Use of semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist (RA), is associated with a reduced risk of intracranial haemorrhage (ICH) in patients with large vessel occlusion (LVO) treated with reperfusion therapy and a better functional outcome at 90 days in patients not given intravenous thrombolysis (IVT), according to the findings of the phase II GALLOP trial.
In animal models of ischaemic stroke, GLP-1 RAs have been consistently shown to reduce infarct size, counteract reperfusion injury, and attenuate neuroinflammation. [J Cereb Blood Flow Metab 2021;41:14-30; Br J Pharm 2022;179:677-694; Clin Sci (Lond) 2012;122:473-483] Although one prior phase II randomized trial demonstrated that exenatide, a GLP-1 RA, did not improve neurological recovery at 7 days following mainly mild strokes, the potential neuroprotective effects of GLP-1 RAs remain unexplored in patients with a greater severity of stroke undergoing reperfusion therapy. [Stroke 2023;54:2962-2971]
Researchers from the Affiliated Hospital of Shandong Second Medical University in Linyi, China, and the Chinese University of Hong Kong hypothesized that in LVO stroke patients with salvageable penumbra, successful reperfusion by endovascular therapy (EVT) may harness the therapeutic potential of GLP-1 RAs through enabling better delivery of the agent and its secondary mediators to vulnerable brain tissues with ischaemic injury, counteraction of reperfusion injury and neuroinflammation following restoration of blood flow, and stabilization of the blood–brain barrier (BBB). “Therefore, investigating the use of a potent GLP-1 RA in the context of LVO strokes reperfused by EVT may uncover the neuroprotective effects of GLP-1 RAs in human subjects,” they wrote. [Nat Commun 2025;16:11274]
GALLOP was a phase II, investigator-initiated, prospective, randomized, open-label, blinded-endpoint trial, which randomized 69 patients to receive subcutaneous semaglutide 0.5 mg before arterial puncture and 7 days after EVT, and 71 patients to receive EVT alone.
The primary outcome of achieving a modified Rankin Scale (mRS) of 0–2 (representing minimal to slight disability) at 90 days after LVO occurred in 56.5 vs 54.9 percent of patients in the semaglutide vs EVT alone group. However, use of semaglutide vs EVT alone was associated with a higher likelihood of mRS of 0–1 at 90 days (39.1 vs 29.6 percent; adjusted risk ratio [RR], 1.18; 95 percent confidence interval [CI], 1.01–1.37), as well as a reduced risk of ICH (5.8 vs 15.5 percent; adjusted RR, 0.91; 95 percent CI, 0.83–0.99). No severe adverse events (AEs) were attributed to semaglutide treatment.
IVT was performed in approximately half of the patients in the semaglutide and EVT alone groups. Among those who did not receive IVT, the primary outcome occurred in 64.7 vs 44.1 percent of patients in the semaglutide vs EVT alone group (adjusted RR, 1.18; 95 percent CI, 1.02–1.36). The researchers noted that this finding was unexpected. “GLP-1 RA 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. Downregulation of PAI-1 with coadministration of IVT may thus indirectly potentiate plasmin generation and undesired effects of thrombolytic agents, such as BBB disruption, brain oedema, and neurotoxicity,” they suggested.
“In conclusion, semaglutide treatment did not improve functional recovery in the overall population but was associated with lower risk of ICH and improved neurological outcome in patients who did not receive IVT. These preliminary observations should be confirmed in a large phase III trial,” recommended the researchers.
