354-OR: Cotadutide (medi0382), a Dual Receptor Agonist with Glucagon-Like Peptide-1 and Glucagon Activity, Modulates Hepatic Glycogen and Fat Content

Abstract

Background and Aims: Cotadutide, a dual receptor agonist with glucagon-like peptide-1 (GLP-1) and glucagon activity, is being researched for the potential treatment of nonalcoholic steatohepatitis. Given the known effects of glucagon on hepatic glycogen and lipid metabolism, the aim of this phase 2a study was to investigate the effect of cotadutide on hepatic glycogen. Methods: In this double-blind, placebo-controlled study, 21 overweight or obese adults with type 2 diabetes mellitus (HbA1c ≤ 8%) were randomized to receive once-daily subcutaneous cotadutide (n = 12) or placebo (n = 9) for 28 days. Following 48 hours of standardized meals, serial magnetic resonance spectroscopy scans relying on signals from naturally abundant 13C were performed to measure glycogen, and liver fat was also estimated. Fasting amino acid and ketone levels were also assessed. Results: Significant reductions from baseline in postprandial hepatic glycogen content were observed with cotadutide (-100.2 mmol/L; 90% CI: -150.2, -50.1) vs. placebo (+5.5 mmol/L; 90% CI: -47.2, 58.3; P = 0.023). Statistically significant reductions in hepatic glycogen content were observed across serial measures and after a 14-hour fast (P < 0.05), with an overall change in glycogen AUC24h of -27.3% (P = 0.003) vs. placebo. In addition, a relative reduction in liver fat of 33.2% vs. placebo was reported (P = 0.006), and significant reductions in fasting alanine, glutamate, glycine, lysine, and threonine levels were also observed with cotadutide vs. placebo (all P ≤ 0.05). Beta-hydroxybutyrate and acetoacetate levels were not significantly different between the two arms. Conclusions: Cotadutide promoted a generalized reduction in hepatic glycogen and selected amino acid levels. Substantial reductions in liver fat were also observed with cotadutide, suggesting glucagon receptor engagement. Disclosure D. Robertson: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. L. Hansen: Employee; Self; AstraZeneca. P. Ambery: Employee; Self; AstraZeneca. R.L. Esterline: Employee; Self; AstraZeneca. L. Jermutus: Employee; Self; AstraZeneca. Stock/Shareholder; Self; AstraZeneca. Y. Chang: None. M. Petrone: Employee; Self; AstraZeneca. E. Johansson: None. L. Johansson: Employee; Self; Antaros Medical AB. Stock/Shareholder; Self; Antaros Medical AB. F.B. Sjöberg: None. V. Parker: None. Funding AstraZeneca