Pioglitazone after Ischemic Stroke

Posted by • April 8th, 2016

2016-04-01_11-30-19The thiazolidinedione class of peroxisome proliferator–activated receptor γ (PPAR-γ) agonists are among the most potent insulin-sensitizing drugs available. One medication in this class, pioglitazone, may reduce the risk of cardiovascular events, including stroke, in patients with type 2 diabetes, for whom the drug is currently approved as a glucose-lowering agent. Kernan et al. designed the multicenter, double-blind Insulin Resistance Intervention after Stroke (IRIS) trial to test the hypothesis that pioglitazone would reduce the rates of stroke and myocardial infarction after ischemic stroke or transient ischemic attack (TIA) in patients without diabetes who have insulin resistance.

In this trial in nondiabetic patients with insulin resistance and a recent ischemic stroke or transient ischemic attack, pioglitazone was associated with a lower risk of stroke and MI than was placebo but with a higher risk of weight gain, edema, and bone fracture. A new Original Article summarizes.

Clinical Pearl

• Insulin resistance is present in what percentage of patients without diabetes who have had an ischemic stroke or a TIA?

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

Clinical Pearl

• Does pioglitazone reduce the rate of new stroke or myocardial infarction in patients without diabetes who have already had an ischemic stroke or TIA?

In the study by Kernan et al., the primary outcome was a first fatal or nonfatal stroke or fatal or nonfatal myocardial infarction. In the study, the rate of the primary outcome was lower among patients who received pioglitazone than among those who received placebo. The incidence of a new diagnosis of diabetes was also lower with pioglitazone.

Table 2. Primary and Secondary Outcomes.

Figure 1. Primary Outcome.

Morning Report Questions

Q: What adverse effects are associated with pioglitazone?

A: Weight gain with PPAR-γ agonists, such as pioglitazone, reflects an increase in adipose tissue mass and a tendency for fluid accumulation owing to renal sodium retention. Sodium retention, if unchecked, can also increase the risk of heart failure. In the IRIS trial, patients in the pioglitazone group had more weight gain, edema, and shortness of breath than did patients in the placebo group. However, the authors did not observe a greater incidence of heart failure in the pioglitazone group than in the placebo group, which was probably because the study excluded patients with a history of heart failure and used safety algorithms that triggered dose reduction for excessive weight gain or edema. Pioglitazone has also been associated with an increased risk of bone fracture. In the IRIS study, rates of serious bone fracture (i.e., requiring hospitalization or surgery) were higher in the pioglitazone group than in the placebo group, which were reported in 99 patients and 62 patients, respectively (5.1% vs. 3.2%, P=0.003).

Q: Did the study by Kernan et al. support a possible link between pioglitazone and an increased risk of bladder cancer?

A: Observational research conducted in 2011 and 2012 suggested that pioglitazone may increase the risk of bladder cancer. However, more recent studies showed no significant association for any dose or duration of therapy. Other research suggests that PPAR-γ agonists might prevent certain cancers. Although the study by Kernan et al. did not observe a significant effect of treatment on the incidence of total or any specific cancer, the study was not powered to address these questions.

Table 3. Adverse Events, According to Severity.

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