Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

Abstract

Background: 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.

Methods: In this multicenter, double-blind trial, we 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. The primary outcome was fatal or nonfatal stroke or myocardial infarction.

Results: 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).

Conclusions: 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. (Funded by the National Institute of Neurological Disorders and Stroke; ClinicalTrials.gov number, NCT00091949.).

Figure 1. Primary Outcome

By 5 years, the primary outcome (fatal or nonfatal stroke or fatal or nonfatal myocardial infarction) had occurred in 175 of 1939 patients (9.0%) in the pioglitazone group and in 228 of 1937 (11.8%) in the placebo group. The inset shows the same data on an enlarged y axis. The numbers at risk were the numbers of patients who were alive without an event and still being followed at the beginning of each time point.

Figure 2. Subgroup Analyses of the Primary Outcome

Shown is the relative benefit of pioglitazone as compared with placebo in 13 subgroups that were examined for their interaction with the treatment. P values have not been adjusted for multiple comparisons. (P = 0.94 after adjustment for multiple comparisons in each subgroup.) The size of the squares corresponds to the number of patients in each subgroup. The body-mass index is the weight in kilograms divided by the square of the height in meters. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for triglycerides to millimoles per liter, multiply by 0.01129. HDL denotes high-density lipoprotein, and HOMA-IR homeostasis model assessment of insulin resistance.