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

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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.

Original languageEnglish
Pages (from-to)613-20
Number of pages8
JournalBritish journal of clinical pharmacology
Issue number4
Publication statusPublished - Apr 2016


  • Adult
  • Blood Glucose
  • Body Mass Index
  • Clinical Trial
  • Cross-Over Studies
  • GLP-1 receptor agonist
  • Glucagon-Like Peptide 1
  • Healthy Volunteers
  • Heart Rate
  • Humans
  • Journal Article
  • Lipids
  • Male
  • Overweight
  • Peptides
  • Research Support, Non-U.S. Gov't
  • Sympathetic Nervous System
  • Vascular Resistance
  • Venoms
  • Young Adult
  • haemodynamics
  • sympathetic nervous system activity

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