progression to diabetes
evitable
Prevention of Diabetes is Possible
Medication
Behavior
Study
Subjects
Intervention
Relative Risk Reduction
Da Quing1
IGT
Diet or Exercise or Both
42% / 49% / 34%
Finnish DPS2
IGT
Lifestyle
58%
DPP3
IGT
Lifestyle
58%
DPP3
IGT /“IFG”
Metformin
31%
STOP-NIDDM4
IGT
Acarbose
25%
EDIP5
IFG
Acarbose
NS
XENDOS6
IGT
Orlistat
45%
TRIPOD7
Prior GDM
Troglitazone
55%
DREAM8,9
IFG
Rosiglitazone / Ramipril
62% / NS
ACT NOW10
IGT
Pioglitazone
72%
IGT / “IFG”
Insulin Glargine / Omega-3

ORIGIN11
IFG: impaired fasting glucose
IGT: impaired glucose tolerance
GDM: gestational diabetes mellitus
NS: not significant
1Li
G et al. Lancet. 2008;371:1783-1789 | 2Tuomilehto J et al. N Engl J Med. 2001;344:1343-1350 | 3Diabetes
Prevention Program Research Group. N Engl J Med. 2002;346:393-403 | 4Chiasson JL et al. Lancet. 2002;359:20722077| 5Kirkman MS et al. Diabetes Care. 2006;29:2095-2101 | 6Torgerson JS et al. Diabetes Care. 2004;27:155-161 |
8DREAM Trial Investigators. Lancet. 2006;368;1096-1105 | 9DREAM Trial Investigators. N Engl J Med. 2006;355:15511562 | 10DeFronzo RA et al. N Engl J Med. 2011;364:1104-1115 | 11ORIGIN Trial Investigators. Am Heart J.
2008;155:26-32.
Finnish Diabetes Prevention Study
522 patients with a mean BMI=31 kg/m2 patients and IGT† were
randomized to intervention‡ or usual care for 3 years
0.25
23%
0.2
Intervention
Control
0.15
0.1
11%
0.05
0
% with Diabetes Mellitus
Lifestyle modification reduces the risk of developing DM
†Defined
as a glucose >140 mg/dl 2 hours after an oral glucose challenge
‡
Aimed at reducing weight (>5%), total intake of fat (<30% total calories) and saturated fat
(<10% total calories); increasing uptake of fiber (>15 g/1000 cal); and physical activity
(moderate at least 30 min/day)
Tuomilehto J et al. NEJM 2001;344:1343-1350
Diabetes Reduction Assessment with
Ramipril and Rosiglitazone Medication
(DREAM) Trial
Incident DM or Death
5,269 patients with IFG and/or IGT, but without known CVD randomized to
rosiglitazone (8 mg) or placebo for a median of 3 years
0.6
Placebo
Rosiglitazone
0.4
0.2
60% RRR, P<0.0001
0.0
0
1
2
3
4
Years
Thiazolidinediones reduce the risk of developing DM
Benefit observed regardless of ethnicity, sex, age, weight, and fat distribution
51
Gerstein HC et al. Lancet 2006;368:1096-1105
Diabetes Prevention Program and Outcome
Study (DPP and DPPOS)
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.. .
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. ..
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Diabetes Prevention Program (DPP)
To determine whether diet and exercise or metformin could
prevent or delay the onset of type 2 diabetes in persons
with impaired glucose tolerance
Adults at high risk for type 2 diabetes / Presence of IGT
Mean age 51 years
Mean BMI 34
68% women
45% minority groups
African Americans
Hispanics/Latinos
American Indians
Asian Americans and Pacific Islanders
Average follow-up 2.8 years
DPP Research Group. N Engl J Med 2002; 346:6
Diabetes Prevention Program (DPP)
Lifestyle intervention
5% to 7% weight reduction
Healthy low-calorie, low-fat diet
30 minutes of physical activity, 5 days a week
Diet
Taught one-on-one
Exercise
by case managers
Behavior change modification
Metformin 850 mg po q12h + Standard Lifestyle
Oral diabetes drug
Placebo + Standard Lifestyle
DPP Research Group. N Engl J Med 2002; 346:6
Percent
developingof
diabetes
DPP
Incidence
Diabetes
All participants
Placebo (n=1082)
Metformin (n=1073, p<0.001 vs. Placebo)
Lifestyle (n=1079, p<0.001 vs. Met , p<0.001 vs. Plac )
Lifestyle (n=1073,
(n=1079,p<0.001
p<0.001
Metformin,
Metformin
vs.vs.
Plac)
Placebo (n=1082)
p<0.001 vs. Placebo)
Cumulative incidence (%)
40
30
20
Risk reduction
31% by metformin
58% by lifestyle
10
0
0
1
2
3
4
Years from randomization
DPP Research Group. N Engl J Med 2002; 346:6
DPP Outcome Study
Weight Change Over Time – Overall
DPP Research Group. Lancet. 2009; 374:1677-1686
DPPOS Incidence of Diabetes – Overall
Risk reduction
19% by metformin
34% by lifestyle
DPP Research Group. Lancet. 2009; 374:1677-1686
After 10 years follow-up
Lifestyle Intervention;
reduced the rate of developing diabetes by 34%
reduced the rate of developing diabetes by 49% in those age 60 and older
delayed diabetes by about 4 years
reduced cardiovascular risk factors
reduced A1C and FPG
Metformin;
reduced the rate of developing diabetes by 18% compared with placebo.
delayed diabetes by 2 years compared with placebo.
reduced A1C and fasting glucose compared with placebo.
DPP Research Group. The Lancet 2009: Vol.374, No. 9702.
How to Treat Diabetes?
ABC for Diabetes Care
A A1c Target
Aspirin Daily
B Blood Pressure Control
C Cholesterol Management
Cigarette Smoking Cessation
D Diabetes and Pre-Diabetes
Management
E Exercise
F Food Choices
What is the HbA1c Goal?
Blood Glucose
Parameter
ADA1
AACE2
A1C
<7%
≤6.5%
70-130 mg/dL
<110 mg/dL
<180 mg/dL
<140 mg/dL
Preprandial
Glucose/FPG
Peak PPG*/2-h PPG
1-American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61. 2
2- Rodbard HW, et al. Endocr Pract. 2007;13(suppl 1):3-68
How Does A1C Compare with Blood
Sugar Readings?
A1c (%)
Average Blood
Sugar (mg/dL)
6
126
7
154
8
183
9
212
10
240
11
269
12
298
*ADA target fasting sugar level: 70-130 mg/dL
American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61.
Effect of Intensive Glycemic Control
United Kingdom Prospective Diabetes Study (UKPDS)
3,867 patients with diabetes randomized to intensive therapy with a sulphonylurea or
insulin (mean HbA1C 7.0%) or conventional therapy (mean HbA1C 7.9%) for 10 years
0
-10
-20
-30
-25
P<0.01
-21
P=0.02
-16
P=0.05
-12
P=0.03
-33
P<0.01
-40
-50
Microalbuminuria at 12 years
Retinopathy
Any DM endpoint
Microvascular complications
Myocardial infarction
Intensive glycemic control in DM reduces
the risk of microvascular complications
UKPDS Group. Lancet 1998;352:837-853
Tight Glycemic Control Reduces
Complications
United Kingdom Prospective Diabetes Study (UKPDS)
21%
Deaths related to diabetes*
37%
Micro complications
14%
Heart attack *
43%
Amputation or fatal PVD
12%
Stroke **
HbA1c
1%
* p<0.0001
** p=0.035
Stratton IM et al. UKPDS 35. BMJ 2000; 321: 405–412
MEDICATIONS
Primary sites of action of
oral antidiabetic agents
-glucosidase
inhibitors
Sulfonylureas/
meglitinides
 Carbohydrate
breakdown/
absorption
 Insulin
secretion
Biguanides
Thiazolidinediones
 Glucose
output
 Insulin resistance
 Insulin
resistance
Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.
Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
Selection Oral Hypoglycemic Therapy
Consider Metformin;
• Obesity
• Normal liver/renal function
Contraindicated:
• Creatinin > 1.4 ( women), > 1.5 (men)
• IV contrast
• CHF
• Dehydration
• Alcohol excess
• > 80 years old unless CrCl is normal
Selection Oral Hypoglycemic Therapy
Consider Thiazolidinedione (TZD);
• Obesity, insulin resistance
• Normal liver function
Do not start if initial ALT is 2.5 times > N
After Rx;
If ALT is 2.5 times > N, check weekly
If ALT is 3 times > N, discontinue Rx
Contraindicated:
• Class III and IV CHF
• LFTs > 2.5 times higher than normal
The dual action of
thiazolidinediones reduces HbA1c
Insulin
resistance
IR
+

-cell
function
HbA1c
Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.
Selection Oral Hypoglycemic Therapy
Consider Insulin Secretagogue
(Sulfonylurea);
• Non-obesity or mild obese
• Repaglinide (Prandin) or Nateglinide (Starlix)
are useful for post-prandial hyperglycemia
(non-sulfonylurea insulin secretagogues)
Contraindicated:
• Severe liver or renal disease
Selection Oral Hypoglycemic Therapy
Consider α-Glucosidase Inhibitor;
• Milder presentation
• Useful for post-prandial hyperglycemia
Contraindicated:
• Chronic intestinal disorders,
• Liver and renal failure
Does decreasing insulin resistance
decrease macrovascular complications?
Sulfonylureas/insulin
Metformin
Myocardial
infarction
All-cause
mortality
Myocardial
infarction
All-cause
mortality
21%
8%
39%
36%
Not significant
Not significant
Significant
Significant
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.
