GLP-1 Receptor Agonist in Primary Intracerebral Hemorrhage: A Phase 2 Randomized Trial

Plain-language summary

Intracerebral hemorrhage (ICH) is a devastating form of acute stroke with poor clinical outcomes. Although ICH accounted only for 28.8% of incident strokes, it was responsible for nearly half of the long-term burden of stroke measured in disability-adjusted life years . In contrast to the improving outcomes seen in ischemic stroke with advances in reperfusion therapy, outcomes of patients with ICH have shown little progress over the past two decades. Current standard care focuses primarily on blood pressure control and supportive management, yet rate of functional independence remained modest. Randomized evidence suggested that fewer than half of the ICH patients achieved independent activities of daily living even with intensive blood pressure lowering. A cascade of pathophysiological events is thought to determine the prognosis of ICH. First, the mass effect of the hematoma and its expansion with uncontrolled blood pressure cause primary neuronal injury. Second, neuroinflammation involving blood-brain barrier (BBB) dysfunction, activated microglia and astrocytes, together with neutrophil infiltration in response to extravascular blood, propagates neuronal injury, leading to perihematomal edema. Third, the direct neurotoxicity of blood breakdown products and oxidative stress may further amplify neuroinflammation. Mitigating hematoma expansion through intensive blood pressure control therefore only addresses one of these three pathophysiological processes, and is constrained by a short treatment window, mostly within 6 hours. Therapeutic strategies targeting secondary neuroinflammation should therefore be actively pursued. In addition, multimodal studies incorporating longitudinal imaging and omics markers are needed to elucidate the key pathways mediating neuroinflammation following ICH. Recent preclinical evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RA) may offer neuroprotective benefits in ICH. In animal models of ICH, intracerebroventricular liraglutide suppressed neuroinflammation, prevented brain edema, and reduced neurologic deficits. Previous work from our group has also shown that, across several animal models, GLP-1RA attenuates BBB dysfunction and suppresses neuroinflammatory signaling via microglial modulation. Importantly, a recent translational clinical trial by our team has also provided preliminary evidence that GLP-1RA exerts neuroprotective effects in patients with large vessel occlusion strokes. We therefore hypothesize that compared to standard therapy, administration of GLP-1RA in patients with primary ICH may limit perihaematomal edema, reduce secondary brain injury, and improve neurological outcomes. In this phase 2, randomized, open-label pilot study with blinded endpoint assessment, we aim to determine the safety and signals for efficacy of GLP-1RA in patients with primary ICH.

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