Back grey_arrow_rt.gif
 
 
Risk of Bladder Cancer Among Diabetic Patients Treated With Pioglitazone
 
 
  Interim report of a longitudinal cohort study
 
DIABETES CARE, VOLUME 34, APRIL 2011 JAMES D. LEWIS, MD, MSCE1,2,3 ASSIAMIRA FERRARA, MD, PHD4 TIFFANY PENG, MA4 MONIQUE HEDDERSON, PHD4 WARREN B. BILKER, PHD1,2 CHARLES P. QUESENBERRY JR., PHD4 DAVID J. VAUGHN, MD3 LISA NESSEL, MSS, MLSP1 JOSEPH SELBY, MD4 BRIAN L. STROM, MD, MPH1,2,5 From the 1Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania; the 2Department of Biostatistics and Epidemiology, University of Pennsylvania, Phila- delphia, Pennsylvania; the 3Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; the 4Division of Research, Kaiser Permanente Northern California, Oakland, California; and the 5Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania. Corresponding author: James D. Lewis, lewisjd@mail.med.upenn.edu
 
Abstract
 
OBJECTIVE Some preclinical in vivo studies and limited human data suggest a possible increased risk of bladder cancer with pioglitazone therapy. This is an interim report of an ongoing cohort study examining the association between pioglitazone therapy and the risk of bladder cancer in patients with diabetes.
 
RESEARCH DESIGN AND METHODS This study includes 193,099 patients in the Kaiser Permanente Northern California diabetes registry who were ≥40 years of age between 1997 and 2002. Those with prior bladder cancer were excluded. Ever use of each diabetes medication (defined as two or more prescriptions within 6 months) was treated as a time-dependent variable. Cox regression-generated hazard ratios (HRs) compared pioglitazone use with nonpioglitazone use adjusted for age, sex, race/ethnicity, diabetes medications, A1C, heart failure, household income, renal function, other bladder conditions, and smoking.
 
RESULTS The group treated with pioglitazone comprised 30,173 patients. There were 90 cases of bladder cancer among pioglitazone users and 791 cases of bladder cancer among nonpioglitazone users. Overall, ever use of pioglitazone was not associated with risk of bladder cancer (HR 1.2 [95% CI 0.9-1.5]), with similar results in men and women (test for interaction P = 0.8). However, in the a priori category of >24 months of therapy, there was an increased risk (1.4 [1.03-2.0]). Ninety-five percent of cancers diagnosed among pioglitazone users were detected at early stage.
 
CONCLUSIONS In this cohort of patients with diabetes, short-term use of pioglitazone was not associated with an increased incidence of bladder cancer, but use for more than 2 years was weakly associated with increased risk.
 
Peroxisome proliferator-activated receptor (PPAR)γ has been detected in normal uroepithelial tissue by some but not all investigators and is generally detectable in bladder tumors (1-3). Thiazolidinedione (TZD) PPARγ ligands have been shown to alter cell proliferation rates and differentiation in human cancer cell lines, including bladder cancer cells (1-7).
 
Pioglitazone (ACTOS) is a thiazolidinedione PPARγ ligand used in the treatment of type 2 diabetes. It is indicated as an adjunct to diet and exercise to improve glycemic control. However, it is not generally used as a first-line therapy (8). In preclinical studies, male rats treated with pioglitazone developed more bladder tumors than male rats treated with placebo. This was not observed with female rats at the same dose or with mice of either sex at higher doses (9). However, bladder tumors have also been reported in laboratory animals taking experimental drugs with dual PPARα and PPARγ activity (10).
 
Others have reported on potential associations between treatment with TZDs and risk of cancer at other sites (11-14). However, there are limited data in humans to address this question. The data available mostly come from the PROactive study, which found a nonsignificant excess of bladder tumors among patients treated with pioglitazone (15). In 2003, the U.S. Food and Drug Administration (FDA) requested that the manufacturer of pioglitazone conduct a safety study to assess whether therapy with pioglitazone increases the risk of bladder cancer. The authors of this study drafted the initial protocol that was subsequently reviewed by the FDA and revised accordingly. At the request of the FDA, the study was planned to be conducted over 10 years. This report describes the results of the planned midpoint interim analysis.
 
