A review on thiazolidinediones and bladder cancer in human studies.

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A Review on Thiazolidinediones and Bladder Cancer in Human Studies ab

Chin-Hsiao Tseng a

Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan b

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Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan Published online: 05 Mar 2014.

To cite this article: Chin-Hsiao Tseng (2014) A Review on Thiazolidinediones and Bladder Cancer in Human Studies, Journal of Environmental Science and Health, Part C: Environmental Carcinogenesis and Ecotoxicology Reviews, 32:1, 1-45, DOI: 10.1080/10590501.2014.877645 To link to this article: http://dx.doi.org/10.1080/10590501.2014.877645

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Journal of Environmental Science and Health, Part C, 32:1–45, 2014 C Taylor & Francis Group, LLC Copyright ISSN: 1059-0501 print / 1532-4095 online DOI: 10.1080/10590501.2014.877645


A Review on Thiazolidinediones and Bladder Cancer in Human Studies Chin-Hsiao Tseng1,2 1 Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan 2 Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan

There is a concern of an increased risk of bladder cancer associated with the use of thiazolidinediones, a class of oral glucose-lowering drugs commonly used in patients with type 2 diabetes with a mechanism of improving insulin resistance. Human studies on related issues are reviewed, followed by a discussion on potential concerns on the causal inference in current studies. Pioglitazone and rosiglitazone are discussed separately, and findings from different geographical regions are presented. Randomized controlled trials designed for primarily answering such a cancer link are lacking, and evidence from clinical trials with available data for evaluating the association may not be informative. Observational studies have been reported with the use of population-based administrative databases, single-hospital records, drug adverse event reporting system, and case series collection. Meta-analysis has also been performed by six different groups of investigators. These studies showed a signal of higher risk of bladder cancer associated with pioglitazone, especially at a higher cumulative dose or after prolonged exposure; however, a weaker signal or null association is observed with rosiglitazone. In addition, there are some concerns on the causal inference, which may be related to the use of secondary databases, biases in sampling, differential detection, and confounding by indications. Lack of full control of smoking and potential biases related to study designs and statistical approaches such as prevalent user bias and immortal time bias may be major limitations in some studies. Overlapping populations and opposing conclusions in studies using the same databases may be of concern and weaken the reported conclusions of the studies. Because randomized controlled trials are expensive and unethical in providing an answer to this cancer issue, observational studies are expected to be the main source in providing an answer in the future. Furthermore, international comparison studies using well-designed and uniform methodology to clarify the risk in specific sexes, ethnicities, and other subgroups and to evaluate the interaction with other environmental risk factors or medications will be helpful to identify patients at risk.

Address correspondence to Chin-Hsiao Tseng, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei (100), Taiwan. E-mail: [email protected]

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C.-H. Tseng Keywords: Bladder cancer; epidemiological study; pioglitazone; rosiglitazone; thiazolidinediones; type 2 diabetes


INTRODUCTION Thiazolidinediones (TZDs) are a class of oral glucose-lowering drugs that activate the nuclear peroxisome proliferator-activated receptor γ (PPARγ) by forming heterodimers with retinoid X receptor [1]. Insulin sensitivity is enhanced and insulin resistance is improved, resulting in blood glucose lowering in patients with type 2 diabetes who use the drugs [1]. Three TZDs have ever been approved for human use: troglitazone, rosiglitazone, and pioglitazone. Troglitazone had been marketed for only a short period from 1997 to 2000, and had been taken off the world market because of its rare but fatal adverse effect of hepatic failure [2]. Actually troglitazone had not been marketed in many countries, including Taiwan. Rosiglitazone has been withdrawn from the market of some countries in 2010 for a potential risk of myocardial infarction. On the contrary, pioglitazone may show a beneficial effect on cardiovascular disease [3]. TZDs have demonstrated antitumor effects in a variety of cancer cell types in many in vitro and in vivo studies [4–8] except for pioglitazone, which may show an increased risk of bladder cancer in preclinical animal studies [1]. In a clinical trial (PROactive: PROspective pioglitAzone Clinical Trial In macroVascular Events) published in 2005, pioglitazone was associated with outnumbered incident cases of bladder cancer compared to patients using placebo [3]. Despite inconsistency in conclusions from different subsequent observational studies, the potential link between pioglitazone and bladder cancer risk was supported by some population-based cohort studies showing a 20%–40% higher risk after two years of its use [9,10]. The International Agency for Research on Cancer /World Health Organization summoned a meeting in Lyon, France, on June 2–11, 2013, to evaluate the risk of cancer related to 14 drugs and herbal products by collaborating with a group of 23 experts from nine countries. The risk of cancer, especially bladder cancer, associated with the use of TZDs was one of the main themes discussed. A summary of the conclusions of this meeting has been published recently, showing that pioglitazone and rosiglitazone may have different cancer risks, with pioglitazone classified as group 2A (probably carcinogenic to humans) and rosiglitazone as group 3 (not classifiable as to its carcinogenicity to humans) [11]. Humans can be exposed to environmental and anthropogenic carcinogens [12–22], and diabetic patients may have a higher risk for a variety of cancers [23–34]. Diabetes is increasing in prevalence and incidence and affects hundreds of millions of people worldwide [35–37]. Because most patients with diabetes are treated with multiple drugs for the management of hyperglycemia


Thiazolidinediones and Bladder Cancer

and other related comorbidities, the safety of the commonly used medications in this highly prevalent disease is of great public health concern. In this article, studies conducted in humans investigating the risk of bladder cancer associated with the use of TZDs are reviewed. Because troglitazone had been used in clinical practice for only a short period and the information regarding its association with bladder cancer is sparse, only studies referring to pioglitazone and/or rosiglitazone are reviewed here. Because these two agents may exert different effects, they are reviewed separately, followed by any TZDs without specifying pioglitazone or rosiglitazone. Recent meta-analyses on related topics are also presented. Finally, potential limitations in causal inference and future perspectives to clarify the association are discussed.

