1. Incretins: The New Frontier in Diabetes Therapy
Augusto D. Litonjua, M.D., FPCP, FPSEM, FACE
Professor Emeritus
UP College Of Medicine

2. Present Anti-Diabetic Medications
Insulin Secretagogues
Sulfonylureas
Glinides
Insulin Sensitizers
Glitazones
(?) Metformin
Insulin

3. But, is insulin the only hormone involved in Diabetes Mellitus?

4. Islet a-Cell and b-Cell Hormones Regulate Glucose Homeostasis
Islet of Langerhans
a Cells (orange)
b Cells (yellow)
Amyloid Plaques
Type 2 Diabetic Subjects
 cells dysfunction secrete inappropriately high levels of glucagon
Fewer  cells: secrete insufficient levels of insulin
Healthy Subjects
 cells secrete glucagon
 cells secrete insulin
Rhodes CJ Science: 2005: 307:

6. GLUCAGON, the forgotten islet hormone
Does it have a place in Diabetes Mellitus?
Is Type 2 DM a state of insulin deficiency and glucagon over-secretion?

7. Incretins IN In
cret
testinal in
cret
Se ion of In
sulin

8. The Incretin Effect in Healthy Subjects
Oral Glucose Intravenous (IV) Glucose
Plasma Glucose (mg/dL)
C-Peptide (nmol/L)
2.0 *
200
1.5
Not Required
DISCUSSION POINTS:
The increasing plasma glucose resulting from ingestion of 50 g oral glucose (white line in left-side graph) results in an increase of C-peptide (a measure of insulin secretion) (white line in right-side graph).
An isoglycemic intravenous glucose infusion designed to mimic the plasma glucose excursion achieved by the oral glucose load was later administered to the same study patients (orange line in left-side graph). The resulting beta-cell response, measured as C-peptide, is shown on the right-side graph.
Despite the same plasma glucose profiles, there are significant differences in the beta-cell response, as measured by C-peptide.
This difference prompted study into the role of incretins – factors secreted from the intestinal tract, upon the ingestion of food, that enhance the secretion of insulin – that would account for the greater insulin response to oral glucose.
This incretin effect suggested that incretins, and not merely the direct actions of plasma glucose, affect the insulin secretory response.
SLIDE BACKGROUND:
Young healthy subjects (n = 6), given 50 g oral glucose load or isoglycemic intravenous glucose infusion.
Incretins are defined as insulinotropic factors of the gut released by nutrients and stimulating insulin secretion in physiological concentrations in the presence of elevated blood glucose levels ( Creutzfeldt W. Exp Clin Endocrinol Diabetes. 2001;109[Suppl 2]:S288-S303).
Food elicits dynamic changes in insulin secretion, beginning with the cephalic phase, in which anticipation of a meal results in CNS-mediated release of insulin. An early prandial phase, mediated by gut-derived incretin hormones (e.g., GLP-1 and GIP) occurs after food intake but before the ingested nutrients appear in the circulation.
Cleavage of proinsulin generates both insulin and the C-peptide, which are stored together and cosecreted. Therefore, C-peptide serves as a marker for insulin secretion.
Incretin Effect
1.0
100
0.5
0.0 60
120
180 60
120
180
Time (min)
Crossover of Healthy Subjects (n = 6)
Mean ± SE; *P0.05 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:

9. Incretins The major incretins are: GLP-1 (glucagonlike peptide 1)
GIP (glucose-dependent insulinotropic polypeptide)

10. Comparison of the Incretins
Site of Production
GLP L-Cells (Ileum and Colon)
GIP K-Cells (Duodenum and Jejunum)
Decreases secretion in T2DM
Yes No
Inhibits glucagon secretion postprandially
Reduces food intake
Slows gastric emptying
Stimulates b-cell mass/growth
Promotes insulin biosynthesis
Knockout mice (result in IGT)
Adapted from Mayo KE, et al Pharmacol Rev 2003; 55:
Adapted from Drucker DJ Diabetes Care 2003; 26:
Adapted from Nauck M. et al. Diabetologia 1986:29:46-52

11. GLP-1 Is Derived From Proglucagon
Amino acid residue:
GRPP
Glucagon
IP-1
GLP-1
IP-2
GLP-2 1 30 64 69 78
107/8
126
158 33 61 72
111
123
Glicentin
MPGF
Oxyntomodulin
Glucagon
Osyntomodulin
GLP-1
GLP-2
IP-2
Glucagon
MPGF
Intestin Brain
Pancreas
Adapted from Drucker DJ Mol Endocrinol. 2003:17:

