NEJM study finds Actos holds off repeat strokes, heart attacks in insulin-resistant patients

The diabetes drug Actos (pioglitazone), once under intense scrutiny for possible risks to the heart, now has study data showing a cardiovascular benefit. In patients who'd recently suffered a stroke, the Takeda drug beat placebo at holding off additional strokes and heart attacks.

Led by researchers at Yale University, funded by the National Institute of Neurological Disorders and Stroke, and published in The New England Journal of Medicine, the study involved more than 3,800 patients with insulin resistance, but not diabetes. They all had a recent history of ischemic stroke or transient ischemic attack. Among patients in the pioglitazone arm, 175 patients suffered another stroke or a heart attack, or about 9%, compared with 228 placebo patients, or 11.8%. More than twice as many patients in the placebo arm developed diabetes--149, compared with 73 in the pioglitazone group.

The drug did trigger significant side effects, with more than half of patients gaining more than 4.5 kg of weight during the trial, compared with about one-third of the placebo group. The pioglitazone patients also suffered more serious bone fractures, at 5.1% in that group compared with 3.2% in the placebo arm.

"The findings suggest that the administration of pioglitazone in 100 patients similar to those in our trial for about 5 years could prevent 3 patients from having a stroke or myocardial infarction," the article states. "However, during the same period, the treatment would be expected to result in bone fractures requiring surgery or hospitalization in 2 patients."

The study results aren't likely to do much for Actos or Takeda, given that there are multiple generics on the market. Given the risk of side effects, doctors would think twice about using the drug to prevent strokes, particularly in patients with, say, an existing fracture risk. But the study authors did see pioglitazone as "a new option" for preventive health. And they seemed excited by the prospect that putting a damper on insulin resistance--as any number of diabetes treatments do--could play a role in stroke prevention.

"The IRIS trial explored a novel approach to prevention of vascular disease in patients with stroke," said Dr. Walter Kernan, a Yale School of Medicine professor and lead author of the study. "We hope that the findings will stimulate more research in this therapeutic area."

Dr. Silvio Inzucchi

In a statement, Dr. Silvio Inzucchi, the trial's principal endocrinologist, harked back to the previous debate over Actos' effects on cardiovascular health. After researchers in 2007 flagged an apparent increase in heart attack risk with GlaxoSmithKline's ($GSK) Avandia, both the GSK drug and Actos fell under suspicion. The FDA cleared Actos of a heart attack link rather quickly, though some European countries pulled it from the market. Both sets of watchdogs cracked down on Avandia, with Europe banning the med and the FDA allowing its use under a strict risk-management program. Eventually, however, the FDA reconsidered on Avandia, too; late last year, the agency lifted the final layer of safety regulations on the med.

"After years of controversy, pioglitazone is now proven to have cardiovascular benefits," Inzucchi said. "It's exciting to think that metabolic therapy may now be poised to take its place beside aspirin and cholesterol- and blood pressure-lowering therapies for preventing stroke in non-diabetic patients."

The study didn't mention another red flag on Actos: bladder cancer. In 2011, the FDA added a black-box warning about a potential increase in bladder cancer risk to the drug's official label, and the Japanese drugmaker has fought a series of liability lawsuits filed by cancer patients. In fact, it fell on the wrong side of a $9 billion judgment in on bladder cancer case in 2014. Last April, Takeda offered $2.2 billion to settle thousands of bladder-cancer claims from Actos patients, a deal that experts called a "bargain."

- here's the NEJM piece
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