Semaglutide Linked to Improved Neurological Outcomes in Large Vessel Occlusion Without IV Thrombolysis

A recently published phase 2, investigator-initiated, randomized trial of patients with disabling large-vessel occlusion (LVO) showed that use of semaglutide (Ozempic; Novo Nordisk) before and after endovascular thrombectomy (EVT) did not lead to improved functional recovery; however, an exploratory analysis revealed more sustained neurological improvement among those who did not receive intravenous thrombolysis (IVT).¹

Published in Nature, the findings also showed that semaglutide was safe and well-tolerated for this patient population, and was also associated with a lower risk of intracranial hemorrhage (ICH). Otherwise known as the GALLOP trial, the study authors noted that these preliminary findings should be replicated in a larger phase 3 study.

In this prospective, open-label, blinded end point (PROBE) trial, 140 patients with disabling LVO undergoing EVT were randomly assigned to semaglutide therapy (0.5 mg subcutaneous [SC] before and 1 week after EVT) or standard therapy, using modified Rankin Scale (mRS) scores of 0-2 at 90 days as the primary outcome. During this time period, from August 2023 to July 2024, the primary outcome occurred in 56.5% (n = 39) of patients in the semaglutide group and in 54.9% (n = 39) of those in the standard therapy group, suggesting no between-group differences (adjusted RR, 1.05; 95% CI, 0.95-1.15; P = .37).

Led by Bonaventure Y. Ip, MBChB, MRCP, FHKCP, an assistant professor in the department of Medicine & Therapeutics at The Chinese University of Hong Kong, treatment effect modification was observed through IVT on semaglutide (P interaction = 0.02); thus, an exploratory analysis was performed. In patients who did not receive IVT, the primary outcome occurred in 22 (64.7%) patients in the semglutide group (n = 34) and 15 (44.1%) patients in the standard therapy group (n = 34; adjusted RR, 1.18; 95% CI, 1.02-1.36). Among those who received IVT, the primary outcome occurred in 17 (48.6%) patients in the semaglutide group and 24 (64.9%) patients in the standard therapy group (adjusted RR, 0.96; 95% CI, 0.85-1.08).

In the exploratory analysis, median last-known-well–to–puncture time was shorter in the IVT stratum compared with the no-IVT stratum (262 [171–397] minutes vs 359 [248–521] minutes; P = 0.002). Proportional odds ordinal logistic regression analyses indicated a treatment-by-IVT interaction effect on the ordinal mRS shift. In the no-IVT stratum, semaglutide therapy was associated with a shift toward better functional outcomes (adjusted OR, 2.92; 95% CI, 1.21–7.2).

At 90 days, there was a higher proportion of patients in the no-IVT stratum with mRS scores of 0-1 (44.1% vs 26.5%; adjusted RR, 1.18; 95% CI, 1.02-1.37) and 0-3 (73.5% vs 55.9%; adjusted RR, 1.14; 95% CI, 1.00-1.30) with semaglutide therapy. In addition, treatment with the GLP-1 within this sub-cohort led to greater reduction in day 3 National Institutes of Health Stroke Scale (NIHSS) scores (−8 [−12, −4] vs. −3.5 [−6, −0.8]), and a lower day-3 blood glucose (6.4 [±1.4] mmol/L vs. 7.8 [±3.1] mmol/L).

READ MORE: Repositioning GLP-1 Drugs for Neurologic Disease: Evidence, Advances, and Outlook

"The treatment effect modification observed with IVT on semaglutide was unexpected," Ip et al wrote. "At present, there are no available preclinical or clinical studies that evaluated potential interactions between semaglutide and tenecteplase or alteplase. Any potential pharmacokinetic interaction between GLP-1RA and tissue plasminogen activators should be excluded. On the other hand, GLP-1RA may inhibit the expression of plasminogen activator inhibitor-1 (PAI-1), a molecule that inhibits tissue plasminogen activators and the conversion of plasminogen to plasmin."

They added, "Downregulation of PAI-1 with co-administration of IVT may thus indirectly potentiate plasmin generation and undesired effects of thrombolytic agents, such as BBB disruption, brain edema, and neurotoxicity. Nonetheless, these postulations require further confirmation. Importantly, the interaction between semaglutide and IVT could be confounded by time metrics, as IVT administration is a proxy of early presentation."

In the overall cohort predating exploratory analyses, the composite safety outcome, which comprised death, malignant brain edema, and ICH, occurred in 23.2% (n = 16) of semaglutide-treated patients vs 23.9% (n = 17) of those in the standard therapy group (adjusted RR, 0.99; 95% CI, 0.89-1.11). Notably, semaglutide was associated with a lower risk of ICH (5.8% vs 15.5%; adjusted RR, 0.91; 95% CI, 0.83-0.99) and a higher likelihood of mRS 0-1 at 90 days (39.1% vs 29.6%; adjusted RR, 1.18; 95% CI, 1.01-1.37).

In terms of safety, the rate of death occurred at a similar frequency between the semaglutide (15.9%) and standard therapy group (15.4%; unadjusted RR, 1.00; 95% CI, 0.9-1.11). Symptomatic ICH, defined as ICH with NIHSS increase of at least 4 points, was found in 1 patient (1.4%) in the semaglutide group vs 7 (9.9%) patients in the standard therapy group (unadjusted RR, 0.92; 95% CI, 0.85-0.98).

Prior to the GALLOP study, there has been minimal work done exploring the use of GLP-1s like semaglutide in acute ischemic stroke. The most notable trial to date was the phase 2 TEXAIS trial, which showed that use of exenatide in patients with acute ischemic stroke within 9 hours of onset did not have benefit on the primary end point of NIHSS improvement at 7 days post-stroke.² The GALLOP trial differed from TEXAIS by enrolling only patients with severe ischemic stroke eligible for EVT, thereby avoiding milder cases with limited therapeutic window, and by using semaglutide—which may offer greater cardiovascular and anti-inflammatory benefits than exenatide—potentially creating conditions more comparable to transient MCA occlusion models.²

REFERENCES
1. Wang H, Ko H, Leung TW, et al. Glucagon-like peptide-1 receptor agonist in large vessel occlusion treated by reperfusion therapy—a phase 2 randomized trial. Nat Commun. Published online December 19, 2025. doi:10.1038/s41467-025-66167-z
2. Bladin, C. F. et al. Management of poststroke hyperglycemia: results of the TEXAIS randomized clinical trial. Stroke. 2023;54:2962–2971. doi:10.1161/STROKEAHA.123.044568