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European drug agency extends review of safety of pioglitazone

BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d4105 (Published 29 June 2011) Cite this as: BMJ 2011;342:d4105
  1. Ray Moynihan
  1. 1Byron Bay, Australia

The European Medicines Agency will decide the fate of the type 2 diabetes treatment pioglitazone later in July, after the release of new data indicating that long term use is associated with a slightly raised risk of bladder cancer.

New warnings have been issued in the United States, while French authorities have suspended use of drugs containing pioglitazone, which is sold under brand names including Actos, Glustin, Competact, Glubrava, and Tandemact.

Marketed for more than a decade, pioglitazone had total sales last year of almost £3bn (€3.4bn; $4.8bn) and is an important earner for the Japanese company Takeda. A competitor drug, rosiglitazone (sold as Avandia), was withdrawn from the European market last year after evidence that its use was associated with an increased risk of heart attacks (BMJ 2010;341:c5291, doi:10.1136/bmj.c5291).

The latest data come from a retrospective study in France that in early June found that use of pioglitazone was linked with a small increase in the risk of bladder cancer and that the risk increased with higher cumulative doses and longer term use.

Analysis of a long term observational study in the US recently identified a 40% rise in the risk of bladder cancer among those taking the drug for longer than one year. The US Food and Drug Administration said that this relative risk increase translates into an estimated 27 excess cases of bladder cancer in every 100 000 person years of follow up.

In March the European Medicines Agency announced that a review of pioglitazone would be conducted by its Committee for Medicinal Products for Human Use, which said last week, after looking at the totality of the data, that the suggested link to bladder cancer “represents a clinically relevant signal which requires further evaluation.”

However, the committee said that the French study had several “methodological limitations” and that “numerous issues still needed to be resolved” before it could make a recommendation on the drug’s future use. A special scientific advisory committee on diabetes will investigate the safety issues and report back to the agency in July, including reporting on possible “risk minimisation measures” for people using the drugs.

Takeda says it will continue to work with regulators to “share and review all available data” but that it is “confident in the therapeutic benefits of pioglitazone and its importance as a treatment for type 2 diabetes.”

Although pioglitazone is known to reduce blood sugar concentrations, its overall risk-benefit ratio remains uncertain. A 2006 Cochrane review found that long term studies “did not provide convincing evidence that patient-oriented outcomes like mortality, morbidity, adverse effects and health-related quality of life are positively influenced by this compound” (Cochrane Database of Systematic Reviews 2006;(4):CD006060, doi:10.1002/14651858.CD006060.pub2).

A 2011 article in JAMA concluded that there was still “insufficient evidence from clinical trials to support the choice of one specific class of glucose lowering agents over another with respect to long-term outcomes” (2011;305:820-1, doi:10.1001/jama.2011.193). But because of concerns that glitazones raise the risk of heart failure and other adverse events, the authors argued that they did not match the “safety, tolerability, and low cost of metformin,” a much cheaper drug.

Edwin Gale, emeritus professor of diabetes at Bristol University and someone who has advised the European Medicines Agency, said that on the basis of the current evidence he believes that pioglitazone should not be withdrawn from the market, although it has only a “limited niche use,” he added.

Notes

Cite this as: BMJ 2011;342:d4105

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