Beyond neuroprotection: Context-dependent effects of GLP-1 receptor agonists on seizure susceptibility

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are widely used in type 2 diabetes mellitus and obesity and are increasingly considered to exert neuroprotective effects. Recent large-scale clinical and real-world studies report a predominantly neutral to protective association between GLP-1 RA use and seizure- or epilepsy-related diagnoses. However, how these agents affect neuronal excitability in patients with established epileptogenic networks remains insufficiently understood. This narrative review critically examines the experimental and clinical evidence from GLP-1 RA effects on neuronal excitability and seizure susceptibility, with a focus on possible discrepancies between population-level outcomes and individual network-level vulnerability. Preclinical studies demonstrate heterogeneous, network-dependent effects of GLP-1 RAs. Although anticonvulsant and neuroprotective properties are observed in chemically induced seizure models, paradoxical pro-seizure effects occur in genetic absence epilepsy models. In contrast, population-level analyses report neutral to reduced rates of incident epilepsy or seizure-related outcomes under GLP-1 RA therapy. However, these findings are based largely on administrative diagnostic codes, lack epileptological phenotyping, and are not designed to capture transient, exposure-dependent alterations in neuronal excitability or short-term seizure dynamics. Additional factors, including delayed gastric emptying affecting anti-seizure medication absorption, rapid metabolic shifts during titration, blood-brain barrier dysfunction, and agent-specific pharmacokinetics, may further modulate individual susceptibility. We propose that GLP-1 RA effects on neuronal excitability are context dependent, shaped by epilepsy subtype, network vulnerability, exposure dynamics, and treatment phase. Targeted prospective studies incorporating clinical phenotyping, therapeutic drug monitoring, and temporal seizure assessment are required to ensure neurological safety in patients with epilepsy.