Transcript Module 01and 02 Epid Diag Criteria 8Mar06

Pathophysiology of Type 2 Diabetes
GLP1: the new era in diabetes management
Prof. Khalifa M. Abdallah
Professor of Internal Medicine
Diabetes, Metabolism & Lipidology Unit
Alexandria Faculty of Medicine
1
Overview

Pathophysiology of Tpye 2 DM

Background on incretin hormones

Incretin therapies for T2 DM: Exenatide

Take home message
2
Insulin and Glucagon Regulate
Normal Glucose Homeostasis
Fasting state
Glucagon
(alpha cell)
Fed state
Pancreas
Insulin
(beta cell)
Glucose uptake
Glucose output
 Blood glucose

Liver
Muscle
Adipose
tissue
Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254.
Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed.
Lippincott Williams & Wilkins; 2005:145–168.
3
4
5
Major Pathophysiologic Defects in
Type 2 Diabetes
Impaired
Incretin Action
Insulin
Resistance
B-cell
Dysfunction
Type 2 DM
6
Overview

Pathophysiology of Tpye 2 DM

Background on incretin hormones

Incretin therapies for T2 DM: Exenatide

Take home message
7
Proof of a Gastrointestinal ‘Incretin Effect’: Different
Responses to Oral vs IV Glucose
Oral Glucose Tolerance Test and Matched IV Infusion
400
50 g Glucose
Plasma Insulin (pmol/L)
Plasma Glucose (mg/dL)
200
150
100
50
0
200
100
0
–30
N=6
300
0
30
60 90 120 150 180 210
Time (Min)
Oral
–30
0
30
60 90 120 150 180 210
Time (Min)
IV
IV=intravenous
Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.
8
Incretin Hormones
Incretin Hormones are hormones produced in
GI tract in response to nutrients which in turn
stimulates insulin secretion
Predominant Hormones are:
GLP-1 and GIP
GLP-1: Glucagon-like peptide-1
GIP: Glucose-dependent insulinotropic peptide
9
Mechanism of Action of Incretin
Ingestion
of food
GI tract
Glucose
dependent
 Insulin
(GLP-1and
GIP)
Pancreas
Release of
active incretins
GLP-1 and GIP
DPP-4
enzyme
Beta cells
Inactive
GIP
 Blood glucose
in fasting and
postprandial
states
Alpha cells
Glucosedependent
 Glucagon
(GLP-1)
Inactive
GLP-1
 Glucose
uptake by
peripheral
tissue
 Hepatic
glucose
production
10
GLP-1 and GIP Are the Two Major Incretins
•
•
•
•
GLP-1
GIP
Secreted by L-cells in the distal gut • Secreted by K-cells in the
(ileum and colon)
proximal gut (duodenum)
Stimulates glucose-dependent
• Stimulates glucose-dependent
insulin release
insulin release
Suppresses hepatic glucose output
by inhibiting glucagon secretion in
a glucose-dependent manner
Enhances beta-cell proliferation
• Enhances beta-cell
and survival in animal models and
proliferation and survival
isolated human islets
in islet cell lines
GLP-1=glucagon-like peptide 1; GIP=glucose-dependent insulinotropic polypeptide
