Introduction
Pioglitazone is an oral hypoglycaemic agent that has been marketed in the USA since 1999 and in Europe since 2000 (France since 2002). According to the European public assessment report for pioglitazone [
1], pre-clinical studies in rats have shown an association between pioglitazone exposure and bladder tumours. However, pioglitazone was not genotoxic or carcinogenic in mice, and tumours were observed only in male rats. A possible biological association exists, with a potential mechanism linked to the ‘predisposing’ capacity of peroxisome proliferator-activated receptor (PPAR) and/or PPARα agonists for bladder tumours [
2,
3].
A randomised clinical trial (PROspective pioglitAzone Clinical Trial In macroVascular Events; the PROactive study) evaluated pioglitazone with a mean follow-up of 34.5 months [
4,
5]. Fourteen cases of bladder cancer were observed in the pioglitazone group (0.5%) vs six in the placebo group (0.2%). After a blinded review with external experts, bladder cancer was diagnosed during the second year of exposure in six cases in the pioglitazone group vs three in the placebo group [
4,
5].
A cohort study of the Kaiser Permanente Northern California (KPNC) database [
6] included 193,099 patients (30,173 patients exposed to pioglitazone and 162,926 not exposed). The median time from first prescription for pioglitazone to the end of follow-up was 3.3 years. The de novo bladder cancer incidence rate was 81.5 per 100,000 person-years for patients exposed to pioglitazone vs 68.8 per 100,000 person-years for patients not exposed. After adjusting for age, sex and use of other glucose-lowering drugs, the association between pioglitazone use and bladder cancer risk was not significant (HR 1.2 [95% CI 0.9, 1.5]). Another analysis of a similar cohort found no association between pioglitazone exposure and cancer in several other sites [
7]. However, the study revealed a significantly increased risk with exposure duration >24 months (fully adjusted HR 1.4 [95% CI 1.03, 2.0]). Long-term follow-up of this cohort is ongoing.
On the basis of these findings, the US Food and Drug Administration (FDA) issued a safety announcement in 2010 informing healthcare professionals and patients about its ongoing safety review but did not conclude that pioglitazone increases the risk of bladder cancer [
8].
On the initiative of the French medicines agency (Agence Française de Sécurité Sanitaire des Produits de Santé; AFSSAPS), we conducted this study to investigate a possible association between pioglitazone use and bladder cancer incidence in a historical cohort of patients with diabetes mellitus in France. We used a methodology similar to that used in the KPNC study but with a much larger population. To assess the specificity of a possible increased risk of bladder cancer associated with pioglitazone exposure, we also investigated the association between pioglitazone exposure and cancer in other sites.
The results of this pioglitazone study were presented to the AFSSAPS, which decided to suspend the use of pioglitazone in France in June 2011 [
9].
Discussion
We conducted this cohort study at the request of the AFSSAPS in response to a pharmacovigilance signal and the results of a US epidemiological study based on the KPNC database [
6], suggesting a possible relationship between prolonged exposure (>2 years) to pioglitazone and increased risk of bladder cancer. Analysis of this cohort of 1.5 million diabetic patients, followed between 2006 and 2009, with median duration of pioglitazone exposure 1.5 years, showed that pioglitazone exposure was significantly associated with increased risk of bladder cancer (adjusted HR 1.22 [95% CI 1.05, 1.43]). Higher HRs were observed for high cumulative doses of pioglitazone (≥28,000 mg, adjusted HR 1.75 [95% CI 1.22, 2.50]) and long duration of exposure (≥24 months, adjusted HR 1.36 [95% CI 1.04, 1.79]). Sensitivity analyses of various models showed the robustness of the results.
These results confirm those of the KPNC study [
6], based on 193,099 patients, including 30,173 exposed to pioglitazone with a median duration of exposure of 2.0 years: adjusted HR 1.2 [95% CI 0.9, 1.5]. The KPNC study revealed a comparable dose–effect relationship for exposure duration ≥24 months: adjusted HR 1.4 [95% CI 1.03, 2.0]. The similarity of the results between these two studies, conducted in different countries with distinct health systems and data-collection procedures, is striking and provides support for a causal association. In July 2011, the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) reported the results of a meta-analysis of randomised controlled clinical studies: 19 of 12,506 patients receiving pioglitazone had bladder cancer (0.15%) as compared with 7 of 10,212 patients not receiving pioglitazone (0.07%) [
13].
One of the strengths of our study is that it used two comprehensive databases that were independent in terms of data collection. Data for medicinal product reimbursement are regularly and exhaustively submitted by all French pharmacists to the national health insurance network by electronic data interchange, and all French hospitals regularly submit their discharge data to the agency for information on hospital care (Agence Technique de l'Information sur l'Hospitalisation; ATIH) for planning and funding purposes. The a posteriori linkage between these two databases should have prevented observation bias, because identification of bladder cancer incidence is completely independent of measurement of pioglitazone exposure, in that this drug is mainly prescribed out of hospital.
Another strong point of the study is the systematic availability of data for all drugs eligible for reimbursement. The data on glucose-lowering drug use should therefore be comprehensive, because no self-prescribed medication for diabetes has marketing authorisation, and all glucose-lowering products are reimbursed by the national health insurance.
