We describe the interim results of an ongoing cohort study being conducted at the request of the FDA in response to animal studies suggesting a possible increased risk of bladder cancer among patients treated with pioglitazone. This association was initially observed in male rats but not in female rats or in mice of either sex (9
). Subsequent research suggested that this effect in male rats can be prevented with dietary modification, suggesting a mechanism related to the bladder anatomy and acid milieu of urine in male rats (20
). However, a more recent study in a different animal model, hydroxybutyl(butyl)nitrosamine (OH-BBN), proposed that rosiglitazone, another TZD, may be a tumor promoter even in late stages of bladder cancer development (21
). At the time of this interim report, we did not observe a significant association between any pioglitazone exposure and bladder cancer risk in our cohort study overall. However, we observed an increased risk of bladder cancer among patients with the longest exposure to pioglitazone. A post hoc analysis suggests further increased risk with even longer exposure periods. Finally, there was no evidence of a stage shift to more advanced bladder cancer among the pioglitazone-exposed patients.
There are several major strengths of this study. The KPNC diabetes registry includes a large population of individuals with diabetes. The diabetes registry uses active surveillance based on diagnoses, laboratory tests, and pharmacy data and as such is also able to identify individuals with diabetes who are not treated with medications. We used the KPNC cancer registry to identify patients with bladder cancer. The cancer registry, which contributes data to SEER, is held to SEER’s very high quality standards. Another strength is the availability of the KPNC pharmacy data. By requiring patients to fill two prescriptions within a 6-month period, we have minimized misclassification of unexposed patients as exposed. Patients who filled only a single pioglitazone prescription (n = 4,679) or who filled two or more prescriptions that were never within 6 months of each other (n = 580) were not categorized as exposed according to our definition. Some of these patients may have actually been exposed to pioglitazone. However, this misclassification is unlikely to be important given that such a small duration of therapy would be unlikely to change the risk of cancer. Furthermore, because these patients represented a small proportion of those who filled at least one pioglitazone prescription and an even smaller proportion of the population categorized as unexposed, their potential impact on the estimated HR is limited. Finally, the large number of patients who have been prescribed pioglitazone and that >50% of these have taken the medication for >2 years are major strengths of the study.
Considering potential limitations, our cohort study had incomplete or missing data on several variables known to be associated with bladder cancer, such as smoking and occupational exposures. However, our nested case-control study demonstrated that these unmeasured or incompletely measured confounders known to be associated with bladder cancer were unlikely to have influenced our cohort study results. In addition, in the case-control analysis we were able to more precisely categorize smoking according to cumulative exposure in pack-years. Despite this, smoking was not a confounder of the pioglitazone-bladder cancer analysis. Our analysis of the stage of cancer allows us to consider the potential for detection bias. Stage at diagnosis of bladder cancer was not significantly different between the pioglitazone-treated patients and those not treated with pioglitazone. However, there were proportionately more in situ cancers among the pioglitazone users. This might be observed if pioglitazone-treated patients underwent greater surveillance for bladder cancer or if pioglitazone increases the risk of bladder cancer by its effect on the early stages of development. To account for the possibility of increased surveillance, we adjusted for recorded bladder conditions that might prompt increased testing. Furthermore, we cannot determine whether there were patients with undiagnosed bladder cancer at the start of follow-up. However, this should not have been differential between those who did and those who did not receive treatment with pioglitazone. Further, the positive associations that we observed were with long-term exposure. Therefore, it is unlikely that this would be explained by an imbalance in prevalent yet undiagnosed cancer at the time of cohort entry.
Eight percent of patients ever exposed to pioglitazone were documented to have received their first prescription within 4 months of entry into the cohort. For this small group, we may have underestimated the cumulative duration of exposure. However, this would potentially overestimate the relative risk of short- and intermediate-term exposure if long-term use of pioglitazone is associated with an increased risk of bladder cancer. Thus, any misclassification from this left censoring is unlikely to have changed the results.
Although several studies have suggested an increased risk of bladder cancer among patients with diabetes irrespective of medication exposure (22
), there are limited controlled data on the relative risk of bladder cancer among patients treated with pioglitazone. The PROactive study included 2,605 patients treated with pioglitazone and 2,633 treated with placebo, and there was a nonsignificant excess of bladder tumors among patients treated with pioglitazone (14 vs. 6) (15
). In that study, average follow-up time was 34.5 months, yet much of the excess in bladder cancer incidence (eight pioglitazone versus three placebo) occurred in the first year of follow-up. After the first year, there were six cases of cancer in the pioglitazone arm versus three in the placebo arm. In 4 years of observational follow-up of the PROactive population after the end of the randomized phase of the study, the relative incidence of bladder cancer among the patients treated with pioglitazone during the initial clinical trial phase has not increased further. However, most subjects did not receive any TZDs during the observational follow-up period (I. Ahmad, personal communication). In our study, the HRs were 0.8 for <1 year and 1.4 for both 1–2 years and >2 years of therapy. In a post hoc analysis, the HR was even higher for those with >36 months of exposure and >48 months of exposure, with a significant test for trend for increasing risk with increasing duration of exposure. Although these longer durations were not statistically significant in the fully adjusted models, this may have been due to low statistical power because the results were similar to the age- and sex-adjusted model. A recent observational cohort study using claims data did not observe an increased risk of bladder cancer with TZD exposure. However, that study was limited by a small number of bladder cancer cases and reliance on administrative data to establish the diagnosis of bladder cancer, did not distinguish between pioglitazone and rosiglitazone, and, perhaps most importantly, did not report data on duration of exposure (11
It is possible that any increased risk of bladder cancer observed with pioglitazone could be attributed to other diabetes medications that reduce the risk of bladder cancer. Some research suggests that metformin use is associated with a reduced risk for various cancers (23
); others have suggested that insulin use might increase the risk of cancer (24
). However, we did not observe any association between ever use of other diabetes medications and bladder cancer risk. In addition, we could not compare pioglitazone with other TZDs because there had been little use of the latter in this cohort.
In summary, we did not observed a statistically significant increased risk of bladder cancer among patients treated with pioglitazone for <2 years. However, the analyses addressing increasing exposure to pioglitazone observed a weak increased risk with longer-term therapy. Additional follow-up is planned to explore this association. Regardless, it is reassuring that only 3 of the 90 patients diagnosed with bladder cancer and treated with pioglitazone were at advanced stage.