SGLT2 Inhibitor Therapy and Risk of Incident Atrial Fibrillation in Patients With HFpEF and Type 2 Diabetes

Background Atrial fibrillation (AF) frequently coexists with Heart Failure with Preserved Ejection Fraction, particularly in patients with Type 2 Diabetes, due to shared cardiometabolic and inflammatory mechanisms. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefit in HFpEF, but data regarding prevention of incident AF remain limited. Objectives To evaluate the association between SGLT2 inhibitor therapy and incident atrial fibrillation/flutter in patients with HFpEF and diabetes mellitus. Methods We performed a retrospective propensity score-matched cohort study using the TriNetX Research Network. Adults aged ≥18 years with HFpEF and diabetes mellitus receiving oral antihyperglycemic therapy were identified. Patients receiving SGLT2 inhibitors were matched 1:1 with those receiving Dipeptidyl peptidase-4 inhibitors. The primary outcome was incident AF/flutter. Secondary outcomes included all-cause mortality, ischemic stroke, and composite major adverse cardiovascular events (cMACE; all-cause mortality, ischemic stroke, or acute myocardial infarction). Associations were assessed using hazard ratios (HRs) and risk ratios (RRs). Results After propensity matching, 37,108 patients were included (18,554 per group). Compared with DPP4 inhibitor therapy, SGLT2 inhibitor use was associated with lower incidence of AF/flutter (17.8% vs 19.2%; HR 0.84, RR 0.93), all-cause mortality (12.5% vs 21.4%; HR 0.53, RR 0.59), ischemic stroke (7.4% vs 8.7%; HR 0.78, RR 0.85), and cMACE (24.4% vs 33.0%; HR 0.66, RR 0.74). Conclusions In patients with HFpEF and diabetes mellitus, SGLT2 inhibitor therapy was associated with lower rates of incident AF/flutter and adverse cardiovascular outcomes, supporting a potential role for SGLT2 inhibitors in modifying arrhythmic risk in addition to established cardiometabolic benefits.