INCRETINS
Incretin Effect on Insulin Secretion
People with Type 2 diabetes (n=14)
80
80
60
60
Incretin
effect
40
20
0
Insulin (mU/l)
Insulin (mU/l)
Control subjects (n=8)
40
20
0
0
60
120
180
Time (min)
Oral glucose load
Intravenous glucose infusion
Nauck et al. Diabetologia. 1986
0
60
120
Time (min)
180
GLP-1: Effects in Humans
After food ingestion…
• Stimulates glucosedependent insulin secretion
• Suppresses glucagon
secretion
• Slows gastric emptying
GLP-1 is secreted from
L-cells of the jejunum
and ileum
That in turn…
• Leads to a reduction of
food intake
• Improves insulin sensitivity
Long-term effects
in animal models:
• Increase of β-cell mass
and improved β-cell function
Drucker. Curr Pharm Des. 2001
Drucker. Mol Endocrinol. 2003
Effect of GLP-1 on β-cell mass in
Zucker diabetic fatty rats
β-Cell mass
β-Cell proliferation
30
12
8
4
Proliferating β-cells (%)
P<0.01
P<0.05
2.0
1.5
1.0
0.5
Control
GLP-1
treated
Farilla et al. Endocrinology. 2002
20
P<0.001
10
0
0
0
Apoptotic β-cells (%)
2.5
16
β-Cell mass (mg)
β-Cell apoptosis
Control
GLP-1
treated
Control
GLP-1
treated
GLP-1 Enhancement
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
•
exenatide
•
liraglutide
Injectables
Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
Block DPP-4, the
enzyme that degrades
GLP-1:
• sitagliptin
• vildagliptin
Oral agents
Incretin mimetics and DPP-4 inhibitors:
major differences
Properties/effect
Incretin mimetics
DPP-4 inhibitors
Mechanism of stimulation of insulin
secretion exclusively through GLP-1
effect
Yes
Unknown
Restitution of insulin secretion (2 phases) Yes (exenatide)
Yes
Hypoglycaemia
No
No
Maintained counter-regulation by
glucagon in hypoglycaemia
Yes
Not tested
Inhibition of gastric emptying
Yes
Marginal
Effect on body weight
Weight loss
Weight neutral
Side effects
Nausea
None observed
Administration
Subcutaneous
Oral
Gallwitz. Eur Endocr Dis. 2006
Selection Hypoglycemic Therapy
Glucagon Like Peptide-1 (Exenatide)
• Produced by the L-cells of the small bowel
• Increases endogenous insulin secretion
in a glucose-dependent fashion,
• Controls gastric emptying
• Inhibits appetite
• Restore functioning beta cell mass
• Modulates secretion of glucagon, somatostatin
• Start 5 mcg SC BID, then 10 mcg SC BID
Selection Hypoglycemic Therapy
Sitagliptine (Januvia)
• DPP-4 inhibitor
• Allows elevated and prolonged
plasma levels of GLP-1
• Approved in 2006
• Long acting
• Promote beta-cell preservation in animal
models
DM Management with Oral
Hypoglycemics
• Titrate the dose over 2 months
• Reinforce Medical Nutrition Therapy and
exercise
• Add drug of another class
If FPG > 130 mg/dl or
2 h PP PG > 180 mg/dl
A1c > 7%
• If goal PG is not achieved and DM > 5 yrs
• Add third oral medication or INSULIN
INSULIN
Insulin Secretion
Insulin Receptor and Signaling
Insulin Secretion
Insulin
Insulin Type
Product
Onset
Peak
Duration
Aspart Analog
NovoLog
10-30 min
0.5-3 hrs
3-5 hrs
Lispro Anolog
Humalog
Regular
Humulin, Novolin R
30 min
1-5 hrs
8 hrs
NPH
Humulin, Novolin N
1-4 hrs
4-15 hrs
16-26 hrs
Glargine
Lantus,Levemir
1-2 hrs
------
24 hrs
Premixed
70/30, 75/25, 50/50
“
“
“
Insulin Injections
Overcoming Barriers to Insulin
Therapy
Delays in initiating insulin therapy;
Clinician concerns;
• Hypoglycemia
• Weight gain
• Increasing CVD risk
Patients concerns;
• Sign of personal failure,
• Misconceptions
• Labor intensive and complicated
Many
concerns may
be addressed
through
education and
setting
appropriate
expectations
Basal Insulin with Oral
Hypoglycemics
• A1c 8.5% to 10%
• Initial dose of Lantus or NPH 10-20 units/day
(0.2 to 0.3 units/kg)
• Monitor FBG and adjust the dose
• Increase the dose by 2 Units if FBG >140 for 3 d
• Rate of hypoglycemia is lower with Lantus
• AM dosing of Lantus are comparable with PM
dose
Basal-Prandial Insulin with Oral
Hypoglycemics
• A1c > 10%
• High postprandial glucose despite normalization
of FBG
• Initial dose of Lantus 0.3 units/kg
• Give approximately same dose as prandial
insulin divided into 3
• 2hpp BG Goal: 80-150 mg/dl
• Correction dose: 1500/daily total insulin
• Carb to insulin ratio: Usually 1 Unit /15 g of Carb
Nutrition
NOT EVERYONE NEEDS
1800 CAL/D ADA DIET
IBW for woman; 5’= 100 lb + every 1’ x 5
IBW for man;
5’= 110 lb + every 1’ x 5
If weight 10 lb more than IBW, daily
requirement will be:
10 x IBW
IBW
• Males: IBW =
50 kg + 2.3 kg for each inch over 5 feet.
• Females: IBW =
45.5 kg + 2.3 kg for each inch over 5 feet.
Recommended calorie intake
• Calories needed to maintain weight depends
upon your age, sex, height, weight, and
activity level.
• Men, active women - 15 cal/lb
• Most women, sedentary men, and adults over
55 years - 13 cal/lb
• Sedentary women, obese adults - 10 cal/lb
• Pregnant, lactating women - 15 to 17 cal/lb
Recommended calorie intake
• To lose 1 to 2 pounds per week (a safe rate
of weight loss), subtract 500 to 1000 calories
from the total number of calories needed to
maintain weight.
• Example, an overweight man who weighs
250 lbs would need to eat 2500 calories per
day to maintain his weight.
• To lose 1 to 2 pounds per week, he should
eat 1500 to 2000 calories per day. As weight
is lost, the recommended calorie intake
should be recalculated.
Nutrition
Carb. intake:
45-65 % of total calories
Protein intake:
15-20 % of total calories
Diabetics with any degree of CKD should be have 0.8
g/kg, around 10 % of total calories
Fat intake:
25-35 % of total calories
Saturated fat intake should be < 7% of total calories
Intake of trans fat should be minimized
ADA Guidelines
1. Diabetic focused visit : Every 3-6 months
• Review physical activities, diet, BMI
• Review Meds and frequency of low blood sugars
2. HbA1c should be checked every 3 –6 month (Goal<7%)
3. Urine for microalbumin should be checked every year
• If >30 mcg/mg creatinine or >30 mg/24 hr,
start on ACE inhibitor unless contraindicated
4. Yearly lipid profile with a goal of :
• Triglyceride < 150 mg/dl
• HDL
> 40 mg/dl (men), > 50 mg/dl (women)
• LDL
< 100 mg/dl
ADA Guidelines
6. Blood pressure should be <130/85 and < 125/75 if
diabetic nephropathy
7. Aspirin prophylaxis for every one unless
contraindicated
8. Yearly dilated eye examination by ophthalmologist
or referrals if needed
9. Yearly comprehensive lower extremities
examination including monofilament test
10. Dental examination every 6 month for dentate
person and every 1 year for edentate
11. Nutrition therapy by dietitian every 6-12 months
Recent Trials Show No Reduction in CV
Events with More Intensive Glycemic Control
ACCORD
ADVANCE
10,251 participants
11,140 participants
Mean age: 62 y
Mean age: 66 y
Median duration of diabetes: 10 y
Mean duration of diabetes: 8 y
Mean A1C at entry: 8.3%
Mean A1C at entry: 7.48%
Known heart disease or
History of major CV event or
at least 2 risk factors
at least 1 risk factor
Standard
Intensive
Standard
Intensive
A1C 7.0%–7.9%
A1C < 6.0%
A1C usual care
A1C ≤ 6.5%
CONCLUSION: Intensive glucose-lowering
did not significantly reduce CVD events
(primary outcome) may cause harm in highrisk patients with type 2 diabetes ( 20%
increased in mortality).
CONCLUSION: Intensive glucose-lowering
did not significantly reduce CVD events
(primary outcome) reduces renal
complications in high-risk patients by 21%
(95% CI, 7–34%) and did not increase
mortality
ACCORD Study Group. N Engl J Med. 2008;358:2545-2559
ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572
What is the HbA1c Goal?
HbA1C value of <7.0% is appropriate and well
supported by clinical trial results:
There are no data to support an A1C goal of <7.0% for
reducing cardiovascular risk
For individual patients, intensifying the regimen should
be weighed by the potential risks and benefits:
History of severe hypoglycemia
Limited life expectancy
Children
Comorbid conditions
Longstanding diabetes and minimal or stable microvascular
complications
Inzucchi SE et al. Diabetes Care 2012;35:1364-1379.
