IRIS: Diabetes Drug Reduces Recurrent Stroke, MI in Patients With Insulin Resistance

Susan Jeffrey

February 17, 2016

LOS ANGELES — New randomized trial results show that in patients with insulin resistance, no frank diabetes, and a history of stroke or transient ischemic attack, treatment with diabetes drug pioglitazone (Actos, Takeda Pharmaceuticals) reduced the risk for recurrent stroke or myocardial infarction (MI) vs placebo.

While treatment was associated with a lower risk for diabetes, patients receiving pioglitazone also had higher rates of weight gain, edema, and bone fracture requiring surgery or hospitalization.

"For the first time, a therapy directed at insulin resistance has been shown to prevent cardiovascular and cerebrovascular events for these patients," lead author Walter N. Kernan, MD, professor of medicine, Yale School of Medicine, New Haven, Connecticut, said at a press conference here.

Dr Walter N. Kernan

"Very practically," he added, the findings indicate that "very possibly, pioglitazone is a new option for patients who've had a stroke or TIA [transient ischemic attack] to prevent future cardiac events and strokes. However, we have to recognize that pioglitazone is not approved for use in nondiabetic 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."

The results though do show "fairly persuasively" that insulin resistance is a new target for prevention in cardiovascular disease, he added. "This is the first trial to show that a drug directed at insulin resistance…is effective in reducing stroke and MI. It is also the first diabetes drug that has ever been shown to prevent macrovascular disease, stroke, and heart attack — the first diabetes drug to be shown to prevent major cardiovascular events in a trial using its primary endpoint."

These results from the Insulin Resistance Intervention after Stroke (IRIS) trial are published online February 17 in the New England Journal of Medicine to coincide with their presentation here at the International Stroke Conference (ISC) 2016.

New Preventive Strategy

Insulin resistance is "nearly universal" in patients with type 2 diabetes but is also present in more than 50% of patients without diabetes who have had an ischemic stroke or TIA, the authors write. Insulin sensitivity is known to increase the risk for vascular disease, possibly because of associated hypertension, hyperglycemia, hyperinsulinemia, and other vascular issues.

"Treatment of insulin resistance represents a potential new preventive strategy that could be added to standard care after ischemic stroke or TIA," they write.

In the IRIS trial, researchers tested that hypothesis in 3876 patients with insulin resistance, defined as a score of more than 3.0 on the homeostasis model assessment of insulin resistance (HOMA-IR) index, and a recent history of stroke or TIA.

Participants were randomly assigned to receive pioglitazone, 45 mg daily, or placebo. The primary endpoint was a combination of fatal or nonfatal stroke or MI.

After 4.8 years of follow-up, significantly more primary outcome events occurred in those receiving placebo than in those receiving pioglitazone.

Those receiving active treatment also had less new diabetes, but all-cause mortality was not different between the groups.

Table 1. IRIS: Primary and Secondary Endpoints

Endpoint Pioglitazone (%) Placebo (%) Hazard Ratio (95% Confidence Interval) P Value
Fatal or nonfatal stroke or MI (primary endpoint) 9.0 11.8 0.76 (0.62 - 0.93) .007
New diabetes 3.8 7.7 0.48 (0.33 - 0.69) < .001
All-cause mortality 7.0 7.5 0.93 (0.73 - 1.17) .52


Nonfatal stroke accounted for the bulk of the difference between treatment arms.

Table 2. IRIS: Primary Endpoint Events by Type

Endpoint Pioglitazone, n (%) Placebo, n (%)
Total stroke 123 (6.3) 150 (7.7)
  Fatal stroke 9 (0.5) 13 (0.7)
  Nonfatal stroke 114 (5.9) 137 (7.1)
Total MI 52 (2.7) 78 (4.0)
  Fatal MI 7 (0.4) 14 (0.7)
  Nonfatal MI 45 (2.3) 64 (3.3)


However, treatment with pioglitazone was also associated with an increase in adverse effects, including weight gain exceeding 4.5 kg, edema, and bone fracture requiring surgery or hospitalization.

Table 3. IRIS: Safety Outcomes

Endpoint Pioglitazone (%) Placebo (%) P Value
Weight gain > 4.5 kg 52.2 33.7 <.001
Edema 35.6 24.9 <.001
Bone fracture requiring surgery or hospitalization 5.1 3.2 .003


"Although shortness of breath was reported more frequently in the pioglitazone group than in the placebo group, there was no significant between-group difference in the number of patients with heart failure (74 in the pioglitazone group and 71 in the placebo group, P = .80) or in the number of patients hospitalized for heart failure (51 and 42, respectively, P = .35)," the authors note.

Incident bladder cancer occurred in 12 patients in the pioglitazone group vs 8 in the placebo group (P = .37), and total cancer incidence did not differ between groups.

Dr Kernan and colleagues conclude that their findings suggest pioglitazone treatment in 100 patients similar to those in this trial for about 5 years would prevent three patients from having a stroke or MI, but bone fractures requiring surgery would be expected to occur 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 conclude.

"This study represents a novel approach to prevent recurrent vascular events by reversing a specific metabolic abnormality thought to increase the risk for future heart attack or stroke," said Walter J. Koroshetz, MD, director of the National Institute of Neurological Disorders and Stroke, in a statement.

"Long, Strange Trip"

In an editorial accompanying the publication, Clay F. Semenkovich, MD, from the Division of Endocrinology, Metabolism and Lipid Research at Washington University, St Louis, Missouri, compares the story of treatment of insulin resistance to an album by The Grateful Dead, What a Long, Strange Trip It's Been.

Pioglitazone is in the class of drugs called thiazolidinediones, which were approved to treat diabetes and gained wide acceptance. One drug in the class, troglitazone, that had been used in the landmark Diabetes Prevention Program was taken off the market because of liver toxicity. Rosiglitazone and pioglitazone were found to be associated with heart failure.

In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROActive) trial, use of pioglitazone in patients with diabetes reduced a composite endpoint of death, nonfatal MI, and stroke but increased rates of edema, weight gain, heart failure, and bladder cancer.

"Thiazolidinediones fell from grace," Dr Semenkovich writes. In this context, results of the IRIS trial are "surprising," he notes, showing a 24% reduction in stroke and MI in treated patients with insulin resistance.

"These findings may tempt clinicians to rush to prescribe pioglitazone, but many caveats remain," he said. Patients met strict criteria, including exclusion for heart failure, for example, and had little neurologic impairment from their prior stroke.

Still, "pioglitazone represents a potentially important therapy for the secondary prevention of vascular events in appropriately selected patients with cerebrovascular disease," he writes.

"Insulin-sensitizing drugs have been exalted as metabolic saviors and vilified as a threat to public health," Dr Semenkovich concludes. "The trip has been long and strange, but it may yet lead to strategies for improving the health of people like Jerry Garcia [of The Grateful Dead], whose premature death was related to insulin resistance."

Here at the meeting, press conference moderator Kyra Becker, MD, professor of neurology and neurological surgery at the University of Washington, Seattle, and chair of the ISC 2016 program committee was cautious in her assessment of the data.

Dr Kyra Becker

"As Dr Kernan said, the whole idea of a target of insulin resistance for preventing vascular events seems to be proved, although one never knows what exactly the mechanism of the medication is that's leading to the benefit in a patient," Dr Becker told Medscape Medical News. "You know what the pharmacology is, but often it's an off-target effect.

"Having said that, we do know how to improve insulin resistance, and that's weight loss and exercise and a healthy diet," she added. "I think that we sometimes lose our focus in trying to create a drug to do these things, and we should focus more on better lifestyles. Doctors should be incentivized to help their patients have a healthier lifestyle.

"If this drug was gangbusters effective, that would be one thing, but the data showed for every 100 patients you treat for 5 years with the drug, you prevent three MIs or strokes, but you have two serious bone fractures, lots of weight gain, and side effects. What I'd like to see is a quality-of-life analysis; how do patients feel on this medication? I think that would be fairly telling."

Still, she added, "it's a fantastic study and I congratulate the investigators. I think we're going to have to figure out how we're going to incorporate these data into our practice though."

Ralph Sacco, MD, chairman of neurology, Olemberg Family Chair in Neurological Disorders, Miller Professor of Neurology, Epidemiology and Public Health Sciences, Human Genetics, and Neurosurgery, and executive director of the Evelyn McKnight Brain Institute at the Miller School of Medicine, University of Miami, Florida, called the IRIS trial "a very important study."

"One, it tells us that insulin resistance is something we need to begin to look for among our patients with stroke," he told Medscape Medical News. "It's been recognized as a risk factor in other studies, and now in this study we know that if you treat the insulin resistance with a drug like pioglitazone, you can reduce the risk of a recurrent stroke. It's been many years since we've had another drug or another approach to reducing the risk of recurrent stroke," he said.

How these data will be picked up by the American Heart Association/American Stroke Association, which writes evidence-based guidelines, and how it will be viewed by the US Food and Drug Administration, since this would be a new market indication for pioglitazone, he said, "still remains to be seen."

Ways to address insulin resistance are now a "burgeoning area" in diabetes research, Dr Sacco noted, with many agents having been shown to positively affect it, including old drugs such as metformin and several new classes of drugs, "but none of them have been evaluated in secondary stroke prevention. So this opens up to us a whole new frontier of new opportunities for us to be doing studies to evaluate treatment of insulin resistance to prevent both primary and secondary stroke."

The IRIS trial was funded by the National Institute of Neurological Disorders and Stroke. Pioglitazone and placebo were provided by Takeda Pharmaceuticals International. Dr Kernan reports grant support from the US National Institute of Neurological Disorders and Stroke, as well as grant and nonfinancial support from Takeda Pharmaceuticals International Inc, during the conduct of the study. Disclosures for other coauthors and editorialist can be found at

N Engl J Med. Published online February 17, 2016. Abstract Editorial

International Stroke Conference (ISC) 2016. Abstract LB1. Presented February 17, 2016.


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