Association of glucagon-like peptide-1 receptor agonists with cardiac arrhythmias in patients with type 2 diabetes or obesity: a systematic review and meta-analysis of randomized controlled trials

Abstract

Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been highly recommended for glycemic control and weight reduction. However, evidence has accumulated that GLP-1 RAs treatment is related to an increase in heart rate, which could potentially induce cardiac arrhythmias. This study aims to investigate the association of GLP-1 RAs therapy with incident arrhythmias in diabetic and obese patients. Methods MEDLINE, EMBASE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception up to May 25, 2022. Randomized controlled trials (RCTs) comparing GLP-1 RAs with placebo or active control for adults with type 2 diabetes or obesity were included. The outcomes of interest were prespecified as incident atrial fibrillation (AF), atrial flutter (AFL), ventricular arrhythmias (VAs), and sudden cardiac death (SCD). Mantel-Haenszel relative risk (MH-RR) with a corresponding 95% confidence interval (95% CI) was estimated using a fixed-effects model. Results A total of 56 RCTs involving 79,720 participants (44,028 GLP-1 RAs vs 35,692 control: mean age 57.3 years) were included from 7692 citations. GLP-1 RAs use overall did not significantly increase the risk of AF (RR 0.97, 95% CI 0.83–1.12), AFL (RR 0.83, 95% CI 0.59–1.17), VAs (RR 1.24, 95% CI 0.92–1.67), and SCD (RR 0.89, 95% CI 0.67–1.19), compared with controls. In further subgroup analyses, we observed an increasing trend toward incident AF with dulaglutide (RR 1.40, 95% CI 1.03–1.90) while an inverse trend with oral semaglutide (RR 0.43, 95% CI 0.21–0.87). Additionally, higher doses of GLP-1 RAs (RR 1.63, 95% CI 1.11–2.40) and higher baseline BMI (RR 1.60, 95% CI 1.04–2.48) might significantly increase the risk of VAs. No significant differences were identified in other subgroup analyses. Conclusions GLP-1 RAs therapy was not associated with an overall higher risk of arrhythmias, demonstrating an assuring cardiovascular safety profile. Further studies are required to determine whether the potential antiarrhythmic or arrhythmogenic effect of GLP-1 RAs is drug-specific and varies from doses or baseline BMI. Trial registration: PROSPERO Identifier: CRD42022339389.

A diabetic patient increased premature ventricular contractions after using liraglutide: a case report

“…GLP-1 can increase heart rate by enhancing sympathetic nervous system activation and reducing parasympathetic tone, or by direct involvement of GLP-1RA in the atrioventricular node ( 13 ). The meta-analysis by Wu S et al ( 1 ) indicated that the overall arrhythmogenic risk of this class of drugs was low, and it was linked to obesity and high-dose usage. Lorenz M et al ( 14 ) compared the extent and duration of the effects of different GLP-1RA on heart rate in healthy individuals and patients with T2DM.…”

“…Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are relatively novel anti-hyperglycemic drugs that mimic the effects of endogenous GLP-1 and contribute to improved glycemic control and weight loss. Evidence has accumulated that GLP-1RAs could also be associated with improved cardiovascular outcomes and a reduction in major adverse cardiovascular events (MACEs) ( 1 ). Recent findings have shown that liraglutide significantly reduced the combined primary outcome of major adverse cardiovascular events in large cardiovascular outcome trials, elevating the importance of understanding how activation of the GLP-1R translates into clinical cardiovascular benefit ( 2 ).…”

Anti-Arrhythmic Effects of Heart Failure Guideline-Directed Medical Therapy and Their Role in the Prevention of Sudden Cardiac Death: From Beta-Blockers to Sodium-Glucose Cotransporter 2 Inhibitors and Beyond

“…This brings concerns about the risk of VAs and SCD in HFrEF patients. Multiple meta-analyses regarding the T2DM population did not reveal an increased risk for VAs or SCD with GLP-1 RA use [ 123 , 124 ]. The overall impact of GLP-1 RAs on VA and SCD in the HFrEF population remains inconclusive, as does their general effect in HFrEF management.…”

Impact of a dual glucose‐dependent insulinotropic peptide/glucagon‐like peptide‐1 receptor agonist tirzepatide on heart rate among patients with type 2 diabetes: A systematic review and pairwise and network meta‐analysis

“…[3][4][5] However, research on the use of GLP-1RAs has shown an association of such treatment with an increase in heart rate. [6][7][8][9] Heart rate is directly inversely associated with survival in the general population and in individuals with cardiovascular conditions. 10,11 For every 5-bpm increase in heart rate in patients with coronary artery disease and left ventricular dysfunction, the risk of cardiovascular mortality and hospital admission for worsening heart failure increased by 16%.…”

“…With the growing prevalence of T2DM, glucagon‐like peptide‐1 receptor agonists (GLP‐1RAs) have become widely used due to their clinically proven benefits in decreasing blood glucose levels and body weight 3–5 . However, research on the use of GLP‐1RAs has shown an association of such treatment with an increase in heart rate 6–9 . Heart rate is directly inversely associated with survival in the general population and in individuals with cardiovascular conditions 10,11 .…”