American Diabetes Association. Diabetes Care. 2008;31:S12-S54
Individualizing HbA1c Targets in Diabetes
Most Intensive
Least Intensive
Less Intensive
6.0%
8.0%
7.0%
Psychosocioeconomic Considerations
Highly Motivated, Adherent, Knowledgeable, Excellent
Less Motivated, Nonadherent, Limited Insight, Poor
Self-Care Capacities, Comprehensive Support Systems
Self-Care Capacities, Weak Support Systems
Hypoglycemia Risk
Moderate
Low
High
Patient Age
45
40
55
50
60
65
70
75
Disease Duration
5
15
10
20
Other Comorbidities
None
Few/Mild
Multiple/Severe
Established Vascular Complications
None
Early Microvascular
Cardiovascular
Advanced Microvascular
Ismail-Beigi F et al. Ann Intern Med 2011;154: 554-559
Therapeutic Landscape of Diabetes
Agent
Examples
Mechanism
Action
SUs
glyburide, glipizide,
glimepiride
Closes KATP channels
 Pancreatic insulin secretion
‘Glinides
repaglinide,
nateglinide
Closes KATP channels
 Pancreatic insulin secretion
Biguanides
metformin
Activates AMP-kinase
 Hepatic glucose production
TZDs
rosiglitazone,
pioglitazone
Activates PPAR-
 Peripheral insulin sensitivity
-GIs
acarbose, miglitol
Blocks small bowel
-glucosidase
 Intestinal carbohydrate absorption
GLP-1 R
agonists
exenatide, liraglutide
Activates GLP-1
receptors
 Pancreatic insulin secretion;
 glucagon secretion; delays gastric
emptying;  satiety
Amylinomimetics
pramlintide
Activates amylin
receptors
 Pancreatic glucagon secretion;
delays gastric emptying;  satiety
DPP-4
inhibitors
sitagliptin, saxagliptin
Inhibits DPP-4,
 endogenous incretins
 Pancreatic insulin secretion;
 pancreatic glucagon secretion
Bile acid
sequestrants
colesevelam
Binds bile acid
cholesterol
?
SGLT
inhibitors
dapagliflozin,
canagliflozin
Selectively inhibits
SGLT2
 Renal glucose elimination
Inzucchi SE et al. Diabetes Care 2012;35:1364-1379
Therapeutic Landscape of Diabetes
Agent
A1c
SUs
1–2%
‘Glinides
Biguanides
1–1.5%
1–2%
Advantages
Disadvantages
Microvasc risk
Hypo, wt gain,
-cell exhaust
PPG
Hypo, wt gain, -cell
exhaust, dose frequency
Wt loss, no hypo,
CVD, ?  malignancy
GI, lactic acidosis
B12-deficiency
Cost
$
$$$
$
TZDs
1–1.5%
No hypo; -cell preserv
TG HDL BP ? CVD (pio)
Wt gain, edema / HF
Bone fxs, ? CVD (rosi)
-GIs
0.5–1%
PPG, ? CVD;
GI, dose frequency
Wt loss,? -cell preserv,
? CV benefits
GI; ? pancreatitis,
injections
$$$
Wt loss, PPG
GI, dose frequency,
injections
$$$
No hypo
Urticaria / Angioedema;
? pancreatitis
$$$
No hypo; LDL-C
GI; TGs
$$$
No hypo
UTI
$$$
GLP-1 R
agonists
1%
Amylinomimetics
0.5%
DPP-4
inhibitors
0.6–0.8%
Bile acid
sequestrants
SGLT
inhibitors
0.5%
1%
$$$
$$
Inzucchi SE et al. Diabetes Care 2012;35:1364-1379
Insulin Secretion
Insulin Secretion
Insulin Coverage
Insulin Type
Product
Onset
Peak
Aspart Analog
NovoLog
10-30 min
0.5-3 hrs
Lispro Anolog
Humalog
Regular
Humulin, Novolin R
30 min
1-5 hrs
8 hrs
NPH
Humulin, Novolin N
1-4 hrs
4-15 hrs
16-26 hrs
Glargine, Detemir
Lantus,Levemir
1-2 hrs
Premixed
70/30, 75/25, 50/50
“
“
------
Duration
3-5 hrs
“
24 hrs
Overcoming Barriers to Insulin Therapy
Delays in initiating insulin therapy;
Clinician concerns;
Hypoglycemia
Weight gain
Increasing CVD risk
Patients concerns;
Sign of personal failure,
Misconceptions
Labor intensive and complicated
Many concerns may
be addressed through
education and setting
appropriate
expectations
Basal Insulin with Oral Hypoglycemics
A1c 8.5% or more
Initial dose of basal insulin 0.2 to 0.3 units/kg
Monitor FBG and adjust the dose
Increase the dose by 2 Units if FBG >110 for 3 days
Rate of hypoglycemia is lower with long acting insulin
than NPH
AM dosing of basal insulin are comparable with PM dose
Treatment Targets in Diabetes Provide a
Basis for Improved Outcomes
Tight blood
glucose control
Microvascular
complications1
Tight blood
pressure control
Macrovascular
complications2
Tight cholesterol
control
Cardiovascular
events3
1. UKPDS
Group. Lancet 1998; 352: 837–53
2. UKPDS. BMJ 1998; 317: 703–13
3. Colhoun HM et al. Lancet 2004; 364: 685–96
ABC for Diabetes Care
A A1c Target
Aspirin Daily
B Blood Pressure Control
C Cholesterol Management
Cigarette Smoking Cessation
D Diabetes and Pre-Diabetes
Management
E Exercise
F Food Choices
Are We Achieving our the Goal?
National Health and Nutrition Examination Survey
(NHANES) from 2007 to 2010
52% of patients reached HbA1C goal of < 7%
18% of adults with diabetes have the
combination of
HbA1C < 7%,
BP < 130/80 mm Hg,
Total Cholesterol < 200 mg/dl
78% of our patients with diabetes have not
met the basic treatment goals
Casagrande S. Diabetes Care 2013;doi: 10.2337/dc12-2258
Inpatient Diabetes Care
Patients with Known Diabetes Who are Able to Eat
Not Critically Ill
A- Patient who is on oral anti-diabetic medication (OAD):
•
Assess if there are contra-indications for OAD use
(CHF, renal or hepatic dysfunction, etc.)
•
If no contraindication and glucose is in the “target” range
(~110-180 mg/dl), continue with OAD’s and monitor
blood glucose (BG)
•
If there are contra-indications to OAD’s or the patient is
hyperglycemic (above “target” range), start insulin using
basal and prandial standard orders.
Patients with Known Diabetes Who are Able to Eat
Not Critically Ill
B- Patient who is on insulin before admission should
(minimally) receive their usual insulin program
• Patients should receive their usual insulin program
• REMEMBER; that the patients’ usual insulin may be
inadequate in the face of inter-current illness
• No matter what the prior insulin program was, be sure
that your orders provide for the basal and prandial
insulin replacement
• Patients’ prior insulin dose gives an index of insulin
sensitivity. Use it to derive the “correction doses”.
Patients with Known Diabetes Who are Able to Eat
Not Critically Ill
C- Patients made NPO for a procedure in the AM
• Give usual dose of basal insulin the evening before
and start D5W at 100 cc/min in the morning
• If the patient is on NPH BID, can give ½ the usual AM
dose and start D5W at 100 cc/min in the morning
• Continue with the sliding scale coverage
Patients with Known Diabetes Who are Unable to Eat
Not in the ICU or CCU,
• “Target” BG
Fasting: ~110 mg/dl
Throughout the day: ~140 (110-180)
• If the patient is persistently above the “target” start insulin
therapy
• Principles:
1- NO SLIDING SCALE ALONE!
The usual “sliding scale” order (only short-acting insulin
given when the patient is above target) is non-physiologic
and does not work to control glucose!
May be used to supplement basal and prandial insulin.
Patients with Known Diabetes Who are Unable to Eat
Not in the ICU or CCU,
2- Physiologic replacement requires both “basal and
prandial” insulin
3- Analog short acting insulin is designed to be used with
each meal. Regular insulin should be used only when IV
insulin is needed
• If the patient was not previously on insulin, do this (finger
sticks a.c. and h.s)
Daily insulin requirement is 0.5 units/kg
Start basal insulin (as Glargine) at doses of 0.2 to 0.3
units/kg body weight/day
Patients with Known Diabetes Who are Unable to Eat
Not in the ICU or CCU,
e.g.: a 70 kg individual should start with 14 units of basal
insulin SQ qhs]
Give approximately the same total daily dose of prandial
insulin as the basal insulin dose- use 1/3 of daily dose with
each meal
[e.g.: if the basal dose is 14 units, give 4 units of short acting
with each meal if the pre-meal glucose is within the
“desirable range of 110-160mg/dl
Patients with Known Diabetes Who are Unable to Eat
Not in the ICU or CCU,
REMEMBER; short acting insulin works fast. The order
should advise the nurse to give the pre-prandial insulin when
the meal is in the patients’ room and ready to be eaten.
If the pre-meal glucose is above 160 mg/dl, add “correction
dose” of short acting insulin
In general, the “correction dose” is calculated by dividing the
patients’ daily requirement dose into 1500. The result is the
predicted glucose lowering effect of 1 unit of insulin.
Patients with Known Diabetes Who are Unable to Eat
Not in the ICU or CCU,
e.g.: if the patient’s total insulin is 30 units/day, 1 unit of
insulin should lower the glucose by 50 mg/dl (1500/30=50).
Therefore, add 1 unit of insulin per 50 mg/dl glucose above
160. If the pre-meal glucose were 250 mg/dl, the preprandial insulin dose should be 2 units + usual dose- in the
above example, 4+2 =6 units.
Patients with Known Diabetes Who are Unable to Eat
Not in the ICU or CCU,
Adjust the basal insulin dose every 24-48 hours based on
the fasting (pre-breakfast) glucose value- make the
appropriate changes in the prandial doses as well
For patients coming of insulin drip, begin basal insulin 2
hours before the drip is stopped and start short acting insulin
as soon as the patient is able to eat.
THANK YOU
Newsweek, September 4,
2000
Time, September 4, 2000
Type 2 Diabetes is Characterized by Insulin
Resistance and Progressive ß-cell Failure
Stages of Type 2 Diabetes in
Relationship to ß-cell Function
Beta Cell Function (%)
100
75
50
25
Impaired
glucose
tolerance
-12
-10
Postprandial
hyperglycemia
-6
Type 2 diabetes
phase III
Type 2
diabetes
phase I
-2
0
Type 2
diabetes
phase II
2
6
10
14
Years from Diagnosis
50% of ß-cell function is already lost at diagnosis
Elevated PPG occurs before diagnosis
Lebovitz HE. Diabetes Review 1999;7(3):139 153
More than 80% of Patients Progressing to
Diabetes are Insulin Resistant
Insulin sensitive;
low insulin secretion
(16%)
Insulin sensitive;
good insulin
secretion (1%)
San Antonio Heart Study
N = 1,734
11% (n=105) progressed to Diabetes in 7 years
Insulin resistant;
low insulin secretion
(54%)
83%
Insulin resistant;
good insulin secretion
(29%)
Haffner SM, et al. Circulation 2000; 101:975–980
How does Insulin Work?
