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Background Acute ischemic stroke (AIS) is a leading cause of morbidity and mortality, especially among patients with type 2 diabetes mellitus (T2DM). Semaglutide (Ozempic), a glucagon-like peptide-1 receptor agonist (GLP-1 RA), reduces cardiovascular risk, but its effect on stroke outcomes remains unclear. This study evaluated the association between semaglutide use and mortality in AIS patients across nationwide and institutional datasets.Methods We performed a retrospective cohort analysis using two sources: (1) the University of Wisconsin-Madison institutional dataset, and (2) the TriNetX Global Collaborative Network. AIS was identified by ICD-10-CM codes and semaglutide exposure by RxNorm pharmacy records. Propensity score matching on 32 characteristics including stroke severity (NIHSS scores), comorbidities, social determinants of health, and glycemic control (HbA1c) adjusted for confounding. Primary outcome was all-cause mortality at 30 days, 90 days, and 1 year.Results In the nationwide TriNetX cohort, 62,824 propensity score-matched pairs demonstrated substantially reduced mortality at 30 days (1.0% vs. 3.9%; HR 0.243, 95% CI: 0.223-0.265), 90 days (1.5% vs. 5.5%; HR 0.262, 95% CI: 0.244-0.282), and 1 year (2.6% vs. 8.7%; HR 0.270, 95% CI: 0.255-0.285). In the institutional cohort after propensity score matching (n=180 matched pairs), 30-day mortality was 0% vs. 11.1% (p<0.001).Conclusions Semaglutide use was associated with lower mortality following AIS in a large nationwide cohort with propensity score matching that included stroke severity adjustment. These findings are hypothesis-generating and suggest a potential cerebrovascular protective effect, though causality cannot be inferred from observational data. Prospective randomized controlled trials are warranted.Disclosures A. Elbayomy: None. M. Stenerson: None. T. Lhamo: None. A. Ahmed: None. L. Mcguire: None.