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Original Investigation
February 7, 2019

Pioglitazone Therapy in Patients With Stroke and Prediabetes: A Post Hoc Analysis of the IRIS Randomized Clinical Trial

Author Affiliations
  • 1Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, Ontario, Canada
  • 2Department of Medicine, Yale School of Medicine, New Haven, Connecticut
  • 3Department of Neurology, Yale School of Medicine, New Haven, Connecticut
  • 4Radcliffe Department of Medicine, University of Oxford, United Kingdom
  • 5Department of Neurology, Maine Medical Center, Portland, Maine
  • 6Warren Alpert Medical School of Brown University, Providence, Rhode Island
JAMA Neurol. 2019;76(5):526-535. doi:10.1001/jamaneurol.2019.0079
Key Points

Question  Does pioglitazone reduce cardiovascular events in patients with prediabetes?

Findings  In this post hoc analysis of 2885 individuals with prediabetes enrolled in a randomized clinical trial, there was a significant reduction of cardiovascular events and new-onset diabetes. The association was amplified in participants with good adherence (≥80% of protocol dose taken), with stroke/myocardial infarction reduced by 40%, stroke by 33%, and new-onset diabetes by 80%.

Meaning  Pioglitazone may be an effective therapy for secondary stroke prevention in patients with prediabetes.


Importance  In the Insulin Resistance Intervention After Stroke (IRIS) randomized clinical trial, pioglitazone, an insulin-sensitizing agent, reduced the risk for recurrent stroke or myocardial infarction (MI) among patients with insulin resistance. However, insulin resistance is not commonly measured in clinical practice.

Objective  To analyze the effects of pioglitazone in patients with good adherence as well as intention-to-treat effects of pioglitazone in patients with prediabetes in the IRIS trial.

Design, Setting, and Participants  The IRIS trial was a randomized multicenter clinical trial in patients with prior stroke or transient ischemic attack as well as insulin resistance but not diabetes. Patients were enrolled from February 2005 to January 2013, and the median follow-up was 4.8 years. The post hoc analyses reported here were performed from June to September 2018. Per American Diabetes Association criteria, prediabetes was defined as having a hemoglobin A1c level of 5.7% to 6.4% or fasting plasma glucose level of 100 mg/dL to 125 mg/dL (to convert to mmol/L, multiply by 0.0555). Good adherence was defined as taking 80% or more of the protocol dose. Fasting glucose and hemoglobin A1c, used to define prediabetes, and adherence of 80% or higher, stipulated in the protocol as defining good adherence, were prespecified subgroups in the analysis plan.

Interventions  Participants were randomized to 15 mg of pioglitazone, with dose titrated to target of 45 mg daily, or matching placebo.

Main Outcomes and Measures  The primary outcome was recurrent stroke or MI. Secondary outcomes included stroke, acute coronary syndrome, stroke/MI/hospitalization for heart failure, and progression to diabetes.

Results  Among 3876 participants analyzed in the IRIS trial, 2885 were included in this analysis (1456 in the pioglitazone cohort and 1429 in the placebo cohort). The mean (SD) age of patients was 64 (11) years, and 974 (66.9%) and 908 (63.5%) of patients were men in the pioglitazone and placebo cohort, respectively. In the prediabetic population with good adherence (644 of 1456 individuals [44.2%] in the pioglitazone group and 810 of 1429 [56.7%] in the placebo group), the hazard ratios (95% CI) were 0.57 (0.39-0.84) for stroke/MI, 0.64 (0.42-0.99) for stroke, 0.47 (0.26-0.85) for acute coronary syndrome, 0.61 (0.42-0.88) for stroke/MI/hospitalization for heart failure, and 0.18 (0.10-0.33) for progression to diabetes. There was a nonsignificant reduction in overall mortality, cancer, and hospitalization, a slight increase in serious bone fractures, and an increase in weight gain and edema. Intention-to-treat results also showed significant reduction of events but to a lesser degree. Hazard ratios (95% CI) were 0.70 (0.56-0.88) for stroke/MI, 0.72 (0.56-0.92) for stroke, 0.72 (0.52-1.00) for acute coronary syndrome, 0.78 (0.63-0.96), for stroke/MI/hospitalization for heart failure, and 0.46 (0.35 to 0.61) for progression to diabetes.

Conclusions and Relevance  Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence.

Trial Registration  ClinicalTrials.gov identifier: NCT00091949