Abstract
Pioglitazone, a peroxisome proliferator-activated receptors (PPAR) agonist, has been authorized for the management of type 2 diabetes since 1999 in the US and since 2000 in Europe. Since then, the risk of bladder cancer associated with pioglitazone use has been a serious concern. Following a warning from the Agence Française de Sécurité Sanitaire des Produits de Santé (Afssaps) [the French Agency for the Safety of Health Products], use of pioglitazone was suspended in France and Germany in June 2011. Elsewhere, restrictions on prescriptions were implemented, though for both the European Medicines Agency and the US Food and Drug Administration, the risk-benefit ratio remains favourable. Since the development of pioglitazone, its risk assessment has suffered from several inaccuracies such as its alleged specificity for the male rat, untrustworthy selective agonism for PPARγ and mistaken risk evaluation in the large PROactive trial (PROspective pioglitAzone Clinical Trial In macroVascular Events), where one case with a benign tumour in the placebo group was counted as a cancer case. It took until 2011 for the epidemiological data to be sufficiently numerous and conclusive to initiate application of safety measures. Today, the increased risk of bladder cancer associated with pioglitazone seems to be real, but the absolute risk is relatively low. However, in the context of weak efficacy in an extensive population of patients exposed to pioglitazone, the risk-benefit balance is now difficult to assess, and prescription restrictions do not ensure safety. For future risk management, the authors propose several suggestions, which involve an increasing role of health authorities and academic organizations.