Glucose Management in Acute Stroke: results of the TEXAIS study

Hyperglycemia after acute stroke is a common phenomenon, reported in up to one third of acute stroke patients, affecting both diabetic and non-diabetic patients.¹ Admission hyperglycemia has been associated with a pathophysiological sequalae that may lead to poor outcomes in stroke patients, including higher mortality and unfavorable functional recovery post-stroke.^1,2 In ischemic stroke patients receiving reperfusion therapies, increased glucose values at admission have also been related with lower recanalization rates^3,4 and higher likelihood of symptomatic intracranial hemorrhage.^3,5 Therefore, appropriate glucose management in the acute setting is expected to lead to better functional results of the stroke patients.

Yet, the results of the largest-to-date study in the field, the SHINE trial, did not demonstrate any significant difference in efficacy outcomes among acute stroke patients administered intensive treatment with continuous intravenous insulin compared to the standard of care.⁶ On the other hand, the patients receiving the intensive treatment showed significantly more hypoglycemic episodes.⁶ Following the somewhat discouraging results of the SHINE trial, testing of other hypoglycemic treatment options that take hypoglycemic risk and glycemic variability into account was thought to be of significant value. Glycemic variability is considered the third component of dysglycemia (along with hyperglycemia and hypoglycemia) and has been also associated with lower likelihood of recovery among acute stroke patients.

Recently, during the ESOC 2022, the result of TEXAIS (Trial of EXenatide in Acute Ischaemic Stroke) trial were presented.^7,8 In this phase II, multi-center, prospective, randomized, open label, blinded endpoint (PROBE) trial, acute ischemic stroke patients were randomized to receive subcutaneous injections of exenatide (n=177) versus standard of care (n=173). Hypoglycemic treatment was initiated within 9 hours of symptom onset and was administered for a total duration of 5 days. The advantage of exenatide, which is a glucagon-like peptide 1 (GLP-1) agonist, is that its action is blood glucose-dependent, meaning that exenatide has no effect when blood glucose values return to normal, thus protecting from downward fluctuations and hypoglycemia.

TEXAIS study showed that, indeed, glucose correction was more stable in the exenatide-treatment group, considering that the daily frequency of hyperglycemic episodes was significantly lower in the active group compared to the usual care. Importantly, no hypoglycemic episodes were recorded in any of the treatment groups. Yet, stroke outcomes were again neutral; no difference was noted regarding the neurological improvement at 7 days or the functional outcomes at 3-months. However, the study was terminated early due to COVID-19-related constraints and was ultimately of limited power to show statistically significant efficacy results.

Professor Christopher Bladin that presented the results on behalf of the TEXAIS investigators, highlighted that the favorable safety profile and the successful glucose management following exenatide treatment are quite promising and should justify a larger phase III trial. Surely, as in the case of blood pressure management, a more individualized approach for glucose management in the acute stroke setting, using agents and algorithms that prevent glucose fluctuations, should be pursued.

Conflict of interest statement

Dr. Palaiodimou reports no conflicts of interest.

References

1. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyperglycemia and prognosis of stroke in nondiabetic and diabetic patients: a systematic overview. Stroke. 2001;32(10):2426-2432.
2. Bruno A, Biller J, Adams HP, Jr., et al. Acute blood glucose level and outcome from ischemic stroke. Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators. Neurology. 1999;52(2):280-284.
3. Poppe AY, Majumdar SR, Jeerakathil T, Ghali W, Buchan AM, Hill MD. Admission hyperglycemia predicts a worse outcome in stroke patients treated with intravenous thrombolysis. Diabetes Care. 2009;32(4):617-622.
4. Ribo M, Molina C, Montaner J, et al. Acute hyperglycemia state is associated with lower tPA-induced recanalization rates in stroke patients. Stroke. 2005;36(8):1705-1709.
5. Goyal N, Tsivgoulis G, Pandhi A, et al. Admission hyperglycemia and outcomes in large vessel occlusion strokes treated with mechanical thrombectomy. J Neurointerv Surg. 2018;10(2):112-117.
6. Johnston KC, Bruno A, Pauls Q, et al. Intensive vs Standard Treatment of Hyperglycemia and Functional Outcome in Patients With Acute Ischemic Stroke: The SHINE Randomized Clinical Trial. Jama. 2019;322(4):326-335.
7. Bladin C, on behalf of the TEXAIS Investigators. Trial of EXenatide in Acute Ischaemic Stroke (TEXAIS). ESOC 2022. May 6, 2022.
8. Muller C, Cheung NW, Dewey H, et al. Treatment with exenatide in acute ischemic stroke trial protocol: A prospective, randomized, open label, blinded end-point study of exenatide vs. standard care in post stroke hyperglycemia. Int J Stroke. 2018;13(8):857-862.

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