Non-antiarrhythmic pharmacotherapy in cardio-renal-metabolic disease and incident atrial fibrillation: a trial meta-analysis

BACKGROUND AND AIMS: Atrial fibrillation (AF) disease burden is increasing. Pharmacotherapy of cardio-renal-metabolic diseases may prevent incident AF. This meta-analysis estimates the effect of different pharmacotherapies on risk of incident AF across cardio-renal-metabolic diseases. METHODS: The Medline, Embase, and Cochrane Central databases were searched to 7 October 2025 for randomized clinical trials (RCTs) comparing the effect of a non-antiarrhythmic cardio-renal-metabolic medication with control or another agent for incident AF. Random-effects meta-analysis using the Mantel-Haenszel method, with between-study variance estimated using the DerSimonian-Laird method, was performed to synthesize risk ratios (RR) with 95% confidence intervals (CI). RESULTS: Two hundred and forty-nine RCTs involving 745 041 patients were included, of which 207 identified AF through adverse event reports, 161 were placebo-controlled, and 15 had AF as a pre-specified endpoint. In placebo-controlled trials, significant differences in incident AF were observed with treatment of heart failure with reduced ejection fraction with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (RR 0.69, 95% CI 0.60-0.80), mineralocorticoid receptor antagonists (RR 0.62, 95% CI 0.43-0.90), and sodium-glucose co-transporter 2 (SGLT2) inhibitors (RR 0.62, 95% CI 0.44-0.87); treatment of chronic kidney disease with SGLT2 inhibitors (RR 0.53, 95% CI 0.33-0.85); and treatment of obesity with glucagon-like peptide-1 receptor agonists (RR 0.79, 95% CI 0.63-0.99). However, the number of AF events per trial was low and none were adequately powered for incident AF. CONCLUSIONS: Prospective RCTs with AF as a pre-specified outcome should be integrated into the design of future trials of cardio-renal-metabolic medications to determine whether they reduce incident AF.