Glucagon-like peptide-1 receptor agonists reduce atrial fibrillation among patients with heart failure with preserved and mildly reduced ejection fraction – a meta-analysis of randomized controlled trials

Aims: Atrial fibrillation (AF) is more prevalent in heart failure with preserved ejection fraction (HFpEF) than in other heart failure phenotypes and contributes to worse clinical outcomes. Despite structural and metabolic benefits observed with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in HFpEF and heart failure with mildly reduced ejection fraction (HFmrEF), their impact on AF incidence remains unclear. We conducted a meta-analysis of randomized trials to evaluate whether GLP-1 RA therapy reduces incident AF in patients with HFpEF and HFmrEF. Methods and results: We systematically searched MEDLINE, Embase, and Cochrane databases (inception to 28 February 2025) for randomized controlled trials reporting incident AF in HFpEF populations treated with GLP-1 RAs. Four eligible trials were identified (SELECT, FLOW, STEP-HFpEF, STEP-HFpEF DM), enrolling 3743participants with HFpEF or HFmrEF. The primary analysis used a fixed-effect model. GLP-1 RA therapy significantly reduced the risk of incident AF (risk ratio [RR] 0.54; 95% confidence interval [CI] 0.36–0.81; p = 0.003), with moderate heterogeneity (I² = 51%, τ² = 0.21). Secondary outcomes showed significantly greater reductions in body weight, systolic blood pressure, and left atrial volume in the treatment group. Conclusions: Glucagon-like peptide-1 receptor agonist therapy is associated with a significant reduction in incident AF among patients with HFpEF and HFmrEF. These findings support the hypothesis that GLP-1 RAs may offer rhythm-modifying benefits in addition to weight and haemodynamic effects. Dedicated HFpEF trials with adjudicated AF outcomes are warranted.