Clinical Question

In patients with evidence of insulin resistance and a recent stroke or transient ischemic attack (TIA), does pioglitazone (Actos) improve outcomes?

Bottom Line

In patients with a recent stroke or TIA and evidence of insulin resistance, pioglitazone reduces the likelihood of myocardial infarction (MI) or stroke (number needed to treat [NNT] = 36 over five years) but increases the risk of significant weight gain (number needed to treat to harm [NNTH] =14), edema (NNTH = 9), and fracture (NNTH = 53). The risk of receiving a diagnosis of diabetes mellitus is lowered, but that is predictable when you give someone a medicine that lowers blood sugar. (Level of Evidence = 1b)

Synopsis

The researchers in this trial hypothesized that because insulin resistance is common in patients with stroke or TIA, pioglitazone might improve vascular outcomes. They identified patients 40 years and older who had a stroke or TIA in the previous six months and who met criteria for insulin resistance (fasting glucose times fasting insulin level divided by 22.5), placing them in the top 25% among patients without diabetes. A total of 3,895 patients at 179 sites were randomized to receive pioglitazone or placebo. The initial dosage was 15 mg once daily, and it was titrated up to 45 mg once daily if tolerated. Groups were balanced at the start of the study, and analysis was by intention to treat. The mean age of participants was 63 years, 65% were men, and 88% had a history of stroke.

After a median of 4.8 years, there was a lower likelihood of the composite outcome of stroke or MI with pioglitazone (9.0% vs. 11.8%; P = .007; NNT = 36 for 4.8 years). There was also a lower likelihood of progression to diabetes (3.8% vs. 7.7%; P < .001; NNT = 26). Most of that benefit was among patients with nonfatal stroke or MI (2.2% absolute reduction) rather than fatal events (0.5% absolute reduction). There was no difference in all-cause mortality. The harms in the pioglitazone group included an increase in the risk of weight gain of at least 13.6 kg (30 lb; NNTH = 14), edema (NNTH = 9), shortness of breath (NNTH = 25), and fracture (NNTH = 53).

Study design: Randomized controlled trial (double-blinded)

Funding source: Government

Allocation: Uncertain

Setting: Outpatient (any)

Reference: KernanWNViscoliCMFurieKLet alIRIS Trial InvestigatorsPioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med2016;374(14):1321–1331.