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

Abstract

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‐NG‐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.

Different mechanisms involved in liraglutide and glucagon‐like peptide‐1 vasodilatation in rat mesenteric small arteries

“…Agonists at GLP-1 receptors have been suggested to increase heart rate by activation of the sympathetic nervous system (Smits et al, 2016), and therefore, GLP-1 receptor agonists may also regulate vascular tone by interaction with the nerve endings in the vascular wall similar to suggested effects of other gut-derived peptides (Gradin et al, 2006). This has to our knowledge, not been examined before.…”

Blood pressure control in type 2 diabetic patients

“…On the other hand, they have been reported to increase heart rate through sympathetic nervous system activation [98] and this may result in BP elevation. In the recently published Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial [99], patients treated with liraglutide had a mild decrease in systolic BP (1.5 mmHg) and a mild increase in diastolic BP (0.6 mmHg).…”

Heart rate variability in type 2 diabetic subjects randomized to liraglutide or glimepiride treatment, both in combination with metformin: A randomized, open, parallel‐group study

“…This contrast clinical studies where a small reduction in blood pressure with a reciprocal small increase in HR frequently is reported and suggested to be secondarily to vasodilatation, that is reflex tachycardia . However, recent reports have revealed GLP‐1 R expression in the heart only by the sinoatrial node (SAN) myocytes, whereas GLP‐1 RA treatment directly may stimulate SAN to increase HR…”

“…T2D patients treated with different GLP‐1 RA had an increase in HR (acute and after 12 weeks) that was not explained by changes in sympathetic activity, or a reflex to vasodilation, suggesting direct stimulation of SAN involved . Acute administration of exenatide into healthy overweight men and into T2D patients with heart failure increased HR that not was due to reflex tachycardia, however rather to the involvement of sympathetic action or stimulation of SAN. In another recent study where T2D patients received exenatide extended‐release, there was an increase in HR that did not appear to be related to sympathetic influence .…”