A large real‑world study found that people with type‑2 diabetes who start a GLP‑1 receptor agonist (like semaglutide) are about 15‑30% less likely to develop epilepsy compared with those who start a DPP‑4 inhibitor. The protective effect was seen early and persisted for several years, with semaglutide showing the strongest benefit.

Individuals with type 2 diabetes mellitus (T2DM) are at an increased risk of developing epilepsy, particularly in later life. While preclinical studies suggest neuroprotective properties of glucagon-like peptide-1 receptor agonists (GLP-1 RAs), real-world comparative effectiveness data remain limited. We aimed to evaluate whether GLP-1 RA use is associated with a lower risk of incident epilepsy compared with dipeptidyl peptidase-4 inhibitor (DPP-4i) use in adults with T2DM. We conducted a retrospective cohort study using the TriNetX network from 2015 to 2023, including adults aged 18 years or older with T2DM who were new users of either GLP-1 RAs or DPP-4is. Patients with a previous diagnosis of epilepsy or seizure, or those using antiepileptic drugs, were excluded. The primary outcome was incident epilepsy, identified using ICD-10-CM codes. Propensity score matching (1:1) was performed based on demographics, socioeconomic status, body mass index, comorbidities, and baseline medications. Cox proportional hazard models estimated hazard ratios (HRs) with 95% CIs. We also conducted prespecified subgroup and sensitivity analyses to assess the robustness of the findings. After matching, 452,766 patients were included (226,383 in each group; mean age 60.5 years; 47.1% female). During follow-up, 1,670 individuals in the GLP-1 RA group and 1,886 in the DPP-4i group developed epilepsy, corresponding to cumulative incidences of 2.35% vs 2.41%. GLP-1 RA use was associated with a significantly lower risk of epilepsy (HR 0.84, 95% CI 0.78-0.90), with protective associations evident at 1 year (HR 0.71, 95% CI 0.62-0.80), 3 years (HR 0.81, 95% CI 0.74-0.88), and 5 years (HR 0.82, 95% CI 0.76-0.88). Among individual agents, semaglutide showed the strongest association (HR 0.68, 95% CI 0.60-0.77). The results were consistent across major subgroups, including both age and sex. Sensitivity analyses excluding patients with overlapping or switching exposure yielded similar findings (HR 0.71, 95% CI 0.64-0.78). GLP-1 RA therapy was associated with a significantly lower epilepsy risk compared with DPP-4i use in adults with T2DM. These results support the hypothesis that GLP-1 RAs may exert neurologic benefits beyond glycemic control. Limitations include the observational design and potential residual confounding. This study provides Class III evidence that the use of GLP-1 RAs in people with T2DM results in a lower risk of developing epilepsy compared with those treated with DPP-4i.