Sodium-glucose cotransporter 2 inhibitors and stroke risk in patients with diabetes and stroke risk factors: A real-world cohort study

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve the cardiovascular outcomes of patients with type 2 diabetes (T2D). However, whether this effect extends to stroke prevention in high-risk patients remains unclear. Aims: This study aims to investigate the effect of SGLT2i in stroke prevention in patients with T2D and concomitant risk factors. Methods: Patients with T2D and various risk factors for stroke were identified from the TriNetX platform from 2013 to 2024. These patients were divided into two cohorts: one treated with SGLT2i, and the other with metformin or dipeptidyl peptidase-4 inhibitors. Propensity score matching was used to balance the patients’ demographic characteristics, underlying comorbidities, and antiplatelet and anticoagulant drug use patterns. The primary outcome was the development of ischemic or hemorrhagic stroke or the onset of a transient ischemic attack (TIA) within 1 year. Unadjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs). Sensitivity analyses stratified by age, sex, and hemoglobin A1c (HbA1c) levels were performed, and interaction tests were used to assess potential effect modifiers. In addition, the two cohorts were compared for estimation of numbers needed to treat (NNTs). Results: A total of 3,715,058 patients were identified, of whom 971,727 (26.2%) were SGLT2i users. After matching, 932,419 patients were included in each group. SGLT2i use was associated with a significantly reduced risk of ischemic stroke (HR: 0.84, 95% confidence interval (CI): 0.81–0.87; NNT: 669), hemorrhagic stroke (HR: 0.73, 95% CI: 0.68–0.79; NNT: 1837), and TIA (HR: 0.81, 95% CI: 0.77–0.86; NNT: 1615). The protective effect against ischemic stroke was more pronounced in males and individuals aged over 65 years. Greater benefit was observed in patients with chronic kidney disease (NNT: 466), atrial fibrillation (NNT: 492), and heart failure (NNT: 415). In contrast, the protective effect was attenuated in patients with obesity, among whom SGLT2i use was associated with a modestly increased risk of ischemic stroke after 1 year (HR: 1.05, 95% CI: 1.01–1.09). Conclusion: SGLT2i use is associated with a significant reduction in the risk of stroke among selected T2D patients. SGLT2i may be used as a first-line therapy for diabetes patients with concomitant chronic kidney disease, atrial fibrillation, and heart failure.