Glucagon-Like Peptide-1 Receptor Agonists, Semaglutide, and Atrial Fibrillation: An Umbrella Review With...

Multiple meta-analyses report that glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and semaglutide in particular, are associated with lower incident atrial fibrillation (AF) and reduced post-ablation AF recurrence. These reviews have appeared in rapid succession, often drawing on the same trials.

To systematically identify, appraise, and reconcile the published meta-analyses examining GLP-1 RAs/semaglutide and AF across two clinical questions-incident AF and post-ablation AF recurrence.

We conducted an umbrella review following Preferred Reporting Items for Overviews of Reviews (PRIOR) reporting guidance. Eligible units were systematic reviews with meta-analysis reporting a pooled AF estimate for GLP-1 RA/semaglutide versus comparator. Each review was independently appraised in duplicate with A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR-2); overlap of included primary studies was quantified with the corrected covered area (CCA) within clinical domains; certainty was summarized using a Grading of Recommendations Assessment, Development and Evaluation (GRADE)-informed framework. Between-review discordance was examined against pre-specified analytic features (comparator, statistical model, population, and pivotal-trial inclusion).

Ten meta-analyses were included, comprising seven evaluating incident AF and three assessing post-ablation AF recurrence. One meta-analysis of incident AF was available only as a conference abstract and was reserved for sensitivity analysis. For incident AF, pooled effect estimates ranged from an odds ratio (OR) of 0.54 (95% confidence interval (CI) 0.39-0.77) to 0.83 (95% CI 0.70-0.98). For post-ablation recurrence, hazard ratios (HRs) ranged from 0.58 (95% CI 0.42-0.79) to 0.78 (95% CI 0.61-0.99). AMSTAR 2 ratings indicated low confidence in five reviews and critically low confidence in four; none achieved moderate or high confidence. Primary study overlap was substantial, with CCA values of 34.1% across the five semaglutide-only reviews of incident AF, 22.5% across all six incident AF reviews, and 43.8% across the three recurrence reviews. Two recurrence reviews shared an identical six-study base (pairwise CCA 100%) yet reported different pooled HRs (0.58 vs 0.78). The incident-AF effect gradient tracked comparator (active < placebo), statistical model (fixed < random), and population (type 2 diabetes < obesity).

The current evidence comprises numerous but low-confidence, substantially overlapping meta-analyses whose consistency partly reflects a shared set of primary trials rather than independent replication. GLP-1 RAs/semaglutide are plausibly associated with lower AF burden, but certainty is low (incident AF) to very low (recurrence). Adequately powered randomized trials with adjudicated, systematically monitored AF endpoints are required.