Adapted from Drucker DJ Diabetes Care 2003;26:2929–2940; Ahrén B Curr Diab Rep 2003;3:365–372; Drucker DJ Gastroenterology 2002;122:
531–544; Farilla L et al Endocrinology 2003;144:5149–5158; Trümper A et al Mol Endocrinol 2001;15:1559–1570; Trümper A et al J Endocrinol
2002;174:233–246.
11
GLP-1 Improves -cell Mass in Zucker Diabetic Fatty
Rats
-cell Mass
-cell Proliferation
-cell Apoptosis
N=16
30
2.5
16
P <0.05
P <0.01
Proliferating -cells (%)
-cell Mass (mg)
8
4
Apoptotic -cells (%)
2.0
12
1.5
1.0
20
P <0.001
10
0.5
0
0
Control
GLP-1
Treated*
0
Control
GLP-1
Treated*
Control
GLP-1
Treated*
GLP-1=glucagon-like peptide-1
*GLP-1 infused at 30 pmol/kg/min over 2 days.
Adapted from Farilla L, et al. Endocrinology. 2002; 143: 4397–4408.
12
GLP-1 Modulates Numerous Functions
in Humans
GLP-1: Secreted upon
the ingestion of food
Long Term effects in Animals
 Cell mass
Maintains  Cell func
Reduces  cell apoptosis
Promotes satiety and
reduces appetite
Alpha cells:
 Postprandial
glucagon secretion
Liver:
Beta cells:
 Glucagon reduces
hepatic glucose output
Enhances glucose-dependent
insulin secretion
Stomach:
Helps regulate
gastric emptying
Data from Flint A, et al. J Clin Invest. 1998;101:515-520; Data from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422
Data from Nauck MA, et al. Diabetologia. 1996;39:1546-1553; Data from Drucker DJ. Diabetes. 1998;47:159-169
13
Meal Test Study
GLP-1 Levels Decreased in Type 2 Diabetes
NGT (n=33)
Type 2 diabetes (n=54)
20
GLP-1 (pmol/L)
*
*
*
*
*
15
*
*
10
5
0
0
60
120
180
240
Time (minutes)
*p<0.05, type 2 diabetes vs. NGT
Meal started at time 0 and finished at 10–15 minutes.
Adapted from Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:3717–3723.
14
GLP-1 Action Remained Intact
in Patients with Type 2 Diabetes
Hyperglycemic Clamp Study
GLP-1 infusion (low rate)*
GLP-1 infusion (high rate)**
60
51.4
P=NS***
50
38.2
40
30
20
10
P=NS***
7.4
7.5
0
NGT (n=9)
Type 2 diabetes (n=9)
*Low rate=0.4 pmol kg–1 min–1
**High rate=1.2 pmol kg–1 min–1
***vs. corresponding NGT group
Study included four examinations per patient: 1) an oral glucose challenge; and hyperglycemic clamp
experiments with administration of 2) glucagon; 3) GIP; and 4) GLP-1. Only results for GLP-1 are shown.
Adapted from Nauck MA et al J Clin Invest 1993;91:301–307.
15
Pharmacologic Approaches to Enhancing GLP-1
Action in Diabetes
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
DPP-4=dipeptidyl peptidase 4
Block DPP-4, the
enzyme that degrades
GLP-1:
• sitagliptin
• vildagliptin
Oral agents
Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
16
Overview

