Efficacy, safety, and mechanistic insights of cotadutide a dual receptor glucagon-like peptide-1 and glucagon agonist.

Abstract

CONTEXT\nCotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 (GLP-1) and glucagon activity.\n\n\nOBJECTIVE\nTo evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects.\n\n\nDESIGN/SETTING\nRandomized, double-blind, phase 2a study conducted in two cohorts at five clinical trial sites.\n\n\nPATIENTS\n65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.\n\n\nINTERVENTION\nOnce-daily subcutaneous cotadutide or placebo for 49 days. Doses (50-300 µg) were uptitrated weekly (cohort 1) or biweekly (cohort 2).\n\n\nMAIN OUTCOME MEASURES\nCoprimary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose AUC0-4h post-mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2).\n\n\nRESULTS\nPatients received cotadutide (cohort 1, n=26; cohort 2, n=20) or placebo (cohort 1, n=13; cohort 2, n=6). Significant reductions were observed with cotadutide vs placebo in glucose AUC0-4h post MMTT (LS mean [90% CI]: -21.52% [-25.68, -17.37] vs 6.32% [0.45, 12.20]; P<0.001) and body weight (-3.41% [-4.37, -2.44] vs -0.08% [-1.45, 1.28]; P=0.002). A significant increase in insulin AUC0-4h post MMTT was observed with cotadutide (19.3 mU.h/L [5.9, 32.6]; P=0.008) and GET was prolonged on day 43 with cotadutide vs placebo (t½: 117.2 minutes vs -42.9 minutes; P=0.0392).\n\n\nCONCLUSION\nThese results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.