Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

TY - JOUR

T1 - Pioglitazone after Ischemic Stroke or Transient Ischemic Attack

AU - Kernan, Walter N

AU - Viscoli, Catherine M

AU - Furie, Karen L

AU - Young, Lawrence H

AU - Inzucchi, Silvio E

AU - Gorman, Mark

AU - Guarino, Peter D

AU - Lovejoy, Anne M

AU - Peduzzi, Peter N

AU - Conwit, Robin

AU - Brass, Lawrence M

AU - Schwartz, Gregory G

AU - Adams, Harold P

AU - Berger, Leo

AU - Carolei, Antonio

AU - Clark, Wayne

AU - Coull, Bruce

AU - Ford, Gary A

AU - Kleindorfer, Dawn

AU - O'Leary, John R

AU - Parsons, Mark W

AU - Sen, Souvik

AU - Spence, J David

AU - Wang, David

AU - Winder, Toni R

AU - IRIS Trial Investigators

AU - Thomalla, Götz

PY - 2016/4/7

Y1 - 2016/4/7

N2 - 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.).

AB - 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.).

KW - Aged

KW - Brain Ischemia

KW - Double-Blind Method

KW - Female

KW - Fractures, Bone

KW - Humans

KW - Hypoglycemic Agents

KW - Insulin Resistance

KW - Ischemic Attack, Transient

KW - Male

KW - Middle Aged

KW - Myocardial Infarction

KW - Peroxisome Proliferator-Activated Receptors

KW - Secondary Prevention

KW - Stroke

KW - Thiazolidinediones

KW - Weight Gain

KW - Journal Article

KW - Multicenter Study

KW - Randomized Controlled Trial

KW - Research Support, N.I.H., Extramural

U2 - 10.1056/NEJMoa1506930

DO - 10.1056/NEJMoa1506930

M3 - SCORING: Journal article

C2 - 26886418

VL - 374

SP - 1321

EP - 1331

JO - NEW ENGL J MED

JF - NEW ENGL J MED

SN - 0028-4793

IS - 14

ER -