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\ua0=\ua01112; active-treatment arms). HR effects observed in two independent head-to-head trials of lixisenatide and liraglutide (N\ua0=\ua0202; active-treatment arms) are also reviewed. Short-acting GLP-1 RAs, exenatide and lixisenatide, are associated with a transient (1\u201312\ua0h) mean placebo- and baseline-adjusted 24-h HR increase of 1\u20133\ua0beats 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\u201310\ua0bpm compared with dulaglutide and exenatide LAR at 3\u20134\ua0bpm. 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\ua0h. 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

Effects of liraglutide on diastolic function parameters in patients with type 2 diabetes and coronary artery disease: a randomized crossover study

AbstractBackgroundDiastolic dysfunction is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and is associated with overweight, glucose dysregulation and coronary artery disease (CAD). The GLP-1 receptor agonist, liraglutide, has shown to induce weight loss and improve metabolic factors, thus modulating factors associated with diastolic dysfunction. We have previously reported the effects of liraglutide on systolic function, and in this current study we explore the effects of liraglutide on diastolic function parameters in patients with stable CAD, preserved left ventricular ejection fraction (LVEF), and newly diagnosed T2DM.MethodsThirty subjects were randomized to liraglutide or placebo intervention for 12 + 12-weeks in this double-blind cross-over study. 2D-echocardiography using tissue velocity imaging was used for assessment of diastolic function parameters. Early diastolic filling velocity (E), late atrial filling velocity (A), E-wave deceleration time (EDT) and E/A ratio was assessed from the pulse wave (PW)-Doppler velocity recording of the mitral inflow. Peak early diastolic annular velocities (e′) was measured from color tissue doppler images.ResultsLiraglutide, when compared to placebo, induced a significant reduction in average e′ and lateral e′ velocities (– 0.57 cm/s [– 1.05 to − 0.08] and –0.74 cm/s [–1.32 to –0.15], respectively). Adjusted for the concomitant increase in HR (+ 6.16 bpm [0.79 to 11.54], the changes were not significant. No significant changes in other diastolic function parameters were observed.ConclusionsLiraglutide therapy did not improve any diastolic function parameters in subjects with T2DM, CAD, and preserved LVEF. Instead, a deterioration in e’ was observed, which was associated to an increase in heart rate induced by liraglutide therapy.Trial registrationClinical Trial Registration:http://www.clinicaltrials.gov(unique identifier: NCT01595789) (first submitted May 8, 2012)</jats:sec

Adding liraglutide to the backbone therapy of biguanide in patients with coronary artery disease and newly diagnosed type-2 diabetes (the AddHope2 study):a randomised controlled study protocol

INTRODUCTION: Newly diagnosed type 2 diabetes mellitus (T2DM) in patients with coronary artery disease (CAD) more than doubles the risk of death compared with otherwise matched glucose tolerant patients. The biguanide metformin is the drug of choice in treatment of T2DM and has shown to ameliorate cardiovascular morbidity in patients with T2DM and myocardial infarction (MI). The incretin hormone, glucagon-like peptide-1 (GLP-1) improves β-cell function, insulin sensitivity and causes weight loss and has been suggested to have beneficial effects on cardiac function. The GLP-1 receptor agonist (GLP-1RA), liraglutide, is currently used for treatment of T2DM but its potential effect on cardiac function has not been investigated in detail. We hypothesised that liraglutide added to metformin backbone therapy in patients with CAD and newly diagnosed T2DM will improve β-cell function and left ventricular systolic function during dobutamine stress. METHODS AND ANALYSES: 40 patients with CAD and newly diagnosed T2DM will receive the intervention liraglutide+metformin and placebo+metformin in this investigator-initiated, double blind, randomised, placebo-controlled, cross-over 12 plus 12 weeks intervention study with a 2-week washout period. The primary cardiovascular end point is changes in left ventricular ejection fraction during stress echocardiography. The primary endocrine end point is β-cell function evaluated during a frequently sampled intravenous glucose tolerance test. Secondary end points include heart rate variability, diurnal blood pressure, glucagon suppression and inflammatory response (urine, blood and adipose tissue). ETHICS AND DISSEMINATION: This study is approved by the Danish Medicines Agency, the Danish Dataprotection Agency and the Regional Committee on Biomedical Research Ethics of the Capital Region of Denmark. The trial will be carried out under the guidance from the GCP unit at Copenhagen University Hospital of Bispebjerg and in accordance with the ICH-GCP guidelines and the Helsinki Declaration. TRIAL REGISTRATIONS NUMBER: Clinicaltrials.gov ID: NCT01595789, EudraCT: 2011-005405-78