Insulin Resistance Intervention After Stroke Trial of Pioglitazone
Is This Perhaps the End of the Beginning?
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The completion of the Insulin Resistance Intervention After Stroke (IRIS) trial culminated a long process to design, fund, and recruit patients to test, for the first time, whether treatment with an approved antidiabetic drug at the prediabetic stage of insulin resistance (IR) improves outcomes in patients with cerebrovascular disease.1 In the IRIS trial, pioglitazone, a member of the thiazolidinedione class of peroxisome proliferator–activated receptor γ (PPAR-γ) agonists, was compared with placebo. Nondiabetic subjects with recent (<6 months) stroke or transient ischemic attack, who met inclusion criteria for IR, defined as Homeostatic Model of Assessment of Insulin Resistance (HOMA-IR) >3.0, were enrolled. Major exclusions included heart failure (HF) because of the known potential for thiazolidinediones to precipitate/worsen HF, active liver disease because of the association of another thiazolidinedione (troglitazone) with hepatotoxicity, and either the occurrence or risk factors for bladder cancer because of data from other trials suggesting an imbalance of bladder cancer in pioglitazone-treated diabetics.2 After 5 years, pioglitazone-treated patients had 24% reduction in cardiovascular outcomes above and beyond a generally modern approach to secondary stroke prevention. Stroke reduction was entirely for the ischemic type, and interestingly, the biggest relative reduction was in the lacunar subtype although unfortunately almost 2 of 3 had no identified stroke mechanism, making this finding tentative. Consistent with previous studies in diabetics where thiazolidinediones reduced the need for insulin introduction,3 in the IRIS trial, pioglitazone reduced by half the development of diabetes mellitus. Despite a higher incidence of shortness of breath and edema, HF mortality/hospitalization did not increase, potentially because of the strict definition of HF in contrast to previous studies.3,4 Also, the investigators found only a slight …