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Pioglitazone May Lower Risk for Recurrent Stroke in Prediabetic Stroke Patients
Why Some Neurologists Are Not Ready to Prescribe It

Article In Brief

Investigators reported that pioglitazone lowered the risk of stroke among patients who had prediabetes but concerns remain about some of the drug's side effects.

Stroke patients who have prediabetes might significantly lower their risk for another cardiovascular event by taking the diabetes drug pioglitazone, according to a post-hoc analysis of a previously published randomized clinical trial.

The new analysis of the data found that the combined incidence of recurrent stroke and myocardial infarction was 40 percent lower among stroke/transient ischemic attack participants with prediabetes who had good adherence to taking pioglitazone compared with those who took a placebo. For stroke alone, the incidence was 33 percent lower over a median follow-up of 4.8 years. New-onset diabetes was reduced by 80 percent.

But pioglitazone also increased the risk of some concerning side effects, including serious bone fractures, edema, and weight gain of 10 percent or more. Despite the downside, the study concluded that the benefit of pioglitazone appeared to outweigh the risk.

“Pioglitazone may be effective for secondary prevention in patients with stroke/transient ischemic attack and with prediabetes, particularly in those with good adherence,” the researchers reported in the February 7 online edition of JAMA Neurology.

J. David Spence, MD, lead author of the report, told NeurologyToday that he believes that doctors who work with stroke patients with prediabetes need to consider the use of pioglitazone, which he said has a bad reputation in the diabetes field because of potential problems such as fractures and weight gain. Many doctors stay clear of the drug, which is designed to reduce insulin resistance, because of concerns about its side effects, including suggestions that the drug could increase the risk for bladder cancer and heart failure, he pointed.

“The effects [pioglitazone's potential in stroke reduction] are so big, it needs to be rethought,” said Dr. Spence, of the Stroke Prevention & Atherosclerosis Research Centre at Western University in Ontario, Canada.

An editorial accompanying the study acknowledged the well-known concerns about side effects, but said the new findings related to stoke prevention are noteworthy.

“The study adds important data to the strategies for secondary prevention of stroke and cardiovascular events in this high-risk population (prediabetes) that might be a particularly relevant target for intervention, especially if the results could be extended in the future to the population of patients with prediabetes without a history of stroke,” Leonardo Pantoni, MD, PhD, of University of Milan's department of biomedical and clinical sciences, wrote in the editorial.

Some neurologists interviewed by NeurologyToday expressed doubt that pioglitazone would become a regular part of stroke prevention efforts, though they said the new analysis provides useful information.

“It is always good to see something positive in stroke prevention,” said Askiel Bruno, MD, FAAN, professor of neurology and a stroke specialist at Medical College of Georgia at Augusta University. “But,” he cautioned, “the trial on pioglitazone is not as exciting as it could have been because there are side effects associated with this treatment that counteract a small positive effect seen in stroke prevention.”

Dr. Bruno said that while stroke prevention efforts need to be improved, pioglitazone for that use “is not going to become standard in this subgroup of patients unless it is confirmed by a prospective randomized trial.”

Figure

The effects [pioglitazone's potential in stroke reduction] are so big, it needs to be rethought.”

—DR. J. DAVID SPENCE

According to background information in the new analysis, “adverse cardiovascular effects of diabetes are associated with insulin resistance, which is present in 50 [percent] of patients with stroke or transient ischemic attack. Insulin resistance is associated with increased blood pressure, serum low-density lipoprotein cholesterol, triglycerides, coagulation, inflammatory markers, platelet reactivity, reduced high-density lipoprotein cholesterol, and vascular reactivity.”

It noted that in addition to its ability to reduce insulin resistance, pioglitazone also has an anti-atherosclerotic effect.

Study Design, Findings

The new report is based on a post-hoc analysis of data collected during the Insulin Resistance Intervention After Stroke (IRIS) randomized clinical trial, which was published in the NewEnglandJournalofMedicine in 2016. In the initial analysis, researchers focused on patients with “insulin resistance,” as defined by a HOMA-IR score higher than 3. Participants without diabetes with ischemic stroke or ischemic attack who met the definition of insulin resistance were randomized 1:1 to 45 mg pioglitazone daily or placebo.

Figure

“It is always good to see something positive in stroke prevention. But “the trial on pioglitazone is not exciting as it could have been because there are side effects associated with this treatment that counteract a small positive effect seen in stroke prevention.”

—DR. ASKIEL BRUNO

Figure

“Perhaps clinicians should be open-minded and rethink this medicine by looking at the new data. Encouraging stroke patients to exercise, whether they have prediabetes or not, is probably the best advice a doctor can give.”

—DR. WUWEI (WAYNE) W. FENG

The IRIS trial reported that pioglitazone “reduced new-onset diabetes by half and reduced stroke or myocardial infarction (MI) by 24 percent,” according to a recap in the new analysis. Researchers decided to take a new, perhaps more relevant, look at the data using instead the definition of “prediabetes” because it is more common in routine clinical practice for patients to be diagnosed with that condition rather than insulin resistance. They selected their cohort for the post-hoc analysis using the American Diabetes Association definition of prediabetes (a hemoglobin A10 level of 5.7-6.4 percent or a fasting plasma glucose level of 100 mg/dL–125 mg/dL).

In addition, “because we wished to assess the potential benefit of pioglitazone in real-world practice, we emphasized the results in participants who were adherent to therapy, with adherence defined as taking 80 [percent] or more of the protocol dose over the course of the study,” the researchers said.

