Safety and Efficacy of GLP-1 Receptor Agonists in Adults With Epilepsy, Obesity, and Type 2 Diabetes.

OBJECTIVE: Managing obesity in patients with epilepsy is complicated by the weight-gaining properties of essential antiseizure medications (ASMs) such as valproate and pregabalin. We evaluated the safety and efficacy of initiating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in this population. METHODS: We conducted a retrospective cohort study using the NIH All of Us Research Program database, identifying adults with comorbid epilepsy, type 2 diabetes, and obesity. New initiators of GLP-1 RAs were compared with matched controls using 1:1 propensity score matching that included baseline weight-gaining ASM use. The primary safety outcome was a composite of seizure-related hospitalization or new ASM addition. Secondary efficacy endpoints (weight and HbA1c change at 12 months) were stratified by concomitant weight-gaining ASM use. RESULTS: The propensity-matched cohort included 610 patients with well-balanced baseline characteristics. GLP-1 RA initiation was not associated with failure to control seizure compared with standard care (hazard ratio 0.92, 95% CI 0.68-1.23; p = 0.57); given the observed events, the study could detect a hazard ratio of 1.53 or greater. GLP-1 RA users achieved a mean adjusted weight loss of -5.73% (p = 0.001) and an HbA1c reduction of -0.71% (p = 0.018). Significant weight reduction was achieved even among patients concomitantly treated with weight-gaining ASMs (adjusted difference -4.15%, p = 0.003). INTERPRETATION: GLP-1 RAs showed no evidence of seizure worsening and remained effective for weight loss even among patients receiving weight-gaining ASMs, supporting their use for metabolic benefit in patients with epilepsy.