Reactive Oxygen Species
Nutrient Composition of
Therapeutic Lifestyle Changes Diet
Nutrient
• Saturated fat
• Polyunsaturated fat
• Monounsaturated fat
• Total fat
• Carbohydrate
• Fiber
• Protein
• Cholesterol
• Total calories (energy)
Recommended Intake
Less than 7% of total calories
Up to 10% of total calories
Up to 20% of total calories
25–35% of total calories
50–60% of total calories
20–30 grams per day
Approximately 15% of total
calories
Less than 200 mg/day
Balance energy intake and
expenditure to maintain
desirable body weight/
prevent weight gain
Sodium intake should be <1500 mg/day (AHA 2011)
Pathophysiology of Diabetes
Decreased
Incretin Effect
Decreased Insulin
Secretion
Increased
Lipolysis
Islet– cell
ETIOLOGY OF T2DM
Impaired Insulin
Secretion
Increased Lipolysis
Hyperglycemia
Increased
HGP
Decreased Glucose
Uptake
DEFN75-3/99
HYPERGLYCEMIA
Increased
Glucagon
Secretion
Increased
Hepatic Glucose
Production
Increased
Glucose
Reabsorption
Decreased Glucose
Uptake
Neurotransmitter
Dysfunction
DeFronzo R et al. Diabetes. 2009;58:773-795.
-cell Failure
Oversecretion of
insulin to compensate
for insulin resistance1,2
Glucotoxicity
Chronic
hyperglycemia
Lipotoxicity
Pancreas
High circulating
free fatty acids
-cell
dysfunction
Boden G & Shulman GI. Eur J Clin Invest 2002; 32:14–23
Insulin Resistance is Linked to
Cardiovascular Risk Factors
Hyperglycemia
Dyslipidemia
IR
Hypertension
Damage to blood
vessels
Clotting abnormalities
Atherosclerosis
Inflammation
Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.
Screening and Diagnosis of
Disorders of Glucose Metabolism
Screen for Diabetes:
Fasting plasma glucose or
2-hour, 75-g oral glucose
tolerance test
IFG or IGT
IFG and IGT
+ Other Features*
Diabetes
Lifestyle Intervention
Lifestyle Intervention
and / or Metformin
Lifestyle Intervention
+ Metformin
IFG=impaired fasting glucose; IGT=impaired glucose tolerance
• IFG: fasting (8 hours) plasma glucose 100–125 mg/dL
• IGT: 2-hour value in 75-g OGTT 140–199 mg/dL
• Diabetes: FPG ≥ 126 mg/dL or 2-hour OGTT ≥ 200 mg/dL; should be confirmed on a separate
day
*<60 years of age, reduced HDL-C, BMI ≥35 kg/m2, hypertension, elevated
triglycerides, A1C >6.0%, family history of diabetes in first-degree relative
Age-adjusted CVD death rate
per 10,000 person years
Age-Adjusted CVD Death Rates
Multiple Risk Factor Intervention Trial
(MRFIT)
No. of risk factors (total cholesterol, HTN, smoking)
Stamler J et al. Diabetes Care. 1993;16:434-444
Types of Diabetes
•
•
•
•
Type 1 Diabetes Mellitus
Type 2 Diabetes Mellitus
Gestational Diabetes
Other types:
• LADA (latent autoimmune diabetes of adults)
• MODY (maturity-onset diabetes of youth)
• Secondary Diabetes Mellitus
Patient Characteristics at Time of
Diagnosis
Type 1
Age
<20
Body habitus
Thin
Insulin secretion None
Insulin resistance None
Concomitant
None
Condition
Ethnicity
White
Type 2
>40
Central obesity
Variable
Excessive
HTN
dyslipidemia
atherosclerosis
Hispanic, AA
Gestational Diabetes
• Diagnosed in some women during pregnancy
• Occurs more frequently among African Americans,
Hispanic/Latino Americans, and American Indians.
Also more common among obese women and
women with a family history of diabetes.
• Requires treatment to normalize maternal blood
glucose levels to avoid complications in the infant.
• After pregnancy, 5% to 10% of women with
gestational diabetes are found to have type 2
diabetes.
• Women who have had gestational diabetes have a
20% to 50% chance of developing diabetes in the
next 5-10 years.
Latent Autoimmune Diabetes in Adults
• A form of autoimmune diabetes which is
diagnosed in individuals who are older than the
usual age of onset of type 1 DM
• Alternate terms for "LADA" include
– Late-onset Autoimmune Diabetes of Adulthood
– Slow Onset Type 1 diabetes
– Type 1.5
• Often, patients with LADA are mistakenly thought
to have type 2 diabetes, based on their age at
the time of diagnosis.
LADA
• About 80% of adults with recently diagnosed
type 2 diabetes but with GAD auto-antibodies
(i.e. LADA) progress to insulin requirement
within 6 years.
• The potential value of identifying this group at
high risk of progression to insulin
dependence includes:
– the avoidance of using metformin treatment
– the early introduction of insulin therapy
Maturity Onset Diabetes of the Young
• MODY is a monogenic form of diabetes with
an autosomal dominant mode of inheritance:
– Mutations in any one of several transcription factors or in the
enzyme glucokinase lead to insufficient insulin release from
pancreatic ß-cells
– Different subtypes of MODY are identified based on the
mutated gene.
• Diagnosis of MODY was based on presence
of non-ketotic hyperglycemia in adolescents
or young adults in conjunction with a family
history of diabetes.
• However, genetic testing has shown that
MODY can occur at any age and that a family
history of diabetes is not always obvious.
Secondary Causes of Diabetes
Diseases of the exocrine pancreas
Extensive damage to pancreas, Includes:
• Trauma, Infection
• Chronic necrotizing pancreatitis
• Pancreatic carcinoma
• Cystic fibrosis and Hemochromatosis
Endocrinopathies
• Acromegaly
• Cushing's syndrome
• Glucagonoma
Drug/chemical induced diabetes
• Synthetic glucocorticoids
• Cyclosporin A
• Nicotinic acid
• Interferon
• Pentamidine
• Thiazide diuretics (occasionally)
Infections
• Congenital rubella (the most common virus implicated
in the development of diabetes)
• Coxsackievirus B
• Adenovirus
• Mumps
• Cytomegalovirus
Secondary Causes of Diabetes
•
•
•
•
•
•
•
Acromegaly
Cushing syndrome
Thyrotoxicosis
Pheochromocytoma
Chronic pancreatitis
Cancer
Drug induced hyperglycemia:
– Atypical Antipsychotics - Alter receptor binding characteristics, leading to IR
– Beta-blockers - Inhibit insulin secretion.
– Calcium Channel Blockers - Inhibits secretion of insulin by interfering with
cytosolic calcium release.
– Corticosteroids - Cause peripheral insulin resistance and gluconeogensis.
– Fluoroquinolones - Inhibits insulin secretion by blocking ATP sensitive
potassium channels.
– Naicin - Increases insulin resistance due to increased free fatty acid mobilization.
– Phenothiazines - Inhibit insulin secretion.
– Protease Inhibitors - Inhibit the conversion of proinsulin to insulin.
– Thiazide Diuretics - Inhibit insulin secretion due to hypokalemia. They also
cause increased insulin resistance due to increased free fatty acid mobilization.
Insulin resistance and -cell
dysfunction are core defects of type 2
diabetes
Genetic susceptibility,
obesity, Western
lifestyle
Insulin
resistance

IR
-cell
dysfunction
Type 2 diabetes
Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
Insulin resistance – reduced response
to circulating insulin
Insulin
resistance
Liver
IR
Adipose
tissue
Muscle
 Glucose output
 Glucose uptake
 Glucose uptake
Hyperglycemia
Insulin resistance is linked to a range
of cardiovascular risk factors
Hyperglycemia
Dyslipidemia
Insulin
resistance
IR
Hypertension
Damage to blood
vessels
Clotting abnormalities
Atherosclerosis
Inflammation
Zimmet P. Trends Cardiovasc Med 2002; 12:354–362.
Why does the -cell fail?
Oversecretion of
insulin to compensate
for insulin resistance1,2
Glucotoxicity2
Chronic
hyperglycemia
Lipotoxicity3
High circulating
free fatty acids
Pancreas
-cell
dysfunction
3Finegood
1Boden
G & Shulman GI. Eur J Clin Invest 2002; 32:14–23.
2Kaiser
N, et al. J Pediatr Endocrinol Metab 2003; 16:5–22.
DT & Topp B. Diabetes Obes Metab 2001; 3 (Suppl. 1):S20–S27.
