GLP-1 Receptor Agonists in Epilepsy: Separating Evidence for Antiseizure Activity, Neuroprotection, and Disease Modification.

GLP-1 receptor (GLP-1R) agonists are increasingly investigated in epilepsy, but antiseizure activity, neuroprotection, and disease modification are distinct therapeutic claims. This critical narrative review with structured evidence mapping separates these claims across 21 preclinical primary publications and eight human studies identified through 6 August 2026. Selected GLP-1R-related interventions show antiseizure and anti-kindling signals, but effects vary across compounds, models, treatment timing, and seizure types; null and pro-seizure findings in absence epilepsy preclude a uniform class-wide antiseizure effect, and concurrent anti-kindling does not establish antiepileptogenesis. Neuroprotective evidence is broader, although direct neuronal or tissue preservation is demonstrated only in selected studies; many findings remain biomarker-based, and seizure reduction may itself lessen downstream injury. Evidence for durable disease modification remains suggestive rather than established. Causal support is strongest at the receptor level, whereas most downstream synaptic, inflammatory, glial, oxidative, and mitochondrial evidence remains associative. Semaglutide has high translational relevance but remains directly under-tested in epilepsy, and human evidence is predominantly observational or safety-oriented and does not establish therapeutic epilepsy efficacy. Progress requires chronic epilepsy studies with longitudinal EEG/video-EEG and baseline seizure burden, post-insult designs controlling initial-insult severity and assessing persistence after withdrawal, and linked pharmacokinetic, target-engagement, and causal mechanistic testing.