GLP-1 Receptor Agonists as Treatment of Nondiabetic Ischemic Stroke—A Systematic Review and Meta-Analysis

BACKGROUND: Reperfusion therapies for ischemic stroke are a cornerstone of acute treatment, though only available for a subset of patients due to a narrow time window. Other supplementary treatment is warranted, as only half of the patients reach functional independence. GLP-1 RA (glucagon-like peptide-1 receptor agonists) are associated with decreased cardiovascular disease, mainly driven by reduced stroke risk, and have gained interest as therapeutic agents for stroke recovery in experimental stroke models. This review aims to evaluate the current data on the effect and safety of GLP-1 RA in nondiabetic patients with ischemic stroke and in animal models of cerebral ischemia. We will describe its potential neuroprotective mechanisms. METHODS: On June 20, 2024, keyword-based literature searches were conducted in PubMed and Embase and repeated on March 6, 2025. Records evaluating GLP-1-based therapies in animals and patients with ischemic stroke who did not have diabetes were included. RESULTS: In total, 35 studies, 31 preclinical and 4 clinical, applying 9 different GLP-1 therapies were reviewed. GLP-1 RA improved functional outcome and induced a marked infarct volume reduction compared with vehicle (placebo) in preclinical animal stroke models. The proposed mechanisms include reduced oxidative stress, hypoxia-triggered cell death, and inflammatory response following acute ischemic stroke. Despite these neuroprotective effects observed in stroke models, evidence for improved clinical outcomes in humans remains limited. Recent randomized trials have not shown a significant effect on stroke incidence or neurological recovery in patients without diabetes who are treated with GLP-1 RA. GLP-1 RA appears safe and well-tolerated in both acute and chronic settings. CONCLUSIONS: GLP-1 RA improves functional outcome and reduces infarct volume in preclinical animal stroke models without diabetes. Translating these promising preclinical findings into clinical benefits remains a key challenge and a critical opportunity for future research.