Excessive hepatic glucose
production in Type 2 diabetes
Hepatic
glucose
output
Insulin; IR
Glucagon
Fasting &
postprandial
hyperglycaemia
Plasma glucose
concentration
IR=insulin resistance
Action of Glucagon
Glycogen
Glucose
Low blood glucose promotes
glucagon release from
-cells of pancreas
Glucagon stimulates
breakdown of glycogen
Raises blood glucose
β-Cell function and glucagon
in Type 2 diabetes
• Loss of β-cell function and glucagon oversecretion both play key roles in development
• Progressive β-cell decline is coupled with
inadequate insulin secretion
• Glucagon is not suppressed during the
postprandial period
• Hepatic glucose production is increased
during the fasting period and is not
suppressed during the postprandial period
Long-term Complications of
Type 2 Diabetes
Hyperglycemia
Macrovascular Disease
Damage to medium
and large blood vessels
Coronary Artery
Disease
Cerebrovascular
Disease
Peripheral vascular
disease
Microvascular Disease
Damage to small
blood vessels
Retinopathy
Nephropathy
Neuropathy
Feet
Diabetic foot
Complications are
the most common
cause of nontraumatic
lower extremity
amputations in
the industrialized world
Risk
Factors
of DM
•Age > 35
•Family Hx of DM
•Hyperlipidemia
•HTN
•Gestational DM
100 mg/dl
•Weight loss
•Polyuira, polydypsia
Sx
•Polyphagia
of DM •Lethargy
•Pruritis vulvae, balanitis
100-126 mg/dl
> 126 mg/dl
75 mg oral glucose test
2 hour blood glucose
< 126 mg/dl
< 140 mg/dl
140-200
mg/dl
<-140-200 mg/dl
> 200 mg/dl
> 126 mg/dl
Diagnosis of Diabetes
ADA & AACE
Fasting
Plasma
Glucose
(mg/dL)
No
Diabetes
Prediabetes
Diabetes
Postprandial
Plasma
Glucose
(mg/dL)
ADA
HbA1c
<100
<140
<5.7%
100-125
140-199
5.7%-6.4%
≥126
≥200
≥6.5%
1. American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61. 2.
2. Rodbard HW, et al. Endocr Pract. 2007;13(suppl 1):3-68.
What are the Goals?
Blood Glucose
Parameter
ADA1
AACE2
A1C
<7%
≤6.5%
70-130 mg/dL
<110 mg/dL
<180 mg/dL
<140 mg/dL
Preprandial
Glucose/FPG
Peak PPG*/2-h PPG
1. American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61. 2.
2. Rodbard HW, et al. Endocr Pract. 2007;13(suppl 1):3-68.
How Does A1C Compare with Blood
Sugar Readings?
A1C (%)
6
7
8
9
10
11
12
Average Blood
Sugar* (mg/dL)
126
154
183
212
240
269
298
*ADA target fasting sugar level: 70-130 mg/dL
American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61.
Use the Guidelines to Improve
Patient Care
• Primary care providers and their office staff
are at the forefront of the diabetes epidemic
• Help patients understand and control their
“ABCs”
– A − A1C
– B − Blood pressure
– C − Cholesterol
• Always remember the basics
– Eye exam, foot exam, urine test
– Review nutrition, exercise, and smoking
Recommendations for Screening
of DM Complications in Stable Patients
Retinopathy
Dilated and
complete eye
exam— document
each year
Neuropathy
Visual foot inspection
and monofilament
testing each year
American Diabetes Association. Diabetes Care. 2010;33(suppl 1):S11-S61.
Cardiovascular Disease
Check blood pressure
at each visit and lipids
(cholesterol) each year
Nephropathy
Check urine albumin
and serum creatinine
level each year
Peripheral Vascular
Disease
Foot exam that includes
checking pedal pulses
each year
Goals for Patients With Diabetes
• National Health and Nutrition Examination Survey
(NHANES) from 1999 to 2000;
• 37% of patients reached HbA1C goal of < 7%
• 7% of adults with DM have the combination of
HbA1C < 7%,
BP < 130/80 mm Hg,
total cholesterol < 200 mg/dl
• 93% of our patients with DM have not met the
basic treatment goals
Achieving Control in Diabetes Can Be a
Challenge: A Cycle of Frustration
The health care
provider is frustrated
and may blame
the patient
The patient is given an
overwhelming or vague goal:
Cycle of
Frustration
“ Follow a meal and exercise
plan, take medications,
and check blood sugars”
How Do We
Break the Cycle?
• Support patient with
education and coaching
The patient may feel
like a failure if his or her
disease is not controlled
Seley JJ. Am J Nurs. 2007;107(suppl 6):4-5.
• Need time, knowledge,
good communication,
and caring
Glucose Monitoring
• Self-monitoring is an important component of treatment
- Helps to gauge treatment efficacy
- Help in treatment plan
- Provide feedback
- Provide patterns that assist in medication selection
- Assist in daily insulin dose adjustments
• 2 - 4 times daily is recommended
• SMBG should be reviewed during each visit
Goal of Glycemic Control for
People with DM
Plasma Glucose
Normal
Goal
Action Sugg.
( mg/dl )
---------------------------------------------------------------------------------Fasting or
Preprandial PG
< 100
90-130
< 80, > 140
2 h PP PG
< 140
< 160
> 180
Bed time PG
< 120
110-150
< 110, > 160
A1c (%)
<6
< 6.5
>7
---------------------------------------------------------------------------------* Plasma glucose values are 10-15 % higher than whole blood glucose
values
MEDICATIONS
Primary sites of action of
oral antidiabetic agents
-glucosidase
inhibitors
Sulfonylureas/
meglitinides
 Carbohydrate
breakdown/
absorption
 Insulin
secretion
Biguanides
Thiazolidinediones
 Glucose
output
 Insulin resistance
 Insulin
resistance
Kobayashi M. Diabetes Obes Metab 1999; 1 (Suppl. 1):S32–S40.
Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329.
Selection Oral Hypoglycemic Therapy
Consider Metformin;
• Obesity
• Normal liver/renal function
Contraindicated:
• Creatinin > 1.4 ( women), > 1.5 (men)
• IV contrast
• CHF
• Dehydration
• Alcohol excess
• > 80 years old unless CrCl is normal
Selection Oral Hypoglycemic Therapy
Consider Thiazolidinedione (TZD);
• Obesity, insulin resistance
• Normal liver function
Do not start if initial ALT is 2.5 times > N
After Rx;
If ALT is 2.5 times > N, check weekly
If ALT is 3 times > N, discontinue Rx
Contraindicated:
• Class III and IV CHF
• LFTs > 2.5 times higher than normal
The dual action of
thiazolidinediones reduces HbA1c
Insulin
resistance
IR
+

-cell
function
HbA1c
Lebovitz HE, et al. J Clin Endocrinol Metab 2001; 86:280–288.
Selection Oral Hypoglycemic Therapy
Consider Insulin Secretagogue
(Sulfonylurea);
• Non-obesity or mild obese
• Repaglinide (Prandin) or Nateglinide (Starlix)
are useful for post-prandial hyperglycemia
(non-sulfonylurea insulin secretagogues)
Contraindicated:
• Severe liver or renal disease
Selection Oral Hypoglycemic Therapy
Consider α-Glucosidase Inhibitor;
• Milder presentation
• Useful for post-prandial hyperglycemia
Contraindicated:
• Chronic intestinal disorders,
• Liver and renal failure
Does decreasing insulin resistance
decrease macrovascular complications?
Sulfonylureas/insulin
Metformin
Myocardial
infarction
All-cause
mortality
Myocardial
infarction
All-cause
mortality
21%
8%
39%
36%
Not significant
Not significant
Significant
Significant
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352:854–865.
INCRETINS
Incretin Effect on Insulin Secretion
People with Type 2 diabetes (n=14)
80
80
60
60
Incretin
effect
40
20
0
Insulin (mU/l)
Insulin (mU/l)
Control subjects (n=8)
40
20
0
0
60
120
180
Time (min)
Oral glucose load
Intravenous glucose infusion
Nauck et al. Diabetologia. 1986
0
60
120
Time (min)
180
GLP-1: Effects in Humans
After food ingestion…
• Stimulates glucosedependent insulin secretion
• Suppresses glucagon
secretion
• Slows gastric emptying
GLP-1 is secreted from
L-cells of the jejunum
and ileum
That in turn…
• Leads to a reduction of
food intake
• Improves insulin sensitivity
Long-term effects
in animal models:
• Increase of β-cell mass
and improved β-cell function
Drucker. Curr Pharm Des. 2001
Drucker. Mol Endocrinol. 2003
Effect of GLP-1 on β-cell mass in
Zucker diabetic fatty rats
β-Cell mass
β-Cell proliferation
30
12
8
4
Proliferating β-cells (%)
P<0.01
P<0.05
2.0
1.5
1.0
0.5
Control
GLP-1
treated
Farilla et al. Endocrinology. 2002
20
P<0.001
10
0
0
0
Apoptotic β-cells (%)
2.5
16
β-Cell mass (mg)
β-Cell apoptosis
Control
GLP-1
treated
Control
GLP-1
treated
GLP-1 Enhancement
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
•
exenatide
•
liraglutide
Injectables
Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
Block DPP-4, the
enzyme that degrades
GLP-1:
• sitagliptin
• vildagliptin
Oral agents
Incretin mimetics and DPP-4 inhibitors:
major differences
Properties/effect
Incretin mimetics
DPP-4 inhibitors
Mechanism of stimulation of insulin
secretion exclusively through GLP-1
effect
Yes
Unknown
Restitution of insulin secretion (2 phases) Yes (exenatide)
Yes
Hypoglycaemia
No
No
Maintained counter-regulation by
glucagon in hypoglycaemia
Yes
Not tested
Inhibition of gastric emptying
Yes
Marginal
Effect on body weight
Weight loss
Weight neutral
Side effects
Nausea
None observed
Administration
Subcutaneous
Oral
Gallwitz. Eur Endocr Dis. 2006
Selection Hypoglycemic Therapy
Glucagon Like Peptide-1 (Exenatide)
• Produced by the L-cells of the small bowel
• Increases endogenous insulin secretion
in a glucose-dependent fashion,
• Controls gastric emptying
• Inhibits appetite
• Restore functioning beta cell mass
• Modulates secretion of glucagon, somatostatin
• Start 5 mcg SC BID, then 10 mcg SC BID
Selection Hypoglycemic Therapy
Sitagliptine (Januvia)
• DPP-4 inhibitor
• Allows elevated and prolonged
plasma levels of GLP-1
• Approved in 2006
• Long acting
• Promote beta-cell preservation in animal
models
DM Management with Oral
Hypoglycemics
• Titrate the dose over 2 months
• Reinforce Medical Nutrition Therapy and
exercise
• Add drug of another class
If FPG > 130 mg/dl or
2 h PP PG > 180 mg/dl
A1c > 7%
• If goal PG is not achieved and DM > 5 yrs
• Add third oral medication or INSULIN
INSULIN
Insulin Secretion
Insulin Receptor and Signaling
Insulin Secretion
Insulin
Insulin Type
Product
Onset
Peak
Duration
Aspart Analog
NovoLog
10-30 min
0.5-3 hrs
3-5 hrs
Lispro Anolog
Humalog
Regular
Humulin, Novolin R
30 min
1-5 hrs
8 hrs
NPH
Humulin, Novolin N
1-4 hrs
4-15 hrs
16-26 hrs
Glargine
Lantus,Levemir
1-2 hrs
------
24 hrs
Premixed
70/30, 75/25, 50/50
“
“
“
Insulin Injections
Overcoming Barriers to Insulin
Therapy
Delays in initiating insulin therapy;
Clinician concerns;
• Hypoglycemia
• Weight gain
• Increasing CVD risk
Patients concerns;
• Sign of personal failure,
• Misconceptions
• Labor intensive and complicated
Many
concerns may
be addressed
through
education and
setting
appropriate
expectations
Basal Insulin with Oral
Hypoglycemics
• A1c 8.5% to 10%
• Initial dose of Lantus or NPH 10-20 units/day
(0.2 to 0.3 units/kg)
• Monitor FBG and adjust the dose
• Increase the dose by 2 Units if FBG >140 for 3 d
• Rate of hypoglycemia is lower with Lantus
• AM dosing of Lantus are comparable with PM
dose
Basal-Prandial Insulin with Oral
Hypoglycemics
• A1c > 10%
• High postprandial glucose despite normalization
of FBG
• Initial dose of Lantus 0.3 units/kg
• Give approximately same dose as prandial
insulin divided into 3
• 2hpp BG Goal: 80-150 mg/dl
• Correction dose: 1500/daily total insulin
• Carb to insulin ratio: Usually 1 Unit /15 g of Carb
Nutrition
NOT EVERYONE NEEDS
1800 CAL/D ADA DIET
IBW for woman; 5’= 100 lb + every 1’ x 5
IBW for man;
5’= 110 lb + every 1’ x 5
If weight 10 lb more than IBW, daily
requirement will be:
10 x IBW
IBW
• Males: IBW =
50 kg + 2.3 kg for each inch over 5 feet.
