Pioglitazone Reduces Composite Outcome of Stroke or Myocardial Infarction in Patients with Ischemic Stroke and Insulin Resistance

EBM Focus - Volume 11, Issue 15

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Reference - IRIS trial (N Engl J Med 2016 Apr 7;374(14):1321) (level 1 [likely reliable] evidence)

  • Insulin resistance is common in patients with a recent ischemic stroke or transient ischemic attack (TIA).
  • The effect of oral glucose-lowering medications on the risk of subsequent macrovascular outcomes (stroke and cardiovascular disease) in patients with insulin resistance is unknown.
  • Pioglitazone significantly reduced the composite outcome of stroke or myocardial infarction in patients with an ischemic stroke or TIA in the previous 6 months plus insulin resistance. It also reduced the incidence of newly diagnosed diabetes.
  • Pioglitazone was also associated with an increased risk of adverse events including weight gain, bone fracture, edema, and shortness of breath, suggesting the risk and benefits must be carefully considered for each patient before initiating pioglitazone treatment.

Factors associated with prediabetes, including insulin resistance and impaired glucose tolerance, are also associated with an increased risk for stroke and cardiovascular disease (BMJ 2012 Jun 7;344:e3564, AHRQ 2005 Sep:128). In fact, insulin resistance has been reported in 30-50% of patients without diabetes experiencing a recent ischemic stroke or TIA (Cerebrovasc Dis 2014;37(6):393, Cerebrovasc Dis 2013;36(4):283). A previous study suggested that pioglitazone may reduce the composite risk of myocardial infarction, stroke, and death in patients with type 2 diabetes (Lancet 2005 Oct 8;366(9493):1279). However, the effects of pioglitazone for the prevention of secondary stroke in patients with insulin resistance is unknown.

The IRIS trial randomized 3,895 patients ≥ 40 years old (mean age 64 years, 65% male) with a recent ischemic stroke or TIA plus insulin resistance to pioglitazone vs. placebo and were followed for up to 5 years. Insulin resistance was defined as a homeostasis model assessment of insulin resistance index score ≥ 3.0 measured ≥ 14 days after qualifying event. Patients with diabetes, New York Heart Association class 3 or 4 heart failure, or New York Heart Association class 2 heart failure with reduced ejection fraction were excluded. During the median follow-up of 4.8 years, 8.4% of patients withdrew or were lost to follow up, but 99.5% of patients were included in the analysis. The primary composite outcome was defined as the first event of fatal or nonfatal stroke or myocardial infarction. Comparing pioglitazone vs. placebo, this composite outcome occurred in 9% vs. 11.8% (p = 0.007, NNT 36). Diabetes developed in 3.8% with pioglitazone vs. 7.7% with placebo (p

< 0.001, NNT 26). The rates of acute coronary syndrome (myocardial infarction or unstable angina) and stroke were both lower with pioglitazone, but not significantly. Pioglitazone was also significantly associated with an increase in adverse events including weight gain, bone fracture, edema, and shortness of breath. There were no significant differences between groups in cognition, mortality, hospitalization, incident cancer (including bladder cancer), heart failure, or macular edema.

The American Heart Association/American Stroke Association suggests screening patients for diabetes after an ischemic stroke or transient ischemic attack and managing patients according to American Diabetic Association guidelines (

Stroke 2014 Jul;45(7):2160). Prediabetes is typically treated with lifestyle interventions and not medications, but the results of this trial suggest that treating insulin resistance may reduce the risk of recurrent stroke and myocardial infarction in patients after an ischemic stroke or TIA. These results are consistent with another recently published trial investigating pioglitazone in patients with recent stroke or TIA plus impaired glucose tolerance or newly diagnosed diabetes; however that trial was underpowered and the lower rate of recurrent stroke was not significant (J Atheroscler Thromb 2015;22(12):1305). While pioglitazone was effective for preventing adverse macrovascular outcomes, there are conflicting studies on whether there may be an increased risk of bladder cancer with long term use (BMJ 2016 Mar 30;352:i1541, JAMA 2015 Jul 21;314(3):265). Given the high rates of adverse events including weight gain and edema, pioglitazone may not be suitable for all patients with a recent ischemic event and insulin resistance. Instead, the benefits and risks of pioglitazone treatment must be carefully weighed for each patient.

For more information, see the Prediabetes and Glitazones topics in DynaMed Plus. DynaMed users click here and here.


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