Pioglitazone May Prevent Recurrent Stroke, Heart Attack in Patients Without Diabetes

Risk Factors
Risk Factors
Patients taking pioglitazone saw a 24% reduction in risk for recurrent stroke or myocardial infarction compared to placebo.

LOS ANGELES — Pioglitazone may reduce the risk of recurrent stroke or myocardial infarction in non-diabetic patients with insulin resistance with a recent history of ischemic stroke or transient ischemic attack (TIA).

The results of the Insulin Resistance Intervention after Stroke (IRIS) trial, which suggest a promising new preventive method for high risk patients, were presented at the 2016 International Stroke Conference.

Previous research has suggested that insulin resistance is a risk factor for stroke and myocardial infarction, leading study author Walter N. Kernan, MD, of Yale School of Medicine in New Haven, Conn., and colleagues to explore the benefit of the common diabetes drug in this high-risk population.

The study was supported by the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).

Data was collected from 179 hospitals and clinics in 7 countries from 2005 through 2013. Eligible patients were at least 40 years of age and had an ischemic stroke or TIA in the previous 6 months, as well as an insulin resistance value of >3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index. Patients with diabetes, heart failure, liver disease, bladder cancer, edema, and those using estrogen-containing contraception were excluded. Primary outcome was fatal or nonfatal stroke or myocardial infarction, and secondary outcomes included all-cause mortality, diabetes onset, and cognitive decline.

Overall, 3876 patients (mean age 63.5 years; 66% men) were included in the analysis. Patients were randomly assigned in a 1:1 ratio to receive either pioglitazone or placebo, with treatment initiated at 15 mg/day and titrated to 45 mg/day over 12 weeks. Patients were followed up every 4 months (mean 4.1 years) with participation discontinued at 5 years or last scheduled contact.

Stroke or myocardial infarction occurred in 9% of patients in the pioglitazone group compared to 11.8% in the placebo group (hazard ratio (HR) in the pioglitazone group, 0.76; 95% confidence interval [CI], 0.62 to 0.93; P=0.007), a relative risk decrease of 24%. The results translate to 28 strokes or myocardical infarctions prevented for every 1000 patients taking pioglitazone for up to 5 years.

Progression to diabetes was also significantly lower in the pioglitazone group compared with placebo, with an observed risk reduction of 52% (HR, 0.48; 95% CI, 0.33 to 0.69; P<0.001). No significant effect on cognition was observed in the pioglitazone group compared with placebo. After 1 year, HOMA-IR index and C-reactive protein levels were lower in the pioglitazone group, as well as levels of fasting glucose, triglycerides, and systolic and diastolic blood pressure.

Notably, patients taking pioglitazone had more weight gain, edema, shortness of breath, and bone fractures—a known side effect of the drug—than patients in the placebo group.

“More research is needed to determine the mechanisms by which pioglitazone decreases risk for stroke and heart attack and increases bone fracture risk, with the hope of developing strategies that maximize benefit and minimize serious side effects in our patients,” Dr Kernan said in a statement.

The IRIS trial results are in contrast to previous findings in patients with type 2 diabetes, suggesting a novel yet uncertain mechanism in this cohort. The study is the first to provide evidence that targeting cell metabolism may help to prevent recurrent stroke and myocardial infarction prior to development of diabetes. The study authors note, however, that pioglitazone is not currently approved by the FDA for the uses studied in the trial.  

“The IRIS trial supports the value of more research to test the vascular benefits of other interventions such as exercise, diet, and medications that have similar effects on metabolism as pioglitazone,” Dr Kernan added.

For more coverage of ISC 2016, go here.


Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after Ischemic Stroke or Transient Ischemic Attack. N Engl J Med. 2016; doi:10.1056/NEJMoa1506930. Presented at: International Stroke Conference; Feb. 16-19, 2016; Los Angeles.