title: Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males.
abstract: OBJECTIVE
  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.
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam.
authors.forename: Mark M
authors.initials: MM
authors.lastname: Smits
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam.
authors.forename: Marcel H A
authors.initials: MH
authors.lastname: Muskiet
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam.
authors.forename: Lennart
authors.initials: L
authors.lastname: Tonneijck
authors.affiliation: Department of Health Sciences and the EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam.|Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Trynke
authors.initials: T
authors.lastname: Hoekstra
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam.
authors.forename: Mark H H
authors.initials: MH
authors.lastname: Kramer
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam.
authors.forename: Michaela
authors.initials: M
authors.lastname: Diamant
authors.affiliation: Diabetes Center, Department of Internal Medicine, VU University Medical Center, Amsterdam.
authors.forename: Daniël H
authors.initials: DH
authors.lastname: van Raalte
mesh_terms: D000328:Adult; D001786:Blood Glucose / Q000032:analysis; D015992:Body Mass Index; D018592:Cross-Over Studies; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists*; D064368:Healthy Volunteers; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008055:Lipids / Q000097:blood; D008297:Male; D050177:Overweight / Q000097:blood; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D014688:Venoms / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D001786:Blood Glucose; D008055:Lipids; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: GLP-1 receptor agonist; haemodynamics; heart rate; sympathetic nervous system activity