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

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 < .01). In Part B (n = 12, median age 24 years, interquartile range 22-26 years), exenatide increased heart rate by 4 bpm (95% CI 2-6 bpm, P < .001). Glucagon (low) increased heart rate by 4 bpm (95% CI 1-7 bpm, P < .001). Co-infusion of glucagon (low) and exenatide increased heart rate by 7 bpm (95% CI 4-9 bpm, P < .001) and the rate pressure product by 793 mmHg*bpm (95% CI 460-1127 mmHg*bpm, P < .001). There were no differences in cardiac output, blood pressure or heart rate variability. CONCLUSIONS: In healthy males, exenatide and glucagon co-infusion acutely increases the rate pressure product, an indirect measure of cardiac work. This increase is driven by an increase in heart rate, rather than any change in systolic blood pressure.