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Transcript
Basal Insulin Therapy in the
Treatment of Insulin Resistant
Type 2 Diabetes:
The Role of the Pharmacist
in Ensuring Their Safe and
Effective Use in Patients
Susan Cornell, BS, Pharm.D., CDE, FAPhA, FAADE
Midwestern University Chicago College of Pharmacy
Objectives
1.  Describe the reasons for the use of high concentration insulin
formulations in the treatment of type 2 diabetes
2.  Discuss the clinical, pharmacokinetic and pharmacodynamic
profiles for current and emerging basal insulins
3.  Implement strategies for safely converting between U-100
and concentrated insulin formulations using different syringes
and pen devices in patients with type 2 diabetes
4.  Review currently available insulin pens and syringes used for
the administration of insulin
5.  Explain and apply strategies to overcome the barriers to
insulin-mediated glucose control
Disclosures
• Susan Cornell, Pharm.D., CDE,
FAPhA, FAADE has no real or
potential conflicts of interest to report.
How to Receive Credit
•  You must complete an online evaluation in order
to receive credit for this program. The link to the
evaluation will be emailed to you after the
program.
•  If you did not pre-register for this program, please
complete a Request for Credit form at the
registration desk today and include your email
address.
Pre-Activity Questions 1-4
Pre-test Question #1
Which of the following does NOT represent a reason
for using high concentration insulin formulations in
the treatment of type 2 diabetes?
1.  Volume of insulin dose is physically too large for a
single SC administration
2.  Patient cannot manipulate vials and syringes
3.  Multiple injections are required to deliver a single
insulin dose
4.  Discomfort
5.  Unpredictable insulin absorption
Pre-test Question #2
A 55 year old female, high school teacher with Type 2
diabetes is referred to you for dosing of U500 insulin. Her
current meds are NPH 100 units twice daily, lispro 10-30
units with meals plus correction, and metformin 1000mg
daily. Her A1C is 7.1% and Scr is 1.1. How would you instruct
the patient to draw up 110 units of U500 insulin?
1)  Using a U100 syringe, draw to the 50 units marking
2)  Using a U100 syringe, draw to the 25 units marking
3)  Using a tuberculin syringe, draw 0.2 mL
4)  Using a tuberculin syringe, draw 0.4 mL
Pre-test Question #3
Which of the following is NOT a strategy to overcome
the barriers to insulin therapy?
1.  Avoid using insulin as a “threat” and discuss it as
an option early
2.  Dose NPH insulin twice daily to minimize
hypoglycemia
3.  Use insulin pens and regimens that offer maximum
flexibility
4.  Give a “limited” trial of insulin
Pre-test Question #4
Which of the following statements is INCORRECT regarding
the new basal insulin U300 glargine?
1.  It is associated with less nocturnal hypoglycemia
2.  It has a flatter PK profile and a duration of action ≤36 hrs
3.  It is only available in a pen with 1.5 mL of U300 glargine
4.  Current pen allows for a max of 240 units of insulin per
shot
5.  Patients switching from twice daily NPH to U300 glargine
should start with 80% of total daily NPH dosage
The Diabetes Epidemic
Diabetes in the United States
•  29.1 million people (9.3% of the population) have diabetes
•  8.1 million are undiagnosed
•  CDC estimates that 1 in 3 adult Americans will have diabetes
by 2050
•  Type 2 Diabetes (T2DM)
–  Associated with obesity, older age, decreased physical activity,
and race/ethnicity
–  Incidence in children and adolescents is increasing
•  Estimated total costs in 2012: $245 billion
http://www.cdc.gov/media/pressrel/2010/r101022.html. Accessed February 5, 2015. CDC. National Diabetes
Statistics Report, 2014. http://www.cdc.gov/diabetes/pubs/statsreport14/national-diabetes-report-web.pdf.
Accessed April 15, 2015.
Type 2 Diabetes
•  Characterized by chronic hyperglycemia
•  Associated with microvascular and
macrovascular complications
•  Generally arises from a combination
of insulin resistance and β-cell dysfunction
Scheen AJ. Acta Clin Belg. 2003;58(6):335-41.
? By the time a person is diagnosed
with type 2 diabetes, approximately
how much β-cell function has been lost?
1.  <10%
2.  10–30%
3.  30–50%
4.  50–80%
5.  100%
Progressive Deterioration in
β-Cell Function Over Time
Beta-Cell Function
(%, HOMA)
100
Monotherapy
75
Combination
Therapy
Insulin
50
Intensive or
in Combination
25
0
-12
-10
-8
-6
-4
-2
0
2
4
6
Years from Diagnosis
HOMA = homeostasis model assessment.
Based on data of UKPDS 16. Diabetes. 1995;4(11):1249-1258.
8
10
12
14
Pathophysiologic Defects in
Type 2 Diabetes: The Ominous Octet
Decreased Incretin Effect
Impaired
Insulin
Secretion
Increased
Glucagon
Secretion
Islet β-cell
Increased
Lipolysis
Islet α-cell
Hyperglycemia
Increased
Glucose
Reabsorption
Decreased
Glucose
Uptake
Increased
HGP
Neurotransmitter Dysfunction
DeFronzo RA. Diabetes. 2009;58(4):773-795.
