Pioglitazone Benefit Unclear, Cochrane Review Concludes

October 18, 2006

October 18, 2006 (Dusseldorf, Germany) — Until new evidence becomes available, the benefit/risk ratio of the diabetes drug pioglitazone (Actos, Takeda Pharmaceuticals) remains unclear, with no definite evidence of benefit to hard clinical end points, according to a new Cochrane review of the drug [1]. In addition, different therapeutic indications for pioglitazone in the US and Europe also need to be clarified to reduce uncertainties among patients and physicians, the review notes.

The authors, led by Dr Bernd Richter (Heinrich-Heine University, Düsseldorf, Germany), searched MEDLINE, EMBASE, and the Cochrane Library for randomized controlled trials of at least 24 weeks in duration of pioglitazone in patients with type 2 diabetes. They found 22 such trials, which randomized approximately 6200 people to pioglitazone treatment. Longest duration of therapy was 34.5 months.

They found that these studies did not provide convincing evidence that patient-oriented outcomes such as mortality, morbidity, adverse effects, costs, and health-related quality of life are positively influenced by pioglitazone. Metabolic control measured by glycosylated hemoglobin A1c as a surrogate end point did not demonstrate clinically relevant differences from other oral antidiabetic drugs, and the occurrence of edema was significantly raised with pioglitazone. In addition, no study has investigated the economic costs of pioglitazone therapy, they point out.

Proactive study needs confirmation

The authors also note that 21 of the 22 included studies reported only surrogate outcomes, and the one single trial with relevant clinical end points—the PROactive study—showed mixed results. The PROactive study showed a trend toward benefit of pioglitazone vs placebo on the primary composite end point (time to all-cause mortality, nonfatal MI, stroke, acute coronary syndrome, endovascular or surgical intervention on the coronary or leg arteries, or amputation above the ankle), but this was not significant—hazard ratio 0.90 (95% CI 0.80-1.02; p=0.095).

Although a secondary end point of time to death from any cause, MI, and stroke was significant in favor of pioglitazone, the Cochrane review authors note that there has been some controversy about whether this end point was prespecified or not. They also point out that LDL-cholesterol levels rose more in the pioglitazone group and that significantly more patients developed edema and heart failure with pioglitazone than with placebo, although blood pressure was reduced more with pioglitazone.

"The hypothesis-generating positive findings of secondary end points with regard to cardiovascular outcomes of the PROactive study need confirmation. Future trials should avoid confusion about outcomes by clear a priori definition and statistical justification of anticipated end points," they conclude.

"Until new evidence becomes available, the place of pioglitazone in the treatment of type 2 diabetes mellitus remains unclear," Richter et al say. However, they note that at least five studies are ongoing—ACCORD, BARI-2D, CHICAGO, PERISCOPE, and PPAR—which eventually could contribute valuable information about the role of pioglitazone treatment in type 2 diabetes mellitus, adding: "Until new results from these trials are available, the benefit/risk ratio for pioglitazone is ambiguous."

Use metformin first

In an interview with heartwire , Richter elaborated on these comments. "I don't think doctors should use pioglitazone as a first-line drug as treatment for type 2 diabetes, as it does not have a proven benefit. Metformin should be the first drug of choice, as it showed reduced mortality in the UK PDS trial. I would recommend pioglitazone only if there were very good reasons not to use metformin." He added that he was especially concerned about the possibility of an increased incidence of heart failure with pioglitazone, noting that this was also suggested with rosiglitazone in the recently published DREAM study. "People may not believe that a small increase in the incidence of heart failure is a big problem, but if 2 or 3 million patients take this drug and it is associated with a 2% to 3% increase in CHF, this is a big problem. Also, these drugs are used in the community, where patients may not be closely monitored for the occurrence of heart failure, which makes me more worried," he said.


Different labeling in US/Europe causes confusion

The Cochrane report also makes the point that different labeling of pioglitazone in Europe and the US is causing confusion. In Europe, the indication appears to be more restrictive—with pioglitazone recommended mainly for patients who can't take metformin or for combination treatment in patients who need additional glycemic control when already on maximal tolerated doses of either metformin or a sulfonylurea. In the US, pioglitazone has a more general indication—as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes either as monotherapy or in combination with a sulfonylurea, metformin, or insulin.

The Cochrane review authors write: "Patients and physicians alike need to know why the two biggest drug agencies in the world established different criteria for the therapeutic indication of pioglitazone usage. Supposedly, both received very similar data from the manufacturer of pioglitazone." They add: "Consumers and physicians need clear guidance and transparent information about which studies exactly are used for the decisions of the relevant drug authorities."

To heartwire , Richter commented: "I think the European label is better, as it does suggest that pioglitazone should be used as a second-line drug after metformin, which is what the data support. The US data is too lax, to my mind. This could lead to inappropriate prescribing of pioglitazone, especially as it has a big marketing push behind it, whereas metformin is off patent, so does not have the same support."

Focus on other risk factors, too

Richter also made the point that doctors should not just focus on plasma glucose levels in diabetic patients, but that traditional cardiovascular risk factors such as blood pressure and lipids were just as important, and diet and exercise should be emphasized more. "Doctors need to look at the big picture. Glucose is not the only problem in these patients, and all the other risk factors need to be addressed as well," he told heartwire .


  1. Richter B, Bandeira-Echtler E, Bergerhoff K, et al. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev 2006; (4);CD006060. DOI: 10.1002/14651858.CD006060.pub2. Available at: https://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD006060/frame.html.

The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.


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