Epilepsy is a recognized neurological comorbidity in people with Type 2 diabetes mellitus (T2DM), but data on the potential neurologic effects of glucose-lowering therapies remain limited. A real-world target trial emulation published in Diabetology evaluated whether sodium–glucose cotransporter-2 inhibitors (SGLT2i) were associated with lower epilepsy incidence compared with dipeptidyl peptidase-4 inhibitors (DPP-4i).

The retrospective observational cohort included adults with T2DM initiating either SGLT2i or DPP-4i therapy from a large real-world database. Propensity scores were estimated using a SuperLearner algorithm, and stabilized inverse probability of treatment weighting was applied to balance baseline characteristics between groups. Weighted Kaplan-Meier analyses and Cox regression models were used to estimate incident epilepsy risk.

The study included 176,728 patients with a mean age of 68 years, and 39% were women. Overall, 43% of patients initiated SGLT2i therapy.

Findings

• The weighted incidence of epilepsy was 2.05 per 1000 person-years in the SGLT2i group and 2.45 per 1000 person-years in the DPP-4i group.
• SGLT2i initiation was associated with a significantly lower risk of epilepsy compared with DPP-4i use (HR 0.72; 95% CI 0.61-0.86; P<0.001).
• Absolute epilepsy event rates remained low in both treatment groups despite the relative risk difference.
• Residual confounding could not be excluded because of the observational study design.

The findings suggested that SGLT2 inhibitor initiation was associated with lower epilepsy incidence compared with DPP-4 inhibitors in adults with T2DM. However, the modest absolute risk difference and potential for residual confounding support cautious interpretation of these results.