Insulin Resistance
~90% of People with
Type 2 Diabetes
are Overweight or Obese
World Health Organization, 2005. http://www.who.int/dietphysicalactivity/publications/facts/obesity.
Insulin Resistance
•  Major defect in individuals with type 2 diabetes
•  Reduced biological response to insulin
•  Closely associated with obesity
•  Associated with cardiovascular risk
•  Type 1 diabetes patients can be insulin resistant
as well…
1. American Diabetes Association. Diabetes Care. 1998; 21:310-314. 2. Beck-Nielsen H, Groop LC. J Clin
Invest 1994; 94:1714-1721. 3. Bloomgarden ZT. Clin Ther 1998; 20:216-231. 4. Boden G. Diabetes 1997;
46:3-10.
More than 80% of Patients
Progressing to Type 2 Diabetes
are Insulin Resistant
Insulin sensitive;
low insulin secretion
(16%)
Insulin sensitive;
good insulin secretion
(1%)
Insulin resistant;
good insulin secretion
(29%)
83%
Haffner SM, et al. Circulation. 2000;101:975-980.
Insulin resistant;
low insulin secretion
(54%)
Insulin Resistance Reduces
Response to Circulating Insulin
Insulin
resistance
Liver
IR
Adipose
tissue
Muscle
↑ Glucose output
↑ Insulin/medication
requirements needed
to maintain
glycemic control
↓ Glucose uptake
↓ Glucose uptake
Hyperglycemia
Treatment Options for
Type 2 Diabetes
12 Pharmacotherapy Options
Insulin
•  Bolus insulin
– 
– 
– 
– 
– 
Insulin lispro (Humalog)
Insulin aspart (NovoLog)
Insulin glulisine (Apidra)
Insulin human inhaled (Afrezza)
Regular human insulin
•  (Humulin R)
•  (Novolin R)
•  Basal insulin
– 
Insulin NPH
•  (Humulin N)
•  (Novolin N)
– 
– 
– 
Insulin detemir (Levemir)
Insulin glargine U-100 (Lantus)
Insulin glargine U-300 (Toujeo)
Oral Medications
• 
• 
• 
• 
α-glucosidase inhibitors (AGI)
Biguanides
Bile acid sequestrants (BAS)
Dipeptidyl peptidase-4 (DPP-4)
inhibitors (gliptins)
•  Dopamine agonists
•  Glitinides
•  Sulfonylureas
•  Sodium glucose co-transporter-2
inhibitors
•  Thiazolidinediones (TZDs or glitazones)
Non-insulin injectable agents
•  Glucagon-like peptide-1 (GLP-1)
agonists
•  Amylinomimetics
Cornell S, et al. Postgrad Med. 2012;124(4):84-94. http://www.pdr.net/search-results?q=afrezza. Accessed
January 30, 2015. http://www.pdr.net/full-prescribing-information/toujeo?druglabelid=3688. Accessed March
26, 2015.
Glucose-Lowering Comparison
Monotherapy
Route of
Administration
Targets Insulin
Resistance
Target Glucose:
FPG or PPG
A1C Reduction
(%)
Sulfonylurea
Oral
No
Both
1.5–2.0
Metformin
Oral
Yes
FPG
1.5
Glitazones
Oral
Yes
Both
1.0–1.5
Meglitinides
Oral
No
PPG
0.5–2.0
AGIs
Oral
No
PPG
0.5–1.0
DDP-4 inhibitors
Oral
No
PPG
0.5–0.7
Bile acid sequestrant
Oral
No
PPG
0.4
Dopamine agonists
Oral
No
PPG
0.4
SGLT-2 inhibitors
Oral
↓ glucose toxicity
FPG
0.7–1.1
GLP-1 agonists
Injectable
No
Short-acting – PPG
Long-acting – Both
0.8–1.5
Amylin analogs
Injectable
No
PPG
0.6
Insulin
Injectable
↓ glucose toxicity
Basal – FPG
Bolus – PPG
↓ as much as
needed
FPG = fasting plasma glucose; PPG = postprandial glucose.
Unger J, et al. Postgrad Med. 2010;122(3):145-157. Cornell S, et al. Postgrad Med. 2012;124(4):84-94.
Basal Insulin Therapy:
Concept and Physiology
UKPDS: Progressive Deterioration
in Glycemic Control Over Time
HbA1C Level
Median A1C (%)
9
8
7
Conventional
Intensive
6
0
0
3
6
9
12
15
Time from Randomization (y)
UKPDS Group. Lancet. 1998;352:837-853. Holman RR. Diabetes Res Clin Pract. 1998;40(suppl):S21-S25.
Currently Available Insulins
Insulin Type
Onset
Peak, h
Duration of Action, h
Rapid-acting analogs
Insulin lispro, aspart,
glulisine
Insulin human inhaled
15 min
12–15 min
0.5–1.5
~1.0
3–5
2.5–3.0
Short-acting
Regular human (U-100)
Regular human (U-500)
30–60 min
30–60 min
2–4
4–8
5–8
14–15
Intermediate-acting
Human NPH insulin
1–3 h
6–12
12–24
Long-acting (basal)
Insulin glargine
Insulin detemir
2–4 h
1–3 h
No pronounced
peak
20–24
18–20
6h
No pronounced peak
≤36
Ultralong-acting (basal)
Insulin glargine U-300
Walia M and Molitch M. JAMA. 2014;311:2315-2325. Accessed March 24, 2014. http://www.pdr.net/fullprescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015. http://www.pdr.net/fullprescribing-information/afrezza?druglabelid=3540. Accessed April 5, 2015.
Thinking Like a Pancreas
More for “waking up”
No food
Meals
Less overnight
8 AM
12 NOON
3 PM 6 PM Time
9 PM 3 AM
7 AM
PK Profile of Currently Available
Inhaled insulin
Insulins
Plasma Insulin Levels
Aspart, Lispro, Glulisine
Regular
Intermediate (NPH insulin)
Long (Insulin detemir)
Long (Insulin glargine)
Ultralong (U300 glargine)
0
2
4
6
8
10
12
14
16
18
20
22
24
26
28
30
32
Time (hours)
PK = pharmacokinetic; NPH = neutral protamine Hagedorn.
Adapted from Hirsh IB. NEJM. 2005;352:174-183. Flood TM. J Fam Pract. 2007;56(suppl 1):S1-S12.
Becker RH, et al. Diabetes Care. 2014;pii:DC_140006. http://www.pdr.net/full-prescribing-information/
afrezza?druglabelid=3540. Accessed April 5, 2015.
34
36
Insulin Regimens Used in T2DM
•  Basal only
–  1 injection
–  Added to oral agents
•  Basal plus
–  2 injections or 1 injection + 1 inhalation
–  Adding one rapid-acting analog sequentially starting
with largest meal
•  Basal bolus
–  4 injections or 1 injection + 3 inhalations
–  Rapid-acting analog before each meal
•  Pre-mixed
–  2 injections
American Diabetes Association. Diabetes Care. 2015;38(suppl 1):S41-S48.
The Basal-Bolus Concept
•  Basal insulin – 50% of daily needs
–  Controls nighttime and between meal glucose
•  At a nearly constant level
•  Bolus insulin – 50% of daily needs
–  Controls mealtime glucose
–  10–20 % of total daily insulin requirement at each
meal
•  Correction dose (sensitivity factor)
–  Correct hyperglycemia reactively
Sisson EM, et al. Pharmacotherapy for glucose management. Diabetes Desk Reference. American
Association of Diabetes Educators. 2014;491-540.
Insulin Therapy in Patients with
Insulin Resistance
•  Insulin, insulin, and yet more insulin!
–  Causes weight gain and fluid retention
–  Increased risk of hypoglycemia
–  Expensive at high volumes (especially the pens)
–  Multiple injections per day often needed
•  Pumps not practical with high volume insulin
usage
High Doses of Insulin
•  Concerns:
–  Hypoglycemia
–  Medication errors in dosing
–  Absorption issues
•  Problems:
–  Over-basalization
–  Failure to treat the physiological defects
•  Insulin resistance
•  Decrease satiety
Concentrated Insulin
Why Concentrated Insulin?
•  When daily insulin requirements are in excess of
200 units/day, the volume of U-100 injected insulin
becomes a challenge:
–  Physically too large for a single SC administration
–  Multiple injections are required to deliver a single dose
–  Increased injections may lead to adherence issues and
poor glycemic control
–  Discomfort
–  Unpredictable absorption (rate-limiting step in insulin
activity)
Cochran E. Diabetes Spectrum. 2009;22(2):116-122. Kelly JL. Am J Health-Syst Pharm. 2010;67(suppl
8):S9-S16.
Patients Who May Require
Concentrated Insulin
•  Patients with insulin resistance
–  Patients with inherited insulin receptor abnormalities or
presence of autoantibodies to insulin receptor
–  Diabetes patients with insulin antibodies
–  Type 2 diabetes patients
–  Overweight/obese Type 1 diabetes patients
•  Other patients
–  Obstetrics patients
–  Patients receiving high-dose glucocorticoid therapy
Cochran E. Diabetes Spectrum. 2009;22(2):116-122. Kelly JL. Am J Health-Syst Pharm. 2010;67(suppl
8):S9-S16.
Currently Available Concentrated
Insulins
Regular human insulin U-500
(Humulin R U-500)
Insulin glargine U-300
(Toujeo)
1. http://www.pdr.net/drug-summary/humulin-r-u-500?druglabelid=293. Accessed March 28, 2015. 2. http://
www.pdr.net/full-prescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015.
U-500 Regular Human Insulin
•  U-500 is highly concentrated and
contains five times as much insulin in
1 mL as standard U-100 insulin
•  U-500 vial
–  U-500 : contains 20 mL
–  U-100: contains 10 mL
•  U-500 vial
–  Marked with a band of diagonal brown
stripes to distinguish it from the U-100 vial,
which has no stripes
–  “U-500” is also highlighted in red on the
label
http://www.pdr.net/drug-summary/humulin-r-u-500?druglabelid=293. Accessed March 28, 2015.
U-100 Insulin vs U-500 Insulin
•  Both have onset of action of 30 minutes
•  U-500 insulin exhibits a delayed and lower peak
effect relative to U-100
•  U-500 insulin typically has a longer duration of
action compared to U-100 (up to 24 hours
following a single dose)
•  Clinical experience has shown that U-500 insulin
frequently has time action characteristics
reflecting both prandial and basal activity
de la Peña A, et al. Diabetes Care. 2011;34(12):2496-501.