12. Glucagonlike Peptide 1 (GLP-1)
30 amino acid peptide
Secreted by L cells, primarily in the ileum and colon
Stimulated by oral ingestion of nutrients
Receptors in the islet cells, CNS, elsewhere
Metabolized by DPP-4
Secretion impaired in type 2 diabetes

13. Glucagonlike Peptide 1 (GLP-1) Actions
Slows gastric emptying
Suppresses glucagon secretion
Enhances glucose-dependent insulin secretion
Enhances b-cell proliferation
Possible improves insulin sensitivity

14. Release and Action of GLP-1
Intestinal GLP-1 Release
Mixed Meal
GLP-1 (7-36) Active
GLP-1 actions that combine to control glycemia:
Inhibits glucagon secretion and hepatic glucose production
Augments glucose induced insulin secretion
Slows gastric emptying
Promotes satiety
Additional characteristics of GLP-1 – based therapies:
Restores b-cell function
Increases insulin biosynthesis
Promotes b-cell differentiation
DPP-4
Rapid inactivation (>80% of pool)
GLP-1 (9-36) Inactive

15. Insulin and GLP-1 Responses to Meals
Insulin (pmol/L)
400
200 40
GLP-1 (pmol/L) 20
9 AM
1 PM
7 PM
10 PM
9 AM
Hours
Orskov C. et al. Scand J Gastroenterol: 1996:31;

16. Incretin Effect in Subjects Without and With Type 2 Diabetes
Intravenous Glucose
Oral Glucose 20 40 60 80
Insulin (mU/L) 30 90
120
150
180
Time (min) *
Control Subjects
(n=8)
Incretin effect 20 40 60 80 30 90
120
150
180
Time (min) *
Patients With Type 2 Diabetes
(n=14)
The Incretin effect is diminished in T2 Diabetes
*P ≤.05 compared with respective value after oral load.
Nauck MA, et al. Diabetologia. 1986;29:46-52.

17. GLP-1 Release Is Reduced in Type 2 Diabetes
Normal Glucose Tolerance Impaired Glucose Tolerance
Type 2 Diabetes
Meal 20 * 15
GLP-1 (pmol/L) 10 5 60
120
180
240
Time (min)
Mean ± SE; N = 102; *P <.05 between T2DM and NGT groups.
Toft-Nielsen M, et al. J Clin Endocrinol Metab. 2001;86:

18. GLP-1 Modulates Numerous Functions in Humans
Promotes satiety and reduces appetite
Alpha cells:
↓ Postprandial glucagon secretion
Liver: ↓ Glucagon reduces hepatic glucose output
Beta-cells: Enhance glucose-dependent insulin secretion
Stomach: Helps regulate gastric emptying
Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes. 1998;47:

19. Can GLP-1 be used in the therapy of Type 2 DM?

20. 6-Week Continuous GLP-1 Infusion Improved Glycaemic Control
HbA1c
8-hour Plasma Glucose Profile 12
450 10
9.2% *
DISCUSSION
GLP-1 lowered fasting plasma glucose and reduced HbA1c.
The GLP-1 group had a reduction in both fasting and postprandial glucose concentrations, starting at Week 1 and persisting through the 6 weeks of the study.
The GLP-1 group also had a statistically significant 14% reduction (P = .003) of HbA1c from Week 0 to Week 6.
BACKGROUND
This study investigated the long-term effects of continuous GLP-1 administration.
20 patients (n=10 placebo; n=10 GLP-1) with type 2 diabetes received a 6-week continuous infusion via insulin pump.
This placebo-controlled proof of concept study demonstrated that GLP-1 administration via continuous subcutaneous infusion had effects on glycaemic control, body weight, insulin resistance, and -cell function in a group of patients with type 2 diabetes.
Several assessments were performed at baseline, Week 1, and Week 6 including:
HbA1c and fructosamine
-cell function (using hyperglycaemic clamps)
Meal tolerance (tests of 8-hour glucose, insulin, C-peptide, glucagon, and free fatty acid profiles)
Appetite and side-effect ratings during the meal tolerance tests
Peripheral insulin sensitivity (using euglycaemic hyperinsulinaemic clamps)
7.9%
360 8
270
Mean (SE) Glucose Concentration in Plasma (mg/dL) 6
Mean (SE) HbA1c (%)
180 4 90 2 1 2 3 4 5 6 7 8
Week 0
Week 6
Time (hour)
Mean ± SE; N = 20; Only data of patients treated with GLP-1 shown; *P = .003.
Zander M, et al. Lancet. 2002;359:

