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

Abstract

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Participants were 65 adult overweight/obese patients with type 2 diabetes mellitus; 63 completed the study; 2 were withdrawn due to AEs.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 µg) 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 [AUC0–4h]) 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 AUC0–4h 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 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). Conclusion These results suggest that the glucose-lowering effects of cotadutide are mediated by enhanced insulin secretion and delayed gastric emptying. Trial Registration ClinicalTrials.gov, NCT03244800.

OXM-104, a potential candidate for the treatment of obesity, NASH and type 2 diabetes

“…Interestingly plasma BCAA levels were lowered by OXM-104, cotadutide, and semaglutide, suggesting a correction of metabolic imbalances, especially by OXM-104 and cotadutide. In line with this, cotadutide has previously shown a tendency towards lowered BCAA levels after 49 days of treatment 49 .…”

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“…Despite these results, there are no ongoing clinical studies of SAR425899. Cotadutide was administered once daily for 49 days to overweight or obese subjects with T2D [ 59 ]. While cotadutide attenuated meal-related glycemic excursion and inhibited gastric emptying, body weight loss was ∼3.4%, substantially less than reported in preclinical studies.…”

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