Seizure recurrence after GLP-1 receptor agonist initiation in adults with epilepsy.

OBJECTIVE: To examine whether initiation of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is associated with seizure recurrence and related outcomes in adults with epilepsy and type 2 diabetes. METHODS: We conducted a retrospective cohort study using de-identified electronic health records from the TriNetX Research Network (January 2003-August 2025), including adults ≥18 years with ≥3 epilepsy or recurrent seizure diagnoses. Patients initiating a GLP-1 RA (exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide, or tirzepatide) without prior comparator therapy were compared with those initiating other glucose-lowering agents (sodium-glucose cotransporter 2 inhibitors, dipeptidyl peptidase 4 inhibitors, sulfonylureas, or insulin) without GLP-1 RA exposure. Propensity score matching (1:1) was performed on 82 covariates, yielding 8688 matched pairs. Outcomes were assessed using Cox proportional hazards models. RESULTS: After matching, the mean age was 52.6 years, and 67.6% were female. Median follow-up was 514 days (interquartile range [IQR] 671) for GLP-1 RA initiators and 415 days (IQR 769) for comparators. GLP-1 RA initiation was associated with lower risk of seizure recurrence (HR .82, 95% confidence interval [CI] .78-.86; RD -2.1%), hospitalization (HR .35, 95% CI .29-.43; RD -2.6%), and all-cause mortality (HR .40, 95% CI .34-.47; RD -4.8%). Associations with status epilepticus (HR .75, 95% CI .66-.85; RD -.7%) and ICU admission (HR .82, 95% CI .69-.96; RD -.3%) were smaller; the latter was not statistically significant. SIGNIFICANCE: In this large multinational cohort, GLP-1 RA initiation was associated with reduced risks of seizure recurrence, hospitalization, and mortality compared with other glucose-lowering therapies. These hypothesis-generating findings warrant confirmation in prospective studies before translation into clinical practice.