Tirzepatide in Thrombectomy-Treated Acute Ischemic Stroke: A Randomized Trial

Acute ischemic stroke caused by blockage of a large artery in the brain is one of the leading causes of death and long-term disability worldwide. For patients with this type of stroke, endovascular thrombectomy (EVT), a procedure that removes the blood clot and restores blood flow to the brain, has become the standard treatment. However, even when blood flow is successfully restored, many patients continue to experience disability because of ongoing brain injury caused by inflammation, oxidative stress, and damage to brain cells after the stroke. This study aims to evaluate whether tirzepatide, a medication that activates both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) pathways, can improve recovery in patients with acute ischemic stroke caused by large vessel occlusion who receive thrombectomy. Tirzepatide is currently approved for the treatment of conditions such as type 2 diabetes and obesity. Previous studies have shown that tirzepatide can improve blood sugar control, reduce body weight, and provide beneficial effects on cardiovascular health. Laboratory studies and early clinical evidence suggest that medications targeting GLP-1 and GIP pathways may also have protective effects on the brain by reducing inflammation, protecting brain cells, improving blood vessel function, and supporting recovery after stroke. In this study, eligible patients with acute ischemic stroke caused by blockage of a major brain artery will be randomly assigned to receive either tirzepatide plus standard stroke care or standard stroke care alone. Participants will receive two subcutaneous injections of tirzepatide: the first dose before the thrombectomy procedure and the second dose 7 days after the procedure. The study will include multiple hospitals and will use independent assessment of outcomes to ensure reliable evaluation of treatment effects. The primary purpose of this study is to determine whether early treatment with tirzepatide can improve functional recovery 90 days after stroke, measured by the patient's ability to perform daily activities and live independently. The study will also evaluate whether tirzepatide is safe in patients with acute ischemic stroke by monitoring adverse events, complications, and other clinical outcomes. The findings from this study may provide important evidence for a new treatment approach to improve recovery after thrombectomy and reduce disability among patients with severe ischemic stroke.

Inclusion Criteria: Participants must meet all of the following criteria: 1. Age \>18 years and ≤80 years; 2. Acute ischemic stroke with imaging-confirmed anterior large vessel occlusion at: * Terminal ICA, * M1 segment of the middle cerebral artery, or * Dominant M2 segment; 3. NIHSS score between 6 and 25 prior to randomization; 4. Alberta Stroke Program Early CT Score (ASPECTS) of 6-10 before randomization; 5. Time from symptom onset (or last known well) to planned endovascular thrombectomy within 24 hours; 6. Pre-stroke mRS score of 0-1; 7. Patients presenting within 6 hours of symptom onset are eligible for direct EVT. Patients presenting between 6 and 24 hours after symptom onset must undergo advanced imaging demonstrating a salvageable perfusion mismatch and meet the DEFUSE-3 criteria: an infarct core volume \15 mL, and a mismatch ratio \>1.8; 8. Written informed consent provided by the participant or a legally authorized representative. Exclusion Criteria: Participants meeting any of the following criteria will be excluded: 1. Posterior-circulation large vessel occlusion stroke; 2. Receipt of intravenous thrombolysis prior to randomization; 3. Simultaneous bilateral anterior-circulation occlusions or concurrent anterior- and posterior-circulation occlusions; 4. Intracranial hemorrhage on baseline CT or MRI, including subarachnoid hemorrhage or intracerebral hemorrhage; evidence of large established infarction, defined as: * ASPECTS \1/3 of the middle cerebral artery territory; 5. Active bleeding within the previous month (e.g., gastrointestinal, genitourinary, or retinal hemorrhage), major organ surgery or biopsy within 14 days before stroke onset, or known bleeding diathesis; 6. Refractory hypertension despite treatment, defined as persistent systolic blood pressure \>180 mmHg or diastolic blood pressure \>110 mmHg; 7. Severe hepatic or renal impairment, including: * Estimated glomerular filtration rate (eGFR) \200 μmol/L, * Child-Pugh Class C or higher liver disease, * Recurrent unexplained hypoglycemia; 8. Blood glucose \22.2 mmol/L; platelet count \1.7; 9. Previous use of GLP-1 receptor agonists or GIP receptor agonists, or known hypersensitivity to these agents; 10. Personal or family history of medullary thyroid carcinoma (MTC) or diagnosis of Multiple Endocrine Neoplasia Type 2 (MEN2); 11. History of severe anxiety or depression prior to stroke onset; 12. Severe underlying disease with life expectancy \