An experimental medicine protocol for exploring the haemodynamic effects of dual agonism at the glucagon-like peptide-1 and glucagon receptor in healthy subjects

Abstract

Aims: Glucagon-like peptide-1 (GLP-1) and glucagon dual receptor agonists are in clinical development for a range of metabolic conditions, including type 2 diabetes and obesity. The cardiovascular actions at these receptors are well studied, but less is known about their combination. The aim was to explore the acute haemodynamic effects of dual agonism at the GLP-1 and glucagon receptor. Methods: Healthy male participants attended randomized, saline-controlled intravenous infusion studies using glucagon (low, 25 ng/kg/min), glucagon (high, 50 ng/kg/min), exenatide (loading dose 50 ng/min for 30 min then 25 ng/min) and exenatide:glucagon co-infusion for 120 min in Part A (glucagon dose-comparison study) and 60 min in Part B (dual-agonism study). Results: In Part A (n = 7, median age 21 years, interquartile range 21-32 years), glucagon (high) increased heart rate by 11 beats per minute (bpm) (95% confidence interval [CI] 4-17 bpm, P