Pioglitazone (ActosTM) has long been recognized as an effective medication in the management of diabetes, and has been previously recorded as a best-selling drug. It has been widely used as both monotherapy and as part of a multidrug regimen to address insulin resistance. Although, no warnings regarding the potential for urothelial carcinogenesis were made upon initial release, preclinical rodent studies demonstrated a propensity for development of bladder tumors following treatment with PPAR-γ agonists, a phenomenon potentially lessened by urinary acidification. Additionally, studies on human bladder tumor specimens have demonstrated an increased density of PPAR-γ receptors compared to normal bladder tissue, with increased expression among higher-grade tumors. While preclinical studies demonstrated pro-neoplastic effects of PPAR-γ agonists, this class of medication received a largely favorable safety profile due in part to cardioprotective effects[7, 9].
At the conclusion of the PROactive study, pioglitazone was associated with a significant decrease in all cause mortality, non-fatal myocardial infarction, and stroke. Considering only bladder cancer that was diagnosed a year or more after the onset of the study, tumors were seen in six patients in the pioglitazone arm and in three patients in the placebo arm, one of which was later reported to have benign pathology. This finding was not statistically significant, and remained non-significant in 4 years of follow-up. Hillaire-Buys et al. performed an updated repeat analysis of the PROactive data excluding one case in the placebo group that actually showed benign pathology, and only then was a statistically significant increase in bladder cancer incidence determined for pioglitazone users.
The FDA has commissioned a 10-year epidemiologic study gathered retrospective data on 193,099 diabetic patients and identified 30,173 pioglitazone users, with 90 of these having developed bladder tumors. Although the 5-year midterm analysis found that pioglitazone use for more than 2 years had a weak association with increased cancer risk, there was no statistically significant short-term use risk and no evidence of a tumor stage shift. Additional epidemiologic studies led to suspension of the use of pioglitazone in France, and a warning in Germany to avoid prescriptions for non-users. On June 15, 2011, the USFDA officially issued a similar warning.
Despite the work investigating an association between pioglitazone and the development of bladder cancer, no reports have shown a detailed comparison of pathologic tumor staging and patient outcomes between users of this medication when compared to other patients. Based on a PubMed literature search at the time of manuscript preparation, our study is the first to examine the association of pioglitazone use on pathologic staging of cystectomy specimens, surgical presence of lymph node involvement, or cancer-specific survival. Although our cohort is small, the cancers associated with pioglitazone use in our series were unique to male patients. Preclinical rodent studies have found the same sexual predilection. This may suggest a hormonal or chromosomal factor yet unidentified. Our cohort also demonstrated a higher propensity for muscle invasive disease among pioglitazone users. Although this did not reach statistical significance, perhaps a larger cohort would better elucidate this relationship.
This investigation was limited by the retrospective nature of the database, and small number of pioglitazone users identified. Also, the cumulative dose and dose duration was not fully accounted for, secondary to reliance on retrospective data and recall bias on the part of patients. Moving forward, we are collecting this data on patients and also giving attention to findings such as urine pH. Information on use of diabetic medications that could reduce the incidence of bladder cancer should also be gathered. Metformin, for example, has been shown in some studies to protect against bladder cancer development, and the interaction between metformin and pioglitazone could further define treatment strategies for management of Type II diabetes. Future efforts will also include analysis of those bladder cancer patients not undergoing cystectomy (e.g., TURBT +/- adjuvant therapies). We will also aim to determine PPAR-γ receptor density among cases. Furthermore, drawing data from larger sources (e.g., SEER database) may serve to shed more light on this matter.