Understanding Different Types of Insulin

1
Understanding Different Types of Insulin

• Martin J. Abrahamson, MD
• Medical Director and Senior Vice President
• Joslin Diabetes Center
• Associate Professor of Medicine
• Harvard Medical School
• Boston, Massachusetts

2
Learning Objectives

• Describe the pharmacokinetics and
  pharmacodynamics of human and analog insulins
• Compare the clinical advantages of analog vs.
  human insulins
• Describe the role of different insulins in
  clinical practice
• Enumerate the principles of advancing insulin
  therapy in type 2 diabetes

3
Physiologic Insulin Secretion 24-hour Profile
4
Insulins Available for Clinical Use

• Mealtime insulin
• Short acting (human) regular
• Rapid acting (analog) aspart, lispro, glulisine
• Basal insulin
• Human NPH
• Analogs glargine, detemir
• Premixed insulins
• Provide both basal and mealtime cover
• (human and analog available)
• Humalog 75/25 Humalog 50/50
• Novolog 70/30
• Human 70/30

5
Estimated Pharmacokinetics of Current Insulin
Preparations
Barnett AH, Owens DR. Lancet. 199734997-51.
White JR, et al. Postgrad Med. 199710158-70.
Kahn CR, Schechter Y. In Goodman and Gilmans
The Pharmacological Basis of Therapeutics.
19901463-1495. Coates PA, et al. Diabetes.
199544(Suppl 1)130A.
6
Bolus Insulin for Preprandial Administration
Desirable KineticCharacteristics

• Predictable, reproducible time-action profile
• Rapid onsetof action
• Short durationof action

7
Limitations of Human Regular Insulin

• Slow onset of action
• Requires inconvenient administration 20 to 40
  minutes prior to meal
• Risk of hypoglycemia if meal is further delayed
• Mismatch with postprandial hyperglycemic peak
• Long duration of activity
• Up to 12 hours duration
• Increased at higher dosages
• Potential for late postprandial hypoglycemia

8
Advantages of Rapid-Acting Insulin Analogs

• Improve patient convenience
• Modify time action of human insulin toward a more
  physiologic profile
• Reduce postprandial hyperglycemia
• Minimize postprandial hypoglycemia
• Reduce the need for between-meal snacks
• Improve glycemic control
• Reduce hypoglycemia

9
Rapid Acting Insulin Analogs
10
Faster Dissociation
Peak Time 40-50 min
InsulinAspart, Lispro, or Glulisine
CapillaryMembrane
Subcutaneous Tissue
Peak Time 80-120 min
RegularHuman Insulin
11
Pharmacodynamics of Insulin Analog vs. Regular
Human Insulin
Insulin Aspart
800 700 600 500 400 300 200 100 0
Regular Insulin
Glucose Infusion Rate (mg/kgmin)
0
120
240
360
480
600
0.2 IU/kg SC
Time (minutes)
12
Rapid-Acting Insulin Analogs Consistency of
Absorption from Multiple Sites
700 600 500 400 300 200 100 0
? Abdomen ? Deltoid Thigh
Glucose Infusion Rate (mg/kgmin)
0
120
240
360
480
600
Time (minutes)
Insulin Aspart 0.2 IU/kg SC
Mudaliar et al., Diabetes Care 1999 221501.
(Healthy Volunteers)
13
Lower Postprandial Glycemia with Insulin Aspart
in Type 2 Diabetes vs. Regular Human Insulin
? Insulin Aspart with meal ? Regular Insulin
with meal ? Regular insulin -30 min
Serum Glucose (mg/dL)
0
-30
30
60
90
120
150
180
210
240
270
300
330
360
Time (minutes)
0.15 IU/kg SC
Adapted from Lindholm et al. Diabetes Care.
19992280
14
Aspart vs. Regular Insulin in Type 2 Diabetes
SMBG Results at 6 Months
200 180 160 140 120 100
Postprandial target lt180 mg/dL






Blood Glucose (mg/dL)




Preprandial target range 90 to 144 mg/dL


Insulin Aspart
Regular Insulin
0
Pre
Post
Pre
Post
Pre
Post
Breakfast
Lunch
Dinner
Bedtime
2 am
P lt 0.05
Data represent mean SEM
15
Insulin Aspart vs. Regular Human Insulin Effect
on A1C
8.5 8.0 7.5
Insulin Aspart
Regular Insulin
A1C ()


0
0
3
6
Time (months)
P lt 0.05
Data represent mean SEM
16
Insulin Aspart vs. Regular Human Insulin
Hypoglycemic Episodes Per Patient
Postprandial Glucose Levels
Breakfast
PP Blood Glucose (mg/dL)
Lunch
Dinner
PPG levels 90 mins after breakfast, lunch, or
dinner T1 Randomization visit M1 Month 1
visit M3 Month 3 visit
Bretzel et al. Diabetes Care. 2004271023-1027.
17
The Ideal Basal Insulin

