Insulin Resistance Intervention After Stroke - IRIS


The goal of the trial was to assess the efficacy of pioglitazone in patients without diabetes with a history of stroke or transient ischemic attack (TIA) within 6 months.

Contribution to the Literature: The IRIS trial demonstrated that pioglitazone is superior to placebo in reducing the composite of stroke/myocardial infarction (MI) in patients with recent stroke/TIA, no history of type 2 diabetes (DM2), and objective evidence of insulin resistance.

Study Design

Patients were randomized in a 1:1 fashion to either pioglitazone (n = 1,939) or matching placebo (n = 1,937). Pioglitazone was started at 15 mg daily and up-titrated to 30 mg at 4 weeks and 45 mg at 8 weeks if there were no adverse effects.

  • Total number of enrollees: 3,876
  • Duration of follow-up: 4.8 years (median)
  • Mean patient age: 63.5 years
  • Percentage female: 35%

Inclusion criteria:

  • Age ≥40 years
  • Qualifying ischemic stroke or TIA 6 months prior to randomization
  • Insulin resistance, defined as homeostasis model assessment of insulin resistance (HOMA-IR) value >3.0

Exclusion criteria:

  • Diagnosed DM2
  • Glycated hemoglobin ≥7%
  • New York Heart Association (NYHA) class III/IV symptoms
  • NYHA class II with low ejection fraction
  • Active liver disease
  • Alanine amino-transferase >2.5 x upper limit of normal
  • Hemoglobin <8.5 g/dl
  • Moderate or severe pitting edema
  • Carotid revascularization within 14 days
  • Use of estrogen-containing contraceptive or oral glucocorticoid
  • History of congestive heart failure (CHF)
  • Bladder cancer or increased risk of bladder cancer

Other salient features/characteristics:

  • Hypertension: 71.5%
  • Score on Modified Rankin Scale: 1
  • Fasting glucose: 98.3 mg/dl
  • Statin: 82.5%, antiplatelet: 92.2%

Principal Findings:

The primary outcome, stroke or MI, for pioglitazone vs. placebo: 9.0% vs. 11.8% (hazard ratio 0.76, 95% confidence interval 0.62-0.93, p = 0.007)

Secondary outcomes (for pioglitazone vs. placebo, respectively):

  • All strokes for pioglitazone vs. placebo: 6.5% vs. 8.0%, p = 0.19
  • Acute coronary syndrome: 5.0% vs. 6.6%, p = 0.11
  • Stroke, MI, or CHF: 10.6% vs. 12.9%, p = 0.11
  • New-onset DM2: 3.8% vs. 7.7%, p < 0.001
  • All-cause mortality: 7.0% vs. 7.5%, p = 0.52
  • Safety: Bone fracture requiring hospitalization, surgery, or a procedure: 5.1% vs. 3.2%, p = 0.003
  • Weight gain >4.5 kg: 52.2% vs. 33.7%, p < 0.0001
  • Edema: 35.6% vs. 24.9%, p < 0.001
  • CHF: 1.5% vs. 1.7%, p = 0.7


The results of this trial indicate that pioglitazone is superior to placebo in reducing the composite of stroke/MI in patients with recent stroke/TIA, no history of DM2, and objective evidence of insulin resistance. There was an increase in previously described side effects with thiazolidinediones (TZDs), including bone fractures, edema, and weight gain. No differences were noted in CHF, although patients with CHF were excluded from this trial. Further, patients at risk had their dose down-titrated, as part of the protocol.

Pioglitazone is primarily a PPAR-γ agonist, and also has some effect on PPAR-α receptors. The exact mechanism of benefit with pioglitazone in this trial is unclear, but may relate to a favorable effect on insulin sensitivity. Two earlier trials with TZDs in patients with DM2 were negative (PROactive and BARI-2D). It is unclear if other agents that modulate insulin sensitivity, such as metformin, would have beneficial effects in this patient population as well.


Kernan WN, Viscoli CM, Furie KL, et al., on behalf of the IRIS Trial Investigators. Pioglitazone After Ischemic Stroke or Transient Ischemic Attack. N Engl J Med 2016;Feb 17:[Epub ahead of print].

Editorial Comment: Semenkovich CF. Insulin Resistance and a Long, Strange Trip. N Engl J Med 2016;Feb 17:[Epub ahead of print].

Clinical Topics: Acute Coronary Syndromes, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Hypertension

Keywords: Acute Coronary Syndrome, Diabetes Mellitus, Type 2, Edema, Fractures, Bone, Glucose, Heart Failure, Homeostasis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Insulin Resistance, Ischemic Attack, Transient, Myocardial Infarction, Secondary Prevention, Stroke, Thiazolidinediones, Weight Gain, Vascular Diseases

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