Abstract Body: Background: Glucagon-like peptide-1 receptor agonists (GLP1-RA) demonstrated neuroprotective effects in animal stroke models. We aimed to determine the safety and signals for efficacy of semaglutide, a GLP-1RA, in patients with acute large vessel occlusion (LVO) strokes undergoing endovascular therapy (EVT).
Methods: In a phase 2 investigator-initiated, prospective, randomized, open-label, blinded endpoint trial conducted at four hospitals in China, adult patients with disabling LVO who presented within 12 hours of last-known-well were randomized into semaglutide (0.5mg before and 1 week after EVT) or standard therapy. Intravenous thrombolysis (IVT) was administered if indicated. Primary safety outcome was a composite of death, malignant brain edema, and symptomatic intracerebral hemorrhage. Primary efficacy outcome was favourable neurological recovery (modified Rankin Scale [mRS] 0-2 at 90 days). Intention-to-treat analysis was performed adjusting for age, premorbid mRS, IVT use, stroke severity on presentation, last-known-well-to-puncture time, modified Thrombolysis in Cerebral Infarction score and Alberta Stroke Program Early CT Score.
Results: Between August 2023, and July 2024, 140 patients were enrolled and randomly assigned to semaglutide (n=69) or standard therapy (n=71). Mean age of patients was 68.2±10.9 years, 46 (32.9%) were female. Primary safety outcome occurred in 16 (23.2%) in the semaglutide group and 17 (23.9%) in the standard therapy group (adjusted RR 0.91, 95%CI 0.77–1.07, p=0.258). Primary efficacy outcome occurred in 39 (56.5%) in the semaglutide group and 39 (54.9%) in the standard therapy group (adjusted risk ratio 1.17, 95%CI 1.01–1.36, p=0.038). Secondary analyses stratified by IVT status were conducted in view of the small absolute risk difference in primary efficacy outcome, and evidence of treatment effect modification by IVT (P_interaction 0.018). Primary efficacy outcome occurred in 22 (64.7%) patients in the semaglutide group and 15 (44.1%) patients in the standard therapy group (adjusted risk ratio 1.17, 95%CI 1.01–1.35, p=0.032) in the no-IVT stratum (n=68). Primary outcomes were similar between two groups in the IVT-stratum.
Conclusion: Semaglutide was safe and well-tolerated in patients with LVO within 12 hours of onset and was associated with improved neurological outcome in patients not receiving IVT. These preliminary observations should be confirmed in a large phase 3 trial. (NCT05920889)