993-P: A 12-Week, Randomized, Placebo-Controlled Study Assessing the Efficacy and Safety of Three Dose-Escalation Algorithms of Tirzepatide, a Novel Dual GIP and GLP-1 Receptor Agonist, in Patients with Type 2 Diabetes (2019)

Initiating incretin hormone receptor agonist therapy at a low dose with gradual dose escalation may improve gastrointestinal (GI) tolerability. This randomized, double-blind, placebo-controlled study assessed the efficacy and tolerability of tirzepatide, using 3 different dose escalation algorithms in patients with type 2 diabetes compared with placebo after 12 weeks. The dose-escalations included 1 algorithm to achieve 12 mg top dose by the scheme of 4 mg and 8 mg, each for 4 weeks. The scheme for the first 15 mg top dose group (15 mg-1) was 2.5 mg for 2 weeks, followed by 5 mg for 2 weeks, and then 10 mg for 4 weeks. The scheme for the second 15 mg top dose group (15 mg-2) was 2.5 mg followed by 7.5 mg, each for 4 weeks. A total of 111 subjects were randomized. Mean age was 57.4 years, HbA1c was 8.4%, and BMI was 31.9 kg/m2. At Week 12, LS mean HbA1c% (SE) was 8.6 (0.21), 6.7 (0.19), 6.3 (0.20), 6.6 (0.19) in the placebo, 12 mg, 15 mg-1 and 15 mg-2 groups, respectively. Change from baseline (SE) in HbA1c was greater in tirzepatide groups compared with placebo (placebo, +0.2% [0.21]; 12 mg, -1.7% [0.19]; 15 mg-1, -2.0% [0.20]; 15 mg-2, -1.8% [0.19]). Weight loss was greater in tirzepatide groups compared with placebo (placebo, -0.5 kg [0.86]; 12 mg, -5.3 kg [0.78]; 15 mg-1, -5.5 kg [0.80] and 15 mg-2, -5.7 kg [0.79]). The total incidence of nausea, vomiting and/or diarrhea was 11.5% with placebo, and 48.3%, 57.1% and 46.4% with tirzepatide 12 mg, 15 mg-1, and 15 mg-2 groups, respectively. GI AEs were mild to moderate in intensity. Tirzepatide resulted in clinically meaningful improvements in glycemic control and weight loss. A lower starting dose and a longer dose-escalation period resulted in lower incidence of GI AEs than in a previously published Phase 2 study. Disclosure J.P. Frias: Advisory Panel; Self; Becton, Dickinson and Company, Eli Lilly and Company, Gilead Sciences, Inc., Sanofi. Consultant; Self; Echosens, Genentech, Inc., Johnson &amp; Johnson Diabetes Institute, Novo Nordisk Inc., Zafgen, Inc. Research Support; Self; AbbVie Inc., Akcea Therapeutics, Allergan, Amgen Inc., AstraZeneca, Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Cirius Therapeutics, Elcelyx Therapeutics, Inc., Eli Lilly and Company, Enanta Pharmaceuticals, Inc., GENFIT, Intarcia Therapeutics, Inc., Intercept Pharmaceuticals, Inc., Ionis Pharmaceuticals, Inc., Janssen Pharmaceuticals, Inc., Merck &amp; Co., Inc., NGM Biopharmaceuticals, Novartis Pharmaceuticals Corporation, Novo Nordisk A/S, Oramed Pharmaceuticals, Pfizer Inc., Sanofi, TaiwanJ Pharmaceuticals Co., Ltd., Theracos, Inc. Speaker's Bureau; Self; Merck &amp; Co., Inc., Sanofi. M.A. Nauck: Advisory Panel; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Research Support; Self; AstraZeneca, Eli Lilly and Company, GlaxoSmithKline plc., Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S. Speaker's Bureau; Self; AstraZeneca, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sun Pharma. J. Van: Research Support; Self; Eli Lilly and Company, Genentech, Inc., Melior, Merck &amp; Co., Inc., Mylan, Oramed Pharmaceuticals, Sanofi. C. Benson: Employee; Self; Eli Lilly and Company. R. Bray: Employee; Self; Eli Lilly and Company. Z. Milicevic: Employee; Self; Eli Lilly and Company. A. Haupt: Employee; Self; Lilly Diabetes. Stock/Shareholder; Self; Lilly Diabetes. D.A. Robins: Employee; Self; Eli Lilly and Company. Funding Eli Lilly and Company