• Females: IBW =
45.5 kg + 2.3 kg for each inch over 5 feet.
Recommended calorie intake
• Calories needed to maintain weight depends
upon your age, sex, height, weight, and
activity level.
• Men, active women - 15 cal/lb
• Most women, sedentary men, and adults over
55 years - 13 cal/lb
• Sedentary women, obese adults - 10 cal/lb
• Pregnant, lactating women - 15 to 17 cal/lb
Recommended calorie intake
• To lose 1 to 2 pounds per week (a safe rate
of weight loss), subtract 500 to 1000 calories
from the total number of calories needed to
maintain weight.
• Example, an overweight man who weighs
250 lbs would need to eat 2500 calories per
day to maintain his weight.
• To lose 1 to 2 pounds per week, he should
eat 1500 to 2000 calories per day. As weight
is lost, the recommended calorie intake
should be recalculated.
Nutrition
Carb. intake:
45-65 % of total calories
Protein intake:
15-20 % of total calories
Diabetics with any degree of CKD should be have 0.8
g/kg, around 10 % of total calories
Fat intake:
25-35 % of total calories
Saturated fat intake should be < 7% of total calories
Intake of trans fat should be minimized
ADA Guidelines
1. Diabetic focused visit : Every 3-6 months
• Review physical activities, diet, BMI
• Review Meds and frequency of low blood sugars
2. HbA1c should be checked every 3 –6 month (Goal<7%)
3. Urine for microalbumin should be checked every year
• If >30 mcg/mg creatinine or >30 mg/24 hr,
start on ACE inhibitor unless contraindicated
4. Yearly lipid profile with a goal of :
• Triglyceride < 150 mg/dl
• HDL
> 40 mg/dl (men), > 50 mg/dl (women)
• LDL
< 100 mg/dl
ADA Guidelines
6. Blood pressure should be <130/85 and < 125/75 if
diabetic nephropathy
7. Aspirin prophylaxis for every one unless
contraindicated
8. Yearly dilated eye examination by ophthalmologist
or referrals if needed
9. Yearly comprehensive lower extremities
examination including monofilament test
10. Dental examination every 6 month for dentate
person and every 1 year for edentate
11. Nutrition therapy by dietitian every 6-12 months
Road Maps to Achieve Glycemic Control
In Type 2 Diabetes Mellitus
ACE/AACE Diabetes Road Map Task Force
Chairpersons
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Task Force Members
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered, reproduced
or distributed in any form without the express permission of AACE.
Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2)
Achieve ACE
Glycemic Goals†
( FPG, PPG, and A1C )
Initial
A1C%
If ≤ 6.5% A1C Goal
Not Achieved
Initial Therapy
Lifestyle
Modification
6-7
Intervention
Continuous
Titration of Rx
( 2 - 3 months )
Assess FPG
and PPG
Preferred:
• Metformin4
• TZD10,11
• AGI
• DPP-4 Inhibitor
Alternatives
• Glinides
• SU (low dose)
• Prandial insulin5,8
Monitor / adjust Rx
to maximal effective
dose to meet ACE
Glycemic Goals
Intensify Lifestyle
Modification
Intensify or combine Rx
including incretin mimetic*1
If ≤ 6.5% A1C Goal
Not Achieved
Lifestyle
Modification
7-8
Target: PPG
and FPG
Combine Therapies 6,7
Alternatives
• Metformin
• Prandial insulin5,8
• Glinides
• AGI
• Premixed insulin
• TZD
preparations8
• SU
• Basal insulin
• DPP-4 Inhibitor
analog9
†
ACE Glycemic Goals
* Available as exenatide
≤ 6.5% A1C
1 Indicated for patients not at goal despite SU and/or
metformin or TZD therapy; incretin mimetic is not
< 110 mg/dL FPG
indicated for insulin-using patients
< 110 mg/dL Preprandial
4 Preferred first agent in most patients
< 140 mg/dL 2-hr PPG
5 Rapid-acting insulin analog (available as lispro, aspart and
glulisine), inhaled insulin, or regular insulin
6 Appropriate for most patients
7 2 or more agents may be required
8 Analog preparations preferred
9 Available as glargine and detemir
10 A recent report (NEJM; 6/14/07) suggests a possible link of
rosiglitazone to cardiovascular events that requires further evaluation.
11 Cannot be used in NYHA CHF Class 3 or 4
Endocr Pract. 2007;13:260-268
Access Roadmap at:
www.aace.com/pub
Monitor / adjust Rx
to maximal effective
dose to meet ACE
Glycemic Goals
Intensify Lifestyle
Modification
Intensify or combine Rx,
including incretin mimetic
with SU, TZD, and/or
metformin
ACE/AACE Diabetes Road Map Task Force
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.
Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2)
Achieve ACE
Glycemic Goals†
( FPG, PPG, and A1C )
Initial
A1C%
Combine Therapies
to Address FPG and PPG7
Lifestyle
Modification
8-9
Intervention
Target: FPG
and PPG
• Metformin
• TZD10,11
• SU
• Glinides
• DPP-4 Inhibitor
• Basal insulin analog9
• Prandial
• Premixed insulin
preparations8
• NPH
• Other approved
combinations
insulin5,8
Continuous
Titration of Rx
( 2 - 3 months )
If ≤ 6.5% A1C Goal
Not Achieved
Monitor / adjust Rx
to maximal effective
dose to meet ACE
Glycemic Goals
Intensify Lifestyle Modification
Intensify or combine Rx including
prandial insulin5,8, incretin
mimetic1, or amylin analog**
(with prandial insulin5,8)
If ≤ 6.5% A1C Goal
Not Achieved
Lifestyle
Modification
9 - 10
** Available as pramlintide
Target: FPG
and PPG
Combine Therapies
to Address FPG and PPG7
• Prandial insulin5,8
• Metformin
• TZD
• Premixed insulin
preparations8
• SU
• NPH
• Glinides
• Basal insulin analog9 • Other approved
combinations
†ACE
Glycemic Goals
≤ 6.5% A1C
1 Indicated for patients not at goal despite SU and/or
< 110 mg/dL FPG
metformin or TZD therapy; incretin mimetic is not
indicated for insulin-using patients
< 110 mg/dL Preprandial
5 Rapid-acting insulin analog (available as lispro, aspart and
< 140 mg/dL 2-hr PPG
glulisine), inhaled insulin, or regular insulin
7 2 or more agents may be required
8 Analog preparations preferred
9 Available as glargine and detemir
10 A recent report (NEJM; 6/14/07) suggests a possible link of
rosiglitazone to cardiovascular events that requires further evaluation.
11 Cannot be used in NYHA CHF Class 3 or 4
Access Roadmap
Endocr Pract. 2007;13:260-268
at:
www.aace.com/pub
Monitor / adjust Rx
to maximal effective
dose to meet ACE
Glycemic Goals
Intensify Lifestyle Modification
Initiate or intensify insulin
therapy or add incretin mimetic1
ACE/AACE Diabetes Road Map Task Force
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.
Road Map to Achieve Glycemic Goals: Naïve to Therapy (Type 2)
Initial
A1C%
Intervention
Insulin
Therapy2,3
• Basal insulin analog9
or NPH + prandial insulin8,10
• Premixed insulin preparations8
Lifestyle
Modification
> 10
Achieve ACE
Glycemic Goals†
( FPG, PPG, and A1C )
2 For selected patients presenting with an A1C of >10%,
certain oral agent combinations may be effective
3 Insulin sensitizer (metformin preferred) may be combined with
initial insulin therapy
8 Analog preparations preferred
9 Available as glargine and detemir
10 Available as lispro, aspart and glulisine
Endocr Pract. 2007;13:260-268
†ACE
Glycemic Goals
≤ 6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG
Access Roadmap at:
www.aace.com/pub
Continuous
Titration of Rx
( 2 - 3 months )
Monitor / adjust Rx
to maximal effective
dose to meet ACE
Glycemic Goals
If ≤ 6.5% A1C Goal Not
Achieved
Intensify Lifestyle
Modification
ACE/AACE Diabetes Road Map Task Force
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.
