Cardiac Outcomes After Ischemic Stroke or TIA: Effects of Pioglitazone in Patients with Insulin Resistance Without Diabetes
Background—Insulin resistance is highly prevalent among patients with atherosclerosis and is associated with an increased risk for myocardial infarction (MI) and stroke. The Insulin Resistance Intervention after Stroke (IRIS) trial demonstrated that pioglitazone decreased the composite risk for fatal or non-fatal stroke and MI in patients with insulin resistance without diabetes, after a recent ischemic stroke or transient ischemic attack. The type and severity of cardiac events in this population, and the impact of pioglitazone on these events has not been described.
Methods—We performed a secondary analysis of the effects of pioglitazone, compared to placebo, on acute coronary syndromes (ACS) (MI and unstable angina) among IRIS participants. All potential ACS episodes were adjudicated in a blinded fashion by an independent clinical events committee.
Results—The study cohort was composed of 3876 IRIS participants, mean age 63 years, 65% male, 89% white race, and 12% with a history of coronary artery disease. Over a median follow-up of 4.8 years, there were 225 ACS events, including 141 MI's and 84 episodes of unstable angina. The MI's included 28 (19%) with ST-segment elevation. The majority of MI's were type 1 (94, 65%), followed by type 2 (45, 32%). Serum troponin was 10x to 100x upper limit of normal (ULN) in 49 (35%) and >100x ULN in 39 (28%). Pioglitazone reduced the risk of ACS (hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.54, 0.94; p=0.02). Pioglitazone also reduced the risk of type 1 MI (HR 0.62, 95% CI, 0.40, 0.96; log-rank p=0.03) but not type 2 MI (HR 1.05, 95% CI 0.58, 1.91; p=0.87). Similarly, pioglitazone reduced the risk of large MI's with serum troponin >100x ULN (HR 0.44, 95% CI, 0.22, 0.87; p=0.02), but not smaller MI's.
Conclusions—Among patients with insulin resistance without diabetes, pioglitazone reduced the risk for acute coronary syndromes after a recent cerebrovascular event. Pioglitazone appeared to have its most prominent effect in preventing spontaneous type 1 MI's.
Clinical Trial Registration— https://clinicaltrials.gov Unique Identifier: NCT00091949 US Food & Drug Administration IND: 64,622; EudraCT#2008-005546-23
- insulin resistance
- acute coronary syndrome
- acute myocardial infarction
- ischemic stroke
- peroxisome proliferator-activated receptor
- Received August 25, 2016.
- Revision received December 27, 2016.
- Accepted February 17, 2017.