Sulfonylurea drugs for people with severe hemispheric ischemic stroke

Large hemispheric infarction (LHI), caused by occlusion of the internal carotid or middle cerebral artery, is the most malignant type of supratentorial ischemic stroke. Due to severe intracranial edema, mortality fluctuates between 53% and 78%, even after the most effective medical treatment. Decompressive craniectomy can reduce mortality by approximately 17% to 36%, but the neurological outcomes are not satisfactory, and there are contraindications to surgery. Therapeutic hypothermia shows promising effects in preclinical research, but it causes many complications, and clinical studies have not confirmed its efficacy. Glibenclamide is a type of sulfonylurea. Preclinical research shows that glibenclamide can reduce mortality and brain edema and improve neurological outcomes in animal models of ischemic stroke. Sulfonylureas may be a promising treatment for individuals with LHI.

To evaluate the effects of sulfonylurea drugs in people with large hemispheric ischemic stroke.

We searched CENTRAL, MEDLINE, Embase, five other databases, and three trials registers. We also searched gray literature sources, checked the bibliographies of included studies and relevant systematic reviews, and used Cited Reference Search in Google Scholar. The latest search date was 23 March 2024.

We included randomized controlled trials (RCTs) that compared sulfonylureas with placebo, hypothermia, or usual care in people with severe hemispheric ischemic stroke.

We used standard Cochrane methods. Our primary outcomes were neurological and functional outcomes. Our secondary outcomes were death, quality of life, adverse events, and complications. We used GRADE to assess the certainty of the evidence for each outcome.

This review includes two RCTs (N = 621): the GAMES-RP trial (glyburide advantage in malignant edema and stroke) and the CHARM trial (phase 3 study to evaluate the efficacy and safety of intravenous BIIB093 (glibenclamide) for severe cerebral edema following large hemispheric infarction). Both studies compared the effects of intravenous glyburide (0.13 mg bolus intravenous injection for the first 2 minutes, followed by an infusion of 0.16 mg/h for the first 6 hours and then 0.11 mg/h for the remaining 66 hours) to placebo. The GAMES-RP trial (N = 86) was conducted in 18 hospitals in the USA (mean age: intervention = 58 ± 11 years; control = 63 ± 9 years); the CHARM trial (N = 535) was conducted in 20 countries across North and South America and Eurasia (mean age: intervention = 60.5 ± 11.17 years; control = 61.6 ± 10.81 years). The overall risk of bias was high in both trials. Neither trial reported neurological outcomes. Compared with placebo, glyburide may result in little to no difference in functional outcomes, assessed with the modified Rankin Scale (range 0 to 4) at 90 days (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.89 to 1.32; P = 0.43; 2 studies, 508 participants; low-certainty evidence), or death (RR 0.78, 95% CI 0.36 to 1.69; P = 0.53; 2 studies, 595 participants; low-certainty evidence). Glyburide likely results in a large increased risk of hypoglycemia (RR 4.66, 95% CI 1.59 to 13.67; P = 0.005; 2 studies, 601 participants; moderate-certainty evidence) compared to placebo. However, it probably results in little to no difference between groups in cardiac events (RR 0.73, 95% CI 0.47 to 1.14; P = 0.17; 2 studies, 601 participants; moderate-certainty evidence), or pneumonia (RR 0.72, 95% CI 0.36 to 1.44; 1 study, 518 participants; moderate-certainty evidence), and may result in little to no difference between groups in neurological deterioration within three days (RR 0.88, 95% CI 0.61 to 1.27; 1 study, 77 participants; low-certainty evidence).

Compared to placebo, intravenous glyburide may have little to no effect on functional outcomes, assessed with the modified Rankin Scale, or mortality. It may also have little to no effect on neurological deterioration within three days, and probably has little to no effect on cardiac events or pneumonia. However, intravenous glyburide probably results in a large increased risk of hypoglycemia. This review includes only two RCTs at overall high risk of bias. We do not have sufficient evidence to determine the effects of sulfonylureas in people with ischemic stroke. More large studies, which include more sulfonylurea drugs with different routes of administration and dosages, and different age groups with ischemic stroke, would help to reduce the current uncertainties.