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

µg/kg 0.2 µg/kg 0.3 µg/kg 0.4 µg/kg Time (hours after dose) Plasma Exenatide (pg/mL) 1 pg/mL = pM Five-fold higher than normal postprandial levels of intact GLP-1 Plasma Exenatide Levels in Treated Subjects With Type 2 Diabetes Data on file, Amylin Pharmaceuticals, Inc.

Combined Exenatide Pivotal Studies : Effect on Postprandial Glucose Time (min) Baseline Glucose (mg/dL) Week Glucose (mg/dL) Meal Placebo Meal Study Medication Placebo (N = 44) 5 µg BID (N = 42) 10 µg BID (N = 52) Data on file, Amylin Pharmaceuticals, Inc. Mean ± SE Evaluable Meal Tolerance Cohort Results of 30-Week Exenatide Pivotal Studies

Acute Exenatide Infusion Restored First-Phase Insulin Response Fehse F, et al. J Clin Endocrinol Metab. 2005;90: First - (0-10 min) and second - ( min) phase insulin increased in exenatide-treated patients compared with placebo-treated T2DM, P < Second-phase insulin increased in exenatide-treated patients compared with healthy controls, P < Values are mean (SE). N = 25. Type 2 Diabetes, Placebo Type 2 Diabetes, Exenatide Healthy Subjects, Placebo Time (min)Insulin Secretion (pmol kg -1 min -1 ) –

Meal Placebo (n=16) Balas B, et al. J Clin Endocrinol Metab. 2007; 92: *P < :0020:0023:0002:0005:0008:00 Time Active GLP-1 (pmol/L) * * * * * * * * * * * * * Vildagliptin 100 mg (n=16) Meal Vildagliptin increases post-meal intact GLP-1 to the upper normal range

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

Sitagliptin Improved β-Cell Responsiveness to Glucose Monotherapy Studies Φs (10-9/min) P<0.05 for difference in change from baseline PlaceboSita 100 mg Placebo Sitagliptin 100 mg Baseline (dashed) End-treatment period Glucose concentration (mg/dL) Insulin Secretion (pmol/min) Pooled monotherapy studies – subset of patients with frequently sampled MTT Model-based assessment of β-cell function Φs = static component, describes relationship between glucose concentration and insulin secretion Xu L, et al. Diabetologia. 2006;49(Suppl1):653.

Insulin Secretion Glucagon Secretion Progressive GLP-1R activation Physiological GLP-1R–dependent actions DPP- 4i Gastric Emptying Satiety & Weight Loss Satiety & Weight Loss Pharmacological GLP-1R Agonists The Actions of DPP-4 Inhibitors and GLP-1R Agonists in Regulating Glucose Homeostasis

Comparative effects of GLP-1r agonists and DPP-IV inhibitors on HbA1c GLP-1r agonists Amori RE et al, JAMA, 2007 DPP-IV inhibitors 0.95% 0.80%

Comparative effects of GLP-1r agonists and DPP-IV inhibitors on HbA1c GLP-1r agonists Amori RE et al, JAMA, 2007 DPP-IV inhibitors 0.95% 0.80% GLP-1r activity 120 pm 25 pM