LOS ANGELES—Among patients without diabetes who have insulin resistance and a recent history of ischemic stroke or transient ischemic attack (TIA), treatment with pioglitazone reduces the risk of stroke or myocardial infarction by 24% at five years, compared with placebo, according to trial results presented at the International Stroke Conference 2016. The diabetes drug also was associated with higher rates of known adverse effects, including weight gain and bone fracture.

The findings, which simultaneously were published in the New England Journal of Medicine, “indicate that pioglitazone is a new option for patients who have had a stroke or TIA to prevent future cardiac events and strokes,” said Walter N. Kernan, MD, Professor of Medicine at Yale University School of Medicine in New Haven, Connecticut. “However, we have to recognize that pioglitazone is not FDA-approved for use in nondiabetic patients, and we think it’s going to take 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 into clinical practice.”

The IRIS Trial

Prior studies have identified insulin resistance as a risk factor for stroke and myocardial infarction, and pioglitazone improves insulin sensitivity. To test whether pioglitazone reduces rates of stroke or myocardial infarction, investigators conducted the double-blind Insulin Resistance Intervention after Stroke (IRIS) trial between 2005 and 2013. Investigators at 179 sites in seven countries enrolled 3,876 patients who had had an ischemic stroke or TIA in the six months before randomization. Researchers randomly assigned participants to receive pioglitazone (target dose, 45 mg daily) or placebo pills, in addition to standard preventive care. Participants had insulin resistance, as determined by a value of greater than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR). People with diabetes were excluded. Participants were age 40 or older, with an average age of 63.5. Two-thirds of the participants were men, 11% were black, and 4% were Hispanic.

At 4.8 years, fatal or nonfatal stroke or myocardial infarction occurred in 175 of the 1,939 patients in the pioglitazone group and in 228 of the 1,937 patients in the placebo group (9% vs 11.8%; hazard ratio, 0.76). Diabetes developed in 73 patients and 149 patients, respectively (3.8% vs 7.7%; hazard ratio, 0.48). There was no significant difference between groups in all-cause mortality. Compared with placebo, pioglitazone was associated with higher rates of weight gain exceeding 4.5 kg (52.2% vs 33.7%), edema (35.6% vs 24.9%), and bone fracture requiring surgery or hospitalization (5.1% vs 3.2%).

Excluding patients with a history of heart failure and using safety algorithms that triggered dose reduction for excessive weight gain or edema likely prevented a greater incidence of heart failure in the active treatment group, Dr. Kernan said.

Researchers do not know why pioglitazone is associated with an increased risk of fracture, and they hope that future studies will identify ways to reduce the risk, which would make this drug an “even more attractive potential option,” he said.

A New Target

The study “shows fairly persuasively that insulin resistance is a new target for prevention in cardiovascular disease ... [Pioglitazone] is also the first diabetes drug that has ever been shown to prevent … stroke and heart attack,” said Dr. Kernan. The previous PROactive Trial found that pioglitazone had cardiovascular benefits, but those findings used secondary end points and were not widely accepted.

The mechanism responsible for lower rates of stroke and myocardial infarction with pioglitazone is uncertain. In addition to insulin sensitivity, pioglitazone improved blood pressure and circulating levels of glucose, triglycerides, HDL cholesterol, and C-reactive protein. Other unmeasured effects also could have contributed to the drug’s benefit, the researchers said.

“The findings suggest that the administration of pioglitazone in 100 patients similar to those in our trial for about five years could prevent three patients from having a stroke or myocardial infarction,” concluded the investigators. “However, during the same period, the treatment would be expected to result in bone fractures requiring surgery or hospitalization in two patients. It seems reasonable to consider individual treatment preference and risk of drug-related adverse events in addition to potential benefits when making patient-specific decisions regarding therapy.”

Surprising Results

“The results of the trial are surprising,” said Clay F. Semenkovich, MD, Chief of the Division of Endocrinology, Metabolism and Lipid Research at Washington University in St. Louis, in an accompanying editorial. Patients in the pioglitazone group benefited from the therapy “despite having a history of very effective cerebrovascular treatment,” he said.

“These findings may tempt clinicians to rush to prescribe pioglitazone, but many caveats remain,” Dr. Semenkovich said. He noted that patients in the trial met strict enrollment criteria and had little neurologic impairment. Nevertheless, “pioglitazone represents a potentially important therapy for the secondary prevention of vascular events in appropriately selected patients with cerebrovascular disease,” he said. Furthermore, the results should encourage efforts to develop precision-medicine approaches to preventing vascular disease by identifying people with genetic profiles that make them likely to benefit from this therapy.

—Jake Remaly

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