NEW YORK (Reuters Health) - The diabetes drug pioglitazone, given to non-diabetics with a recent history of stroke or transient ischemic attack (TIA), prevented subsequent strokes and reduced their odds of developing type 2 diabetes, a long-term multicenter study has concluded.
But the drug also increased the risk of fracture, weight gain, and edema.
After nearly five years of follow-up, the rate of stroke or heart attack was 11.8% with placebo and 9.0% with the drug (p=0.007). The target dose was 45 mg daily.
"That 25% relative reduction is a huge effect for a stroke trial," coauthor Dr. Wayne Clark, director of the Oregon Stroke Center at Oregon Health and Science University, told Reuters Health by phone. "That's on the same realm as aspirin and a big effect for stroke.
"We're always expecting negative results these days," because so many stroke drugs have failed in previous tests, he said. "This was a positive surprise."
Dr. Clark said he was particularly taken aback by the rate that diabetes developed in pioglitazone recipients. It manifested in 3.8% of drug recipients versus 7.7% of placebo
"I didn't expect that at all," he said. "That has much wider implications and might take confirmatory studies."
The 3,876 volunteers studied at 179 sites worldwide were not diabetic but they had developed insulin resistance at the time of enrollment.
Drug therapy did not reduce mortality.The results of the study, known as IRIS, were presented February 17 at the American Heart Association and the American
Stroke Association's International Stroke Conference in Los Angeles, and online in the New England Journal of Medicine.
"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," the researchers wrote in the Journal. "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," they concluded.
Serious fractures occurred in 5.1% of drug recipients versus 3.2% among placebo patients (p=0.003). A weight gain of more than 4.5 kg was seen in 52.2% of pioglitazone recipientscompared with 33.7% for placebo, and rates of edema were 35.6% with the drug versus 24.9% with placebo (both p<0.001).
The drug has been plagued by suspicions that it might increase the risk of heart failure and bladder cancer. In this study, 74 pioglitazone recipients developed heart failure versus 71 in the placebo group (p=0.80). A dozen drug recipients were diagnosed with bladder cancer compared with eight cases in the placebo group (p=0.37).
Dr. Clark said, "All of the stuff we're doing for risk-factor reduction -- blood pressure reduction, stop smoking and giving aspirin -- they're all on the same level of relative improvement, and all of those are widely used. Aspirin has a list of side effects that will fill up three pages."
At the start of the study, all of the volunteers were insulin resistant, at least 40 years old, and had experienced an ischemic stroke or TIA in the previous six months. Diabetics were excluded as were patients with heart failure, active liver disease, and an increased risk of bladder cancer.
By the end of the study, 60% of the pioglitazone patients were still taking their medicine compared with 67% of placebo recipients. The most common reason for discontinuing was edema or weight gain.
The National Institute of Neurological Disorders and Stroke funded this study. Eleven coauthors reported disclosures.