Sodium-Glucose Cotransporter-2 Inhibitors, Glucagon-Like Peptide-1 Receptor Agonists, and Incident Atrial Fibrillation in Type 2 Diabetes: A Population-Based Target Trial Emulation

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AIMS: The comparative association of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) with incident atrial fibrillation (AF) or atrial flutter remains uncertain, particularly with early use of both classes. We compared three initial treatment strategies in adults with type 2 diabetes. METHODS: We emulated a three-arm target trial using population-based healthcare data from 2015-2025. Participants were assigned to SGLT2i without GLP-1RA, GLP-1RA without SGLT2i, or early combined therapy according to dispensings during a 30-day treatment-assignment period. Follow-up began at the end of this period using a landmark design. Treatment groups were balanced using inverse probability of treatment weighting, and cumulative incidence was estimated using weighted Aalen-Johansen methods accounting for competing mortality. RESULTS: Among 216,293 participants, 114,572 received SGLT2i without GLP-1RA, 91,524 received GLP-1RA without SGLT2i, and 10,197 received early combined therapy. At 5 years, cumulative AF or atrial flutter incidence was 4.3%, 4.8%, and 4.2% among participants receiving SGLT2i without GLP-1RA, GLP-1RA without SGLT2i, and early combined therapy, respectively. SGLT2i without GLP-1RA was associated with lower risk than GLP-1RA without SGLT2i (RR 0.88, 95% CI 0.83-0.94), while risk was similar between SGLT2i without GLP-1RA and combined therapy (RR 1.00, 95% CI 0.84-1.19). CONCLUSIONS: Among adults with type 2 diabetes, treatment strategies incorporating SGLT2i were associated with a lower risk of incident AF or atrial flutter than GLP-1RA without SGLT2i. These findings extend the cardiovascular evidence supporting SGLT2i and provide new comparative data regarding early combined use of SGLT2i and GLP-1RA.

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