Safety and efficacy of glibenclamide on functional outcomes in ischemic and hemorrhagic stroke: a systematic review and meta-analysis of randomized clinical trials

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 Safety and efficacy of glibenclamide on functional outcomes in ischemic and hemorrhagic stroke: a systematic review and meta-analysis of randomized clinical trials

Ola Bin Shilash^1,2*Hussam Alhathlol^1,2Rana Alduhaysh^1,2Razan Almufarriji³Mohammed Bafaquh⁴

• ¹College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
• ²King Abdullah International Medical Research Center, Riyadh, Saudi Arabia
• ³Department of Neurosurgery, National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia
• ⁴Department of Neuro-Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia

Background: Secondary brain injuries, including delayed cerebral ischemia, neuroinflammation, and stroke induced cerebral edema can occur following both ischemic and hemorrhagic strokes, contributing to a negative impact on clinical outcomes. Glibenclamide, a sulfonylurea antidiabetic medication, has shown potential in minimizing these consequences by targeting the SUR1-TRPM4 channel. However, glibenclamide’s therapeutic effectiveness and safety in stroke patients remain unknown. Therefore, this systematic review aims to assess the safety and efficacy of glibenclamide in improving outcomes following both ischemic and hemorrhagic strokes.

Methods: Four databases were searched for RCTs published up to November 2024. Studies were included if they involved adult patients with ischemic stroke, hemorrhagic stroke, or subarachnoid hemorrhage, and reported relevant safety and efficacy outcomes. Efficacy outcomes were measured using the Modified Rankin Scale at 3 and 6 months. Safety outcomes included adverse events such as hypoglycemia, hydrocephalus, and mortality.

Results: Data from six RCTs, involving 555 patients (280 intervention, 275 control), were included: 4 trials in subarachnoid hemorrhage, one trial in ischemic stroke, and one in hemorrhagic stroke. At 3 months, the pooled odds ratio (OR) for poor functional outcomes was 0.98 (95% CI: 0.65–1.48), and at 6 months, 0.52 (95% CI: 0.24–1.12; p = 0.094), with no significant differences between glibenclamide and placebo. Safety analysis showed a significant increase in symptomatic hypoglycemia (OR 4.69, 95% CI: 1.45–15.23; p = 0.010) but no significant differences for hydrocephalus (OR 1.60, 95% CI: 0.76–3.37; p = 0.220) or mortality (OR 0.57, 95% CI: 0.32–1.05; p = 0.071). Delayed cerebral ischemia (DCI) showed a borderline reduction in risk (OR 0.43, 95% CI: 0.18–1.00; p = 0.051) in the treatment group.

Conclusion: In patients with ischemic or hemorrhagic stroke, glibenclamide demonstrates a favorable safety profile but shows limited efficacy in improving functional outcomes. The elevated risk of hypoglycemia emphasizes the necessity of using this medication with caution.

Introduction

Stroke remains one of the leading causes of morbidity and mortality globally, with an increasing burden due to rising incidents and prevalent cases over the past three decades (1). It is broadly categorized into ischemic stroke, caused by vascular occlusion, and hemorrhagic stroke, which includes intracerebral hemorrhage (ICH) (2). Despite advancements in acute stroke care, such as improved diagnostic tools and interventions, long-term outcomes remain suboptimal due to secondary complications like neuroinflammation, cerebral edema, and delayed neuronal injury (1, 2). This highlights the urgent need for novel therapeutic approaches targeting these mechanisms. Current treatments primarily concentrate on managing the acute phase, including reperfusion intervention (1, 2). Nevertheless, there is a considerable deficiency in therapies aimed at the molecular mechanisms that contribute to secondary injury (3). Glibenclamide, a well-known sulfonylurea antidiabetic medication, is one promising therapeutic approach. Glibenclamide works by blocking the sulfonylurea receptor 1 (SUR1)—transient receptor potential melastatin 4 (TRPM4) channel complex, which is essential in the pathophysiology of many central nervous system (CNS) injuries, including aSAH (4). The activation of the SUR1-TRPM4 channel has been linked to vasogenic edema, neuroinflammation aggravation, and neuronal integrity impairment. Glibenclamide, which targets this channel, has the ability to minimize cerebral edema, limit neuronal death, and reduce inflammation, therefore enhancing neurological recovery (5). Preclinical research has provided solid evidence for glibenclamide’s neuroprotective properties (6). In animal models of ischemic brain damage, glibenclamide treatment has been demonstrated to decrease vasogenic edema, reduce infarct volume, and enhance functional recovery (6). Building on this basis, preliminary clinical studies have assessed the function of glibenclamide in the setting of stroke. For example, recent research found that high-dose oral glibenclamide significantly reduced radiological indicators of cerebral edema during 10 days of therapy, implying possible advantages in preventing decompressive surgeries (7). Other trials, however, have shown conflicting results, with some failing to detect substantial increases in functional outcomes or decrease in mortality rates (3). While preliminary data suggests that it can minimize vasospasm and enhance perfusion, inconsistencies in research design, dosage regimens, and outcome measures have restricted the generalizability of findings (5). Furthermore, some concerns do exist about glibenclamide’s safety profile, including its possible impact on glucose homeostasis and other systemic side effects in non-diabetics (4, 8, 9).

To overcome these gaps, this systematic review and meta-analysis will analyze data from randomized controlled trials to assess the effectiveness and safety of glibenclamide in stroke. This study aims to clarify the influence of glibenclamide on major clinical outcomes.

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