In this issue of JAMA Neurology, Spence et al1 discuss the effect of pioglitazone, an insulin-sensitizing agent that has been shown to reduce the risk of recurrent stroke and myocardial infarction in patients with insulin resistance, in patients with prediabetes. Prediabetes was defined according to the American Diabetes Association criteria, ie, a hemoglobin A1c level of 5.7% to 6.4% or a fasting plasma glucose level of 100 to 125 mg/dL. Data were taken from the Insulin Resistance Intervention after Stroke (IRIS) study, an international randomized clinical trial performed in patients with previous stroke or transient ischemic attack and insulin resistance. In the principal IRIS trial results analysis,2 pioglitazone was found to be superior to placebo in terms of prevention of stroke or myocardial infarction in patients without diabetes but who had insulin resistance and a recent history of ischemic stroke or transient ischemic attack. In the same trial, the active drug was able to lower the risk of diabetes but also carried an increased risk of weight gain, edema, and fractures.2