• Mimics normal pancreatic basal insulin
  secretion
• Long-lasting effect 24 hours
• Smooth, peakless profile
• Reproducible and predictable effects
• Reduced risk of nocturnal hypoglycemia
• Once-daily administration

18
Insulin Glargine

• Modifications to human insulin chain
• Substitution of glycine at position A21
• Addition of 2 arginines at position B30
• Gradual release pattern from injection site
• Peakless, long-lasting insulin profile

19
Glargine vs. NPH Insulin in Type 1 Diabetes
Action Profiles by Glucose Clamp
6
5
4
NPH
Glucose utilization rate (mg/kg/h)
3
2
Insulinglargine
1
0
0
10
20
30
Time (h) after sc injection
End of observation period
Lepore M, et al. Diabetes. 2000492142-2148.
20
Longer Acting Insulins Comparison of
Pharmacodynamics
SC insulin
2
4
4
.
0
2
0
3
.
0
n
n
i
1
6
i
m
m
/
/
g
g
k
2
.
0
1
2
k
/
l
/
o
g
m
m
8
µ
1
.
0
4
0
0
0
4
8
1
2
1
6
2
0
2
4
Lepore M et al. Diabetes. 2000492142-2148.
21
Absorption Profiles of Basal Analog vs. NPH
Absorption Profiles of 125I-Insulin Glargine
and 125I-NAPH Insulin (0.3 IU/kg) in 14 T2DM
Patients
100
90
80
70
60
50
Radioactivity ()
40
30
20
Insulin Glargine
10
NPH
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time After Injection (h)
Luzio SD, et al. Horm Metab Res. 200335434-438.
22
Absorption Profile of Basal Insulin Glargine
Absorption Profiles After Injection of
125-I-Insulin Glargine (0.2 IU/kg) in Arm, Leg,
or Abdomen
100
90
80
70
60
Radioactivity ()
50
40
30
20
10
0
0
2
4
6
8
10
12
14
16
18
20
22
24
Time After Injection (h)
Owens DR, et al. Diabetes Care. 200023813-819.
23
Insulin Detemir
LysB29(N-tetradecanoyl)des(B30)human insulin

• Detemir Properties
• Neutral pH
• Long extended action
• More within patient consistency
• Less hypoglycemia
• Less weight gain

24
Consistent Blood Glucose Response
Which is the better insulin profile?
Basal insulin with varying daily profiles
Ideal basal insulin
A
B
hypoglycemic event
Glucose infusion rate (GIR)
Glucose infusion rate (GIR)
hyperglycemia
Time
Time
This is a graphical representation.
25
Blood Glucose Response With Different Long-Acting
Insulins NPH, Glargine, Detemir
NPH
Glargine
Detemir
GIR glucose infusion rate
Adapted from Heise T et al. Diabetes.
2004531614-1620.
26
Consistent Blood Glucose Response with Detemir
vs. NPH and Glargine
NPH
p lt 0.001
Glargine
80
68
Detemir
70
p lt 0.001
60
CV () Glucose infusion rate AUC(024h)
48
50
40
27
30
20
10
0
CV coefficient of variation a measure of
variation in data, relative to the mean of those
data, calculated as 100 x (standard
deviation/mean) and expressed as a
percentage. Based on the results of this study,
no conclusions can be made regarding the
comparative safety or efficacy of Levemir vs.
other insulins.
Adapted from Heise T et al. Diabetes.
2004531614-1620.
27
Treat-to-Target Study Glargine vs. NPH
9
60 of Patients Reached Target A1C
Glargine NPH insulin
8
Mean A1C ()
Target A1C ()
7
6
0
4
8
12
16
20
24
Time (weeks)
Riddle MC, et al. Diabetes Care.
20032630803086.
28
Treat-to-Target Study Glargine vs.
NPHSymptomatic Hypoglycemia by Time of Day
Glargine
Basal insulin
1.4


NPH insulin
1.2


1.0


Events per patient-year
P lt 0.05 vs. glargine
0.8
0.6
0.4
0.2
0
20
22
24
2
4
6
8
10
12
14
16
18
Time of Day (hour)
Hypoglycemia defined as PG ? 72 mg/dL, by hour
Riddle MC, et al. Diabetes Care.
20032630803086.
29
Treating-to-Target Detemir in Addition to OADs
in Type 2 Diabetes

• 475 insulin-naive type 2 diabetes patients
• 58 centers, 10 countries
• 11 randomization

