GLP1 Effectiveness Mechanisms of Action and Potential Part

GLP-1 Effectiveness, Mechanisms of Action and Potential Part 2

Plasma Exenatide Levels in Treated Subjects With Type 2 Diabetes 800 Plasma Exenatide (pg/m. L) 0. 1 µg/kg 700 0. 2 µg/kg 600 0. 3 µg/kg 0. 4 µg/kg 500 400 1 pg/m. L = 0. 239 p. M 300 Five-fold higher than normal postprandial levels of intact GLP-1 200 100 0 0 2. 5 5 7. 5 10 Time (hours after dose) Data on file, Amylin Pharmaceuticals, Inc. 12. 5 15 17. 5

Combined Exenatide Pivotal Studies : Effect on Postprandial Glucose Results of 30 -Week Exenatide Pivotal Studies Week 30 Baseline 300 Placebo Study Medication Meal 250 Glucose (mg/d. L) Placebo (N = 44) 5 µg BID (N = 42) 10 µg BID (N = 52) 200 150 100 250 200 150 100 -30 0 30 60 90 120 150 180 Time (min) Mean ± SE Evaluable Meal Tolerance Cohort Data on file, Amylin Pharmaceuticals, Inc. -30 0 30 60 90 120 150 180 Time (min)

Acute Exenatide Infusion Restored First-Phase Insulin Response Healthy Subjects, Placebo Insulin Secretion (pmol • kg-1 • min-1) 30 Type 2 Diabetes, Placebo 25 Type 2 Diabetes, Exenatide 20 15 10 5 0 – 180 0 10 20 30 60 90 120 Time (min) First- (0 -10 min) and second- (10 -120 min) phase insulin increased in exenatide-treated patients compared with placebo-treated T 2 DM, P <. 0002. Second-phase insulin increased in exenatide-treated patients compared with healthy controls, P <. 0029. Values are mean (SE). N = 25. Fehse F, et al. J Clin Endocrinol Metab. 2005; 90: 5991 -5997.

Vildagliptin increases post-meal intact GLP-1 to the upper normal range 16. 0 Meal Placebo (n=16) * Vildagliptin 100 mg (n=16) Active GLP-1 (pmol/L) * * 12. 0 * * *P <0. 05 ** 8. 0 * * * 4. 0 0. 0 17: 00 20: 00 23: 00 02: 00 Time Balas B, et al. J Clin Endocrinol Metab. 2007; 92: 1249 -1255. 05: 00 08: 00

Sitagliptin Reduced Glucose AUC After a Glucose Load *GLP-1 R Agonists Produce More Potent Postprandial Glucose Control Due to Increased Levels of GLP-1 -like Activity and Inhibition of Gastric Emptying Placebo 320 Sitagliptin 25 mg Plasma Glucose (mg/d. L) 280 Glucose load Drug administered Sitagliptin 200 mg 240 200 160 Dosing at t=0 120 0 1 2 N=55 Adapted from Herman, et al. J Clin End Met. 2006; 91: 4612. 3 Time (hours) 4 5 6

Sitagliptin Improved β-Cell Responsiveness to Glucose Monotherapy Studies Pooled monotherapy studies – subset of patients with frequently sampled MTT Model-based assessment of β-cell function Placebo 1400 P<0. 05 for difference in change from baseline Baseline (dashed) 1200 50 End-treatment period 1000 40 Φs (10 -9/min) Insulin Secretion (pmol/min) Sitagliptin 100 mg 800 600 30 20 400 10 200 0 160 180 200 220 240 260 Glucose concentration (mg/d. L) Φs = static component, describes relationship between glucose concentration and insulin secretion Xu L, et al. Diabetologia. 2006; 49(Suppl 1): 653. Placebo Sita 100 mg

The Actions of DPP-4 Inhibitors and GLP-1 R Agonists in Regulating Glucose Homeostasis GLP-1 R–dependent actions GLP-1 R Agonists Physiological Pharmacological Satiety & Weight Loss Gastric Emptying DPP- 4 i Insulin Secretion Glucagon Secretion Progressive GLP-1 R activation http: //www. glucagon. com/dp_iv_and_diabetes. htm.

Comparative effects of GLP-1 r agonists and DPP-IV inhibitors on Hb. A 1 c GLP-1 r agonists 0. 95% DPP-IV inhibitors 0. 80% Amori RE et al, JAMA, 2007

Comparative effects of GLP-1 r agonists and DPP-IV inhibitors on Hb. A 1 c GLP-1 r agonists DPP-IV inhibitors 0. 95% 0. 80% GLP-1 r activity 120 pm 25 p. M Amori RE et al, JAMA, 2007