Road Map to Achieve Glycemic Goals: Treated Patients (Type 2)
Current
A1C%
Continue Lifestyle
Modification
<6.5%
Current Therapy
* Available as exenatide
** Available as pramlintide
Intervention
• Continue current therapy if all
ACE glycemic goals are met
• Adjust therapy as needed to meet
ACE FPG and PPG goals
Monotherapy
or
Combination Therapy
†ACE
Glycemic Goals
≤ 6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG
1 Analog preparations preferred
2 Prandial insulin (rapid-acting insulin analogs available as lispro,
aspart, glulisine, inhaled insulin, or regular insulin) can be added
to any therapeutic intervention at any time to address persistent
postprandial hyperglycemia
3 Available as glargine and detemir
4 A recent report (NEJM; 6/14/07) suggests a possible link
of rosiglitazone to cardiovascular events that requires further evaluation.
5 Cannot be used in NYHA CHF Class 3 or 4
Endocr Pract. 2007;13:260-268
Access Roadmap at:
www.aace.com/pub
Continuous Titration of
Rx (2-3 months)
Monitor / adjust Rx to
maintain ACE
Glycemic Goals†
ACE/AACE Diabetes Road Map Task Force
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.
Road Map to Achieve Glycemic Goals: Treated Patients (Type 2)
Current
A1C%
to
8.5
Continue Lifestyle Modification
6.5
Current Therapy
* Available as exenatide
** Available as pramlintide
Monotherapy :
Glinides, SU, AGI, metformin,
TZD, DPP-4, premixed insulin
preparations, prandial2 or
basal insulin3
Intervention
Intensify Lifestyle Modification
Initiate Combination Therapy
• Metformin + SU or Glinide • Incretin mimetic +
• Metformin + TZD4,5 or AGI metformin and/or TZD
• TZD + SU
• Basal3 or premixed
• DPP-4 + Metformin
insulin preparations1
• DPP-4 + TZD
• Amylin analog** with
• Incretin mimetic* +
prandial insulin2
metformin and/or SU
Monitor / adjust Rx
to maintain ACE
Glycemic Goals†
Other approved combinations including
approved oral agents with insulin
Continuous Titration of
Rx (2-3 months)
Combination Therapy:
Glinides, SU, DPP-4, AGI,
metformin, TZD, incretin
mimetic*, premixed insulin
preparations, prandial2 or
basal insulin3
Intensify Lifestyle Modification
Maximize Combination Therapy
Maximize Insulin Therapy
• If elevated FPG, add or increase basal insulin3
• If elevated PPG, add or increase prandial insulin2
• If elevated FPG and PPG, add or intensify basal3 +
prandial2 or premixed insulin therapy1
• Combine with approved oral agents
• Amylin analog** with prandial insulin2
Add incretin mimetic to patients on SU, TZD,
and/or metformin
†ACE
Glycemic Goals
≤ 6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG
1 Analog preparations preferred
2 Prandial insulin (rapid-acting insulin analogs available as lispro,
aspart, glulisine, inhaled insulin, or regular insulin) can be added
to any therapeutic intervention at any time to address persistent
postprandial hyperglycemia
3 Available as glargine and detemir
4 A recent report (NEJM; 6/14/07) suggests a possible link
of rosiglitazone to cardiovascular events that requires further evaluation.
5 Cannot be used in NYHA CHF Class 3 or 4
Endocr Pract. 2007;13:260-268
Continuous Titration of
Rx (2-3 months)
Access Roadmap at:
www.aace.com/pub
Monitor / adjust Rx
to maintain ACE
Glycemic Goals†
ACE/AACE Diabetes Road Map Task Force
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.
Road Map to Achieve Glycemic Goals: Treated Patients (Type 2)
Current
A1C%
Continue Lifestyle
Modification
>8.5
Current Therapy
Intervention
Monotherapy
Intensify Lifestyle Modification
Initiate Insulin Therapy (Basal-Bolus)
or
Combination Therapy
1 Analog preparations preferred
2 Prandial insulin (rapid-acting insulin analogs available as lispro,
aspart, glulisine, inhaled insulin, or regular insulin) can be added
to any therapeutic intervention at any time to address persistent
postprandial hyperglycemia
3 Available as glargine and detemir
Endocr Pract. 2007;13:260-268
• Basal3 + prandial insulin2
• Premixed insulin preparations1
Combine with approved oral agents
†ACE
Glycemic Goals
≤ 6.5% A1C
< 110 mg/dL FPG
< 110 mg/dL Preprandial
< 140 mg/dL 2-hr PPG
Access Roadmap at:
www.aace.com/pub
Continuous Titration of
Rx (2-3 months)
Monitor / adjust Rx to
maintain ACE
Glycemic Goals†
ACE/AACE Diabetes Road Map Task Force
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.
Road Map to PREVENT Type 2 Diabetes
Intervention
Early
Identification
Age 30 or above for
Populations at High Risk:
•
•
•
•
•
•
•
•
•
•
•
Family history of diabetes
Cardiovascular disease
Overweight
Sedentary lifestyle
Latino/Hispanic, African
American, Asian American,
Native American, or
Pacific Islander
Previously identified IGT
or IFG
Hypertension
Elevated triglycerides,
low HDL, or both
History of gestational
diabetes
Delivery of a baby weighing
more than 9 lbs
Severe psychiatric illness
Lifestyle
Modification
• Medical Nutrition
Therapy (MNT)
• Physical Fitness
Program
• Weight Loss
• 5-7% reduction in body
weight (if overweight)
• 30 minutes exercise, 5
times per week at the
equivalence of brisk
walking
Pharmacologic
Non-FDA Approved*
• TZD**
• Metformin
• Orlistat
• AGI
•
•
•
•
Hypertension
Dyslipidemia
Physical Fitness
Weight Control
* Shown to be effective in delaying the
onset of type 2 diabetes in clinical studies
** A recent report (NEJM; 6/14/07) suggests
a possible link of rosiglitazone to
cardiovascular events that requires further
evaluation
FPG or 2-h OGTT is the
recommended screening procedure
Endocr Pract. 2007;13:260-268
Persistent
Monitoring of
Glucose and
Risk Reduction
Measures
Access Roadmap at:
www.aace.com/pub
ACE/AACE Diabetes Road Map Task Force
Paul S. Jellinger, MD, MACE, Co-Chair
Jaime A. Davidson, MD, FACE, Co-Chair
Lawrence Blonde, MD, FACP, FACE
Daniel Einhorn, MD, FACP, FACE
George Grunberger, MD, FACP, FACE
Yehuda Handelsman, MD, FACP, FACE
Richard Hellman, MD, FACP, FACE
Harold Lebovitz, MD, FACE
Philip Levy, MD, FACE
Victor L. Roberts, MD, MBA, FACP, FACE
© 2007 AACE. All rights reserved. No portion of the Roadmap may be altered,
reproduced or distributed in any form without the express permission of AACE.
INPATIENT
DIABETES CARE
PATIENTS WITH KNOWN DIABETES (NOT
CRITICALLY ILL) WHO ARE ABLE TO EAT
A- Patient who is on oral anti-diabetic
medication (OAD):
- Consider them if there are contra-indications to
OAD’s (CHF, renal or hepatic dysfunction, etc.).
If not and glucose is in the “target” range (~100180 mg/dl), continue with OAD’s and monitor
blood glucose (BG).
- If there are contra-indications to OAD’s or the
patient is hyperglycemic (above “target” range),
start insulin using basal and prandial standard
orders.
B- Patients admitted to the hospital who
were treated with insulin before admission
should (minimally) receive their usual insulin
program
REMEMBER; that the patients’ usual insulin
may be inadequate in the face of intercurrent
illness
-No matter what the prior insulin program was,
be sure that your orders provide for the basal
and prandial insulin replacement
- Patients’ prior insulin dose gives an index of
insulin sensitivity. Use it to derive the “correction
doses”.
C- Patients made NPO for surgery or a
procedure in the AM
- Can give usual dose of Glargine the evening
before and start D5W at 100 cc/min in the AM
- If the patient is on NPH BID, can give ½ the
usual AM dose and start D5W at 100 cc/min in
the AM
- Continue with the sliding scale coverage
HYPERGLYCEMIC PATIENTS IN THE
HOSPITAL WHO ARE ABLE TO EAT
(NOT in the ICU/CCU/CTU)
A- The “target” BG Fasting: ~110 mg/dl
Throughout the day: ~140 (110-180)
B- If the patient is persistently above the “target”,
start insulin therapy
C- Principles:
1- NO SLIDING SCALE ALONE!
The usual “sliding scale” order (only short-acting
insulin given when the patient is above target) is
non-physiologic and does not work to control
glucose! May be used to supplement basal and
prandial insulin.
2- Physiologic replacement requires both
“basal and prandial” insulin
3- Analog short acting insulin (our hospital
stocks Lispro) is designed to be used with
each meal. Regular insulin should be used
only when IV insulin is needed
If the patient was not previously on insulin, do
this (finger sticks a.c. and h.s)
- Daily insulin requirement is 0.5 units/kg
- Start basal insulin (as Glargine) at doses of
0.2 to 0.3 units/kg BW/day
e.g.: a 70 kg individual should start with 14
units of Glargine SQ qhs]
-Give approximately the same total daily dose
of prandial insulin as the basal insulin doseuse 1/3 of daily dose with each meal
[e.g.: if the basal dose is 14 units, give 4 units
of Lispro with each meal if the pre-meal
glucose is within the “desirable range of 80150mg/dl
REMEMBER; the Lispro insulin works fast.