Pathophysiology of Tpye 2 DM

Background on incretin hormones

Incretin therapies for T2 DM: Exenatide

Take home message
17
Exenatide (Exendin-4) Is a Novel Incretin Mimetic
Amino Acid Sequences
Exendin-4 and GLP-1 have similar
binding affinity at the GLP-1
receptor in vitro
GLP-1 Receptor Binding Affinity*
100
Percent specific binding
Exendin-4 shares about 50% amino
acid identity with GLP-1
80
60
40
20
Synthetic GLP-1
Exendin-4
0
Zero
-11
-10
-9
-8
-7
-6
Peptide concentration (log molar)
*Adapted from Fehmann HC, et al. Peptides. 1994;15:453-456.; Chen YE, Drucker DJ. J Biol Chem. 1997;272:4108-4115.; Neilsen LL, et al.
Regul Pept. 2004;117:77-88. Reprinted from Regulatory Peptides, 117, Nielsen LL, et al, Pharmacology of exenatide (synthetic exendin-4): a
18
potential therapeutic for improved glycaemic control of type 2 diabetes, 77-88, 2004, with permission from Elsevier for English use only.
Exenatide Reduced Fasting Hyperglycaemia
in Patients With Type 2 Diabetes
Fasting Plasma Glucose
12
11
10
9
8
7
6
5
0
2
4
Time (hour)
SC Injection
6
8
Serum Insulin Concentration
(pmol/L)
Plasma Glucose Concentration
(mmol/L)
Placebo
Exenatide 0.05 μg/kg
Exenatide 0.10 μg/kg
Serum Insulin
200
150
90
50
0
0
2
4
6
8
Time (hour)
SC Injection
Mean (SE); N = 12; p<.0001 for glucose; p<.001 for insulin.
Adapted from Kolterman OG, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in
subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:3082-3089. Copyright 2003, The Endocrine Society.
19
Acute Exenatide Infusion Restored First-Phase Insulin
Response in Patients With Type 2 Diabetes
Healthy Subjects, Placebo
Type 2 Diabetes, Placebo
Type 2 Diabetes, Exenatide
Insulin Secretion
(pmol•kg-1•min-1)
p = 0.0002
p = 0.0002
p = 0.0029
Exenatide vs Placebo
Exenatide vs Healthy
Time (min)
Mean (SE); N = 25.
Fehse F, et al. J Clin Endocrinol Metab. 2005 Nov;90(11):5991-5997. Copyright 2005, The Endocrine Society.
20
Exenatide
Dose-Dependently Slowed Gastric Emptying
T50: Half-emptying Time (min)
Placebo
5 µg Exenatide BID
10 µg Exenatide BID
*
*
*
*
Solids
Liquids
Least Squares Geometric Means shown.
*p<.01 vs placebo.
Linnebjerg H, et al. Diabetes. 2006;55(Suppl 1):A28 Abstract 116-OR.
21
Islet Area
(Arbitrary Units X 104)
Exendin-4 Increased Islet Size in
Diabetic Mice After 2 Weeks of Daily Treatment
Saline
3
2
1
0
Saline Exendin-4
Exendin-4
Mean (SE).
Stoffers D, et al. Diabetes. 2000;49:741-748. Copyright © 2000 American Diabetes Association. From Diabetes, Vol 49, 2000; 741-748.
Reprinted with permission from The American Diabetes Association.
22
Phase 3 Clinical Trials of Exenatide
23
Large Phase 3 Clinical Studies:
Study Design
♦ Randomised, double-blind, placebo-controlled, multi-centre
studies in patients with type 2 diabetes
♦ No washout period
• Exenatide or placebo administered subcutaneous before breakfast
and evening meal
Screening
Exenatide 5 µg (0.02 mL) BID
Exenatide
5 µg
Placebo (0.02 mL)
BID
Lead-in
Exenatide 10 µg (0.04 mL) BID
0.02 mL
BID
Placebo
0.02 mL
BID
-4
0
Placebo 5 µg (0.02 mL) or 10 µg (0.04 mL) BID
4
12
24
30
Time (week)
DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.;
Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.
24
Large Phase 3 Clinical Studies:
Exenatide Lowered HbA1c at 30 Weeks
Placebo BID
Exenatide 5 µg BID
Exenatide 10 µg BID
SFU
MET
MET + SFU
Change in HbA1c (%)
