There have been two large randomized clinical trials evaluating the cardiovascular preventive effects of pioglitazone. The PROspective pioglitAzone Clinical Trial In macroVascular Events (PROactive) study was a randomized trial which investigated the secondary preventive effect of pioglitazone in 5238 patients with type 2 diabetes and macrovascular disease [
19]. Compared with our study, which included patients with acute ischemic stroke, the PROactive study included patients who had been more than 6 months since the onset of MI or stroke before study entry. Although the PROactive study failed to show a significant benefit of pioglitazone from primary outcome analysis, there was a significantly reduced rate of fatal or nonfatal stroke with pioglitazone treatment in a subgroup analysis of patients with prior stroke (hazard ratio (HR) 0.53, 95% CI 0.34–0.85, p = 0.009) [
7]. In subgroups without prior stroke, there was no significant preventive effect of pioglitazone on the development of stroke (HR 1.06; 95% CI 0.73–1.52, p = 0.767). The Insulin Resistance Intervention After Stroke (IRIS) trial, performed more recently, was a randomized clinical trial based on the hypothesis that pioglitazone may reduce cardiovascular risk in non-diabetic patients with recent ischemic stroke or TIA (within 6 months) and insulin resistance [
6]. It is well established that people with insulin resistance are at a higher risk of cardiovascular disease, even if non-diabetic, and insulin resistance is common in ischemic stroke patients [
20]. Pioglitazone has been shown to be effective in improving both glycemic control and insulin-resistance [
21]. The IRIS trial showed that treatment with pioglitazone can reduce the risk of both acute coronary events and ischemic stroke in insulin resistant patients who had a recent ischemic stroke or TIA [
22,
23]. In this IRIS trial, primary outcomes of fatal or non-fatal stroke or myocardial infarction had occurred in 9.0% of the pioglitazone group and 11.8% of the placebo group by 4.8 years into the study period (HR 0.76, 95% CI 0.62–0.93, p = 0.007). The Juntendo Stroke Prevention study in Insulin Resistance and Impaired glucose Tolerance (J-SPIRIT) study was another randomized trial consisting of 120 patients with impaired glucose tolerance or newly-diagnosed DM in Japan who had experienced a non-disabling ischemic stroke or a TIA [
24]. Over a median follow-up period of 2.8 years, treatment with pioglitazone was associated with a lower risk of recurrent stroke (HR 0.62, 95% CI 0.13–2.25, p = 0.49), although the difference was not statistically significant and the trial was underpowered to evaluate the effect of pioglitazone. A meta-analysis of the above three trials demonstrated that treatment with pioglitazone in stroke patients with insulin resistance, prediabetes, and DM was associated with a significantly lower risk of recurrent stroke (HR 0.68, 95% CI 0.50–0.92, p = 0.01) and major vascular events (HR 0.75, 95% CI 0.64–0.87, p < 0.01) [
25].