Pioglitazone does not increase cardiovascular events (PROactive)

Clinical Question

What is the effect of pioglitazone (Actos) on the likelihood of cardiovascular events in patients with diabetes at high risk?

Bottom Line

Pioglitazone (Actos), unlike its chemical cousin rosiglitazone (Avandia), does not seem to increase the likelihood of cardiovascular events (N Engl J Med. 2007;356:2457-2471). The researchers conducting this study stretched -- and broke -- the scientific method when claiming benefit, but any claims of benefit are specious. (LOE = 1a-)


Wilcox R, Kupger S, Erdmann E, for the PROactive study investigators. Effects of pioglitazone on major adverse cardiovascular events in high-risk patients with type 2 diabetes: Results from PROspective pioglitAzone Clinical Trial in macro Vascular Events (PROactive 10). Am Heart J 2008;155:712-7.  [PMID:18371481]

Study Design

Randomized controlled trial (double-blinded)






Outpatient (specialty)


To study the effect of pioglitazone on cardiovascular events, these European researchers enrolled 5,238 high-risk patients with diabetes for an average 9.5 years. Most of the patients (75%) had hypertension, half had myocardial infarction in their history, and 19% had experienced a stroke. In additional to their aggressive treatment for all of these risk factors, patients were radomized (allocation concealed) to receive either placebo or pioglitazone, force-titrated to 45 mg/day, for 3 years. Over this time period, approximately 11% of patients experienced at least one of the three events that made up the composite outcome evaluated in this report: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. The researchers report a statistically significant difference between treatment and placebo, though their statistical analysis was suspect and likely improper. Despite having several analyses, they did not adjust the p-value for multiple comparisons. Also, none of the outcomes, when assessed individually, were statistically lower in the treated group. For a composite outcome to be considered valid, at least one of the individual outcomes should be statistically significant. An even greater threat to the validity of this study is that the overall goal of the PROactive study was to evaluate the effect of pioglitazone on a different composite outcome, all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle. There was no difference with therapy on this outcome (Lancet 2005;366:1279-89). Researchers cannot slice-and-dice their data so that they find a significant difference.