BACKGROUND: Atrial fibrillation (AF) and diabetes mellitus (DM) are associated with an increased risk of ischemic stroke, particularly in geriatric populations. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have demonstrated cardiovascular benefits, but their effects on stroke risk may vary by age. This study aimed to explore the age-dependent effects of SGLT2i on stroke risk in patients with AF and DM. METHODS: This historical longitudinal follow-up cohort study included 9,669 patients with AF and DM from the National Taiwan University Hospital database (2010-2020). Patients were stratified into three age groups (<
75, 75-89, and ≥ 90 years) to compare SGLT2i users and non-users within each age group. Cox proportional hazards models were used to evaluate stroke risk, adjusting for CHA₂DS₂-VASc score and oral anticoagulant use. Interaction analysis assessed age-specific SGLT2i effects. RESULTS: In patients aged <
75 years, SGLT2i use significantly reduced stroke risk (HR 0.63, 95% CI 0.44-0.88, P <
0.05). Stroke risk was neutral in patients aged 75-89 years (HR 0.95, 95% CI 0.60-1.50), but significantly increased in those aged ≥ 90 years (HR 5.04, 95% CI 1.20-21.1, P <
0.05). Interaction analysis confirmed a significant age-dependent effect (aged ≥ 90 years x SGLT2i use HR 6.39, 95% CI 1.49-27.40, P <
0.05). CONCLUSIONS: The impact of SGLT2i on stroke risk varies significantly by age. While protective in younger patients, SGLT2i may increase stroke risk in those aged ≥ 90 years. These findings highlight the importance of age-specific considerations in prescribing SGLT2i for patients with AF and DM.