0.5
0.2
0.1
0.1
0
-0.5
-0.4
-0.5
*
-1
*
-0.6
*
-0.8
*
-0.9
*
ITT population; Mean (SE); MET (N = 336), SFU (N = 377), MET + SFU (N = 733); *p<.005 vs placebo.
Mean baseline HbA1c ranged from 8.2% to 8.7% across all trial arms.
DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.;
Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.
-0.8
*
25
Large Phase 3 Clinical Studies: Exenatide Reduced
Fasting Plasma Glucose at 30 Weeks
Placebo BID
Exenatide 5 µg BID
Exenatide 10 µg BID
SFU
MET
Change in FPG (mmol/L)
1.25
+0.8
1.00
MET + SFU
1.25
1.25
1.00
1.00
.75
.75 +0.4
.50
.50
.5
.25
.25
.25
0
0
0
-.25
-.25
-.25
-.50
-.50
-.75
-1.00
-0.4
*
-.75
-0.6
*
-1.00
+0.8
.75
-.50
-0.3
-.75
-0.6
*
-1.00
ITT population; Mean (SE); MET (N = 336), SFU (N = 377), MET + SFU (N = 733); *p<.05 vs placebo.
Mean baseline FPG ranged from 9.3 mmol/L to 10.8 mmol/L across all trial arms.
DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.;
Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.
-0.5
*
-0.6
*
26
Large Phase 3 Clinical Studies: Exenatide Reduced
Postprandial Glucose Over 30 Weeks
Placebo BID
Exenatide 5 µg BID
Exenatide 10 µg BID
Combined Results of Exenatide Phase 3 Studies
Glucose (mmol/L)
Baseline
16
15
14
13
12
11
10
9
8
7
6
5
-30
Placebo
Meal
0
30 60 90 120 150 180
Week 30
16
15
14
13
12
11
10
9
8
7
6
5
-30
Exenatide
Meal
0
Time (min)
Mean (SE); N = 138; Evaluable meal tolerance cohort.
p<.0001 for change in PPG from baseline to week 30, exenatide vs placebo group.
Data on file, Amylin Pharmaceuticals, Inc.
30 60
90 120 150 180
Time (min)
27
Large Phase 3 Clinical Studies: Exenatide
Reduced Body Weight Over 30 Weeks
Placebo BID
Exenatide 5 µg BID
Exenatide 10 µg BID
MET
0
10
SFU
20
30
0
10
20
MET + SFU
30
0
10
20
30
Change in Weight (kg)
0
-0.5
*
-1.0
-1.5
*
*
*
**
-2.0
-2.5
-3.0
-3.5
*
*
*
**
*
*
*
**
**
Time (week)
**
Time (week)
Time (week)
ITT population; Mean (SE); MET (N = 336), SFU (N = 377), MET + SFU (N = 733); *p<.05 vs placebo; **p<.001 vs placebo.
Mean baseline weight ranged from 95 kg to 101 kg across all trial arms.
DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.; Buse JB, et al. Diabetes Care. 2004;27:2628-2635.;
Kendall DM, et al. Diabetes Care. 2005;28:1083-1091. Reprinted with permission from the American Diabetes Association.
28
Large Phase 3 Clinical Studies (Combined):
Exenatide Reduced HbA1c and Weight
Placebo BID
Exenatide 5 µg BID
Exenatide 10 µg BID
+0.1
0
-0.5
-0.6
*
-1
-1.5
-0.9
*
Change in Weight (kg)
Change in HbA1c(%)
0
-0.5
-1.0
-0.7
-1.5
-1.4
-2.0
*
-1.9
*
ITT 30-week data; N = 1446; Mean (SE); *p<0.005; Weight was a secondary endpoint.
Data on file, Amylin Pharmaceuticals, Inc.
29
Large Phase 3 Clinical Studies (Combined):
Common Adverse Events
Combined Results of 30-Week Exenatide Phase 3 Studies
Placebo
(N = 483)
Nausea
5 µg Exenatide
(N = 480)
10 µg Exenatide
(N = 483)
18%
39%
48%
Hypoglycaemia
8%
15%
25%
Diarrhoea
6%
11%
15%
Vomiting
4%
13%
13%
Headache
6%
10%
7%
Feeling Jittery
4%
9%
10%
Data on file, Amylin Pharmaceuticals, Inc.
30
Large Phase 3 Clinical Studies (Combined):
Nausea Decreased Over Time
Placebo
5 µg Exenatide BID
10 µg Exenatide BID
Dose increased from
5 µg to 10 µg at Week 4
% Incidence of Nausea
100
75
60
45
30
15
0
0-4
>4-8
>8-12 >12-16 >16-20 >20-24 >24-28
>28
Time (week)
ITT 30-week data; N = 1446.
Data on file, Amylin Pharmaceuticals, Inc.
