Impact of GLP1Ra and SGLT2i on atrial fibrillation in overweight, non-diabetic patients: A meta-analysis of randomized evidence

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1Ra) are breakthrough therapies for type 2 diabetes (T2DM), exhibiting pleiotropic effects. Their clinical use has expanded to lower-risk populations, including overweight and obese individuals without T2DM. However, although early intervention in dysmetabolic disease appears conceptually advantageous, clear evidence regarding the benefits of these treatments in overweight or obese individuals without diabetes, particularly for the prevention of atrial fibrillation (AF), remains lacking. Our meta-analysis addresses this unmet need by examining whether GLP1Ra and SGLT2i may help prevent AF in overweight or obese individuals without diabetes. A systematic review and meta-analysis of randomized controlled trials (RCTs) investigating the effect of GLP1Ra and SGLT2i on AF was conducted across 22 studies involving 45,171 participants (16,920 treated with GLP1Ra, 6,855 treated with SGLT2i, and 21,396 controls), all enrolling overweight patients without T2DM. The mean follow-up was 18.2 months. A primary analysis including both GLP1Ra and SGLT2i classes was performed. Exploratory analysis included subgroup comparisons of semaglutide versus other GLP1Ra (herein intended as both GLP1Ra and GLP1/GIP Ra). Sensitivity analysis comprised confirmatory analysis of the primary results, bias-addressing subgroup analysis, leave-one-out analysis, and temporal cumulative meta-analysis. Evidence sufficiency was assessed using a trial sequential analysis-like framework. Meta-regression analysis were performed to explore the impact of patient- and trial-related characteristics on AF. Available basic and translational evidence was discussed accordingly. The primary analysis did not demonstrate a reduction in AF/AFL risk with GLP1Ra treatment (RR 0.69, 95% CI 0.43–1.08; p = 0.097), although exploratory exclusion of the HFpEF trial unveiled a hypothesis-generating association with a lower AF/AFl risk (RR 0.52, 95% CI 0.29–0.94; p = 0.034). Interestingly, a robust, albeit exploratory, hypothesis-generating signal favouring semaglutide emerged repeatedly compared with other GLP1Ra (RR 0.41, 95% CI 0.19–0.85; p = 0.024; p for interaction = 0.003), whereas other incretin agonists exhibited a neutral effect (RR 1.34, 95% CI 0.74–2.41; p = 0.29). In contrast, SGLT2i showed no evidence of benefit (RR 1.11, 95% CI 0.88–1.42; p = 0.28), but the corresponding results appeared to be affected by substantial publication bias. The subgroup difference between GLP1Ra and SGLT2i was statistically significant (p = 0.035) although exploratory. Sensitivity analysis were broadly consistent and suggested that the semaglutide-associated signal was unlikely to be driven by model-dependent assumptions, large-trial effects, endpoint ascertainment methods, or the inclusion of HFpEF populations. Trial sequential analysis indicated that additional randomized controlled trials are required before definitive conclusions can be drawn. Current randomized evidence does not establish a reduction in AF/AFL risk among overweight or obese individuals without diabetes. However, exploratory analysis identified a hypothesis-generating signal suggesting a potential protective effect of GLP1Ra in populations without HFpEF. Among GLP-1RAs, sensitivity analysis further supported a resilient, hypothesis-generating association between semaglutide and a lower risk of AF/AFL, independent of population characteristics or large-size trial effect. An interclass difference favouring GLP1Ra repeatedly emerged, although its hypothesis-generating value is limited by the inconclusive SGLT2i evidence. Although supported by multiple sensitivity analysis, these findings remain exploratory and hypothesis-generating and therefore require confirmation in dedicated randomized trials with prespecified arrhythmic endpoints.