Detemir twice daily, n237
2 week run-in
NPH twice daily, n238
Existing OADs continued (both groups)
-2
0
24
12
Weeks
Insulin titrated to target fasting and
pre-dinner PG lt108 mg/dL
OAD oral antidiabetic drug
Hermansen K, et al. Diabetes Care,
2006291269-1274.
30
Detemir vs. NPH in Type 2 Diabetes With a
Treat-to-Target Design
Detemir
10
NPH
9.5
9
8.5
A1C ()
8
7.5
7
6.5
Weeks
-2
0
12
24
Hermansen K, et al. Diabetes Care,
2006291269-1274.
31
Detemir Consistently Demonstrated a Low Risk for
Nocturnal Hypoglycemia vs. NPH in Type 2 DM
Any episode between 11 pm and 6 am
32
Detemir Achieved Glycemic Control Comparable to
Glargine In Type 1 DM
Detemir insulin aspart
9.0
Glargine insulin aspart
8.8
A1C ()
8.6
8.4
8.2
0
2
6
10
14
18
22
26
Weeks
Pieber TR, et al. Diabet Med. 200724635-642.
33
Detemir Achieved Glycemic ControlWith a Low Rate
of Hypoglycemia vs. Glargine
p lt 0.05
p lt 0.05
1


Detemir insulin aspart
0.8
Glargine insulin aspart
Relative Risk
0.6
Episodes per year based on 20-week maintenance
period
0.4
0.2
0
Nocturnal hypoglycemia
Major hypoglycemia
Requiring assistance from another person Any
episode between 11 pm and 6 am
Pieber TR, et al. Diabet Med. 200724635-642.
34
Proportion of Detemir Patients Reaching Goal A1C
Without Hypoglycemia vs. NPH
p lt 0.01
26
Reaching goal without hypos A1C 7.0 with no
PG reading lt 55.8 mg/dL and no confirmed (PG lt
72.0 mg/dL) symptomatic hypoglycemia
Number of patients achieving A1C 7.0 without
hypoglycemia
16
n 230
n 232
Hermansen K, et al. Diabetes Care.
2006291269-1274.
35
Detemir Consistently Demonstrated a LowRisk for
Nocturnal Hypoglycemia in Type 1DM
Detemir NPH Glargine








1.0
0.8
Relative Risk
0.6
0.4
0.2
0.0
Home am hs
Vague
Pieber
Home Q12h
Standl
Pieber am hs
Pieber am dinner
De Leeuw
Robertson
Hermansen
Kølendorf
Russell-Jones
A1C ()
Detemir
8.20
7.88
8.30
7.55
8.02
7.78
7.75
7.65
7.67
7.53
7.60
7.73
Comparator
8.20
8.11
8.41
7.55
7.93
7.94
7.73
7.59
7.64
7.67
plt0.05
Any episode between 11 pm and 6 am
36
Detemir Is Associated With Less Weight Gain
Basal Insulin Trials vs. NPH or Glargine
3.5
p lt 0.001
3
2.5
Glargine PM
p 0.004
NPH BID
NPH PM
2
Change in weight from baseline (kg)
1.5
NPH PM
1
Detemir BID
0.5
Detemir PM
0
Hermansen 2006 24 weeks
Riddle 2003 24 weeks
Philis-Tsimikas 2006 20 weeks
37
Detemir Consistently Demonstrated Less Weight
Gain in Type 2 Diabetes vs. NPH
6.26
Detemir
6
NPH
5
4
p 0.038
Weight ? (lb)
3
2.64
2.48
2
1.12
1
0
Ralová 22 weeks
Hermansen 24 weeks
The clinical significance of the observed
differences has not been established. Whether
these observed differences represent true
differences in the effects of Levemir and NPH
insulin is not known, since these trials were not
blinded and the protocols were not specifically
directed at exploring hypotheses related to
weight effects of the treatments compared.
38
Elliot Joslin (1923)

• Insulin is a remedy primarily for the wise and
  not for the foolish, whether they be patients or
  doctors.
• Everyone knows it requires brains to live long
  with diabetes, but to use insulin successfully
  requires more than brains.

39
Summary

• Compared to human insulin, the analog insulins
  more closely resemble physiologic insulin
• The basal insulin analogs provide superior
  glycemic control with a lower risk of
  hypoglycemia compared to NPH

40
Understanding Different Types of Insulin

• Martin J. Abrahamson, MD
• Medical Director and Senior Vice President
• Joslin Diabetes Center
• Associate Professor of Medicine
• Harvard Medical School
• Boston, Massachusetts

41
Insulin Lispro Lys (B28), Pro (B29)
S S
21
1
A-chain
S
S S
S

B29 PRO
B28 LYS
1
30
B-chain
42
Aspart (Novolog)
Single Amino Acid Substitution
43
Treat-to-target Study Glargine vs. NPH
Mean FPG During Study
200
Glargine
NPH
FPG (mg/dL)
150
120
117
100
0
4
8
12
16
20
24
Time / weeks
Riddle MC, et al. Diabetes Care.
20032630803086.