31
Large Phase 3 Clinical Studies (Combined):
Anti-Exenatide Antibodies
38% of patients had low-titre anti-exenatide antibodies at
30 weeks
 For this group, the HbA1C was generally comparable to that observed
in those without antibody titres
An additional 6% of patients had higher titre antibodies at
30 weeks
In 3% of the total patients given exenatide in the controlled
studies, the glycaemic response to exenatide appeared
diminished
Byetta package insert. San Diego, CA: Amylin Pharmaceuticals, Inc; 2007.
32
Exenatide Sustained A1C Reductions:
3-Year Completers
Placebo-Controlled Trials
10
9
Open-label Uncontrolled Extensions
Baseline A1C: 8.2% ± 0.1%
Week 156
-1.0% (95% CI: -1.1% to -0.8%)
A1C (%)
8
7
6
5
4
0
26
52
78
104
130
156
Treatment (week)
N = 217; Mean ± SE; Reductions from baseline to Wk 12 were sustained to Wk 156 (P<0.0001); A1C, glycosylated hemoglobin A1C;
CI, confidence interval.
Adapted from Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.
34
Exenatide Continued to Reduce Body Weight:
3-Year Completers
Placebo-Controlled Trials
0
Open-label Uncontrolled Extensions
Δ Body Weight (kg)
Baseline Weight: 99.3 ± 1.2 kg
-2
Week 156
-5.3 kg (95% CI: -6.0 to -4.5 kg)
-4
-6
0
26
52
78
104
130
156
Treatment (week)
N = 217; Mean ± SE; Change from baseline to 3 y, P<0.0001
Adapted from Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.
35
Improvement in Cardiovascular Risk Factors With 3.5
Years of Exenatide Treatment (N=151)
Baseline
(Mean ± SEM)
Change from
Baseline
(Mean ± SEM)
Mean
Change
95%
Confidence
Interval
Triglycerides
(mmol/L)
2.5 ± 0.1
-0.5 ± 0.1
-12%
-0.8 to -0.2
Total Cholesterol
(mmol/L)
4.8 ± 0.1
-0.3 ± 0.1
-5%
-0.4 to -0.1
HDL-C (mmol/L)
1.0 ± 0.0
0.2 ± 0.0
+24%
0.2 to 0.3
.0001
LDL-C (mmol/L)
2.9 ± 0.1
-0.3 ± 0.1
-6%
-0.5 to -0.2
.0001
Systolic Blood
Pressure (mmHg)
129.3 ± 1.0
-3.5 ± 1.2
-2%
-5.9 to -1.0
.0063
Diastolic Blood
Pressure (mmHg)
79.2 ± 0.6
-3.3 ± 0.8
-4%
-4.9 to -1.7
.0001
Cardiovascular Risk
Factor
p-value
.0003
.0007
Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286.
36
Summary: Exenatide is a Novel Incretin Mimetic That
Shares Several Glucoregulatory Actions With Human GLP-1
Enhances glucose-dependent insulin secretion
Reduces postprandial glucagon secretion
Slows gastric emptying rate
Reduces food intake and body weight
Restores first phase insulin response
Increases beta-cell mass (animal models) and markers of betacell function
37
Summary of Placebo-controlled Data: Exenatide Improves
Glycaemic Control With Associated Weight Loss
In 30-week phase 3 clinical trials, in type 2 diabetes patients treated
with MET and/or an SFU, 10 µg exenatide:
 Lowered HbA1c 0.8 to 0.9%
 Reduced fasting and postprandial glucose
 Reduced body weight 1.6-2.8 kg
 Similar results in combination with MET and/or SFU
These improved glycaemic effects were sustained over 3 years in
open-label extensions, with progressive body weight reduction
38
Exenatide/Insulin Glargine Comparator Trial: Study
Design
26-week treatment, BID fixed-dose exenatide vs QD insulin glargine
titration
Primary endpoint: Change in HbA1c
Intention-to-treat sample: N = 549 randomised patients with ≥1 postbaseline measurement
Screening (HbA1c >7.0% to <10.0%)
Randomization
Exenatide 5µg
+ MET/SFU
Current
MET/SFU
Therapy
-4
-2
Exenatide 10µg + MET/SFU
Insulin Glargine + MET/SFU
