Efficacy, Safety, and Mechanistic Insights of Cotadutide, a Dual Receptor Glucagon-Like Peptide-1 and Glucagon Agonist

Context: Cotadutide is a dual receptor agonist with balanced glucagon-like peptide-1 and glucagon activity. Objective: To evaluate different doses of cotadutide and investigate underlying mechanisms for its glucose-lowering effects. Design/setting: Randomized, double-blind, phase 2a study conducted in 2 cohorts at 5 clinical trial sites. Patients: Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs. Intervention: Once-daily subcutaneous cotadutide or placebo for 49 days. Doses (50-300 mu g) were uptitrated weekly (cohort 1) or biweekly (cohort 2). Main outcome measures: Co-primary end points (cohort 1) were percentage changes from baseline to end of treatment in glucose (area under the curve from 0 to 4 hours [AUC(0-4h)]) post-mixed-meal tolerance test (MMTT) and weight. Exploratory measures included postprandial insulin and gastric emptying time (GET; cohort 2). Results: Patients 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 AUC(0-4h) post MMTT (least squares 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 AUC(0-4h) 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 (t(1/2) : 117.2 minutes vs -42.9 minutes; P = 0.0392). Conclusion: These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying.