Study: Targeting insulin resistance reduces stroke, heart attack risk


Enthusiasm is again surrounding a once best-selling diabetes drug that flamed out over the past decade – but this time it’s being looked at for helping certain stroke survivors, not diabetes patients.

Researchers for the first time have found that using pioglitazone, formerly known by the brand name Actos, to make the body sensitive to insulin can lower the risk of strokes and heart attacks in stroke survivors who have built up a resistance to the hormone.

The findings, experts say, could convince neurologists to start screening survivors for so-called insulin resistance – a precursor to Type 2 diabetes in which the body cannot properly use insulin. Drugmakers may also now see more incentive to develop newer medicines to treat insulin resistance.

“This is the very beginning of our exploration of insulin resistance as a target for vascular prevention,” said the study’s lead researcher Walter Kernan, M.D., a professor at Yale University School of Medicine. “We’re at the very beginning of what I hope will be a scientific advance.”

But critics say the increased risk of bone fractures and other potential side effects of the daily pill may outweigh the benefits.

The federally funded study, presented Wednesday at the American Heart Association’s International Stroke Conference, was published simultaneously in the New England Journal of Medicine.

The Insulin Resistance Intervention after Stroke, or IRIS, study included 3,876 patients who had suffered a stroke or transient ischemic attack, or TIA – a “warning” stroke. The risk of having a heart attack or stroke within about five years fell by 24 percent, from 11.8 percent among patients who took a placebo to 9 percent for those taking pioglitazone.

Other research suggests 16 percent of stroke and TIA patients will have another stroke within four years and 9 percent will have a heart attack.

Researchers reported that the drug also cut the risk of developing diabetes by half, from 7.7 percent in the placebo group to 3.8 percent in those taking pioglitazone.

About 6.6 million American adults have had a stroke, and another 5 million have had a TIA. It’s unknown how many of them are insulin-resistant, but in the IRIS study, nearly two-thirds of survivors without diabetes tested positive for insulin resistance.

“This is one of the under told stories of cardiovascular disease – how frequent insulin resistance is a risk factor,” said endocrinologist Silvio Inzucchi, M.D., director of the Yale Diabetes Center and a co-investigator on the trial.

Most patients in the study were already being treated with a cholesterol-lowering statin, a blood thinner and blood pressure medication.

“That makes the results even more impressive, that this reduction was on top of current standard therapies,” Inzucchi said.

The new findings come at a time when pioglitazone, now available as a low-cost generic, is prescribed much less often to diabetes patients. Its near demise came after studies suggested the drug increased the risk for bladder cancer and heart failure, problems that later research showed were not due to the drug.

But by then, a number of drug companies’ development pipelines had dropped thiazolidinediones, or TZDs – the class of medicines to which pioglitazone belongs, Inzucchi said.

“That set the field back 10 years,” he said. “But these new findings might encourage the pharmaceutical industry to rethink the notion of insulin sensitizers as vasculoprotective and to develop better and safer drugs, whether it’s of the TZD class or not.”

The findings might also prompt the laboratory medicine community to develop a standardized insulin resistance test, Kernan said. Insulin level is currently not part of the standard battery of tests done at routine medical checkups.

Although there was no increased risk for heart failure or bladder cancer, patients taking the drug were more likely to have bone fractures that required hospitalization or surgery. They were also more likely to gain weight.

“It seems like this all comes at a cost,” said Kyra Becker, M.D., director of vascular neurology services at the University of Washington Comprehensive Stroke Center at Harborview Medical Center, who was not involved in the study. “They showed you can prevent three strokes or heart attacks in every 100 patients treated, but two of those 100 will have a serious bone fracture.”

Doctors and patients will have to weigh the prevention of one complication with the induction of another, said Becker, who prefers to treat insulin-resistant patients with lifestyle changes. Insulin resistance most often occurs in people who are overweight or obese, and exercise, a healthy diet and losing weight have been shown to improve insulin sensitivity.

“A lot of society would rather take a drug than go to the gym or walk around their neighborhood,” Becker said. “But we need to keep pushing people to change their behaviors.”

Researchers noted, however, that there is no current evidence that lowering insulin resistance through diet and exercise can lower the risk of heart attacks and strokes, but studies in this area are clearly needed.

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