21. GLP-1 Enhanced First Phase Insulin Response in Patients With Type 2 Diabetes
DISCUSSION
Prolonged (3-hour) GLP-1 infusion enhanced first phase insulin response in subjects with and without type 2 diabetes.
First phase insulin release was not significantly increased by acute administration of GLP-1 alone.
BACKGROUND
The objective of this study was to determine the effects of acute vs prolonged GLP-1 infusion on insulin response.
First phase insulin release (first 10 minutes after glucose challenge) was reduced in subjects with type 2 diabetes.
This slide summarises the measured effects of GLP-1 on insulin release in patients with type 2 diabetes or nondiabetic controls.
Each subject underwent three 60-minute intravenous glucose tolerance test (IVGTT) protocols, administered on separate mornings: 1) IVGTT with saline control infusion; 2) GLP-1 acute IV infusion starting 1-2 minutes before IVGTT and continuing through the IVGTT; 3) GLP-1 IV infusion starting 3 hours before, and continuing through, the IVGTT.
Nine patients with type 2 diabetes were studied: mean 57 years; average body mass index (BMI) = 31; mean duration of diabetes = 8 years; HbA1c range = 6.7% - 8.5%. They were compared with 9 matched (similar age and weight) controls.
Mean ± SE; N = 18; P <.05 prolonged infusion; P = .33 acute infusion; *Note the different scale for insulin data used.
Quddusi S, et al. Diabetes Care. 2003;26:

22. 6-Week Continuous GLP-1 Infusion Improved β-Cell Function
Patients With Type 2 Diabetes
Week 6
P = .006
In the GLP-1 group, insulin sensitivity increased by 77% (P = .002)
700
600
DISCUSSION
This study demonstrated that GLP-1 improved -cell function, as measured by C-peptide, in type 2 diabetes patients over the course of 6 weeks.
GLP-1-treated patients exhibited a robust C-peptide response at Week 6.
The placebo group showed little change in C-peptide concentrations after 6 weeks.
BACKGROUND
This study investigated the long-term effects of continuous GLP-1 administration.
20 patients (n=10 placebo; n=10 GLP-1) with type 2 diabetes received a 6-week continuous infusion via insulin pump.
This placebo-controlled proof of concept study demonstrated that GLP-1 administration via continuous subcutaneous infusion had effects on glycaemic control, body weight, insulin resistance, and -cell function in a group of patients with type 2 diabetes.
Several assessments were performed at baseline, Week 1, and Week 6 including:
HbA1c and fructosamine
-cell function (using hyperglycaemic clamps)
Meal tolerance (tests of 8-hour glucose, insulin, C-peptide, glucagon, and free fatty acid profiles)
Appetite and side-effect ratings during the meal tolerance tests
Peripheral insulin sensitivity (using euglycaemic hyperinsulinaemic clamps)
Immunoassay of C-peptide was used to assess pancreatic -cell secretory function in patients with type 2 diabetes.
500
400
C-peptide (pmol/L)
300
200
100
GLP-1 Group
Saline Group
Mean ± SE; N = 19; difference in change values between groups P = .02.
Zander M, et al. Lancet. 2002;359:

23. GLP-1 Subcutaneous Injection Slowed Gastric Emptying in Type 2 Diabetes
Mean ± SEM; N = 7; *P <.0001.
Nauck MA, et al. Diabetologia. 1996;39:

24. 6-Week Continuous GLP-1 Infusion Increases Satiety and Reduces Food Intake
Mean ± SE; N = 10; Only data of patients treated with GLP-1 shown.
*P <.05 for Week 0 vs Week 6; †P <.05 for Week 0 vs Week 1.
Adapted from Zander M, et al. Lancet. 2002;359:

25. 6-Week Continuous GLP-1 Infusion Reduced Mean Body Weight
Mean ± SE; N = 20; Change between GLP-1 and saline groups not significant (P = .13).
Zander M, et al. Lancet. 2002;359:

