1. Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 4 of 5

2. Exenatide – Exendin-4, isolated from Gila monster saliva, shares 53% of its amino acid identity with GLP-1 1 Exenatide is a synthetic version of exendin-4 1 – In in vitro assays, exendin-4 and GLP-1 have equivalent binding affinities for the GLP-1 receptor 2-4 – In in vitro studies, the degree of GLP ‑ 1 receptor activation by exenatide is at least equivalent to that of native GLP-1 5,6 1. Nielsen LL, et al. Regul Pept. 2004;117:77-88; 2. Raufman JP. Regul Pept. 1996;61:1-18 3. Fehmann HC, et al. Peptides. 1994;15:453-456; 4. Thorens B, et al. Diabetes. 1993;42:1678-1682 5. Parkes D, et al. Drug Dev Res. 2001;53:260-267; 6. Göke R, et al. J Biol Chem. 1993;268:19650-19655

3. Exenatide –Mono or Adjunctive therapy, depended on patient’s needs or desires (not approved for combination with insulin) –BID subcutaneous –Start 5 mcg injected 0-60 minutes before am and pm meal for 1 month (decreased risk nausea if take with first bite) –Or, dose with two largest meals* –Decrease nausea risk by advising patient to stop eating when full –Increase to 10 mcg as needed, and then tolerated with first bite Don’t use if creatinine clearance < 30 ml/min Don’t use in gastroparesis or GI motility disorders

4. Exenatide: Change in A1c and Weight (vs Placebo) Add on to:Duration Exenatide 10 μg bid A1C Change in % (baseline) Weight change in kg (baseline) Monotherapy 24 weeks-0.7 (7.8)-1.5 (86.2) Metformin 30 weeks-0.9 (8.2) -2.4 (100.9) Sulfonylurea 30 weeks-1.0 (8.6)-0.9 (95.2) Metformin + sulfonylurea 30 weeks-1.0 (8.5)-0.7 (98.4) Glitazone ± metformin 16 weeks-0.9 (7.9)-1.5 (97.5) Exenatide prescribing information. Amylin Pharmaceuticals Inc; 2009.

5. Exenatide Lowered PPG and FPG Concentrations in Large Phase 3 Clinical Studies: Combined Data 30-wk pivotal studies; Patients with T2D; Evaluable standard meal tolerance test cohorts; Placebo, n = 44 Exenatide 5 µg BID, n = 42; Exenatide 10 µg BID, n = 52; Mean ± SE; * Least squares (LS) mean difference at Wk 30, P<0.0001; ITT population; Placebo, n = 483; Exenatide 5 µg, n = 480; Exenatide 10 µg, n = 483; Mean ± SE; *P<0.0001 vs placebo; † LS mean difference at Wk 30. Data on file, Amylin Pharmaceuticals, Inc. Exenatide or Placebo Meal Difference From Placebo: -75 to -80 mg/dL * Placebo Exenatide 5 µg BID Exenatide 10 µg BID Δ FPG From Baseline (mg/dL) * * Difference From Placebo: -20 to -23 mg/dL *†*† -20 -10 0 10 20

6. Exenatide 3-Year Completers: A 1c and Weight PBO-ControlledOpen-Label Uncontrolled N = 217; Mean (- SE); P < 0.0001 from baseline to 30 weeks and baseline to 3 years. No diet and exercise regimen was provided. 0265278104130156 4 5 6 7 8 9 10 Time (wk) (Baseline A1C = 8.2%) ± 0.1%-1.1 ± 0.1% % Achieving A1C ≤ 7% A1C (%) Klonoff DC, et al. Current Medical Research and Opinion. 2008;24:275–286. -7 -6 -5 -4 -3 -2 0 1 Change in body weight (kg) (Baseline Weight = 99 kg) -5.3 ± 0.4 kg A1C Weight 5446

7. Changes in Glycemia and Weight in 3 Head-to-Head Studies Exenatide vs. Insulin Heine R, et al. Ann Int Med. 2005;143:559-569. Barnett A, et al. Clin Thera. 2007;29(11):2333-2348. Nauck M, et al. Diabetologia. 2007;50(2):259-267. EXENATIDE AND NO undue HYPOglycemia Added by Dr S

8. Relative differences- sitagliptin vs exenatide

9. ~50% experience nausea or other GI events –Early in course, decrease over time –~5% stop therapy due to nausea or vomiting –To minimized – Start low dose bid for 4 weeks, then titrate to 10 μg bid administer exenatide just before meals until well tolerated SU-related hypoglycemia can be increased –  SU dose when initiating therapy with exenatide Antibodies of unclear significance Pancreatitis – rare Renal failure – rare Exenatide: Adverse Events

10. Pancreatitis With Exenatide and Sitagliptin: Large Database Analysis Analysis of data from large US commercial health insurance database Active drug safety surveillance system June 2005 through June 2008 No increased risk for patients treated with exenatide or sitagliptin compared with metformin (MET) or glyburide (GLY) Dore DD, et al. Curr Med Res Opin. 2009;25:1019-1027. 0.00.51.01.52.02.5 Relative Risk (95% confidence interval) EXN (n = 27,996) vs MET or GLY (n = 27,983) SITA (n = 16,267) vs MET or GLY (n = 16,281) Pancreatitis Occurrence 0.13% of exenatide-treated patients 0.12% of sitagliptin-treated patients

11. Exenatide, DPP-4 Inhibitors and Long-Acting GLP-1 Agonists: Similarities and Differences Properties/EffectExenatide 1 DPP-4 Inhibitor 1 Liraglutide, Exenatide-OW 2,3 Glucose-dependent insulin secretion Yes Glucose-dependent glucagonYes Slows gastric emptyingYesNoLittle or no Effect on body weightWeight lossWeight neutralWeight loss Effect on A1c~1%<1%>1% Effect on fasting glucoseModest Good Effect on postprandial glucoseGoodModest Effect on CVD risk factors Improve (with weight loss) No consistent change Improve Side effects Nausea (?pancre- atitis, CRF) ~ None observed (pancreatitis) Less nausea, skin, (?pancreatitis, ?CRF, ?MTC) Administration Subcutaneous Twice daily Oral Once daily Subcutaneous Daily or weekly 1. Amori RE, et al. JAMA. 2007;298:194-206. 2. Exenatide LAR (once weekly): Drucker DJ, et al. Lancet. 2008;372:1240-1250. 3. Liraglutide: Buse JB, et al. Lancet. 2009;374:39-47. Dr G – Needs to be redesigned/edited if kept