http://www.ncbi.nlm.nih.gov/pubmed/26886418
Kernan WN1, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP Jr, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O'Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR; IRIS Trial Investigators.
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 .).
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 .).
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