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

AIM: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: Our data argue against exenatide-induced reflex tachycardia as a response to vasodilation and rather suggest the involvement of SNS activation in humans.