Peroxisome proliferator-activated receptor (PPAR)g has been detected in normal uroepithelial tissue by some but not all investigators and is generally detectable in bladder tumors (1-3). Thia- zolidinedione (TZD) PPARg ligands have been shown to alter cell proliferation rates and differentiation in human cancer cell lines, including bladder cancer cells (1-7).
 
Pioglitazone (ACTOS) is a thiazolidinedione PPARg ligand used in the treat- ment of type 2 diabetes. It is indicated as an adjunct to diet and exercise to improve glycemic control. However, it is not generally used as a first-line therapy (8). In preclinical studies, male rats treated with pioglitazone developed more bladder tu- mors than male rats treated with placebo. This was not observed with female rats at the same dose or with mice of either sex at higher doses (9). However, bladder tumors have also been reported in laboratory ani- mals taking experimental drugs with dual PPARa and PPARg activity (10). Others have reported on potential associations between treatment with TZDs and risk of cancer at other sites (11-14). However, there are limited data in humans to address this question. The data available mostly come from the PRO- active study, which found a nonsignifi- cant excess of bladder tumors among patients treated with pioglitazone (15). In 2003, the U.S. Food and Drug Admin- istration (FDA) requested that the manu- facturer of pioglitazone conduct a safety study to assess whether therapy with pioglitazone increases the risk of bladder cancer. The authors of this study drafted the initial protocol that was subse- quently reviewed by the FDA and revised accordingly. At the request of the FDA, the study was planned to be conducted over 10 years. This report describes the results of the planned midpoint interim analysis.
 
RESULTS-After application of the exclusion criteria, the final cohort included 193,099 patients with diabetes. Patients who ever used pioglitazone during the study period (n = 30,173) were less likely to be age >70 years and were more likely to have a baseline A1C >10% than patients who never used pioglitazone (Table 1). They were also more likely to have been treated with metformin, sulfonylureas, and insulin prior to, after, or along with pioglitazone. Among patients who ever used pioglitazone, the median time from the first prescription to the end of follow-up was 3.3 years (range 0.2-8.5 years), and the median duration of ther- apy among pioglitazone-treated patients was 2.0 years (0.2-8.5 years) (Table 1). The median follow-up time from cohort entry was 6.2 years (0.1-11.3) in those never treated with pioglitazone and 9.3 years (0.1-11.3) in those ever exposed to pioglitazone (including follow-up before, during, and after pioglitazone therapy).
 
During the follow-up period, there were 881 cases of newly diagnosed bladder cancer cases: 90 among patients who ever used pioglitazone and 791 among patients who never used pioglitazone. The unadjusted bladder cancer incidence rates per 100,000 person-years for ever use of pioglitazone and never use of pioglitazone were 81.5 and 68.8, respectively. By comparison, in SEER, the annual incidence per 100,000 person-years in those aged $50 years ranged from 70.6 to 75.3 during the years 2000-2007 (19). After adjustment for only age, sex, and use of other categories of diabetes medications, there was a slightly elevated but not sig- nificant association of ever use of pioglita- zone with bladder cancer risk (HR 1.2 [95% CI 0.9-1.5]). The fully adjusted model provided nearly identical results (Table 2). The pioglitazone use-bladder cancer association did not differ by sex (men 1.1 [0.9-1.5)] and women 1.4 [0.8- 2.6]; test for interaction P = 0.81). Analyses from the case-control study revealed the absence of residual confounding due to variables that were incompletely measured (smoking and race/ethnicity) or not mea- sured (occupation) in the cohort study (data not shown).
 
When we examined the association between bladder cancer incidence and increasing levels of pioglitazone exposure (Table 2), the risk of bladder cancer slightly increased with increasing dose and duration of pioglitazone use. After adjustment for only age and sex, the risk of bladder cancer was 30% higher among those whose duration of pioglitazone therapy was 12-24 months (HR 1.3 [95% CI 0.9-2.0]) and 50% higher among those with >24 months of expo- sure (1.5 [1.1-2.0]) than that among never users of pioglitazone. The fully adjusted models provided similar results (.24 months of exposure 1.4 [1.03-2.0]).
 
