Negative Association of SGLT2 Inhibitors with Epilepsy Risk Compared with DPP-4 Inhibitors in Type 2 Diabetes: A Target Trial Emulation

Background: Epilepsy is a frequent neurological comorbidity in type 2 diabetes. Sodium–glucose cotransporter-2 inhibitors (SGLT2i) exert metabolic, vascular, and anti-inflammatory actions beyond glucose lowering, suggesting potential neuroprotective properties. We assessed whether SGLT2i use is associated with a reduced incidence of epilepsy compared with dipeptidyl peptidase-4 inhibitors (DPP-4i). Methods: We emulated a target trial using a retrospective observational cohort of adults with type 2 diabetes initiating SGLT2i or DPP-4i from a large real-world database. Propensity scores were estimated using a SuperLearner algorithm, and stabilized inverse probability of treatment weights were applied to balance baseline characteristics. Weighted Kaplan–Meier and Cox regression models were used to estimate hazard ratios (HRs) for incident epilepsy. Results: Among 176,728 patients (mean age 68 years; 39% women), 43% received SGLT2i. The weighted incidence of epilepsy was 2.05 versus 2.45 per 1000 person-years for SGLT2i and DPP-4i, respectively. SGLT2i treatment was associated with a significantly lower risk of epilepsy (HR 0.72, 95% CI 0.61–0.86; p < 0.001). Conclusions: In this large real-world study, initiation of SGLT2 inhibitors was associated with a lower incidence of epilepsy compared with DPP-4 inhibitors. The absolute difference in event rates was small (2.05 vs. 2.45 cases per 1000 person-years), and residual confounding cannot be excluded. These findings should therefore be regarded as hypothesis-generating and warrant prospective research to confirm causality and clarify potential mechanisms.