After a median follow-up period of nearly five years, patients who received pioglitazone following a recent ischemic stroke or transient ischemic attack (TIA) had a lower risk of stroke or MI compared with a placebo group, according to a multicenter, double-blind trial.
The patients who received pioglitazone also had a lower risk of diabetes. Pioglitazone is a commonly prescribed medication to treat type 2 diabetes, but none of the patients in the study had diabetes when they enrolled.
Lead researcher Walter Kernan, MD, of Yale University’s School of Medicine in New Haven, Conn., presented the results in a plenary session at the American Stroke Association’s International Stroke Conference on Feb. 17. The findings were simultaneously published online in the New England Journal of Medicine.
Kernan said in a news conference that pioglitazone’s 24 percent relative risk reduction of stroke or MI was comparable to aspirin or statin therapy.
“[The results] indicate that very possibly pioglitazone is a new option for patients who’ve had a stroke or TIA to prevent future cardiac events and strokes,” Kernan said. “However, we have to recognize pioglitazone is not approved for use in non-diabetic patients and we think it’s going to take a little bit of time for the scientific community and for the neurology clinical community to look at our results and decide how they should or should not be incorporated in clinical practice.”
In this trial, known as IRIS (Insulin Resistance Intervention after Stroke), researchers at 179 hospitals and clinics enrolled 3,876 patients from 2005 to 2013 to receive pioglitazone or placebo. Patients initially received one 15 mg pill of the medication daily. They could increase their dosage to two 15 mg pills at four weeks and three 15 mg pills at eight weeks if they had no new or worsening edema, shortness of breath, myalgia or excessive weight gain. At 12 weeks, they began receiving one 45-mg pioglitazone tablet or placebo tablet daily.
Takeda Pharmaceuticals donated pioglitazone or placebo tablets for the study. The researchers noted that Takeda representatives received a copy of the study protocol, but they did not develop the protocol, conduct the trial, interpret the data or prepare the manuscript.
Patients in the study were required to be at least 40 years old, have insulin resistance and have had a ischemic stroke or TIA in the six months before randomizations. The researchers defined insulin resistance as a value of more than 3 on the homeostasis model assessment of insulin resistance index. Patients were excluded if they had diabetes, a glycated hemoglobin level of 7 percent or more or New York Heart Association class 3 or 4 heart failure or class 2 heart failure with a reduced ejection fraction.
The mean age of patients was 63.5, and approximately two-thirds of patients were males.
During a median follow-up period of 4.8 years, 9 percent of patients in the pioglitazone group and 11.8 percent of patients in the placebo group had a fatal or nonfatal stroke or MI. In addition, 3.8 percent and 7.7 percent of patients, respectively, developed diabetes.
Further, patients who received pioglitazone were more likely to gain at least 4.5 kg, develop edema or sustain a bone fracture requiring surgery or hospitalization. At the end of the study, 60 percent of patients in the pioglitazone group and 67 percent of patients in the placebo group were still taking their medications.
Of the major adverse events, bone fractures were the only one significantly more common in the pioglitazone group compared with the placebo group.
“Our trial shows it’s the first time that this drug works in non-diabetic patients, so we think that this is an important finding for the diabetes community and potentially for the neurology community,” Kernan said. “We think that we’ve demonstrated that insulin resistance is a fruitful target for secondary prevention and a new target, previously undisclosed target, for prevention of vascular disease.”