26. GLP-1 Exerts Multiple Actions in Patients With Type 2 Diabetes
Administration of GLP-1 to patients with type 2 diabetes has been associated with:
Reduced fasting hyperglycaemia
Normalised postprandial glucose excursions
Suppression of inappropriately high glucagon secretion
Improved β-cell responsiveness and maximal insulin secretory capacity
Reduced food intake and weight loss
Significant reductions in HbA1c (6-week continuous infusion)
Drucker DJ. Diabetes Care. 2003;26: ; Zander M, et al. Lancet. 2002;359:

27. Rapid Degradation of GLP-1 by DPP-IV Limits its Duration of Action
Mean ± SEM;N = 4-7 (rats); P <.05.
Adapted from Parkes D, et al. Drug Dev Res. 2001;53: ; Eng J, et al. J Biol Chem. 1992;267:

28. The Therapeutic Potential of GLP-1 Is Limited by Its Rapid Inactivation
Rapid inactivation (DPP-IV),
Short elimination half-life (~1-2 min)
GLP-1 must be administered continuously (infusion)
Inconvenient for treating a chronic disease like type 2 diabetes
Drucker DJ, et al. Diabetes Care. 2003;26:

29. So, what is the next step?

30. Development of Exenatide: An Incretin Mimetic
Exenatide (Exendin-4)
Synthetic version of salivary protein found in the Gila monster
Approximately 50% identity with human GLP-1
Binds to known human GLP-1 receptors on  cells in vitro
Resistant to DPP-IV inactivation
Exenatide
H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S – NH2
GLP-1
Human
H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R – NH2
Site of DPP-IV Inactivation
Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88.; Fineman MS, et al. Diabetes Care. 2003;26:
Reprinted from Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes, 77-88, Copyright 2004, with permission from Elsevier.

31. Current GLP-1-based Approaches for Improving Glycaemic Control
Agents that mimic the actions of GLP-1 (incretin mimetics)
DPP-IV–resistant GLP-1 derivatives
GLP-1 analogues, albumin-bound GLP-1
Novel peptides that mimic the glucoregulatory actions of GLP-1
Exenatide
Agents that prolong the activity of endogenous GLP-1
DPP-IV inhibitors
Drucker DJ, et al. Diabetes Care. 2003;26: ; Baggio LL, et al. Diabetes. 2004;53:

32. Now available!

33. Does Exenatide work?

35. BYETTA Restored First-Phase Insulin Response

36. BYETTA Sustained A1C Reductions at 2 Years
8.5
Open-Label Extension
Mean Baseline A1C
8.0
10 mcg BYETTA BID
8.3%
REQUIRED
DISCUSSION POINTS:
Shown is 104-week data for 283 patients, combined from Cohorts 1 and 2, who had received 2 years of exposure to BYETTA
Cohort 1: Patients who received BYETTA (not placebo) in the 30-week placebo-controlled trials continued BYETTA treatment throughout participation in the open-label extension trials and subsequent long-term maintenance trial
Therefore, Cohort 1 completed 104 weeks of BYETTA exposure at study Week 104
Cohort 2: Patients who received placebo in the placebo-controlled trials, then received BYETTA treatment from Week 30, the start of the open-label extension trials, and continued in the subsequent long-term maintenance trial
Therefore, Cohort 2 completed 104 weeks of BYETTA exposure at study Week 134
Mean A1C change from baseline was sustained and it was –1.1% ± 0.1% (95% Confidence Interval [CI]: –1.3 to –1.0%, P<0.05) at 2 years
50% of subjects completing 2 years of BYETTA treatment achieved A1C ≤7%
31% of subjects completing 2 years of BYETTA treatment achieved A1C ≤6.5%
Reduction in A1C from baseline in the 2-year, eligible ITT population was –0.8 ± 0.1%
Adverse events were similar to those observed in 30- and 82-week data
SLIDE BACKGROUND:
Sustained reduction in fasting plasma glucose (FPG) concentration after 2 years of –25 ± 3 mg/dL (95% CI: –30.8 to –19.7 mg/dL, P<0.05)
Patients with T2DM treated with MET and/or SFU were randomized to receive placebo or BYETTA in the original placebo-controlled, double-blind, Phase 3, randomized trials and received BYETTA in the subsequent open-label extensions
Of the 1446 patients who entered the 30-week placebo-controlled trials, 1125 (78%) completed the trials; reasons for withdrawal included
Withdrawal of consent (6.5%)
Adverse event (5.9%)
Loss of glucose control (4.1%)
Of the 974 patients who entered the open-label extensions, 521 enrolled such that they could achieve 2 years of BYETTA treatment by the time of this analysis; these 521 patients are designated the 2-year eligible ITT population
Of the 2-year eligible ITT population (N = 521), 283 (54%) completed 2 years of BYETTA (2-year completers); reasons for withdrawal during the open-label extension included
Withdrawal of consent (15%)
Adverse event (9%)
Loss of glucose control (3%)
Other (18%) including investigator decision, protocol violation, administrative reason, missing, lost to follow-up
7.5
Mean  A1C (%)
Mean  A1C at 2 y
-1.1 ± 0.1%
7.0
6.5 10 20 30 40 50 60 70 80 90
100
110
Time (wk)
N = 283; Mean (± SE); P<0.05.
Buse JB, et. al, Clin Ther. 2007;29:

