Treatment with the diabetes drug exenatide was associated with a significant decrease in hyperglycemia in acute stroke patients, a new study shows.
The research could offer clinicians an alternative to insulin therapy to treat hyperglycemia and reduce glucose levels, which are elevated in up to 60% of stroke patients and associated with worse outcomes after stroke.
“Use of these diabetes drugs to control glucose in acute stroke has enormous potential,” said lead researcher Christopher Bladin, PhD, professor of neurology at Monash University and Eastern Health Clinical School, Australia.
The findings were presented May 6 at the European Stroke Organisation Conference (ESOC) 2022 annual meeting in Lyon, France.
A Better Fix Than Insulin?
Hyperglycemia is common in stroke patients, including those who have no prior history of diabetes. Among stroke patients with normal blood glucose upon admission, about 30% will develop hyperglycemia within 48 hours of stroke onset.
Previous research suggests that hyperglycemia is a poor prognostic factor in patients with stroke and may reduce the efficacy of reperfusion therapies such as thrombolysis and mechanical thrombectomy.
“We’ve been looking for different ways of treating hyperglycemia for quite some time and one of the obvious ways is to use insulin therapy,” Bladin said. “But as we’ve seen from multiple studies, insulin therapy is difficult.”
Insulin treatment is resource-heavy, significantly increases the risk for hypoglycemia, and some studies suggest the therapy isn’t associated with better outcomes.
An advantage to a GLP-1 agonist-like exenatide, Bladin added, is that it’s glucose-dependent. As the glucose level falls, the drug’s efficacy diminishes. It is delivered via an autoinjector and easy to administer.
A Case for More Study
To study exenatide’s efficacy in reducing hyperglycemia and improving neurologic outcomes, researchers developed the phase 2, international, multicenter, randomized controlled TEXAIS trial.
The study enrolled 350 patients following an ischemic stroke. Within 9 hours of stroke onset, patients received either standard care or a subcutaneous injection of 5 mg of exenatide twice daily for 5 days.
On admission, 42% of patients had hyperglycemia, defined as blood glucose > 7.0 mmol/L.
The study’s primary outcome was at least an 8-point improvement in National Institutes of Health Stroke Scale (NIHSS) score by 7 days after treatment with exenatide. Although there was a trend toward better scores with exenatide, the score was not significantly different between groups (56.7% with standard care vs 61.2% with exenatide; adjusted odds ratio, 1.22; P = .38).
However, when the researchers examined hyperglycemia frequency, they found significantly lower incidence in patients treated with exenatide (P = .002).
There were no cases of hypoglycemia in either group, and only 4% of the study group reported nausea or vomiting.
“Clearly exenatide is having some benefit in terms of keeping glucose under control, reducing hyperglycemia,” Bladin said. “It certainly lends itself to a larger phase 3 study which can look at this more completely.”
Value to Clinicians
Commenting on the findings for Medscape Medical News, Yvonne Chun, PHD, honorary senior clinical lecturer at University of Edinburgh, United Kingdom, noted that, even though the study didn’t find a significant association with improved neurological outcomes, the reduced risk for hypoglycemia makes exenatide an attractive alternative to insulin therapy in stroke patients.
”The results are of value to clinicians as exenatide could potentially be a safer medication to administer than an insulin infusion in acute stroke patients with hyperglycemia,” Chun said. “There is less risk of hypoglycemia with exenatide compared to standard care.”
However, Chun noted that more study is needed before exenatide can replace standard care. Bladin agrees and would like to pursue a phase 3 trial with a modified design to answer questions raised by Chun and others.
“The next phase could consider changing the primary outcome to an ordinal shift analysis on modified Rankin Scale — a very commonly used primary outcome in stroke clinical trials to assess improvement in disability,” Chun said. “The primary outcome used in the presented trial — an 8-point improvement on NIHSS — seemed too ambitious and does not inform disability of the patient post-stroke.”
Bladin said he would also like to see the next phase enroll more patients, examine a higher dose of exenatide, and include better stratification of patients with a history of diabetes. Such a trial could yield findings demonstrating the drug’s effectiveness at reducing hyperglycemia and improving outcomes after stroke, he said.
“I can see the day patients will come in with acute stroke and as they’re coming into the emergency department, they’ll simply get their shot of exenatide because we know it’s safe to use and it doesn’t cause hypoglycemia,” Bladin said. “And from the moment that patient arrives the glucose control is underway.”
European Stroke Organisation Conference (ESOC) 2022 annual meeting. Abstract #1756. Presented May 6, 2022.
Bladin and Chun reported no relevant financial relationships. Study funding was not disclosed.