There were no clear patterns between increasing time since initiation of pioglita- zone and bladder cancer risk. Among men, after adjustment for age there was a significant increase in the relative hazard of bladder cancer with more than 24 months of exposure (HR 1.6 [95% CI 1.2-2.3]) and with a >28,000-mg cumulative dose (1.8 [1.2-2.6]). Because there were only 14 women treated with pioglitazone who were diagnosed with bladder cancer, estimates of dose and duration were unstable and are not reported.
 
In a post hoc analysis to assess whether the increased incidence of blad-der cancer was greater with even longer duration of exposure, we further subdi- vided the category of >24 months of exposure. This analysis demonstrated an additional increase in the relative hazard of bladder cancer with longer duration of therapy. Among 6,670 patients with >48 months of pioglitazone exposure, the age- and sex-adjusted HR was 1.7 (95% CI 1.1-2.9), and the fully adjusted hazard ratio was 1.6 (0.96-2.7). The age- and sex-adjusted point estimates compared with those of unexposed subjects went from 0.8 for ,12 months of use to 1.3 for 12-24 months, 1.3 for 24-36 months, 1.5 for 36-48 months, and 1.7 for >48 months (test for trend treating duration of exposure as an ordinal variable with levels 0 [no exposure] to 5 [.48 months of ex- posure], P = 0.01 in age- and sex-adjusted and P = 0.02 in fully adjusted models). There were proportionately more in situ cancers among the pioglitazone users (data not shown). Only 3% of bladder cancers in the patients who ever used pioglitazone were of regional or advanced stage at the time of diagnosis. In contrast, 9% of bladder cancers in the patients who never used pioglitazone had regional or advanced stage disease at the time of diagnosis (two-sided Fisher's exact P = 0.10 excluding 2% of pioglitazone-exposed cancers and 4% of nonpioglitazone-exposed cancers with undetermined stage).
 
CONCLUSIONS-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, hydroxy- butyl(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 con- tributes 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 piogli- tazone. 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. Fur- thermore, 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 pio- glitazone and that .50% of these have taken the medication for .2 years are ma- jor strengths of the study.
 
Considering potential limitations, our cohort study had incomplete or miss- ing 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 ac- cording 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 po- tential 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 pro- portionately more in situ cancers among the pioglitazone users. This might be observed if pioglitazone-treated patients underwent greater surveillance for blad- der 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 blad- der 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 underesti- mated the cumulative duration of exposure. However, this would potentially over- estimate 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 censor- ing is unlikely to have changed the results.
 
Although several studies have sug- gested 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 af- ter 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 communi- cation). 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 analy- sis, 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 in- creasing 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 reli- ance on administrative data to establish the diagnosis of bladder cancer, did not distinguish between pioglitazone and ro- siglitazone, and, perhaps most impor- tantly, 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 blad- der cancer. Some research suggests that metformin use is associated with a re- duced risk for various cancers (23,24); others have suggested that insulin use might increase the risk of cancer (24,25). 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 ex- plore this association. Regardless, it is re- assuring that only 3 of the 90 patients diagnosed with bladder cancer and treated with pioglitazone were at advanced stage.

table2.gif

Acknowledgments-This study was funded by a grant from Takeda Global Research & Development Center, Inc. The sponsor was given the opportunity to review and comment on the manuscript before submission. How- ever, the opinions expressed are those of the authors. J.D.L. reports receipt of other research funding from Takeda and GlaxoSmithKline and having served as a consultant to Takeda and to GlaxoSmithKline. A.F. reports having received additional research funding from Takeda and Lilly. B.L.S. reports receipt of research funding from Takeda and having served as a consultant to GlaxoSmithKline and Lilly. No other potential conflicts of interest relevant to this article were reported.
 
J.D.L. and A.F. designed the study, in- terpreted data, and drafted and edited the manuscript. T.P. collected, analyzed, and in- terpreted data and edited the manuscript. M.H. collected, analyzed, and interpreted data; edited the manuscript; and provided adminis- trative support. W.B.B., C.P.Q., and D.J.V. de- signed the study, interpreted data, and edited the manuscript. L.N. interpreted data, edited the manuscript, and provided administrative support. J.S. and B.L.S. designed the study, in- terpreted data, and edited the manuscript.
 
 
 
 
  icon paper stack View Older Articles   Back to Top   www.natap.org