37. BYETTA Continued to Reduce Weight at Two Years-2
Baseline Weight
10 mcg BYETTA BID
220 lbs -4
Mean  Weight (lbs) -6 -8
Mean  Weight at 2 y
-10.4 ± 0.8 lbs
REQUIRED
DISCUSSION POINTS:
Shown is 104-week data for 283 patients, combined from Cohorts 1 and 2, who had received 2 years of exposure to BYETTA
Cohort 1: Patients who received BYETTA (not placebo) in the 30-week placebo-controlled trials continued BYETTA treatment throughout participation in the open-label extension trials and subsequent long-term maintenance trial
Therefore, Cohort 1 completed 104 weeks of BYETTA exposure at study Week 104
Cohort 2: Patients who received placebo in the placebo-controlled trials, then received BYETTA treatment from Week 30, the start of the open-label extension trials, and continued in the subsequent long-term maintenance trial
Therefore, Cohort 2 completed 104 weeks of BYETTA exposure at study Week 134
BYETTA treatment resulted in progressive reductions in body weight of –5.3 lbs at 30 weeks and –10.4 ± 0.8 lbs (mean ± SE, 95% CI: –11.9 to –8.8 lbs, P <0.05 from baseline) at 2 years
Reduction in body weight from baseline in the 2-year, eligible ITT population was -7.9 ± 0.4 lbs
Adverse events were similar to those observed in 30- and 82-week data
In a previous slide set, data were presented for 195 patients who were from Cohort 1 only; the mean reduction in body weight for those 195 patients was –11.5 lbs at study Week 104; therefore, in the current data presented for 283 subjects, combined from 2 different study Cohorts (1 and 2), the mean reduction in body weight at study Week 104 was –10.4 ± lbs
SLIDE BACKGROUND:
Patients with T2DM treated with MET and/or SFU were randomized to receive placebo or BYETTA in the original placebo-controlled, double-blind, Phase 3, randomized trials and received BYETTA in the subsequent open-label extensions
Of the 1446 patients who entered the 30-week placebo-controlled trials, 1125 (78%) completed the trials; reasons for withdrawal included
Withdrawal of consent (6.5%)
Adverse event (5.9%)
Loss of glucose control (4.1%)
Of the 974 patients who entered the open-label extensions, 521 enrolled such that they could achieve 2 years of BYETTA treatment by the time of this analysis; these 521 patients are designated the 2-year eligible ITT population
Of the 2-year eligible ITT population (N=521), 283 (54%) completed 2 years of BYETTA (2-year completers); reasons for withdrawal during the open-label extension included
Withdrawal of consent (15%)
Adverse event (9%)
Loss of glucose control (3%)
Other (18%) including investigator decision, protocol violation, administrative reason, missing, lost to follow-up
Patients were not required to follow any specified diet or exercise plan
-10
-12 10 20 30 40 50 60 70 80 90
100
110
Time (wk)
No diet and exercise regimen was provided; N = 283; Mean (± SE); P<0.05.
Henry R, et al. Diabetes 2006; 55:A116.

