Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males

Abstract

Clinical use of glucagon-like peptide-1 receptor agonists (GLP-1RA) is consistently associated with heart rate (HR) acceleration in type 2 diabetes patients. We explored the mechanisms underlying this potential safety concern. Ten healthy overweight males (aged 20–27 years) were examined in an open label, crossover study. Automated oscillometric blood pressure measurements and finger photoplethysmography were performed throughout intravenous administration of placebo (saline 0.9%), exenatide (targeting therapeutic concentrations) and a combination of exenatide and the nitric oxide synthase inhibitor L-N^G-monomethyl arginine (L-NMMA). Sympathetic nervous system (SNS) activity was measured by heart rate variability and rate-pressure product. Exenatide increased HR by a mean maximum of 6.8 (95% CI 1.7, 11.9) beats min^–1 (P < 0.05), systolic blood pressure (SBP) by 9.8 (95% CI 3.5, 16.1) mmHg (P < 0.01) and markers of SNS activity (P < 0.05). No changes in total peripheral resistance were observed. Increases in HR, SBP and sympathetic activity were preserved during concomitant L-NMMA infusion. Our data argue against exenatide-induced reflex tachycardia as a response to vasodilation and rather suggest the involvement of SNS activation in humans.