Could pioglitazone (Actos) be useful as secondary prevention against cardiovascular events, even in non-diabetic patients? The answer may be yes, according to a new study of nearly 3900 patients with insulin resistance but not diabetes and a recent history of ischemic stroke or transient ischemic attack (TIA). Patients were randomized to pioglitazone (45 mg daily) or placebo and followed for nearly 5 years. The primary outcome, fatal or nonfatal stroke or myocardial infarction, occurred in 9% of the pioglitazone group and 11.8% of the placebo group (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.62-0.98; P = 0.007). Diabetes developed in 3.8% of the pioglitazone group and 7.7% of the placebo group (HR, 0.48; 95% CI, 0.33-0.69; P < 0.001). There was no difference in all-cause mortality, although pioglitazone was associated with greater frequency of weight gain exceeding 4.5 kg, edema, and bone fractures requiring surgery or hospitalization. The authors suggested that in patients without diabetes but with insulin resistance along with a history of ischemic stroke or TIA, pioglitazone reduced the risk of stroke or myocardial infarction compared to placebo (N Engl J Med Published online Feb. 17, 2016. doi:10.1056/NEJMoa1506930). An accompanying editorial says, “it has taken two decades to show that an insulin sensitizer decreases vascular events in patients selected for insulin resistance.” However, the editorialist also suggested these patients were highly selected, and there are many caveats before clinicians rush to prescribe pioglitazone for secondary prevention (N Engl J Med Published online Feb. 17, 2016. doi:10.1056/NEJMe1600962).