Glucose Infusion
Rate (mg/min)
Mean Serum IRI
Concentration (pmol/L)
PK and PD Profiles for U-500 vs
U-100 Human Insulin
1400
1400
50-Unit Dose
1200
1000
1000
800
800
600
600
400
400
200
200
0
0
1000
1000
50-Unit Dose
800
600
400
400
200
200
0
0
4
8
12
16
20
Human
Regular
U-500 Insulin
Human
Regular
U-100 Insulin
100-Unit Dose
800
600
0
100-Unit Dose
1200
24
Time (hours)
IRI = immunoreactive insulin.
de la Peña A, et al. Diabetes Care. 2011;34:2496-2501.
0
4
8
12
16
Time (hours)
20
24
Safety Concerns with
Concentrated Insulin
Medication Errors Associated with
U-500 Insulin
•  Some health care professionals may not be aware of U-500 insulin,
increasing the chance of dispensing errors
–  From the shelf during dispensing
–  From the computer screen when prescribing
–  Communication errors during medication reconciliation
•  Dosing errors
–  No insulin syringe designed to measure U-500 insulin
•  Due to increasing medication errors with U-500 insulin and the lack of
a U-500 specific syringe, The Institute for Safe Medication Practices
suggests “It’s time to rethink safe use of strengths above U-100”
http://www.consumermedsafety.org/insulin-safety-center/item/499. Accessed March 28, 2015. http://
www.ismp.org/newsletters/acutecare/showarticle.aspx?id=62. Accessed March 28, 2015.
U-500 Insulin Dosing Conversion
U-500 Insulin Dose
(Actual units)
25
50
75
100
125
150
175
200
225
250
275
300
325
350
375
400
425
450
475
500
U-100 Syringe
(Unit markings)
5
10
15
20
25
30
35
40
45
50
55
60
65
70
75
80
85
90
95
100
Volume for Tuberculin
Syringe (mL)
0.05
0.10
0.15
0.20
0.25
0.30
0.35
.040
0.45
050
0.55
0.60
0.65
0.70
0.75
0.80
0.85
0.90
0.95
1.00
*The following dosing formulas may also be used: dose (actual units) x 0.2 = unit markings in a
U-100 insulin syringe, dose (actual units) x 0.002 = volume (mL) in a tuberculin syringe.
Food and Drug Administration. Humulin R-U-500 (concentrated) Insulin Human Injection. [email protected] .gov.
New and Emerging
Basal Insulins
Quest for Better Insulin Products
1.  Efficacy
–  Reductions in A1C
–  Reductions in FBG and PPG
2.  Convenience
–  Pen dosing
–  Flexible dosing (any time of day)
–  Different concentrations
–  Ability to mix with other insulin and non-insulin agents
3.  Safety
–  Low incidence of hypoglycemia
–  Low incidence of nocturnal hypoglycemia
–  Less individual variability
–  Less weight gain
Newly Approved U-300 Insulin
Glargine
•  U-300 insulin glargine offers a smaller depot surface area
leading to a reduced rate of absorption
•  Provides a flatter and prolonged pharmacokinetic and
pharmacodynamic profiles and more consistency
•  Half-life is ~23 hours
•  Steady state in 4 days
•  Duration of action ≤36 hours
•  Associated with less hypoglycemia especially nocturnal
hypoglycemia
•  FDA approved February 25, 2015
Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al.
Diabetes Metab Res Rev. 2014;30(2):104-19. Steinstraesser A, et al. Diabetes Obes Metab. 2014 Feb 26.
[Epub ahead of print]. http://www.australianprescriber.com/magazine/19/3/76/8. Accessed March 11, 2014.
PK and PD of U-300 Insulin Glargine
vs U-100 Insulin Glargine
INS
[µU/mL-1]
25
20
15
10
5
LLOQ
GIR
[mg/kg-1/min-1]
0
3
Gla-100 0.4 U/kg-1
Gla-300 0.4 U/kg-1
2
N = 30
1
0
0
6
12
18
24
30
36
Time (h)
U-300 glargine displays a more even and prolonged PK/PD profile
compared with U-100 glargine, offering blood glucose control beyond 24 hours
LLOQ = lower limit of quantification; GIR = glucose infusion rate; PK = pharmacokinetic; PD =
pharmacodynamic.
Becker RH, et al. Diabetes Care. 2014;pii:DC_140006.
U-300 Glargine vs U-100 Glargine in T2DM:
Meta-Analysis of Phase III Trials EDITION 1, 2, & 3
Baseline to Month 6
Glar U-300
(N=1247)
Glar U-100
(N=1249)
RR (95% CI)
A1C (%), LS mean
–1.02
–1.02
NS
Weight (kg), LS mean
0.49
0.75
P = 0.058
Any hypo in 24 hr*
67.8
73.8
0.92 (0.87–0.96)
Any nocturnal hypo*
31.7
41.3
0.77 (0.69–0.85)
Confirmed BG <54 mg/dl
or severe hypo*
26.9
33.3
0.81 (0.72–0.90)
Confirmed nocturnal BG
<54 mg/dl or severe hypo*
9.7
13.2
0.73 (0.59–0.91)
*% people ≥1 event.
