Glucagon-Like Peptide-1 Receptor Agonists, Semaglutide, and Atrial Fibrillation: An Umbrella Review With Methodological Appraisal of Overlapping Meta-Analyses.

Authors

David Ramzy, Rouba Isshak, Disha Patel, Michael Elmasry, Noma Shri, Jesus Romero, Proggya Paromita, Tashifa Nazmee, Fayez Shamoon

Published in

Cureus. Volume 18. Issue 7. Pages e113641. Epub Jul 30, 2026.

Abstract

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.

PMID:
42668799
Bibliographic data and abstract were imported from PubMed on 30 Aug 2026.

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