Tackling insulin resistance may reduce recurrence after stroke

By Eleanor McDermid

Giving pioglitazone to stroke survivors with insulin resistance but no overt diabetes reduces their risk of having a recurrent vascular event, shows the randomised Insulin Resistance Intervention after Stroke (IRIS) trial.

The study, presented today at the International Stroke Conference in Los Angeles, California, USA, and simultaneously published in The New England Journal of Medicine, followed up 3876 patients with a recent ischaemic stroke or transient ischaemic attack (TIA) for an average of 4.8 years.

During this time, 9.0% of patients randomly assigned to receive pioglitazone at a target dose of 45 mg had a fatal or nonfatal stroke or myocardial infarction. This was significantly lower than the 11.8% rate recorded among patients in the placebo group, equating to a 24% risk reduction. The most common event was nonfatal stroke, which occurred in 5.9% of the pioglitazone group versus 7.1% of the placebo group.

In a linked editorial, Clay Semenkovich (Washington University, St Louis, USA) calls the results "surprising", given that the study patients were receiving "very effective cerebrovascular treatment".

At the time of recruitment, at a median of about 80 days after stroke or TIA, more than 80% of the patients were taking a statin, more than 90% were taking antiplatelet medication, about 10% were on oral anticoagulation, more than half were taking an ACE inhibitor or angiotensin receptor blocker and about a third were taking a beta blocker or a diuretic.

Semenkovich believes that pioglitazone is "a potentially important" secondary prevention strategy in stroke patients, but warns against a rush to prescribe it. He says that the IRIS population excluded patients with heart failure and had very minimal or no disability, making it unclear how the treatment might affect patients with substantial neurological deficits.

All the patients had insulin resistance at baseline, defined as a homeostasis model assessment of insulin resistance value greater than 3.0, and during follow-up 3.8% of patients in the pioglitazone group progressed to diabetes, compared with 7.7% of those in the placebo group - a significant difference.

The pioglitazone group had lower blood pressure and fasting triglyceride levels than the placebo group during follow-up, as well as higher levels of high-density lipoprotein cholesterol, but they also had higher levels of low-density lipoprotein cholesterol.

Researcher Walter Kernan (Yale University, New Haven, Connecticut, USA) and colleagues calculate that giving pioglitazone to 100 patients for 5 years would prevent stroke or myocardial infarction in three. However, two patients would have a bone fracture requiring hospitalisation or surgery.

As anticipated with a thiazolidinedione, patients taking pioglitazone had a higher rate of fractures than those taking placebo (6.9 vs 4.9%), as well as oedema (35.6 vs 24.9%) and weight gain.

"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", the team concludes.

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