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Background: The Insulin Resistance Intervention after Stroke (IRIS) trial demonstrated that pioglitazone reduced risk for the composite outcome of stroke or myocardial infarction among non-diabetic patients with insulin resistance and a recent ischemic stroke or TIA. The drug also reduced risk for stroke alone, but the finding did not reach statistical significance. During the trial, the Data & Safety Monitoring Board approved a secondary analysis using updated 2013 consensus criteria for ischemic stroke. Our objective is to examine the effect of pioglitazone, compared with placebo, on risk for stroke alone defined by the 2013 criteria.Methods: Participants were randomized to pioglitazone (45 mg per day target dose) or placebo and followed for a maximum of 5 years. An independent committee, blinded to treatment assignments, adjudicated all potential stroke outcomes. The primary outcome was any stroke, but we also examined type of stroke (ischemic or hemorrhagic), and ischemic stroke subtype.Results: Among 3876 IRIS participants (mean age 63 years, 65% male), 377 stroke events were observed in 319 participants over a median follow-up of 4.8 years (329 stroke events by the original trial criteria plus 48 new events identified by applying the 2013 stroke criteria). Pioglitazone was associated with a 25% risk reduction for any stroke (8.0% compared to 10.7%; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60 to 0.94) and a 28% reduction for ischemic stroke (HR, 0.72; 95% CI, 0.57 to 0.9) but not hemorrhagic stroke (HR, 1.00; 95% CI, 0.50-2.00). Pioglitazone was associated with fewer numbers of all subtypes of ischemic stroke, but the difference from placebo reached or approached significance only for lacunar (HR, 0·46; 95% CI, 0·22-0·93; p=0·03) and large vessel (HR, 0·59; 95% CI, 0·33-1·04; p=0·07) strokes.Conclusion: Pioglitazone prevents recurrent ischemic stroke among non-diabetic patients with insulin resistance.