(insulin titrated to target FPG <5.6 mmol/L by daily monitoring)
0
2
4
8
12
Time (week)
18
26
Heine RJ, et al. Ann Intern Med. 2005;143:559-569.
39
Exenatide/Insulin Glargine Comparator Trial: Patient
Baseline Characteristics
Exenatide
Insulin Glargine
55.0%
56.6%
Age (y)
59.8 ± 8.8
58.0 ± 9.5
Body weight (kg)
87.5 ± 16.9
88.3 ± 17.9
BMI (kg/m2)
31.4 ± 4.4
31.3 ± 4.6
Fasting serum glucose
(mmol/L)
10.1 ± 2.6
10.4 ± 2.9
HbA1c (%)
8.2 ± 1.0
8.3 ± 1.0
Duration of diabetes (y)
9.9 ± 6.0
9.2 ± 5.7
Gender, Male (%)
Mean + SD shown.
Heine RJ, et al. Ann Intern Med. 2005;143:559-569.
40
Exenatide/Insulin Glargine Comparator Trial:
Achieved Equivalent Reductions in HbA1c
Exenatide
Insulin Glargine
60
-0.5
-1.0
-1.1%
-1.5
-1.1%
% Patients Achieving
HbA1c ≤ 7%
% Change in HbA1c
0.0
50
46%
48%
40
30
20
10
0
HbA1c <7%
ITT population; Mean ± SE shown.
Heine RJ, et al. Ann Intern Med. 2005;143:559-569.
41
Exenatide/Insulin Glargine Comparator Trial:
Exenatide Reduced Postprandial Glucose Excursions
Insulin Glargine
Exenatide
Blood Glucose
(mmol/L)
14
Baseline
Week 26
14
12
12
10
10
8
8
6
6
Baseline
Week 26
ITT sample; Mean ± SE shown.
Heine RJ, et al. Ann Intern Med. 2005;143:559-569. Reprinted with permission from The American College of Physicians.
42
Exenatide/Insulin Glargine Comparator Trial:
Exenatide Resulted in Progressive Weight Reductions
Exenatide
Insulin Glargine
Change in Body Weight (kg)
3
2
1
0
*
-1
*
*
-2
*
*
-3
0
2
4
8
12
18
*
26
Time (week)
ITT population; Mean ± SE shown; *p<.0001, exenatide vs insulin glargine at same time point.
Heine RJ, et al. Ann Intern Med. 2005;143:559-569. Reprinted with permission from The American College of Physicians.
43
Exenatide vs Sitagliptin MOA Study:
Study Design
♦ Primary endpoint: comparison of the effects of exenatide and
sitagliptin on 2-hour PPG concentrations in patients with T2D
Randomization
Study
Termination
Crossover
Treatment Period 1
Treatment Period 2
Exenatide 5 µg BID Exenatide 10 µg BID
Exenatide 5 µg BID Exenatide 10 µg BID
Sequence A
Placebo Lead-in
Sequence B
Sitagliptin 100 mg QAM
1 week
Standard
Meal Test
Sitagliptin 100 mg QAM
2 weeks
2 weeks
Standard
Meal Test
Standard
Meal Test
MET background; MOA, mechanism of action; QAM, once per day in the morning
DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.
44
75
Baseline
Exenatide
Sitagliptin
75
63.8
50
50
25
25
15.1
7.2
2-h Plasma Exenatide (pM)
2-h Postprandial Plasma GLP-1 (pM)
Postprandial Plasma Levels of Exenatide Exceeded
Physiologic Levels of GLP-1
7.9
0
0
Plasma GLP-1
Plasma Exenatide
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE; 2-wk posttreatment concentration data
Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.
45
Reductions in 2-Hour PPG Were Greater With Exenatide
Than With Sitagliptin
Exenatide
Sitagliptin
270
250
2-hr PPG (mg/dL)
230
210
190
170
150
130
110
Baseline
End of
Period 1
End of
Period 2
After Period 1, patients were switched to the other therapy; Patients with T2D; Evaluable population: exenatide-sitagliptin, n = 29;
sitagliptin-exenatide, n = 32; Mean ± SE
Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.; Data on file, Amylin Pharmaceuticals, Inc.
46
Reductions in PPG Excursions Were Greater With
Exenatide Than With Sitagliptin
Baseline
Exenatide
Sitagliptin
Glucose (mg/dL)
250
230
210
190
*
**
170
Before
After
Breakfast
Before
After
