title: Differential effects of glucagon-like peptide-1 receptor agonists on heart rate.
abstract: While glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to increase heart rate (HR), it is insufficiently recognized that the extent varies greatly between the various agonists and is affected by the assessment methods employed. Here we review published data from 24-h time-averaged HR monitoring in healthy individuals and subjects with type 2 diabetes mellitus (T2DM) treated with either short-acting GLP-1 RAs, lixisenatide or exenatide, or long-acting GLP-1 RAs, exenatide LAR, liraglutide, albiglutide, or dulaglutide (N = 1112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N = 202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1-12 h) mean placebo- and baseline-adjusted 24-h HR increase of 1-3 beats per minute (bpm). Conversely, long-acting GLP-1 RAs are associated with more pronounced increases in mean 24-h HR; the highest seen with liraglutide and albiglutide at 6-10 bpm compared with dulaglutide and exenatide LAR at 3-4 bpm. For both liraglutide and dulaglutide, HR increases were recorded during both the day and at night. In two head-to-head comparisons, a small, transient mean increase in HR from baseline was observed with lixisenatide; liraglutide induced a substantially greater increase that remained significantly elevated over 24 h. The underlying mechanism for increased HR remains to be elucidated; however, it could be related to a direct effect at the sinus node and/or stimulation of the sympathetic nervous system, with this effect related to the duration of action of the respective GLP-1 RAs. In conclusion, this review indicates that the effects on HR differ within the class of GLP-1 RAs: short-acting GLP-1 RAs are associated with a modest and transient HR increase before returning to baseline levels, while some long-acting GLP-1 RAs are associated with a more pronounced and sustained increase during the day and night. Findings from recently completed trials indicate that a GLP-1 RA-induced increase in HR, regardless of magnitude, does not present an increased cardiovascular risk for subjects with T2DM, although a pronounced increase in HR may be associated with adverse clinical outcomes in those with advanced heart failure.
authors.affiliation: R&D Diabetes Division, Sanofi-Aventis Deutschland GmbH, Industrial Park Höchst, Bldg. H831, 65926, Frankfurt am Main, Germany. martin.lorenz@sanofi.com.
authors.forename: Martin
authors.initials: M
authors.lastname: Lorenz
authors.affiliation: R&D Diabetes Division, Sanofi, Bridgewater, NJ, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lawson
authors.affiliation: Institute of Life Sciences College of Medicine, Swansea University, Swansea, UK.
authors.forename: David
authors.initials: D
authors.lastname: Owens
authors.affiliation: University Hospital Sainte-Marguerite, Marseille, France.
authors.forename: Denis
authors.initials: D
authors.lastname: Raccah
authors.affiliation: R&D Diabetes Division, Sanofi, Chilly-Mazarin, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Roy-Duval
authors.affiliation: R&D Clinical Sciences & Operations, Sanofi-Aventis Deutschland GmbH, Frankfurt am Main, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Lehmann
authors.affiliation: Global Medical Affairs, Sanofi, Bridgewater, NJ, USA.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Perfetti
authors.affiliation: Department of Endocrinology, Frank Riddick Diabetes Institute, Ochsner Medical Center, New Orleans, LA, USA.
authors.forename: Lawrence
authors.initials: L
authors.lastname: Blonde
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000503:physiopathology; D000067757:Glucagon-Like Peptide-1 Receptor / Q000502:physiology*; D004763:Glucagon-Like Peptides / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D007141:Immunoglobulin Fc Fragments / Q000494:pharmacology / Q000627:therapeutic use; D000069450:Liraglutide / Q000494:pharmacology / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012307:Risk Factors; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D011993:Recombinant Fusion Proteins; D004763:Glucagon-Like Peptides; D000069450:Liraglutide; C555680:dulaglutide; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Glucagon-like peptide-1 receptor agonist; Heart rate; Type 2 diabetes mellitus