Honolulu, Hawaii — The dramatic results of a small study testing an intravenous formulation of a common diabetes drug are causing something of a stir in the stroke community.
Although the GAMES (Glyburide Advantage in Malignant Edema and Stroke) study was open-label and included only 10 patients with large strokes, the mortality rate was only 10%, compared with up to 80% in patients with stroke of similar severity. Furthermore, only 2 of the patients developed malignant edema requiring decompressive craniectomy.
"We're biased, but we believe that this is probably the most exciting treatment in acute stroke since the advent of tPA [tissue plasminogen activator]," said lead researcher Kevin N. Sheth, MD, chief, Division of Neuro-critical care and Emergency Neurology, and chief of clinical research, Department of Neurology, Yale University, New Haven, Connecticut.
In recognition of this work, Dr. Sheth and his research team received the Robert G. Siekert New Investigator Award in Stroke here at the International Stroke Conference (ISC) 2013.
Intravenous Glyburide Formulation
The study included 10 patients with stroke from the University of Maryland and Massachusetts General Hospital who had large stroke volumes, 82 mL or greater on MRI, who were at very high risk for edema and poor outcome. "These are the patients that everyone excludes from their studies because they're so sick and we went after them because they're so sick," said Dr. Sheth.
The mean age of the patients was 51 years. "Often, it's the young patients who swell the most because they don't have atrophy and so they don't have room to swell," commented Dr. Sheth.
The patients were included within 10 hours of symptoms onset. Researchers believe that in humans, swelling starts 8 to 14 hours after a stroke.
Nine of the patients received tPA, which Dr. Sheth said works independently and is complementary to the study treatment drug, but is not always effective in these patients because they have a large occlusion.
All the patients received an injection of the treatment drug, followed by a 72-hour continuous infusion.
Glyburide is a sulfonylurea drug that blocks the NC (Ca-ATP) channel, which is expressed in all components of the neurovascular system and is regulated by the SUR1 receptor. This channel is believed to be implicated in the formation of swelling after ischemia.
An oral formulation of glyburide has been available for decades, but this study used an intravenous preparation (RP-1127) that was developed and patented by Remedy Pharmaceuticals. For use in stroke, the drug has to be delivered intravenously because it must be kept at constant levels and get into the brain, explained Dr. Sheth.
Researchers obtained MRI scans at 24, 48, and 72 hours; carefully monitored glucose levels; and assessed modified Rankin Scale scores for functional outcome.
Only 2 patients developed malignant edema and only 1 had died at 30 days, a young man who, according to Dr. Sheth, had carotid dissection and a brain infarct and may have developed a second infarct. The mortality rate in this stroke population is typically 60% to 80%, said Dr. Sheth.
There were no cardiac problems and no episodes of hypoglycemia with treatment in this study, probably because the dose required to get the antiswelling effect (3 mg/day) is sufficiently low, said Dr. Sheth.
Only 2 patients, including the man who died, received decompressive craniectomy to manage edema.
As for functional outcome, 90% of the patients had 90-day modified Rankin Scale scores of 4 or less and 40% had scores of 3 or less.
Even More Benefit?
These results may have been even better had the patients received the drug earlier. "The patients received the drug at 8 or 9 hours; who's to say we would have gotten even more benefit if they had received it at 30 minutes," said Dr. Sheth.
The research team was very encouraged by these study results. "We were excited because right now we have nothing to offer these patients and they often have a poor outcome, and also because the biology is very interesting and very different from what the stroke field has been doing for the last 2 decades," said Dr. Sheth.
Going forward, the research team is planning to start enrolling patients in a larger (50 patients), blinded, placebo-controlled trial of the drug to look at safety and overall efficacy.
The intravenous formulation of glyburide could potentially be useful in areas outside of stroke, including traumatic brain injury, intracerebral hemorrhage, subarachnoid hemorrhage, spinal cord injury, encephalitis, and other conditions involving central nervous system swelling, said Dr. Sheth. He stressed, however, that this is an "incredibly exploratory" area.
Kyra Becker, MD, professor, neurology and co-director, Stroke Center, University of Washington School of Medicine, Seattle, agreed that the data Dr. Sheth presented are encouraging.
However, she stressed that the study was still a pilot. "A randomized trial really needs to be done before we can be as enthusiastic as perhaps the primary investigators are."
Dr. Becker noted that Dr. Sheth and his work received an "endorsement" from his stroke colleagues in the form of a New Investigator award.
She praised the basic science and the discovery of the ion channel on which the rationale for the study was based. "It's a really brilliant piece of science that could actually dramatically change practice."
This research was supported in part by Remedy Pharmaceuticals. Dr. Sheth received various other awards.
International Stroke Conference (ISC) 2013. Abstract 211. Presented February 6, 2013.
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Cite this: Common Diabetes Drug Could Play a Role in Stroke - Medscape - Feb 15, 2013.