LS = least squares; RR = relative risk; BG = blood glucose; CI = confidence interval.
Ritzel RA, et al. Presentation 963, 50th EASD Annual Meeting, September 15-19, 2014, Vienna, Austria.
Flexible vs Fixed Dosing U-300 Glargine:
Sub-Studies of Phase III Trials
6-Month Treatment Period
(main study)
U-300 once daily
every 24 h
6-Month Extension Period
(main study)
U-300 once daily
every 24 ± 3 h
sub-study
U-300 once daily
every 24 h
6 months (randomization, sub-study)
Percentage of
Injections (%)
100
80
60
9 months (end of sub-study)
Edition 1 Sub-Study
Edition 2 Sub-Study
N = 109
N = 89
Flexible dosing
Fixed dosing
•  No difference in A1C
between flexible- vs
fixed-dosing
•  No difference in
severe or nocturnal
hypoglycemia within
each sub-study
40
20
0
24 ± <1 h 24 ± 1-3 h 24 ± >3 h 24 ± <1 h 24 ± 1-3 h 24 ± >3 h
Ritzel R, et al. Presentation 919-P 74th ADA Scientific Sessions June 13-17, 2014, San Francisco, CA.
http://ada.scientificposters.com/epsAbstractADA.cfm?id=6. Accessed August 15, 2014.
U-300 Insulin Glargine
•  Only available in pens
–  300 U/mL, 1.5 mL
–  Max dose per shot is 80 units with current pen
–  New pen in development will allow a max dose of 240 units
–  Just dial the prescribed dose; no conversion needed like U-500
•  U-300 glargine pen is white and green with the concentration
highlighted in orange to distinguish it from U-100 glargine
1. http://www.pdr.net/full-prescribing-information/toujeo?druglabelid=3688. Accessed March 26, 2015.
2. http://www.pdr.net/drug-summary/lantus?druglabelid=520. Accessed March 26, 2015.
U-300 Insulin Glargine Dosing
•  Insulin-Naive Patients:
–  Type 1 Diabetes – Start with 1/3 to 1/2 of the total daily insulin dose
calculated by using 0.2-0.4 U/kg/day; give the remainder of the total
daily insulin dose as a short-acting insulin and divide between each
daily meal
–  Type 2 Diabetes – Start with 0.2 U/kg/day
•  Type 1 or Type 2 Diabetes:
–  Changing from once daily long-acting or intermediate-acting insulin:
•  Initial dose can be the same as the once daily long-acting dose; for patients
controlled on U-100 insulin glargine, expect that a higher daily dose of U-300
glargine will be needed to maintain the same level of glycemic control
–  Changing from twice daily NPH insulin:
•  Initial dose is 80% of the total daily NPH dosage
http://www.pdr.net/drug-summary/toujeo?druglabelid=3688. Accessed March 28, 2015.
Insulin Degludec*
•  Duration of action >42 hours
•  Half-life ~25 hours
–  Detectable for at least 5 days
•  Steady state in 2–3 days
•  FDA denied approval in 2013, research continues
–  Approved in EU
*Not FDA approved.
Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al.
Diabetes Metab Res Rev. 2014;30(2):104-19.
Basal Insulin Degludec
Flat, stable profile of both 100 unit/mL
and 200 unit/mL formulations
Glucose Infusion Rate
Mean 24-Hour GIR Profile of the Two Insulin Degludec
Formulations at Steady State
5
4
3
IDeg 100 U/mL 0.8 U/kg
IDeg 100 U/mL 0.6 U/kg
IDeg 100 U/mL 0.4 U/kg
IDeg 200 U/mL 0.6 U/kg
Half-life at
Steady State
Mean
Half-life
(hours)
IDeg 200 U/mL
0.6 U/kg
26.2 h
2
n = 21
1
n = 37
n = 16
n = 22
0
Day 6
Day 7
GIR = glucose infusion rate.
Heise T, et al. ADA. 2012, Oral 349 Abstract (Trial: NN1250-1987). Nosek L, et al. IDF 2011: P-1452;
Diabetologia. 2011;54(suppl. 1):S429 (1055-P); Diabetes. 2011;60(suppl. 1A):LB14.
Pharmacodynamic Variability with
Insulin Degludec vs Insulin Glargine
Individual Coefficient
of Variation (%)
1200
1100
180
Insulin degludec
160
Insulin glargine
140
120
100
80
60
40
20
0
1
4
7
10
13
16
19
22
25
27
Subjects listed in increasing order of individual coefficient of variation
Heise T, et al. Diabetes Obes Metab. 2012;14(9):859-864.
53 U-200 Insulin Degludec:
Safety and Efficacy
HBA1c (%)
26-week Open-label, Randomized Study of
457 Patients with Type 2 Diabetes
8.5
8.3
8.1
7.9
7.7
7.5
7.3
7.1
6.9
6.7
0.0
IDeg 200 Units/mL OD (n=228)
IGlar OD (n=229)
Treatment
difference:
noninferior
0
2
4
6
8
10
12
14
16
18
20
22
24
26
Time (weeks)
No difference in hypoglycemia between the two treatment groups
Gough SC, et al. Diabetes Care. 2013;36(9):2536-42.
