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Pathophysiology in the Treatment of Type 2 Diabetes Newer Agents Part 4 of 5 Exenatide – Exendin-4, isolated from Gila monster saliva, shares 53% of its amino acid identity with GLP-11 • Exenatide is a synthetic version of exendin-41 – In in vitro assays, exendin-4 and GLP-1 have equivalent binding affinities for the GLP-1 receptor2-4 – In in vitro studies, the degree of GLP-1 receptor activation by exenatide is at least equivalent to that of native GLP-15,6 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 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 Exenatide: Change in A1c and Weight (vs Placebo) Exenatide 10 μg bid Add on to: Duration 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. Exenatide Lowered PPG and FPG Concentrations in Large Phase 3 Clinical Studies: Combined Data Placebo 250 200 150 Difference From Placebo: -75 to -80 mg/dL * 100 -30 0 30 60 90 120 150 180 Exenatide 10 µg BID 20 Exenatide or Placebo Meal Δ FPG From Baseline (mg/dL) Plasma Glucose (mg/dL) 300 Exenatide 5 µg BID 10 0 -10 -20 * Difference From Placebo: † -20 to -23 mg/dL * * Time (min) 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 3-Year Completers: A1c and Weight PBO-Controlled 1 9 0 -1 -1.1 ±0.1% A1C (%) 8 -1.0 ±0.1% -2 -3 7 -4 6 -5.3 ±0.4 kg 5 -5 (Baseline Weight = 99 kg) A1C Weight Change in body weight (kg) (Baseline A1C = 8.2%) 10 Open-Label Uncontrolled -6 54 4 0 26 46 % Achieving A1C ≤ 7% 52 78 104 130 156 Time (wk) N = 217; Mean (- SE); P < 0.0001 from baseline to 30 weeks and baseline to 3 years. No diet and exercise regimen was provided. Klonoff DC, et al. Current Medical Research and Opinion. 2008;24:275–286. -7 Changes in Glycemia and Weight in 3 Head-to-Head Studies Exenatide vs. Insulin Added by Dr S EXENATIDE AND NO undue HYPOglycemia 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. Relative differencessitagliptin vs exenatide Exenatide: Adverse Events • ~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 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) Pancreatitis Occurrence 0.13% of exenatide-treated patients EXN (n = 27,996) vs 0.12% of sitagliptin-treated patients MET or GLY (n = 27,983) SITA (n = 16,267) vs MET or GLY (n = 16,281) 0.0 0.5 1.0 1.5 2.0 Relative Risk (95% confidence interval) Dore DD, et al. Curr Med Res Opin. 2009;25:1019-1027. 2.5 Exenatide, DPP-4 Inhibitors and Long-Acting GLP-1 Agonists: Similarities and Differences Dr G – Needs to be redesigned/edited if kept Properties/Effect Glucose-dependent secretion insulin Glucose-dependent glucagon Slows gastric emptying Effect on body weight Effect on A1c Effect on fasting glucose Effect on postprandial glucose Effect on CVD risk factors Side effects Administration Exenatide1 DPP-4 Inhibitor1 Liraglutide, Exenatide-OW2,3 Yes Yes Yes Yes Yes Yes Yes No Little or no Weight loss Weight neutral Weight loss ~1% <1% >1% Modest Modest Good Good Improve (with weight loss) Modest No consistent change Modest Nausea (?pancreatitis, CRF) ~ None observed (pancreatitis) Less nausea, skin, (?pancreatitis, ?CRF, ?MTC) 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. Improve