The order should advise the nurse to give the
pre-prandial insulin when the meal is in the
patients’ room and ready to be eaten.
-If the pre-meal glucose is above 150 mg/dl,
add “correction dose” of Lispro insulin
In general, the “correction dose” is calculated
by dividing the patients’ daily requirement dose
into 1500. The result is the predicted glucose
lowering effect of 1 unit of insulin.
e.g.: if the patient’s total insulin is 30 units/day,
1 unit of insulin should lower the glucose by 50
mg/dl (1500/30=50). Therefore, add 1 unit of
insulin per 50 mg/dl glucose above 150. If the
pre-meal glucose were 250 mg/dl, the preprandial insulin dose should be 2 units + usual
dose- in the above example, 4+2 =6 units.
- Adjust the basal insulin dose every 24-48
hours based on the fasting (pre-breakfast)
glucose value- make the appropriate changes
in the prandial doses as well
- For patients coming of insulin drip, begin
Glargine 2 hours before the drip is stopped
and start Lispro insulin as soon as the patient
is able to eat.
Intensive Inpatient Insulin treatment
QUESTIONS
Question 1
A 60 yo man is referred to you because of poorly
controlled DM that was dxed 2 months ago. At
that time his weight: 95 kg, BP: 130/80, FBG: 213
mg/dl, A1c:9.6%. CMP and UA was normal. TG:
400 mg/dl. He was instructed a special diet and
exercise program. 2 months later, his weight:95
kg. Exercises twice a week and adheres to diet.
FBG: 199 mg/dl, A1c:9.4%
What should be done next?
Answer 1
A. Continue with diet and exercise
B. Initiate metformin
C. Initiate glyburide
D. Initiate roziglitazone
E. Initiate Insulin
Question 2
A 24 yo woman comes to your office because of
uncontrolled type 1 DM. She is on Humolog and
NPH. Previous NPH was 14-0-0-12 and now 160-0-16.
FBG:
42-325 mg/dl
Noon BG:
112-201mg/dl
Supper BG:
68-167mg/dl
Bed time BG:
189-220 mg/dl
What should be done next?
Answer 2
A. Make no changes
B. Increase both supper humolog and bed time
NPH
C. Increase AM humolog and NPH, increase bed
time NPH
D. Decrease noon humolog and AM NPH and
increase bed time NPH
E. Increase supper humolog and decrease bed
time NPH
Question 3
A 23 yo man with a 13 yr hx of type 1 DM
preparing for a soccer ball tournament. The 1st
game is at 8 AM and he is asking for advise about
his insulin regimen since he was never attempted
soccer ball so early in the day. His usual insulin
dose is NPH 6 U and Lispro 10 U with breakfast
at 7 AM, Lispro 4 U with lunch and NPH 8 U and
Lispro 12 U with dinner at 6 PM. His last A1c:
6.4% and his FBG: 160-200 mg/dl.
Assuming on the day of the game his AM FBG
level is in his usual range, which one is the most
reasonable approach?
Answer 3
A. He should not take his insulin or eat breakfast
but should drink 8oz of OJ just prior to game
B. He should have his usual insulin with breakfast
C. He should omit the insulin Lispro but take the
NPH at the usual dose with breakfast
D. He should omit the NPH but take the insulin
Lispro at the usaual dose withbreakfast
E. He should decrease the insulin Lispro and
NPH and eat his usual breakfast
Question 4
A 58 yo woman with DM for 8 yrs recently moved
to your area and is seeking medical care. She
states she has always kept her DM in moderately
good control. She did not bring any records with
her. Her FBG~ 140-160 mg/dl. Her pp BG~
200mg/dl. Her meds are; Metformin 1000 mg po
bid, Repaglinide 2 mg po bid. On PE, she is mildy
obese, BP: 125/79, otherwise unremarkable.
Labs; FBG: 164, Tchol: 215, TG: 265, HDL: 40,
LDL:110, Cr:0.9, BUN:14, Urine alb/cr:22mcg/mg,
A1c: 7.8 %. What would you rec. to improve BG?
Answer 4
A. Increase Repaglinide to 2 mg po tid
B. Add NPH insulin at bed time
C. Add a TZD
D. No additional therapeutic intervention is
needed as her BG control is adequate.
Question 5
• A 45 year old white male (Bob)
• Past History: Hypertension on
hydrochlorothiazide, BMI 27
• Screened for diabetes mellitus by PCP
with fasting glucose and HbA1C
• Fasting glucose 115, HbA1C 6.6
Should Bob be considered a diabetic?
Criteria for the Diagnosis of Diabetes
1.
A1C > or = to 6.5%
OR
2.
Fasting Plasma Glucose > or = 126 mg/dL
OR
3.
Two-hour plasma glucose > or = 200 mg/dL
during an oral glucose tolerance test (75 g)
OR
Patient with classic symptoms of hyperglycemia
and random glucose > or = 200 mg/dL
4.
American Diabetes Association: Standards of Medical Care in Diabetes-2010.
Diabetes Care 2010;33 (Suppl. 1):S11-S61
Question 5, Part 2
• Follow-up visit to PCP
• Blood pressure (BP) recorded as
135/89
• Only other previous BP reading
recorded in office 138/86
What should Bob’s target BP be?
Blood Pressure Goals in Diabetes
• “Patients with diabetes should be
treated to a systolic blood pressure
< 130 mm Hg.”
• “Patients with diabetes should be
treated to a diastolic blood pressure
< 80 mm Hg.”
American Diabetes Association: Standards of Medical Care in Diabetes-2010.
Diabetes Care 2010;33 (Suppl. 1):S11-S61
Effects of Intensive Blood-Pressure
Control in Type 2 Diabetes Mellitus
Outcome
Intensive
Therapy (rate
per year)
Standard
P-value
Therapy (rate
per year)
Primary outcome*
1.87%
2.09%
0.20
Nonfatal MI
1.13%
1.28%
0.25
Stroke (fatal and nonfatal)
0.32%
0.53%
0.01
Nonfatal stroke
0.30%
0.47%
0.03
Death (any cause)
1.28%
1.19%
0.55
Death (cardiovascular
cause)
0.52%
0.49%
0.40
Major coronary disease
event
2.31%
2.41%
0.50
*Composite of nonfatal MI, nonfatal
stroke, or death from cardiovascular
causes.
The ACCORD Study Group: Effects of Intensive Blood-Pressure
Control in Type 2 Diabetes Mellitus. N Engl J Med 2010;362:15751585
Question 5, Part 3
• Bob works out at the local gym.
• He embraced therapeutic lifestyle
changes.
• His brother Jim (age 50) had a massive
MI two weeks ago.
• He is a voracious reader of online
medical information.
Is daily aspirin therapy indicated for
Bob?
Recommendations for Aspirin:
Primary Prevention
• “Consider aspirin therapy as a primary
prevention strategy in those with type 1 or
type 2 diabetes at increased cardiovascular
risk (10 year risk > 10 %).”
• “There is not sufficient evidence to
recommend aspirin for primary prevention in
lower risk individuals, such as men < 50
years of age or women < 60 years of age
without other major risk factors.”
American Diabetes Association: Standards of Medical Care in Diabetes-2010.
Diabetes Care 2010;33 (Suppl. 1):S11-S61
Question 6
• Bob’s brother Jim recently hospitalized for
acute MI
• Diagnosed with type 2 diabetes with HbA1C
of 8.2
• Required steroids and mechanical ventilation
for COPD exacerbation during admission,
blood glucose readings in the 300’s
What should be Jim’s goal blood glucose
as an inpatient?
Goals for Blood Glucose Levels in
Hospitalized Patient
• Critically ill patient
– Threshold for
treatment of
hyperglycemia with
insulin is 180 mg/dL
– Goal glucose range of
140-180 mg/dL
• Non-critically ill patient
– No clear evidence for
specific blood glucose
goals
– Blood glucose ranging
from 140-180 mg/dL is
recommended if this
target can be safely
achieved
– Consider more
intensive control in
patients with history of
tight glucose control
American Diabetes Association: Standards of Medical Care in Diabetes-2010.
Diabetes Care 2010;33 (Suppl. 1):S11-S61
Question 6
• Jim discharged on metformin and
glyburide
• Attempting to adhere to therapeutic
lifestyle changes
• Now 3 months after hospitalization
• HbA1C of 7.8
What should Jim’s goal HbA1c be?
Goals for Glycemic Control in Adults
• “Lowering A1C to below or around 7%
has been shown to reduce
microvascular and neuropathic
complications of type 1 and type 2
diabetes. Therefore, for microvascular
disease prevention, the A1C goal for
nonpregnant adults in general is < 7%.”
American Diabetes Association: Standards of Medical Care in Diabetes-2010.
Diabetes Care 2010;33 (Suppl. 1):S11-S61
Goals for Glycemic Control in Adults
• Macrovascular disease????
• “Until more evidence becomes
available, the general goal of < 7%
appears reasonable for many adults for
macrovascular risk reduction.”
American Diabetes Association: Standards of Medical Care in Diabetes-2010.
Diabetes Care 2010;33 (Suppl. 1):S11-S61
References
1. American Diabetes Association: Standards of Medical
Care in
Diabetes-2010. Diabetes Care 2010;33 (Suppl.
1):S11-S61
2. The ACCORD Study Group: Effects of Intensive BloodPressure Control in Type 2 Diabetes Mellitus. N Engl J
Med 2010;362:1575-1585
3. NICE-SUGAR Study Investigators, Finfer S, Chittock DR,
Su SY, Blair D, Foster D, Dhingra V, Bellomo R, Cook D,
Dodek P, Henderson WR, Hebert PC, Heritier S, Heyland
DK, McArthur C, McDonald E, Mitchell I, Myburgh JA,
Norton R, Potter J, Robinson BG, Ronco JJ. Intensive
versus conventional glucose control in critically ill patients.
N Engl J Med 2009; 360:1283-1297
Thank you