NEW ORLEANS — Pioglitazone halved the progression to diabetes in people with insulin resistance and cerebrovascular disease, new data from the Insulin Resistance Intervention after Stroke (IRIS) trial show.



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The new findings from the 5-year study were presented June 14 by Silvio E Inzucchi, MD, as part of the president's oral abstract session here at the American Diabetes Association (ADA) 2016 Scientific Sessions.

The main IRIS finding — that pioglitazone reduced by a significant 24% the risk for recurrent stroke or myocardial infarction (MI) in people with insulin resistance, no frank diabetes, and a recent history of stroke or transient ischemic attack — were presented earlier this year at the International Stroke Conference 2016 and simultaneously published in the New England Journal of Medicine. 

In the new analysis, progression to diabetes — a prespecified secondary end point of IRIS — occurred in 3.8% of the 1939 individuals randomized to 45 mg/day of pioglitazone compared with 7.7% of the 1937 receiving placebo, a significant 52% reduction in the time to diabetes onset (< .0001).

The difference was driven primarily by the reduction in patients at highest risk, including those with prediabetes and the greatest degrees of insulin resistance and metabolic syndrome.

The prevention of diabetes and secondary stroke seen together in IRIS is "the first time [both have been] shown in one trial with one drug, although they are not necessarily linked," Dr Inzucchi told 

But this isn't the first time pioglitazone has been shown to reduce the risk of type 2 diabetes, he stressed. In 2011, the Actos Now for Prevention of Diabetes (ACT NOW) study demonstrated a 72% reduction in the conversion rate from impaired glucose tolerance to type 2 diabetes. And a recent look at those patients showed that pioglitazone's protective effect persists at least a year after they stop taking it.

Pioglitazone also previously showed cardiovascular benefit in the 2005 PROactive trial, with a significant 16% reduction in death, MI, and stroke, although it failed to show a statistically significant reduction in the composite primary end point of major adverse cardiac events (MACE).

In August 2012, the US Food and Drug Administration approved the first generic version of pioglitazone.

In Connecticut, it now costs less than $10 a month, approximately 100-fold less than some of the newer oral and injectable type 2 diabetes drugs, Dr Inzucchi pointed out during a press conference held to discuss the findings during the ADA meeting.

"Pioglitazone is the only oral type 2 diabetes drug with clear antiatherosclerosis effects.…Should the role of this inexpensive, generic medication in type 2 diabetes management be reassessed?" he wondered.

Also, he said, "Should the neurology community consider the potential role of pioglitazone for secondary stroke prevention?"

Ralph A DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center, San Antonio, and ACT NOW lead author, believes the time is right to take another look at pioglitazone.

"IRIS was very impressive.…Believe me, if you have a stroke, you should be on that drug. I would think we ought to change our practice of treating stroke," he said in an interview during the ADA meeting.

And regarding the new IRIS data, Dr DeFronzo said: "I think pioglitazone, particularly in lower doses is an ideal drug for prevention of diabetes," adding, "Personally, I think it is the second-best drug for treating people with diabetes."

But Will Safety Concerns Trump Benefit? 

Pioglitazone's use has waned in recent years, due primarily to concerns about the well-supported risk of heart failure generally with the thiazolidinedione (TZD) class of drugs, and the less well-clarified possible risk for bladder cancer specifically with pioglitazone. Studies continue to volley between an increased bladder cancer risk and no risk, and the issue remains controversial.

Weight gain and edema are also common side effects with TZDs generally, and an increased risk for fractures has also been reported.

In IRIS, there was no increased risk for incident cancer with pioglitazone (6.9% vs 7.7%, P = .29) or heart failure (2.6% vs 2.2%, P = .35), but bone fractures did occur at a significantly higher rate with the drug (5.1% vs 3.2%, P < .01). The lack of significance for heart failure was probably due to the study's exclusion of patients with heart failure at baseline and aggressive protocols for managing patients who developed edema during the trial, Dr Inzucchi noted.

Simeon I Taylor, MD, professor of medicine, University of Maryland School of Medicine, Baltimore, told Medscape Medical News that he believes pioglitazone's safety issues, particularly the fracture risk, deserve serious consideration.

"I think that there are a lot of good things about the TZDs and certainly the PROactive study suggested that in that patient population, pioglitazone was safe and, at least, as judged by secondary end points, might possibly have benefit in terms of preventing MACE.…But, I think the bone fractures are really a very substantial risk from a quantitative point of view, particularly with chronic use of the drug."

Previous data suggest about a 3-year time lag to increase in fractures in men and about 1-year delay in women. That, combined with the heart-failure risk, "is important to take into consideration as one judges the benefit/risk profile of the drug," particularly in the context of prevention, Dr Taylor said.

"We've been aware of the bone-fracture issue for years with the TZDs. It is a concern and we don't understand it that well, so it is difficult to make recommendations as to how to prevent them from happening."

Dr Inzucchi said that the additional risk of fractures is about one for every 100 patients using the drug for 1 year, "so it's not a large signal. One might think that preventing a stroke or an MI is more important, but that depends on several factors, including how severe the fracture vs the stroke/MI is.

"In IRIS we did not see a hip-fracture signal, which is gratifying. Nonetheless it needs to be incorporated into decision making with the patient."

Diabetes Prevention 

In IRIS, at baseline, about 42% of the 3876 total patients had impaired fasting glucose (IFG) of 100 to 125 mg/dL (as defined by the American Diabetes Association), while 14% met the World Health Organization/International Diabetes Federation IFG criteria (110–125 mg/dL), and two-thirds had HbA1clevels of 5.7% or greater. Just over half had at least three components of the metabolic syndrome.

At 1 year, fasting plasma glucose was reduced significantly in the pioglitazone group (from 98.2 to 95.1 mg/dL) but remained unchanged in the placebo group (< .0001 for between-group difference). Homeostasis model assessment of insulin resistance (HOMA-IR) also dropped significantly with pioglitazone compared with placebo (P < .0001).

Over an average 4.8 years, there was a 3.9% absolute risk reduction in progression to diabetes with pioglitazone compared with placebo (hazard ratio, 0.48), with greater risk reductions seen among those meeting the ADA definition of IFG at baseline (8.5% vs 0.8%), those with baseline HbA1c 5.7% or greater compared with below (5.6% vs 1.0%), and HOMA-IR 4.6 or above vs below (6.3% vs 1.4%).

Dr Inzucchi told "My belief is that the diabetes community must readjudicate the role of pioglitazone based on these data. It is an extremely cost-effective drug."

However, press briefing moderator Ann Albright, PhD, director of the division of diabetes translation at the US Centers for Disease Control and Prevention, Atlanta, Georgia, made a plea for clinicians not to forget about lifestyle when aiming to help at-risk patients to avoid developing diabetes.

"From our perspective at CDC, the use of medications is clearly a decision that the patient and their clinician needs to discuss. They should be considered tools in the armamentarium that people should be able to call upon, but even if you pursue those, lifestyle is still the foundation."