PEGylated Insulin Lispro*
•  Polyethylene glycol polymer covalently attached
to lispro
•  Half-life 2–3 days
•  Steady state in 7–10 days
•  Duration of action >36 hours
•  Phase II–III clinical trials
*Not FDA-approved.
Garber AJ. Diabetes Obesity Metab; [Epub ahead of print; published online 31 Oct 2013]. Owens DR, et al.
Diabetes Metab Res Rev. 2014;30(2):104-19. Accessed March 11, 2014. Sinha VP, et al. Diabetes Obesity
Metab. 2014;16(4):344-350. https://www.clinicaltrials.gov/ct2/results?term=LY2605541&Search=Search.
PEGylated Insulin Lispro
(LY2605541) Pharmacodynamics
Glucose clamp study in 32 patients, 8 per study arm
Mean GIR (mg/min/kg)
Pegylated Insulin Lispro
5
0.33 U/kg
0.5 U/kg
4
0.67 U/kg
1.0 U/kg
3
2
1
0
0
4
8
12
16
Time (hours)
GIR = glucose infusion rate.
Heise T, et al. Diabetes. 2012;61(suppl 1):A256 [abstract 1000-P].
20
24
PEGylated Insulin Lispro (LY2605541)
vs Glargine U-100 in T1DM
Treatment Period 1
Treatment Period 2
(Crossover)
8.0
LY2605541 Treatment at 8 weeks
A1c (%)
7.8
7.6
•  Significantly lowered A1C vs
glargine
p < 0.001
7.4
•  Significantly reduced weight
(1.2 kg)
7.2
7.0
•  Increased overall hypos
(p = 0.04) but less nocturnal
hypos (p = 0.01)
Weight (kg)
6.8
0
88
87
86
85
84
83
82
81
80
0
•  Lowered prandial insulin dose
•  Significantly increased liver
enzymes
p < 0.0001
0
4
Glargine
8
Week
12
Rosenstock J, et al. Diabetes Care. 2013;36(3):522-528.
16
LY2605541
Is there an alternative to
concentrated insulin for patients
on high doses of insulin?
Combination Basal Insulin and
GLP-1 RAs
Basal Bolus
Basal
plus
GLP-1 RAs
Add Prandial Insulin before Each Meal
Basal Plus
Add Prandial Insulin at Main Meal
Basal
Add Basal Insulin and Titrate
Lifestyle Changes plus Metformin
(± other agents)
Barriers to Insulin-Mediated
Glucose Control
Significant Delay in Insulin Initiation
SOLVE: Baseline A1C Distribution
at Insulin Initiation
8.9%
18
16
Patients (%)
14
12
10
8
6
4
2
0
5
6
7
8
9
10
11
12
13
14
15 16
A1C (%)
Data from Khunti K, et al. SOLVE Study Group. Diabetes. 2011;60(Suppl 1):A306.
The reason for delay in starting
insulin in diabetes management is:
a.  Provider reluctance (clinical inertia)
b.  Patient reluctance
c.  Lack of time
d.  Fear of hypoglycemia
e.  All of the above
Key Barriers to Insulin Therapy
Patient Barriers
Provider Barriers
•  Patient reluctance
•  Clinical inertia
•  Sense of failure
•  Lack of insulin training,
time, and/or support
•  Loss of independence
•  Belief that insulin is
ineffective
•  Fear of hypoglycemia
•  Weight gain
•  Fear of injections
•  Fear of hypoglycemia
•  Weight gain
Adapted from Funnell MM. Clinical Diabetes. 2007;25(1):36-38. Polonsky WH, et al. Curr Med Res Opin.
2011;27(6):1169-1174.
Overcoming the Barriers to
Insulin Therapy
•  Avoid using insulin as a “threat,” but a solution and discuss it
as an option early
•  Use insulin pens and regimens that offer maximum flexibility
•  Give a “limited” trial of insulin
•  Tell patient injection is less painful than finger stick and give an
injection in the office
•  Teach patient to recognize and treat hypoglycemia, and use
basal analog insulins to minimize hypoglycemia risk
•  Meet with dietitian before initiation of insulin
1. Kruger D, et al. Diabetes Educ. 2010;36(suppl 3):44S-72S. 2. Funnell MM. Clinical Diabetes. 2007;25(1):
36-38. 3. Derr RL, et al. Diabetes Spectrum. 2007; 20(3):177-185.
Insulin Administration
Insulin Titration and Education
•  First, do no harm
–  Halt the hypoglycemia
•  Fix the fastings
•  Pare the postprandials
Patient Education
•  Equipment and supplies patients need to
effectively manage their insulin therapy at home
–  Insulin
–  Syringes or pen needles
–  Blood glucose meter and strips
–  Lancets and lancing device
–  Glucagon emergency kit
–  Contact information of diabetes care provider(s)
Expiration of Products
Products/Device
Refrigerated
Unrefrigerated
Once Used (opened)
Vials
Insulin lispro
Insulin aspart
Insulin glulisine
Insulin glargine
Expiration
Date
28 days
28 days
Vials
Insulin human N
Insulin human R
Expiration
Date
31 days
31 days
Pens
Insulin lispro
Insulin aspart
Insulin glulisine
Insulin glargine U-100
Insulin glargine U-300
Expiration
Date
28 days
Do not refrigerate
(lispro, glargine) – 28 days,
(aspart) – 14 days
Vials and pens
Insulin detemir
Expiration
Date
42 days
42 days
(pens should not be refrigerated)
—
Expiration Date
15 days for device
Inhaled: Insulin human
http://www.pdr.net/browse-by-drug-name. Accessed March 28, 2015.
