GLP-1RAs significantly cut stroke and mortality risk in asymptomatic intracranial atherosclerotic disease

Asymptomatic intracranial atherosclerotic arterial stenosis (ICAS) is an underrecognized condition lacking specific primary stroke prevention strategies beyond general vascular risk-factor optimization. Current guidelines do not recommend routine antiplatelet therapy or endovascular intervention for primary prevention in these patients. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are known to reduce major adverse cardiovascular events, including stroke, in high-risk cardiometabolic populations, but their specific impact on outcomes in individuals with asymptomatic ICAS has remained unexamined.

This real-world, propensity-score matched cohort study utilized the TriNetX US Collaborative Network (71 healthcare organizations) to identify adults (≥18 years) with an ICAS diagnosis between January 1, 2016, and December 31, 2025. Patients with prior cerebral infarction, intracranial hemorrhage, or cerebrovascular ischemic syndromes were excluded. Exposure was defined as initiation of any GLP-1 receptor agonist (lixisenatide, semaglutide, liraglutide, tirzepatide, dulaglutide) within 6 months before or on the index ICAS diagnosis date. Outcomes, assessed at 1 year, included ischemic stroke, all-cause mortality, and a composite of ischemic stroke or mortality. Propensity-score matching (1:1) was performed to balance demographics, vascular risk factors, comorbidities, and relevant therapies.

Before 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 significantly associated with a lower 1-year risk of ischemic stroke, observed at 4.40% in users versus 6.10% in non-users (hazard ratio [HR] 0.70, 95% CI 0.52-0.95; p = 0.044). The most pronounced effect was on all-cause mortality.

GLP-1RA users experienced a substantially lower 1-year all-cause mortality rate of 3.40% compared to 9.40% in non-users (HR 0.35, 95% CI 0.26-0.47; p < 0.001). Furthermore, the composite outcome of ischemic stroke or mortality was also significantly reduced in GLP-1RA users (7.50% vs. 15.00%; HR 0.48, 95% CI 0.39-0.59; p < 0.001). These associations suggest a protective effect of GLP-1RAs in this specific high-risk population.