Efficacy and Safety of Dual Antiplatelet Treatment up to 72 Hours in Acute Ischemic Stroke Stratified by Glycemic Status

OBJECTIVE: The objective was to investigate the efficacy and safety of clopidogrel-aspirin versus aspirin alone in patients after ischemic stroke by glycemic status using data from the Intensive Statin and Antiplatelet Therapy for Acute High-risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial. METHODS: Patients with mild ischemic stroke or high-risk transient ischemic attack (TIA) were randomized to clopidogrel-aspirin or aspirin alone. They were categorized into 3 subgroups according to glycemic status based on medical history and diagnosis by a clinician during hospitalization: without type 2 diabetes mellitus, with newly diagnosed type 2 diabetes, and with a history of type 2 diabetes mellitus. The primary efficacy and safety outcomes were new stroke and moderate-to-severe bleeding risk within 90-day follow-up. RESULTS: A total of 6,100 patients were enrolled (3,050 in each arm), with a median age of 65 years (interquartile range [IQR], 57-71) and 2,185 female (35.8%). Clopidogrel-aspirin treatment was associated with a reduction in recurrent stroke compared with aspirin alone in patients without type 2 diabetes mellitus (6.3% vs 8.4%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.59-0.94; p = 0.01) and those with newly diagnosed type 2 diabetes mellitus (5.8% vs 13.0%; HR, 0.30; 95% CI, 0.14-0.66; p = 0.002), but not in those with a history of type 2 diabetes mellitus (10.0% vs 9.9%; HR, 0.98; 95% CI, 0.72-1.33; p = 0.88) (p for interaction = 0.03). Moderate-to-severe bleeding events did not differ significantly by treatment across glycemic subgroups. INTERPRETATION: In the INSPIRES trial, patients without or with type 2 diabetes mellitus derived greater benefit from clopidogrel-aspirin than those with a history of type 2 diabetes mellitus after mild ischemic stroke or high-risk TIA. TRIAL REGISTRATION: INSPIRES, NCT03635749. Registered 15 August 2018, https://clinicaltrials.gov/search?cond=NCT03635749. ANN NEUROL 2025;98:174-182.