Among 3,876 participants in the initial IRIS trial, 2,885 were included in the ad hoc analysis, including 1,456 assigned to receive 45 mg of pioglitazone daily and 1,429 assigned to placebo. The new analysis found more benefit to taking pioglitazone when it was evaluated using prediabetes as the criteria rather than insulin resistance.

“Among IRIS study participants with prediabetes and good adherence, pioglitazone reduced stroke/MI by 40 [percent], stroke by 33 [percent], acute coronary syndrome by 52 [percent], and new-onset diabetes by 80 [percent]” during nearly five years of follow-up, the researchers reported. They also did an intent-to-treat analysis, which found smaller effects: 29 percent, 27 percent, 27 percent, and 53 percent, respectively. In absolute terms, the risk for a stroke/myocardial infarction was 6.1 percent in the adherent pioglitazone group compared with 10.2 percent in the placebo group, Dr. Spence said.

Among the participants with good adherence, serious bone fractures occurred in 3.6 percent (23) in the pioglitazone group compared with 2.8 percent (23) in the placebo group. Weight gain of 10 percent or more occurred in 29.8 percent (192) of those on pioglitazone compared with 12 percent (97) on placebo. Edema occurred in 29.2 percent (118) of the pioglitazone group, compared with 21.6 percent (175) of the placebo group. Heart failure was not increased in the pioglitazone group.

Looking at the data another way, the number needed to treat (NNT) to prevent new-onset diabetes was only 12; the NNT to prevent one stroke or myocardial infarction was 24, while the “number need to harm” for fracture was 125, Dr. Spence said.

Dr. Spence said he became interested as a researcher into looking further into the potential of pioglitazone for preventing recurrent stroke in people with prediabetes because he was having trouble getting the drug approved by the Ontario Health Ministry (which oversees health care in the province) for use in some of his patients. He said there is some research to suggest that pioglitazone may provide some stroke reduction benefit at a dose as low as 7.5 mg, which could reduce the risk of side effects. He said edema, while not welcome, can be treated with amiloride.

Expert Commentary

Other neurologists who were not involved with the study told Neurology Today that pioglitazone is not their favorite choice of drugs for stroke prevention. Most of the time, stroke patients with prediabetes or diabetes go back to their primary care doctor or endocrinologist to manage that disease.

Wuwei (Wayne) W. Feng, MD, professor of neurology and stroke specialist at the Medical University of South Carolina, said pioglitazone was problematic because of the high risk of weight gain and potential elevated risk of bladder cancer.

“I don't as a stroke doctor use this medicine very often,” he said, adding that pioglitazone has been around for 20 years as a treatment for type 2 diabetes, but several newer medications have come along since then.

Dr. Feng said he was impressed with the better results that emerged from the subgroup of patients with prediabetes and medication compliance, but he is still troubled by the high rates of fluid retention or weight gain reported in the post-hoc analysis, noting that subjects tended to already be overweight or obese at baseline.

Still, he said giving pioglitazone to 100 patients who take the drug in good faith for about five years could prevent four patients from having stroke or heart attack. He said the drug might be useful in a subset of stroke patients with prediabetes who may not have a weight issue to begin with.

“Perhaps clinicians should be open-minded and rethink this medicine by looking at the new data,” Dr. Feng said. “Encouraging stroke patients to exercise, whether they have prediabetes or not, is probably the best advice a doctor can give,” he said.

Figure

“You have a real reduction in vascular events, but it comes at a significant cost...”

—DR. MICHAEL T. MULLEN

Michael T. Mullen, MD, assistant professor of neurology at the Perelman School of Medicine at University of Pennsylvania, said he was not convinced by the new analysis that pioglitazone was ready for widespread clinical use in stroke prevention.

“You have a real reduction in vascular events, but it comes at a significant cost, in terms of increased risk for bone fractures, weight gain and edema,” he said. “Ten percent of your body weight is not a small amount of weight.”

He said that many patients “are really sensitive to the issues of weight gain and swelling,” and may not be reassured by the fact that they then could take another drug (such as a diuretic) to take care of side effects caused by pioglitazone.

“Patients are conscious of the number of medications they are on,” he said.

Dr. Mullen said stroke prevention efforts need to be multifaceted, including targeting weight, lipids, blood pressure, diabetes risk, and exercise.

“Pioglitazone could be considered in appropriate patients, but this should be a process of shared decision making with the patient after fully informing them of the potential side effects. For many, those side effects may be unacceptable.”

Disclosures

Dr. Spence and other investigators of the current study were members of the Steering Committee of the IRIS trial but have no financial connections with the manufacturer of pioglitazone. Drs. Feng and Mullen had no competing interests.

Link Up for More Information

• Spence JD, Viscoli CM, Inzucchi SE, et al; for the IRIS Investigators. Pioglitazone therapy in patients with stroke and prediabetes: A post hoc analysis of the IRIS randomized trial https://jamanetwork.com/journals/jamaneurology/fullarticle/10.1001/jamaneurol.2019.0079. JAMA Neurol 2019; Epub 2019 Feb 7.
    • Pantoni L. Editorial: Potential new horizons for the prevention of cerebrovascular diseases and dementia https://jamanetwork.com/journals/jamaneurology/fullarticle/2723652. JAMA Neurol 2019; Epub 2019 Feb 7.
      • Kernan WN, Viscoli CM, Furie KL, et al; for the IRIS Trial Investigators. Pioglitazone after ischemic stroke or transient ischemic attack https://www.nejm.org/doi/full/10.1056/NEJMoa1506930. N Engl J Med 2016; 374(14) 1321–1331.