Pioglitazone-associated bladder cancer: the contribution of spontaneous reporting analysis on the basis of FDA_AERS database

Introduction: In September 2010, FDA announced the ongoing investigation on a possible association between long-term use of pioglitazone and bladder cancer. The aim of our study was to provide the contribution of spontaneous adverse event reporting analysis on causality assessment between bladder cancer and pioglitazone. Methods: Association between antidiabetic drugs and bladder cancer was analyzed by the case/non reports recorded in FDA_AERS (Adverse Event Reporting System) between 2004 and 2009. Cases were represented by the reports of reactions included in the MedDRA high-level term ‘Bladder neoplasms’ for a given drug; non-cases were all the reports of other reactions associated to the same drug. For each drug, the association between such drug and bladder cancer was calculated by using the ADR reporting odds ratio (ROR). To weight the influence on ROR of male and older age, well known risk factors for bladder cancer, stratified analyses were performed. Furthermore, to consider the possible effect of notoriety bias a year-by-year analysis was performed. Results: Overall, 93 reports of bladder cancer were retrieved, Corresponding to 138 drug reaction pairs, with 31 concerning pioglitazone, 29 insulin, 25 metformin, 13 glimepiride, 8 exenatide; 22 others. ROR was significantly >1 for pioglitazione (4.30; 95%CI 2.82–6.52, P < 0.001), gliclazide (3.56; 1.42–8.39, P = 0.001) and acarbose (5.12; 1.61–14.33, P < 0.001), although for the last two drugs only a few cases were reported (6 and 4, respectively). Concerning pioglitazone, ROR resulted statistically significant both in female (5.19; 2.15–12.11) and male (3.86; 2.37–6.26), but only in older patients (>65 years); moreover the stratified year-by-year analysis showed a statistically significant ROR for 2004, 2006, 2007 and 2008. Conclusions: We found a definite signal for bladder cancer associated with pioglitazone use. The demographic characteristics of the selected cases were consistent with bladder cancer epidemiology (male gender, old age). A weaker signal was also associated with gliclazide and a much weaker signal with acarbose. Of note, the occurrence of >5 events, although resulting in a statistically significant ROR, may be considered clinically meaningless because too much open to reporting biases. The presence of a signal for pioglitazone also before main relevant publications (PROactive 2005) supports the importance of this safety issue despite its notoriety among clinicians. This safety signal should stimulate more specific studies to confirm or reject the causality relationship between pioglitazone and bladder cancer, and to quantify the magnitude of the hazard.