GLP-1 Receptor Agonists in Acute Ischemic Stroke and Secondary Stroke Prevention: A Narrative Review of Preclinical and Clinical Evidence

Abstract

Background: Acute ischemic stroke (AIS) is a leading cause of death and disability. Glucagon-like peptide-1 receptor agonists (GLP-1RA) reduce atherosclerotic events in type 2 diabetes and obesity, and meta-analyses of cardiovascular outcome trials (CVOTs) suggest a modest reduction in incident stroke. Their safety and efficacy within acute AIS pathways remain uncertain. Methods: We conducted a narrative review by searching MEDLINE (PubMed), Cochrane CENTRAL, and ClinicalTrials.gov for studies through January 2026. We included in vitro and animal stroke models, observational studies, randomized controlled trials, and meta-analyses reporting AIS-related outcomes or stroke prevention endpoints with GLP-1RA. Results: Experimental models commonly show reduced infarct volume and improved neurological outcomes, with proposed mechanisms including attenuation of excitotoxicity, apoptosis, oxidative stress, neuroinflammation, and blood-brain barrier disruption, alongside signals of angiogenesis and neurogenesis. Translation is limited by heterogeneity of agents, timing, dosing, and routes, and by uncertainty over direct central nervous system versus systemic mediation. CVOTs and meta-analyses support long-term stroke risk reduction, whereas observational studies and small AIS trials mainly inform feasibility, metabolic control, and safety, with efficacy unproven. Ongoing stroke-dedicated trials should define patient selection, exposure–response relationships, and interactions with thrombolysis or thrombectomy, while prospectively incorporating imaging and biomarker endpoints to test mechanisms. Conclusions: Current evidence does not support routine GLP-1RA use as an acute neuroprotective therapy in AIS in humans. At present, GLP-1RA should be considered primarily for secondary prevention in patients with established indications, pending dedicated stroke trials clarifying acute safety, optimal timing/dosing, interactions with reperfusion therapies, and functional endpoints.