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Recent large\u2010scale clinical and real\u2010world studies report a predominantly neutral to protective association between GLP\u20101 RA use and seizure\u2010 or epilepsy\u2010related 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\u20101 RA effects on neuronal excitability and seizure susceptibility, with a focus on possible discrepancies between population\u2010level outcomes and individual network\u2010level vulnerability. Preclinical studies demonstrate heterogeneous, network\u2010dependent effects of GLP\u20101 RAs. Although anticonvulsant and neuroprotective properties are observed in chemically induced seizure models, paradoxical pro\u2010seizure effects occur in genetic absence epilepsy models. In contrast, population\u2010level analyses report neutral to reduced rates of incident epilepsy or seizure\u2010related outcomes under GLP\u20101 RA therapy. However, these findings are based largely on administrative diagnostic codes, lack epileptological phenotyping, and are not designed to capture transient, exposure\u2010dependent alterations in neuronal excitability or short\u2010term seizure dynamics. Additional factors, including delayed gastric emptying affecting anti\u2010seizure medication absorption, rapid metabolic shifts during titration, blood\u2013brain barrier dysfunction, and agent\u2010specific pharmacokinetics, may further modulate individual susceptibility. We propose that GLP\u20101 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.<\/jats:p>","DOI":"10.1002\/epi.70527","type":"journal-article","created":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T04:49:26Z","timestamp":1792471766000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Beyond neuroprotection: Context\u2010dependent effects of\n                    <scp>GLP<\/scp>\n                    \u20101 receptor agonists on seizure susceptibility"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6847-319X","authenticated-orcid":false,"given":"Jelena","family":"Findeis","sequence":"first","affiliation":[{"name":"Department of Neurology Sana Hospital Rummelsberg gGmbH  Schwarzenbruck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7085-8657","authenticated-orcid":false,"given":"Ann\u2010Cathrin","family":"Koschker","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Diabetes, Department of Internal Medicine University Hospital Wuerzburg  Wuerzburg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2364-1973","authenticated-orcid":false,"given":"Martin","family":"Winterholler","sequence":"additional","affiliation":[{"name":"Department of Neurology Sana Hospital Rummelsberg gGmbH  Schwarzenbruck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,10,19]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/2042018821997320"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2022.175439"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2021.721135"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2019.09.010"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2468\u20102667(24)00302\u20105"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/epi.70022"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0000000000214509"},{"key":"e_1_2_11_9_1","doi-asserted-by":"crossref","unstructured":"VashishtR DhruvaSS PatelA DahmL MorrisP GonzalezD et\u00a0al.Phenome\u2010wide risk evaluation of GLP\u20101 receptor agonist use in type 2 diabetes with real\u2010world data across multiple healthcare systems.2025.medRxiv. 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