Lunch
Before
After
Dinner
Patients with T2D; 6-point self-monitored blood glucose concentrations
Evaluable population; Baseline: n = 57, mean ± SE; Exenatide and sitagliptin: n = 61, LS mean ± SE; *P = 0.0016; **P = 0.0383
Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.; Data on file, Amylin Pharmaceuticals, Inc.
47
Exenatide Reduced Postprandial Glucagon Levels to a
Greater Extent Than Sitagliptin
Baseline
Exenatide
Sitagliptin
Plasma Glucagon (pg/mL)
120
110
100
90
80
70
-30
0
30
Standard Meal
60
90
120
150
180
210
240
Time (min)
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SE
Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.
48
Exenatide Slowed Gastric Emptying Compared to
Sitagliptin
Baseline
Exenatide
Sitagliptin
Plasma Acetaminophen (ug/ml)
20.0
17.5
15.0
12.5
10.0
7.5
5.0
2.5
0.0
-30
0
30
Standard Meal
60
90
120
150
180
210
240
Time (min)
Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean ± SD; Acetaminophen was administered immediately
before the standard meal
Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.
49
Exenatide vs Sitagliptin MOA Study: Summary
 2-hr PPG concentration was significantly reduced with exenatide
compared with sitagliptin
 Compared with sitagliptin treatment, exenatide treatment led to
 Greater reductions in
 PPG concentrations over time
 Postprandial glucose excursions
 Postprandial glucagon levels
 Improved insulinogenic index
 Delayed gastric emptying
 Decreased caloric intake
 Changes in FPG concentrations were comparable with exenatide and
sitagliptin
 Both exenatide
and sitagliptin were generally well tolerated
DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.
51
Summary of Safety Data:
Exenatide is Generally Well Tolerated
The most common adverse events associated with exenatide are
mild-to-moderate gastrointestinal effects, most common at
initiation of therapy
Exenatide treatment is associated with low rates of
hypoglycaemia
 When co-administered with MET alone, exenatide was not associated
with an increased risk of hypoglycaemia
 When co-administered with an SFU, exenatide was associated with an
increased incidence of hypoglycaemia compared to SFU alone
 Generally manageable by reduction in SFU dose
53
Summary of Clinical Data
Exenatide is a first-in-class incretin mimetic that shares several
glucoregulatory actions with GLP-1:
 Enhances glucose-dependent insulin secretion
 Reduces postprandial glucagon levels
 Slows gastric emptying rate
 Reduces food intake and body weight
 Beta cell effects
In Phase III placebo-controlled trials, exenatide:
 Lowered HbA1c ~1%
 Reduced body weight 4-5 lbs
 Demonstrated sustained effects in extension studies (2-year data)
When compared to insulin, exenatide provides similar HbA1c
improvements, with the potential advantages of tighter postprandial
control and reduced body weight
54
55
International Diabetes Center (IDC) treatment algorithm
for the management of type 2 diabetes center.
56
Overview

Pathophysiology of Tpye 2 DM

Background on incretin hormones

Incretin therapies for T2 DM: Exenatide

Take home message
57
Take home message
In obese type 2 daibetic patients
 If sustained glycemic control is important
 If avoidance of hypoglycemia is important
 If weight loss is important
 If preservation of B-cell function is important
Then………
Exenatide is a good option
59
Thank you
60