38. BYETTA Reduced A1c MET SFU MET + SFU n Baseline 8.2 8.3 8.2
0.5
0.2
A1C
(%)
0.1
0.1
-0.5 * *
-0.9
-0.6 * *
-0.8
-0.5
-0.4 *
- 0.8
REQUIRED
DISCUSSION POINTS:
Significant A1C reductions were seen with the 5-mcg and 10-mcg BYETTA treatment arms in all three studies (P<0.005 vs placebo).
The A1C lowering in the 10-mcg arm was greater than in the 5-mcg arm (P<0.05).
Baseline A1C: placebo group = 8.5%; 5-mcg BYETTA BID treatment arm = 8.4%; 10-mcg BYETTA BID treatment arm = 8.5%.
BYETTA is associated with reduced A1C no matter the background oral therapy (MET and/or SFU), and disease duration (SFU + MET study patients had longer disease duration).
SLIDE BACKGROUND:
Three 30-week, placebo-controlled, double-blind, Phase 3 studies; subjects with type 2 diabetes randomized to placebo or 5 mcg or 10 mcg BYETTA BID with MET and/or SFU, N = 1446.
Combined pivotals: MET, SFU, MET + SFU; 30-week, double-blind, Phase 3 studies; ITT subjects with type 2 diabetes were randomized to placebo (n = 483), 5 mcg BYETTA BID (n = 480) or 10 mcg BYETTA BID (n = 483). The Last Observation Carried Forward (LOCF) method was applied to the data.
Individual pivotals:
MET (placebo [n = 113 and baseline A1C = 8.2], 5 mcg BYETTA BID [n = 110 and baseline A1C = 8.3], 10 mcg BYETTA BID [n = 113 and baseline A1C=8.2])
SFU (placebo [n = 123 and baseline A1C = 8.7], 5 mcg BYETTA BID [n = 125 and baseline A1C = 8.5], 10 mcg BYETTA BID [n = 129 and baseline A1C = 8.6])
MET + SFU (placebo [n = 247 and baseline A1C = 8.5], 5 mcg BYETTA BID [n = 245 and baseline A1C = 8.5], 10 mcg BYETTA BID [n = 241 and baseline A1C=8.5]) -1 * n
Baseline
Placebo BID
BYETTA 5 mcg BID
BYETTA 10 mcg BID
Mean ± SE; *P<0.005 Data from DeFronzo RA, et al. Diabetes Care. 2005;28: Data from Buse JB, et al. Diabetes Care. 2004;27: Data from Kendall DM, et al. Diabetes Care. 2005;28:

39. BYETTA: Proportion of Patients Achieving A1C < 7%
Placebo BID
BYETTA 5 mcg BID
BYETTA 10 mcg BID
% Achieving A1C ≤7%
MET (N = 240)
MET + SFU (N = 550)
SFU (N = 234) 60 * % 46 * 41 * * 40 * 34 32 33 * 27 20 13 9 9
30-wk data; Mean; *P<0.01 Data from DeFronzo RA, et al. Diabetes Care. 2005;28: Data from Buse JB, et al. Diabetes Care. 2004;27: Data from Kendall DM, et al. Diabetes Care. 2005;28:

40. Exenatide Reduced Weight: Phase 3 Clinical Studies
Placebo
5 mg Exenatide BID
10 mg Exenatide BID
MET
SFU
MET + SFU
ITT 30-wk data; N=1446; Mean (SE); *P < .05; Weight was a secondary endpoint
DeFronzo R.A. et al. Diabetes Care. 2005:28:
Buse JB, et al. Diabetes Care 2004:27;
Kendall DM, et al. Diabetes Care. 2005; 28:

41. Nausea: Phase 3 Clinical Studies - Combined
Most episodes mild to moderate in intensity
Episodes were generally
Intermittent
More frequent at initiation of treatment
Decreased over time
Low incidence of severe nausea (placebo 1%, exenatide 4%
Low dropout rate due to nausea (placebo < 1%, exenatide 3%)
ITT 30-wk data; N = 1446
Exenatide Prescribing Information, 2005

42. Inadequate Glycemic Control Loss of b cells function
Weight Gain
Loss of b cells function

43. Current GLP-1-based Approaches for Improving Glycaemic Control
Agents that mimic the actions of GLP-1 (incretin mimetics)
DPP-IV–resistant GLP-1 derivatives
GLP-1 analogues, albumin-bound GLP-1
Novel peptides that mimic the glucoregulatory actions of GLP-1
Exenatide
Agents that prolong the activity of endogenous GLP-1
DPP-IV inhibitors
Drucker DJ, et al. Diabetes Care. 2003;26: ; Baggio LL, et al. Diabetes. 2004;53:

44. Thank you