By Alan Z. Segal, MD
Synopsis: An exploratory analysis of the CHARM trial suggests intravenous glyburide may improve outcomes in large hemispheric stroke patients with infarct volumes < 125 mL, particularly alongside thrombectomy, reducing edema, mortality, and the need for decompressive surgery, and highlighting a potential neuroprotective role.
Source: Kimberly WT, Saver JL, Campbell BCV, et al. Intravenous glyburide in medical and endovascular-treated large-core stroke: A subgroup analysis of the CHARM randomized clinical trial. Ann Neurol. 2025;98(3):616-624.
Neuronal death in stroke occurs directly as the result of ischemia, but it also results from secondary injury processes, such as malignant edema. One contributor to this edema is the sulfonylurea receptor 1-transient receptor potential melastatin 4 (SUR1-TRPM4) channel. Activation leads to a sustained influx of sodium, followed by water, oncotic cell swelling, and death. The receptor is upregulated by adenosine triphosphate (ATP) depletion and blocked by glyburide, leading to the hypothesis that glyburide might provide a neuroprotective benefit in acute ischemic stroke.
Two prior studies of intravenous glyburide have been negative. This includes the Glyburide Advantage in Malignant Edema (GAMES-RP) study and Glibenclamide for Large Hemispheric Infarction Analyzing mRS and Mortality (CHARM) study.1,2 Both GAMES-RP and CHARM enrolled patients with large hemispheric strokes, in the 80 mL to 300 mL range, many of whom were treated with endovascular reperfusion therapy (EVT). Patients in the upper end of this size spectrum were unsalvageable regardless of treatment, but a subset with core infarct volumes in the 80 mL to 125 mL range showed benefit from EVT. However, this effect was blunted by early neurological deterioration (END) and significant 90-day morbidity and mortality despite short-term improvements. It is these patients who might show potential benefit from a neuroprotective therapy (such as glyburide) to augment the benefits of EVT.
In the current study, the CHARM investigators performed an exploratory analysis on the 327/431 patients in the original trial who had available data on stroke volume by computed tomography (CT) perfusion or diffusion magnetic resonance imaging (MRI). A subset of 147 subjects had infarcts in the < 125 mL range. Among these, using shift analysis, there was an odds ratio of 2.11 favoring glyburide treatment.
When results were dichotomized according to modified Rankin Scale (mRS) score 0-3 (retaining the ability to walk) vs. 4-6, the odds ratio favoring the drug was 4.07. When specifically analyzing patients in the 80 mL to 120 mL range, the favorable odds ratio in shift analysis was 2.50 and was 6.33 in the dichotomized calculation. There was a synergistic effect of glyburide and EVT, with a favorable odds ratio of 8.19 favoring glyburide in patients who underwent thrombectomy. This group also showed fewer decompressive craniectomies (0% glyburide-treated compared to 25% placebo), less midline shift (4.2 mm vs. 7.6 mm), and reduced 90-day mortality (5.6% vs. 31%). Additionally, the study included a meta-analysis with pooled data from CHARM and GAMES-RP. This showed a similar 125 mL threshold, above which glyburide did not provide significant benefit.
Commentary
As the authors note, development of efficacious stroke interventions is dependent on the “instructive nature of serial trials,” as “neutral trials provide key lessons” regarding the identification of target patient populations and tailoring of interventions. Given the dearth of expensive optimal placebo-controlled randomized clinical trials with positive primary endpoints, exploratory investigations such as this one can provide useful insights. They are not sufficient to modify practice.
The question is not whether glyburide has any biological effect, but whether we can apply the “Goldilocks principle” to its study and use. Studies of EVT have optimized patient selection to successfully extend beyond the initial “medium size” target population to both small and large core infarcts, including late time windows and additional populations, such as in the vertebrobasilar system. In contrast, studies of neuroprotective strategies, many funded by the pharmaceutical industry in search of the broadest possible indication, have been considerably more challenging. Failed drugs include, among many others, drugs targeting free radical injury (NXY-059), glutamate-mediated excitotoxic damage (Cerestat), and inflammation (enlimobab). The current National Institutes of Health-funded study, despite its limitations, does provide encouragement that glyburide is not yet ready to be added to this trash heap.
Alan Z. Segal, MD, is Associate Professor of Neurology, Weill Cornell Medicine.
References
1. Sheth KN, Albers GW, Saver JL, et al. Intravenous glibenclamide for cerebral oedema after large hemispheric stroke (CHARM): A phase 3, double-blind, placebo-controlled, randomised trial. Lancet Neurol. 2024;23(12):1205-1213.
2. Sheth KN, Elm JJ, Molyneaux BJ, et al. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): A randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol. 2016;15(11):1160-1169.
