Glucagon-like peptide-1 and atrial fibrillation incidence: Associations independent of weight loss.

BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1s) have been associated with reduced atrial fibrillation (AF) incidence. Although weight loss is a known benefit of GLP-1 therapy and an established AF risk modifier, it remains unclear whether the antiarrhythmic effects of GLP-1s are independent of weight loss. OBJECTIVE: This study aimed to evaluate whether the GLP-1-associated reduction in AF incidence is primarily driven by weight loss, and to assess differences across specific GLP-1 agents and durations of medication use. METHODS: We conducted a retrospective cohort study of 12,812 patients initiated on GLP-1 therapy at a single academic center from 2020 to 2023. A 1:1 matched control cohort was selected using propensity scores based on known AF risk factors. AF incidence was tracked via manual chart review, and weight trend after 6 months of GLP-1 use was recorded. Time-to-event analyses included Fine-Gray competing risk models to account for the competing risk of death, time-varying Cox regressions, and marginal structural models. RESULTS: GLP-1 use was associated with both a lower risk of AF (hazard ratio 0.67, P < .001) and mortality (hazard ratio 0.34, P < .001) compared with controls. This protective effect persisted across all weight change groups, including patients who gained weight. Among GLP-1 agents, only semaglutide showed a statistically significant AF risk reduction. AF risk reduction appeared after 24 months of GLP-1 use. Mortality benefit persisted across all treatment durations. CONCLUSION: GLP-1 therapy significantly reduces AF incidence and mortality even in the absence of weight loss. These findings support potential antiarrhythmic properties of GLP-1s independent of their metabolic effects.