title: Heart rate acceleration with GLP-1 receptor agonists in type 2 diabetes patients: an acute and 12-week randomised, double-blind, placebo-controlled trial.
abstract: OBJECTIVE
  To examine mechanisms underlying resting heart rate (RHR) increments of GLP-1 receptor agonists in type 2 diabetes patients.
  
  
  METHODS
  Acute and 12-week randomised, placebo-controlled, double-blind, single-centre, parallel-group trial.
  
  
  METHODS
  In total, 57 type 2 diabetes patients (mean ± s.d. age: 62.8 ± 6.9 years; BMI: 31.8 ± 4.1 kg/m2; HbA1c: 7.3 ± 0.6%), treated with metformin and/or sulfonylureas, were included between July 2013 and August 2015. In the acute study, the GLP-1 receptor agonist exenatide (n = 29) or placebo (saline 0.9%; n = 28) was infused intravenously. Subsequently, patients were again randomised to receive the GLP-1 receptor agonist liraglutide (n = 19) or matching placebo (n = 17) for 12 weeks. RHR and blood pressure (BP) were measured by oscillometric technique, systemic haemodynamics by finger photoplethysmography, sympathetic nervous system (SNS) activity by heart rate variability and arterial stiffness by applanation tonometry. This trial was registered at ClinicalTrials.gov (Nbib1744236).
  
  
  RESULTS
  Exenatide-infusion increased RHR (mean ± s.e.m. +7.5 ± 0.9 BPM, P < 0.001), and systolic and diastolic BP (both P < 0.05), compared with placebo. Vascular resistance increased during exenatide-infusion, whereas stroke volume and arterial stiffness decreased (P < 0.05). SNS activity and cardiac output were unaffected. Twelve-week treatment with liraglutide increased RHR (+6.6 ± 2.1 BPM), while reducing systolic BP (-12.6 ± 4.7 mmHg) and stroke volume (all P < 0.01). Cardiac output, vascular resistance, arterial stiffness and SNS activity remained unchanged (all P > 0.05).
  
  
  CONCLUSIONS
  RHR acceleration with acute and 12-week GLP-1 receptor agonist treatment in type 2 diabetes patients is not explained by changes in SNS activity, and our data argue against vasodilation. In line with pre-clinical data, direct sino-atrial stimulation may be involved.
authors: Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands mm.smits1@vumc.nl.
authors: Mark M
authors: MM
authors: Smits
authors: Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands.
authors: Lennart
authors: L
authors: Tonneijck
authors: Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands.
authors: Marcel H A
authors: MH
authors: Muskiet
authors: Department of Health Sciences and the EMGO Institute for Health and Care ResearchVU University, Amsterdam, The Netherlands and Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, The Netherlands.
authors: Trynke
authors: T
authors: Hoekstra
authors: Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands.
authors: Mark H H
authors: MH
authors: Kramer
authors: Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands.
authors: Michaela
authors: M
authors: Diamant
authors: Department of Internal MedicineDiabetes Center, VU University Medical Center, Amsterdam, The Netherlands.
authors: Daniël H
authors: DH
authors: van Raalte
mesh_terms: D000368:Aged; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology*; D004311:Double-Blind Method; D000077270:Exenatide; D005260:Female; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D000069450:Liraglutide / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use; D008875:Middle Aged; D010455:Peptides / Q000627:therapeutic use; D013453:Sulfonylurea Compounds / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome; D014688:Venoms / Q000627:therapeutic use
chemical_list: D001786:Blood Glucose; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D013453:Sulfonylurea Compounds; D014688:Venoms; D000069450:Liraglutide; D008687:Metformin; D000077270:Exenatide