Association Between Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists and Atrial Fibrillation Adverse Events: A Systematic Review and Meta-Analysis of Randomized Trials

Atrial fibrillation (AF) is common among individuals with type 2 diabetes mellitus (T2DM) and obesity, populations in which glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely prescribed. These agents improve cardiometabolic profiles by lowering blood pressure, reducing body weight, improving glycemic control, and decreasing systemic inflammation. However, their potential role in AF prevention remains uncertain. This study evaluated whether GLP-1 RA therapy is associated with a reduced risk of new-onset AF by analyzing evidence from randomized controlled trials (RCTs). A systematic search of MEDLINE, Embase, PubMed, Cochrane CENTRAL, Scopus, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP) was conducted from database inception to January 2025. RCTs involving adults treated with GLP-1 RAs that reported AF, atrial flutter, or arrhythmia-related adverse events were included. Risk of bias was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool. AF events across cardiovascular outcome trials (CVOTs) were synthesized using a fixed-effect inverse-variance meta-analysis model, with heterogeneity assessed using Q and I² statistics. The primary outcome was reported AF events as captured in individual trials, typically recorded as adverse events rather than systematically adjudicated endpoints. Although 12 RCTs reported AF or arrhythmia-related adverse events, only six provided sufficient, extractable arm-specific data to permit inclusion in the quantitative meta-analysis. These comprised the major CVOTs-LEADER, SUSTAIN-6, REWIND, EXSCEL, HARMONY Outcomes, and AMPLITUDE-O. Across these studies, reported AF events were infrequent (0.2%-1.2%) and were identified through passive adverse event reporting rather than systematic rhythm monitoring or endpoint adjudication. The pooled analysis yielded a risk ratio of 0.87 (95% confidence interval (CI) 0.64-1.17) with no observed heterogeneity (I² = 0%). While the direction of effect was consistent across trials, the findings represent a statistically non-significant, hypothesis-generating association based on reported AF events rather than systematically ascertained incidence. These findings suggest that GLP-1 RAs may contribute to reduced risk of reported AF events, potentially through improvements in body weight, blood pressure, glycemic control, systemic inflammation, and cardiac loading conditions. However, the available evidence is limited by passive detection of AF events and the relatively low statistical power of existing trials to detect arrhythmia outcomes. Consequently, the results should be interpreted cautiously, and dedicated AF-focused RCTs incorporating systematic rhythm monitoring are required.