After the withdrawal of troglitazone and rosiglitazone, pioglitazone remains the sole thiazolidinedione (TZD) still available.
Pioglitazone is efficacious in improving glycemic control and reduce the risk of cardiovascular events. Although generally well-tolerated,
pioglitazone was withdrawn by some national medicines agencies (e.g. in France and Germany) due to reports of increased incidence of
bladder cancer. In this article, we review the literature on the association between pioglitazone and cancer in several sites, including the
bladder. Pioglitazone, like other TZDs, increased differentiation, inhibited growth and proliferation, while provoked apoptosis in various
cancer cells, including bladder cancer, in vitro and in vivo. However, a rat-specific carcinogenic effect of pioglitazone on the bladder was
noted in vivo. Clinical data for the risk of various cancer sites mostly come from observational studies and are subject to bias. An increased
risk for bladder cancer by pioglitazone was suggested by retrospective analyses. This risk was associated with the time of exposure
and the age, by identifying 24 months and 65 years, respectively, as time ‘thresholds’ above which this risk becomes relevant. In
contrast, no increased risk for bladder cancer was associated with pioglitazone in randomized clinical trials. Pioglitazone was associated
with increased incidence of melanoma and non-Hodgkin lymphoma and decreased risk of renal cancer in one cohort study. These findings
need to be re-evaluated on a prospective basis. There is no convincing evidence that pioglitazone increases or decreases the risk of
cancer in other sites. In contrast, it was suggested that this drug may be useful either in the treatment of cancer complications or as an adjunct
to chemotherapeutic agents. Considering the clinical benefit from the use of pioglitazone it is reasonable to wait until data from ongoing
clinical trials are available before reaching definitive conclusions. Nevertheless, the potential for increased risk of bladder cancer
should be taken into consideration, especially in the presence of other risk factors for bladder carcinogenesis (e.g. smoking).