Sodium‐glucose cotransporter 2 inhibitors and the risk of late onset epilepsy: A real‐world cohort study

OBJECTIVE: Late onset epilepsy (LOE) is associated with substantial morbidity. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) may exert neuroprotective effects. This study evaluated the association between SGLT2i and risk of LOE among older adults with type 2 diabetes mellitus. METHODS: This retrospective cohort study was conducted between 2013 and 2025 with a 3-year follow-up using the TriNetX global network. Patients ≥60 years old with type 2 diabetes mellitus were classified into two cohorts-new SGLT2i users and new dipeptidyl peptidase-4 inhibitors users-following a 6-month washout of other antihyperglycemic agents except metformin. Patients with major neurological diseases or contraindications to SGLT2i were excluded. Propensity score matching was used to balance baseline characteristics between two cohorts. The primary outcomes were incident LOE, status epilepticus, and initiation of antiseizure medications. Unadjusted Cox proportional hazards models were applied to estimate hazard ratios (HRs) and 95% confidence interval (CIs). RESULTS: A total of 1 435 648 patients were identified. After matching, 60 203 patients were included in the SGLT2i cohort (mean age = 67.7 years, 42.3% female) and 60 203 in the control cohort (mean age = 67.7 years, 41.7% female). SGLT2i use was associated with lower risk of LOE (HR = .55, 95% CI = .44-.68), status epilepticus (HR = .38, 95% CI = .21-.69), and antiseizure medication initiation (HR = .63, 95% CI = .58-.69). SGLT2i reduced LOE risk in patients with stroke (HR = .69, 95% CI = .42-.88) and dementia (HR = .44, 95% CI = .25-.78) but not in those with traumatic brain injury or brain tumors. SIGNIFICANCE: SGLT2i use was associated with reduced risk of LOE among selected patients, supporting its role in an etiology-specific therapeutic approach for older adults at risk of epilepsy.