Basal Insulin Delivery Options
Insulin
Concentration
Vial
Pen
NPH
U-100
X
X
Glargine
U-100
X
X
Glargine
U-300
Detemir
U-100
X
Regular Human
U-500
X
X
X
Food and Drug Administration. [email protected] FDA Approved Drug Products. http://www.accessdata.fda.gov
Vial and Syringe
•  Some patients still use vials and syringes
–  Wipe the rubber stopper (on vial) with alcohol swab
–  Put equivalent amount of air into the vial before
drawing up the insulin (based on insulin dose)
•  When mixing insulin:
–  Clear before cloudy
–  Pre-drawn N + R = stable
for 30 days refrigerated
Needles and Syringes
Outer protective cap
Peel foil
Inner protective cap
Needle (cannula)
Needle hub
12.7 mm
(1/2")
8 mm
(5/16")
5 mm
(3/16")
Insulin Pens
Patient Cases
Case 1
•  67-year-old male, retired engineer
–  BMI 45
–  A1c = 8.5%
–  SrCr = 1.2
•  Medications:
–  Glargine (pen) 80 units twice per day
–  Aspart (pen) 30–60 units per meal + correction
–  Lisinopril 10 mg daily
–  Atorvastatin 10mg daily
•  Total daily dose (TDD) insulin: ~300 units per day
•  Largest meal is supper and snacks at night
?
Case #1 – Question #1
•  The physician recently became aware of concentrated
insulin and would like to switch the patient to U-500.
For a total daily dose of 300 units to be given twice daily,
how would you instruct the patient to draw up 150 units of
U-500 insulin?
1)  Using a U-100 syringe, draw to the 60 units marking
2)  Using a U-100 syringe, draw to the 30 units marking
3)  Using a tuberculin syringe, draw 0.2 mL
4)  Using a tuberculin syringe, draw 0.4 mL
Case 1 Continued
•  First assess patient current insulin injection technique
–  If technique is appropriate then…..
•  Start U-500 insulin:
–  300 units divided into two doses = 150 units twice daily
–  150 units of U-500 insulin is equal to 30 units on a
U-100 syringe
–  30 units x 5 (5 times concentration) = 150 units of actual insulin
–  If using tuberculin syringe, 150 units = 0.3 mL
•  U-300 insulin glargine is not a substitute for U-500 insulin
because the current U-300 pen delivers only up to 80
units per injection
Case 2
•  56 year old female, high school principal
– 
BMI 32
– 
A1c = 8.9%
– 
SrCr = 1.1
•  Patient did report occasional episodes nocturnal hypoglycemia
–  ~ 3–5 per month
•  Medications:
– 
NPH (pen) 63 units twice per day
•  Morning (7 AM) and 2 hours before bed (9 PM)
– 
Metformin 1000 mg daily
– 
Sitagliptin 100 mg daily
– 
Lisinopril 10 mg daily
– 
Simvastatin 20 mg daily
•  Total daily dose (TDD) insulin: ~126 units per day
•  Patient does not want to start bolus insulin due to erratic meal and
work schedules
?
Case #2 – Question #1
•  The physician wants to switch the patient to U-300 insulin
glargine. What would be your recommendation for
switching from 63 units twice daily (126 units/day) NPH to
U-300 insulin glargine?
1)  Using a U-100 syringe, draw to 21 units marking
(63 units) and inject twice daily
2)  Using a U-100 syringe, draw to 49 units marking
(126 units) and inject once daily
3)  Using the U-300 pen, dial to 126 units and inject
once daily
4)  Using the U-300 pen, dial to 51 units and inject
twice daily
Case 2
•  Switching to U-300 insulin glargine
–  Determine starting dose:
Prior treatment
Once daily long-acting or
intermediate acting insulin
Twice-daily NPH
No current basal insulin
Start with
1:1
80% total daily basal dose
0.2 U/kg/day
•  126 units x 0.80 = 100.8 units U-300 glargine
–  101 units/2 = 51 units given twice daily; current U-300 pen has max
dose of 80 units per injection
•  To minimize hypoglycemia risk, titrate the dose no more
frequently than every 3–4 days
Summary
•  Type 2 diabetes is a growing epidemic with an evergrowing number of patients requiring high doses of insulin
to maintain glycemic control
•  Insulin resistance is a MAJOR problem among patients
with type 2 diabetes, and combination therapy is often
needed to improve insulin sensitivity
•  A basal-bolus insulin regimen is best to mimic natural
insulin physiology but requires frequent BG monitoring
and provider/patient education
•  Concentrated insulin is ideal for patients with insulin
doses >200 U/day due to the large volume associated
with U-100 insulin
Summary Continued
•  U-500 regular human insulin is associated with a high
incidence of dosing errors due to the lack of a U-500
specific insulin syringe
•  Newly approved U-300 insulin glargine is available in a
pen, avoiding the need for conversion using U-100 or
tuberculin syringes needed with U-500 insulin
•  Insulin in T2DM is often delayed, but in order to optimize
glycemic control, it is important that clinicians recognize
and address the barriers to insulin therapy
•  U-300 insulin glargine and emerging basal insulins have
improved PK/PD profiles compared to current insulins
–  Flatter time–action profiles with less variability
–  Less hypoglycemia, particularly nocturnal hypoglycemia
Post-Activity Questions 1-4
Post-test Question #1
Which of the following does NOT represent a reason
for using high concentration insulin formulations in
the treatment of type 2 diabetes?
