Antidiabetic Therapy and Atrial Fibrillation: Pathophysiological Links, Therapeutic Implications, and Evidence-Based Outcomes

INTRODUCTION: Diabetes Mellitus (DM) is strongly associated with an increased risk, severity, and recurrence of Atrial Fibrillation (AF). This narrative review aims to synthesize the mechanistic links between DM and AF and evaluate the impact of major antidiabetic drug categories on AF incidence, burden, and post-ablation outcomes. METHODS: A focused narrative review of the literature was conducted using predefined eligibility criteria for study selection and specific keywords to search major scientific databases and grey literature. RESULTS: Hyperglycemia, oxidative stress, epicardial adipose tissue expansion, autonomic imbalance, and atrial remodeling represent core pathophysiological mechanisms connecting DM and AF. Among antidiabetic pharmacotherapies, the glucagon-like peptide-1 receptor agonist semaglutide displays a potential to reduce AF incidence. Sodium-glucose transporter 2 inhibitors have similarly been shown to lower the incidence of AF in most of the available evidence, while offering an emerging, preliminary benefit for post-ablation success. Metformin also demonstrates a positive impact across both primary and secondary AF prevention, albeit with less robust evidence. Other incretin therapies, including tirzepatide, exhibit neutral effects, while thiazolidinediones and dipeptidyl peptidase-4 inhibitors yield conflicting results. Data from insulin and sulfonylureas suggest an unfavorable risk profile, though potentially confounded by indication. DISCUSSION: Antidiabetic therapy selection may have clinically meaningful implications for AF risk modification and rhythm-control outcomes. Weight-centric and cardio-protective strategies, particularly SGLT2 inhibitors and semaglutide, alongside the traditional option of metformin, show promising signals. Nevertheless, available data derive largely from unadjudicated adverseevent reporting and observational cohorts, currently precluding definitive class-wide or agentspecific recommendations. CONCLUSION: Incorporating atrial fibrillation risk into the individualization of antidiabetic therapy is a promising and clinically relevant strategy. However, establishing any specific agent as a preferred option for AF management remains premature in the absence of dedicated trials with primary AF endpoints.