Negida, Yasmin

Abstract Background Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefits in type 2 diabetes mellitus (T2DM); however, their association with post-stroke outcomes following acute ischemic stroke (AIS) remains uncertain. Methods We conducted a retrospective propensity score-matched (PSM) cohort study using the TriNetX Global Collaborative Network. Adults with T2DM and AIS between January 2020 and January 2025 were included. Pre-stroke GLP-1 RA users were compared with non-users. Primary outcomes were all-cause mortality, intracerebral hemorrhage (ICH), ICD-10-coded stroke severity (NIHSS categories), and transient ischemic attack (TIA). Results After PSM, GLP-1 RA use was associated with significantly lower all-cause mortality at all time points (RR 0.44–0.52; HR 0.43–0.45; all p<0.001). ICH risk was reduced within 1–3 days (RR 0.683; 95% CI 0.496–0.940; p=0.019) and within 7 days (RR 0.575; 95% CI 0.516–0.641; p<0.001). A severity-dependent gradient was observed across NIHSS categories, with risk reductions ranging from 37% for minor strokes (NIHSS 0–5; RR 0.626) to 67% for very severe strokes (NIHSS >20; RR 0.327; all p<0.001). TIA risk was 29% lower (RR 0.712; 95% CI 0.668–0.759; p<0.001). E-value analysis demonstrated that an unmeasured confounder would need to be associated with both GLP-1 RA use and 30-day mortality by a risk ratio of at least 3.95 to fully explain the observed association, and by a risk ratio of at least 3.53 to shift the confidence interval to include the null. Conclusions In this large real-world cohort, pre-stroke GLP-1 RA use was associated with lower post-stroke mortality, reduced ICH, and a severity-dependent reduction in ICD-10-coded stroke severity among patients with T2DM. Residual confounding cannot be excluded, and these findings warrant confirmation in prospective randomized trials.