Association of Glucagon-like Peptide-1 Receptor Agonist Use with Stroke and Mortality Outcomes in Asymptomatic Intracranial Atherosclerotic Disease: Propensity Score-Matched Real-World Analysis

Journal article

BackgroundAsymptomatic intracranial atherosclerotic arterial stenosis (ICAS) is an underrecognized entity for which vascular risk-factor optimization is the primary management strategy, with no current indication for routine antiplatelet therapy or endovascular intervention for primary stroke prevention. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events, including stroke, in high-risk cardiometabolic populations, but their association with outcomes in asymptomatic ICAS is yet to be evaluated. The present study aims to evaluate the association between GLP-1RA use and cerebrovascular outcomes in adults with asymptomatic ICAS.Materials and methodsWe used the TriNetX US Collaborative Network (71 healthcare organizations) to identify adults (≥18 years) with ICAS between 1 January 2016 and 31 December 2025, and excluded patients with prior cerebral infarction, intracranial hemorrhage, or cerebrovascular ischemic syndromes. Exposure was defined as initiation of any GLP-1 receptor agonist (lixisenatide, semaglutide, liraglutide, tirzepatide, dulaglutide) during the 6 months before or on the date of index ICAS diagnosis. Outcomes were assessed at 1 year, and included ischemic stroke, all-cause mortality, and a composite of ischemic stroke or mortality. Propensity-score matching (1:1) was performed, including demographics, vascular risk factors, comorbidities, antithrombotics, lipid/diabetes therapies, and cardiometabolic laboratory/physiologic measures.ResultsBefore matching, 1746 GLP-1RA users and 71,792 non-users met inclusion criteria; after matching, 1728 patients remained in each cohort. GLP-1RA use was associated with lower 1-year risk of ischemic stroke (4.40% vs. 6.10%; hazard ratio [HR] 0.70, 95% CI 0.52-0.95; p = 0.044), lower all-cause mortality (3.40% vs. 9.40%; HR 0.35, 95% CI 0.26-0.47; p < 0.001), and lower composite outcome risk (7.50% vs. 15.00%; HR 0.48, 95% CI 0.39-0.59; p < 0.001). Notably, these associations were observed despite matching for HbA1c, LDL cholesterol, BMI, and systolic blood pressure, suggesting potential effects beyond measured cardiometabolic risk profiles.ConclusionsIn this large, propensity-matched cohort of adults with a-ICAS, GLP-1RA use was associated with lower ischemic stroke, all-cause mortality, and composite outcome at 1 year. These findings are hypothesis-generating and require further prospective studies to confirm this observation.

Authors: Rai, P; Mandel, D; Bathla, G; Dhaduk, V; Rajeev, R

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: MDPI
• Journal: Neurology International
• Volume: 18
• Issue: 5
• Pages: 98
• Publication date: 2026-05-21
• DOI: 10.3390/neurolint18050098
• EISSN: 2035-8377
• ISSN: 2035-8385
• Pmid: 42188698
• Language: English
• Keywords: Propensity Matching; Glucagon-like Peptide 1 Agonists; Mortality; Semaglutide; Intracranial Atherosclerosis; Stroke