Dual agonism at the glucagon and GLP-1 receptor -- haemodynamic effects in healthy male volunteers

Aim: – GLP-1 and glucagon dual receptor agonists are under clinical development for a range of metabolic conditions including as type 2 diabetes and obesity. The cardiovascular actions of GLP-1 and glucagon receptor agonism are well studied, however less is known about their combination. The aim of this study was to explore the haemodynamic effects of dual agonism at the GLP-1 and glucagon receptor. Methods – Healthy male participants attended a series of randomised, 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 minutes then 25 ng/min) and exenatide:glucagon co-infusion for 120 minutes (Part A, glucagon dose-ranging study), or 60 minutes (Part B, dual-agonism study). Results – In Part A (n=7, 25±7 years), glucagon dose-dependently increased heart rate by 3 bpm with glucagon [low] (p=0.407) and 11 bpm with glucagon [high] (95% CI 4-17 bpm, p<0.01). In Part B (n=12, 25±3 years), exenatide increased heart rate by 4 bpm (95% CI 2-6 bpm, p<0.001). Glucagon [low] increased heart rate by 4 bpm (95% CI 1-7 bpm, p<0.001). Co-infusion increased heart rate by 7 bpm (95% CI 4-9 bpm, p<0.001). There were no differences in stroke volume, cardiac output, blood pressure, or heart rate variability. Conclusion – With the exception of an increase in heart rate, no concerning haemodynamic signals have been detected in studies with GLP-1 and glucagon dual receptor agonists. Our data are consistent with these findings, showing dual agonism acutely increases heart rate in healthy male participants.