1.  Volume of insulin dose is physically too large for a
single SC administration
2.  Patient cannot manipulate vials and syringes
3.  Multiple injections are required to deliver a single
insulin dose
4.  Discomfort
5.  Unpredictable insulin absorption
Post-test Question #2
A 55 year old female, high school teacher with Type 2
diabetes is referred to you for dosing of U500 insulin. Her
current meds are NPH 100 units twice daily, lispro 10-30
units with meals plus correction, and metformin 1000mg
daily. Her A1C is 7.1% and Scr is 1.1. How would you instruct
the patient to draw up 110 units of U500 insulin?
1)  Using a U100 syringe, draw to the 50 units marking
2)  Using a U100 syringe, draw to the 25 units marking
3)  Using a tuberculin syringe, draw 0.2 mL
4)  Using a tuberculin syringe, draw 0.4 mL
Post-test Question #3
Which of the following is NOT a strategy to overcome
the barriers to insulin therapy?
1.  Avoid using insulin as a “threat” and discuss it as
an option early
2.  Dose NPH insulin twice daily to minimize
hypoglycemia
3.  Use insulin pens and regimens that offer maximum
flexibility
4.  Give a “limited” trial of insulin
Post-test Question #4
Which of the following statements is INCORRECT regarding
the new basal insulin U300 glargine?
1.  It is associated with less nocturnal hypoglycemia
2.  It has a flatter PK profile and a duration of action ≤36 hrs
3.  It is only available in a pen with 1.5 mL of U300 glargine
4.  Current pen allows for a max of 240 units of insulin per
shot
5.  Patients switching from twice daily NPH to U300 glargine
should start with 80% of total daily NPH dosage
Backup Slides
In what year was insulin
made available to treat humans?
?
1) 1898
2) 1922
3) 1937
4) 1948
5) 1956
BANTING (1891–1941)
& BEST (1899–1978)
First Commercial
Insulin
Milestones in Insulin Development
Synthetic human
insulin developed (1965)
Insulin discovered (1921)
Insulin lispro approved
in U.S. (1996)
Insulin detemir
approved in U.S.
Recombinant human
(2005)
insulin developed
(1979)
Inhaled insulin
NPH insulin
developed (1946)
(2006)
2014
Degludec (2013)
1920
1930
1940
1950
1960
1970
Lente (zinc) insulins
developed (1952)
Protamine and protamine
zinc insulins developed (1936)
First human treatment
with bovine insulin (1922)
1980
1990
Insulin pen
developed (1981)
Insulin pump
developed (1978?)
2000
2010
Insulin
glulisine
(2004)
2013
2014
In development:
Degludec U-200
Glargine U-300
Pegylated Lispro
Biosimilars
Insulin aspart and
insulin glargine
approved in U.S.
(2000)
1. Tattersall RB. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd ed. Blackwell Science: Malden, MA;
2003:1.1-1.22; 2. [email protected] FDA; http://diabetes.webmd.com/news/20071018/pfizer-quits-inhaled-insulinexubera.
First Time Preparation
•  Check the pen
–  Make sure liquid is clear, colorless,
particle-free (N insulin and mixed insulin
will be cloudy)
–  Wipe the rubber stopper with alcohol
•  Attach the needle
•  Prime the needle
–  Dial 2 to 3 units, hold up and depress
the button
•  Repeat the process until a drop of insulin
appears at the tip of the needle
•  Dial up the dose
Insulin Injection
•  Inject straight into the skin
–  Depress the button to release insulin into SC tissue
•  Hold for 5 to 10 seconds before removing the needle
from skin
•  Remove needle and dispose
into sharps container
•  Always have the patient
demonstrate their technique
–  At first education of the device
–  At first follow-up visit
–  At frequent intervals thereafter
Inject “straight in”
flush with skin
Improper Insulin Injection
Technique
•  The patient did not tip and roll insulin suspension
pen injector to ensure proper mixing
•  The patient put a needle on the pen, dialed to 10
units, pushed the needle into the injection pad,
and then proceeded to dial back to zero
•  The patient omitted the 2-unit air shot prior to
each dose
•  The patient injected his insulin into the orange
(as he was taught) and then ate the orange
Insulin Resistance:
Patient Risk Factors
•  Medical conditions associated with risk:
–  History of gestational diabetes (GDM)
–  Lipodystrophy and other inherited disorders
–  Fatty liver disease
–  Metabolic syndrome (obesity, HTN, mixed hyperlipidemia)
–  Polycystic ovarian syndrome (PCOS)
•  Physical exam/historical markers associated with risk:
–  Obesity
–  Increased waist-to-hip ratio (visceral adiposity)
–  Certain ethnic groups have increased risk
–  Acanthosis nigricans
Andrews L. Overcoming the frustration of severe insulin resistance. American Diabetes Association, 2014
professional Educator Conference.