Clinical Health Updates

Controversial evidence on value of pioglitazone (Actos) for type 2 diabetes

Clinical Question:
Is pioglitazone (Actos) useful in the management of patients with type 2 diabetes mellitus?

Bottom Line:
Based only on studies provided by and conducted directly by the drug manufacturer, this review reports a significantly reduced incidence only of the composite outcome of death, myocardial infarction, and stroke with pioglitazone (Actos) therapy. None of the same outcomes were significantly reduced on an individual basis. An earlier review of pioglitazone therapy in type 2 diabetes by the Cochrane Collaboration of all available published and peer-reviewed clinical trials found no significant evidence of improved patient-oriented outcomes. Similar to the other thiazolidinedione, rosiglitazone (Avandia), pioglitazone also increases the risk of serious heart failure in type 2 diabetics.

Reference:
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. A meta-analysis of randomized trials. JAMA 2007;298:1180-88.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes.

A recently published systematic review (Nissen SE, et al. NEJM 2007;356:2457-71) reported an increased risk of adverse cardiovascular events among type 2 diabetics treated with rosiglitazone (Avandia). In the same issue of this journal a second review of rosiglitazone also similarly reports an increased risk of adverse cardiovascular events (Singh S, et al. JAMA 2007;298:1189-95). Thus, all eyes from clinicians and patients hoping to still receive benefit from treatment for type 2 diabetes with the thiazolidinediones are on the remaining drug, pioglitazone (Actos). A recent Cochrane review reporting on a meta-analysis of 22 peer-reviewed trials comprising approximately 6200 patients found no evidence of improved patient-oriented outcomes with pioglitazone treatment. The same review did, however, report a significantly increased incidence of edema among treated patients.

In this current review, the investigators were contracted to perform a meta-analysis of 19 trials, enrolling 16,390 patients, of pioglitazone therapy in type 2 diabetics conducted by the manufacturer. The authors note that at least 20 other completed trials evaluating pioglitazone therapy not conducted directly by the manufacturer were not included in their summary analysis. No formal search of the medical literature was independently completed by the authors, including not reviewing any evidence-based resources or the Cochrane Registry of Controlled Trials. In this review the composite outcome of death, nonfatal myocardial infarction, or nonfatal stroke was significantly reduced in patients treated with pioglitazone compared to placebo. However, as was also reported in the earlier Cochrane review, no significant benefit was found for any individual patient-oriented outcome, including all cause mortality, myocardial infarction, or stroke. Similarly to the two reviews of rosiglitazone, this review of pioglitazone did report a statistically significant increased incidence of serious heart failure in treated patients compared to controls.