We minimised the misclassification of non-exposed patients as exposed patients by requiring exposed patients to meet the criterion of two pioglitazone prescriptions filled over a 6-month period. Patients who filled only one pioglitazone prescription (n = 15,756) were not classified as exposed. Some of these patients may have stopped treatment (e.g. because of an early adverse event) or never used the dispensed medication (e.g. because of a change in the initial treatment plan). Patients who received several pioglitazone prescriptions but never within a single 6-month period (n = 4,746) were also not classified as exposed. Some of these patients may have been actually exposed to pioglitazone. However, this classification error is unlikely to be substantial in view of the low use level, which is unlikely to modify the cancer risk. Furthermore, because these individuals represent a small proportion (3.1%) of those who met the exposure conditions and a very small proportion (0.4%) of the population classified as non-exposed, the potential impact on the estimate of the association is limited.
Two other elements support the specificity of the association of pioglitazone and bladder cancer: first, we found that use of none of the other oral hypoglycaemic treatments was associated with increased risk of bladder cancer, and second, pioglitazone exposure was not associated with increased risk of cancer in other sites. Insulin use appeared to be linked to increased cancer risk for all cancer sites studied (except for female breast cancer). This observation has been previously reported [
14‐
17]. However, because our study was specifically designed to measure the risk of bladder cancer directly related to pioglitazone exposure, the results concerning use of other glucose-lowering therapies (oral or insulin) or other cancer sites should be interpreted with caution.
We observed a significant risk excess of bladder cancer in men only. Previous research has suggested that this effect in male rats can be prevented with dietary modification, suggesting a mechanism related to the acid milieu and urine bladder anatomy of male rats [
18]. However, we believe that the power of our study is far too low to be sufficient to detect a risk for bladder cancer in women, with only 13 cases in exposed women vs 162 cases observed in exposed men.
Our study has several limitations. First of all, it lacks data on tobacco use, known to be the third main risk factor for bladder cancer after age and male sex [
19,
20]. Nevertheless, several elements seem to address this limitation. First, the results reported by Lewis et al [
6] for KPNC were similar after adjusting for age, sex and additional covariates, particularly smoking. Second, patients using specific drugs for COPD and with a discharge diagnosis related to tobacco were relatively few in the pioglitazone-exposed group, which suggests a lower proportion of tobacco use in exposed patients. Finally, the low risk of lung cancer and head and neck cancer with pioglitazone exposure also suggests a lower exposure to tobacco among pioglitazone users than among non-users. Therefore, the lack of adjustment for smoking would be expected to result, if anything, in an underestimate of the association between pioglitazone exposure and bladder cancer.
In addition, we do not report data on the duration of diabetes. In an additional analysis of patients entitled to full reimbursement for diabetes treatment, we used duration of full reimbursement as a proxy. Additional adjustment for this variable resulted in a similar HR for pioglitazone exposure and the duration of full reimbursement for diabetes treatment was not significantly associated with bladder cancer.
Although our report does not contain information on histological diagnosis, the definition of bladder cancer patients as those requiring relatively aggressive treatment should have minimised misclassification of non-cases as cases. However, bladder cancer patients not treated aggressively would have been missed. The incidence rates of bladder cancer we observed were similar to those reported by French cancer registries [
21] up to the age of 80 years, for both men and women. However, several studies of diabetic populations have reported a slight increase in cancer risk in general [
17] and bladder cancer risk in particular. The meta-analysis by Larsson et al reported an increased risk of bladder cancer (relative risk 1.24 [95% CI 1.08, 1.42]) when comparing type 2 diabetic individuals with non-diabetic individuals [
22]. French cancer registries are population-based and these findings suggest a slight underestimation of the number of bladder cancer cases in our study. However, with our data-collection method (hospital discharge diagnoses and specific therapy), this underestimation concerns both pioglitazone-exposed and non-exposed patients. This non-differential misclassification of disease would be expected to result in an underestimate of the risk associated with exposure to pioglitazone. Furthermore, our analysis using a broader definition of bladder cancer, testing only hospital discharge diagnoses, also indicates a significant association between pioglitazone exposure and bladder cancer risk.
We observed a dose–effect relationship for pioglitazone exposure only. If the increased incidence of bladder cancer was due to deterioration of diabetes and not directly linked to pioglitazone use, we would expect a similar increased risk with the highest doses of metformin. Our findings, therefore, support the theory that the increased bladder cancer risk among patients exposed to pioglitazone cannot be explained by disease progression.
Information on drug exposure before 2006 was not available. About one-third of pioglitazone-exposed patients filled a prescription for pioglitazone during the first 3 months of 2006, but pioglitazone use in France was less frequent before than after 2005 (the number of packages reimbursed in 2004 represented approximately 20% of those reimbursed in 2006). Pre-study exposure to pioglitazone would therefore have concerned a maximum of one-third of exposed patients and the duration of pre-study exposure would rarely have exceeded 1 year. Moreover, the HR estimates of our additional analysis in new users of pioglitazone were in line with those of the main analysis, but the confidence intervals were broader as a result of the smaller number of patients.
The French SNIIRAM and PMSI databases have been extensively used in pharmacoepidemiological studies. A search on 1 June 2009 for published studies involving drug reimbursement data from SNIIRAM found 110 articles [
23]. The combined use of SNIIRAM and PMSI databases in observational pharmacoepidemiological studies is a promising approach to assess the potential for use of a drug to produce serious adverse reactions leading to hospital admission.
In summary, in this cohort of 1.5 million diabetic patients followed between 2006 and 2009, pioglitazone exposure was significantly associated with increased risk of bladder cancer. Risk estimates were similar to those observed in the KPNC cohort [
6] but in a much larger population and in France. Despite its limitations, this study, using linked data from the SNIIRAM health insurance information system and the PMSI database in France, demonstrated that these medico-administrative databases can be helpful in addressing a large number of public health issues such as estimation of disease frequencies and related healthcare spending, as well as assessment of drug safety.