Pioglitazone after ischaemic stroke or transient ischaemic attack in patients with insulin resistance - IRIS trial

Pioglitazone after Ischemic Stroke or Transient Ischemic Attack - Insulin Resistance Intervention after Stroke (IRIS) trial

• patients with ischemic stroke or transient ischemic attack (TIA) are at increased risk for future cardiovascular events despite current preventive therapies. The identification of insulin resistance as a risk factor for stroke and myocardial infarction raised the possibility that pioglitazone, which improves insulin sensitivity, might benefit patients with cerebrovascular disease
  
  
• multicenter, double-blind trial
  • randomly assigned 3876 patients who had had a recent ischemic stroke or TIA to receive either pioglitazone (target dose, 45 mg daily) or placebo
  • eligible patients did not have diabetes but were found to have insulin resistance on the basis of a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index
  • primary outcome was fatal or nonfatal stroke or myocardial infarction
  • pioglitazone (titrated from 15mg/daily to target dose of 45mg once daily over 12 weeks) vs. placebo
    • median daily dose ranged from 29-40mg/day. Pioglitazone dosing titration was adjusted if any symptoms of worsening oedema, shortness of breath, myalgia or excessive weight gain. Pioglitazone was stopped if: a) HF, b) bladder ca, c) .2 low energy fractures. Patients were contacted every 4 months for up to 5 years
      
      
• by 4.8 years, a primary outcome had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group (hazard ratio in the pioglitazone group, 0.76; 95% confidence
  interval [CI], 0.62 to 0.93; P = 0.007)
  • diabetes developed in 73 patients (3.8%) and 149 patients (7.7%), respectively (hazard ratio, 0.48; 95% CI, 0.33 to 0.69; P<0.001)
  • there was no significant between-group difference in all-cause mortality (hazard ratio, 0.93; 95% CI, 0.73 to 1.17; P = 0.52)
  • pioglitazone was associated with a greater frequency of weight gain exceeding 4.5 kg than was placebo (52.2% vs. 33.7%, P<0.001), edema (35.6% vs. 24.9%, P<0.001), and bone fracture requiring surgery or hospitalization (5.1% vs. 3.2%, P = 0.003)
    
    
• in this trial involving patients without diabetes who had insulin resistance along with a recent history of ischemic stroke or TIA, the risk of stroke or myocardial infarction was lower among patients who received pioglitazone than among those who received placebo. Pioglitazone was also associated with a lower risk of diabetes but with higher risks of weight gain, edema, and fracture

Key points:

• for every 100 patients with recent history of stroke, transient ischemic a ttack (TIA) and insulin resistance, but NOT diabetes, giving pioglitazone 45mg daily for ~5 years will result in approximately
  • 3 less cases of stroke or MI,
  • 4 less cases of diabetes,
  • 2 extra cases of serious bone fracture,
  • 7 extra cases of weight gain > 13.6kg,
  • and 11 extra cases of oedema (Note - those with various degrees of heart failure, pitting oedema, etc. were excluded.)

Comment:

• results of the IRIS trial are in contrast to the findings of two trials involving patients with type 2 diabetes
  • Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial
    • the rate of primary outcome of death, myocardial infarction, stroke, acute coronary syndrome, vascular surgery, or amputation was not significantly lower among patients in the pioglitazone group than among those in the placebo group
  • Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI-2D) trial
    • the rate of primary outcome of death, stroke, or myocardial infarction was not significantly lower among patients receiving rosiglitazone and metformin (insulin-sparing strategy) than among those receiving insulin and sulfonylurea therapy (insulin-providing strategy)
• however, the IRIS results are consistent with findings regarding a secondary outcome in the PROactive trial (i.e., that the rates of death, myocardial infarction, or stroke were significantly lower with pioglitazone than with placebo) and with findings of trials showing a favorable effect of pioglitazone on the progression of subclinical atherosclerosis among patients with and those without diabetes

Reference:

• Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, et al; IRIS Trial Investigators. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016 Feb 17.
• Dormandy JA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study. (PROspective pioglitAzone Clinical Trial in macroVascular Events): a RCT. Lancet. 2005; 366: 1279-1289.