The risk of stroke and myocardial infarction is lower in patients without diabetes who have insulin resistance and a recent history of stroke or transient ischemic attack (TIA) and are treated with pioglitazone, compared with a placebo, according to research presented at the 2016 International Stroke Conference and published simultaneously in the New England Journal of Medicine.

“This study represents a novel approach to prevent recurrent vascular events by reversing a specific metabolic abnormality thought to increase the risk for future heart attack or stroke,” said Walter J. Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke (NINDS), which supported the study.

The multicenter, double-blind Insulin Resistance Intervention after Stroke (IRIS) trial focused on patients who had insulin resistance but were not diabetic. Researchers randomly assigned either pioglitazone (45 mg daily) or a placebo to 3,876 participants, all of whom had had either an ischemic stroke or TIA within 6 months prior to study enrollment. Participant insulin resistance was defined as a score greater than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index.

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At median follow-up (4.8 years), the researchers found that either stroke or myocardial infarction occurred in 175 (9%) of the 1,939 participants randomized to the pioglitazone group and in 228 (11.8%) of the 1,937 participants in the placebo group (hazard ratio 0.76). Across both groups, 73 participants (3.8%) and 149 participants (7.7%), respectively, developed diabetes (hazard ratio 0.48); however, pioglitazone reduced the overall risk of diabetes development by 52%. In addition, participants in the pioglitazone group were found to have a higher rate of weight gain, edema, and serious bone fracture.

“More research is needed to determine the mechanisms by which pioglitazone decreases risk for stroke and heart attack and increases bone fracture risk, with the hope of developing strategies that maximize benefit and minimize serious side effects in our patients,” said Walter N. Kernan, MD, professor of general medicine at Yale University School of Medicine and lead study author.


  1. Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. New Engl J Med. 2016; doi: 10.1056/NEJMoa1506930