PIOGLITAZONE Clinical Trials A summary of four multicenter randomized controlled trials (RCTs) with available data for evaluating TZDs and bladder cancer risk is adapted from the meta-analysis by Colmers and colleagues [38] and shown in Table 1. These trials include the PROactive, ADOPT (A Diabetes Outcome Progression Trial), RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes), and a terminated trial on insulin glargine sponsored

Table 1: Four Clinical Trials in the Meta-analysis by Colmers and Colleagues Evaluating Thiazolidinediones and Bladder Cancer (Adapted from Reference 38) Number of Patients Clinical Trial

Exposed Comparison Thiazolidinedione group group

PROactive Pioglitazone

2605

2633

ADOPT

Rosiglitazone

1456

2895

RECORD

Rosiglitazone

2220

2227

SanofiAventis∗

Unspecified

256

130 Overall

RR (95% CI) 2.36 (0.91–6.13) 0.50 (0.11–2.34) 1.20 (0.37–3.94) 2.55 (0.12–52.70) 1.45 (0.75–2.83)

Overall Risk of Covariates Bias NA

Unclear

NA

High

NA

High

NA

High

RR, relative risk; CI, confidence interval; NA, not applicable; PROactive, PROspective pioglitAzone Clinical Trial In macroVascular Events; ADOPT, A Diabetes Outcome Progression Trial; RECORD, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes. ∗ This clinical trial on insulin glargine and sponsored by Sanofi-Aventis has been terminated.

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by Sanofi-Aventis. None of the studies were designed to primarily evaluate the association between TZDs and cancer risk. The PROactive first brought into attention the risk of bladder cancer associated with the use of pioglitazone in humans [3]. This was a multinational, prospective, double-blind, RCT conducted in 19 European countries [3,39]. It was primarily aimed at evaluating the risk of macrovascular morbidity and mortality related to the use of pioglitazone (n = 2605) in comparison to placebo (n = 2633) in patients with type 2 diabetes with evidence of macrovascular disease [3,39]. After an average follow-up of 34.5 months, the primary composite endpoint (all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention in the coronary or leg arteries, and amputation above the ankle) was reduced but without statistical significance [hazard ratio (95% confidence interval, CI): 0.90 (0.80–1.02), p = 0.095]. However, the secondary composite endpoint (all-cause mortality, nonfatal myocardial infarction and stroke) was reduced significantly [hazard ratio (95% CI): 0.84 (0.72–0.98), p = 0.027]. In further subgroup analysis, pioglitazone markedly reduced the risk of recurrent stroke by 47% [hazard ratio (95% CI): 0.53 (0.34–0.85), p = 0.0085] [40,41]. The PROactive trial monitored the incidence of various cancer types and found an imbalance in the case numbers of bladder cancer between pioglitazone and placebo (14 cases versus 6 cases, or 0.5% versus 0.2%, p = 0.069) [3,42], with a calculated relative risk of 2.36 (0.91–6.13) (Table 1) [38]. After excluding one case of bladder cancer in the placebo group, which was found later to show benign histology, the recalculated crude relative risk (95% CI) was 2.83 (1.02–7.85), with a significant p–value (Fisher’s exact test, p = 0.04) [43]. It is worth noting that among the 20 cases of bladder cancer in the original report, 11 (8 in the pioglitazone group and 3 in the placebo group) were diagnosed within one year of randomization, which may refute a causal relation and a bias due to differential detection between the two groups is possible. For the remaining nine cases (six pioglitazone and three placebo), six (four pioglitazone and two placebo) had known risk factors of bladder cancer such as smoking, exposure to potential carcinogens, family history, previous tumor, and urinary tract infection [3]. If these cases were excluded, only three cases of bladder cancer (two pioglitazone and one placebo) remained. The incident case numbers of bladder cancer in both the pioglitazone group and the placebo group were too small for making any definite conclusion. In addition, an imbalance in the case numbers of breast cancer was also noted: 3 in the pioglitazone group and 11 in the placebo group. Therefore, detection bias and residual confounding effects could not be excluded, even though the confounders are balanced at baseline, and any differences in ascertainment are likely nondifferential in a RCT. Erdman and colleagues recently reported the risk of bladder cancer in patients who used pioglitazone versus those who used placebo in the six-year interim analysis of a predetermined 10-year observational follow-up after the



termination of the double-blind period of the PROactive trial [44]. The estimated relative risk (95% CI) of bladder cancer was 0.57 (0.26–1.25) in the analysis of the follow-up period only, and 1.06 (0.59–1.89) in the analysis of the double-blind period plus the follow-up period [44]. None of these suggested a significantly higher risk of bladder cancer associated with the use of pioglitazone. It is also interesting to observe that the beneficial effect of pioglitazone on macrovascular disease subsided if pioglitazone use was not continued during the follow-up period [44].

Observational Studies Because of the suspected higher risk of bladder cancer associated with pioglitazone in the PROactive study, several observational studies have been conducted aimed at confirming the findings. The major population-based cohorts used in these studies are derived from administrative databases, which include the Kaiser Permanente Northern California (KPNC) database in the United States [9,45], the US pharmacy claims database [46], the national health insurance in France (the CNAMTs study: Caisse Nationale d’Assurance Maladie des Travailleurs Salariés) [11], the Health Improvement Network (THIN) or General Practice Research Database (GPRD) in UK [47–49], and the National Health Insurance (NHI) reimbursement databases of Taiwan [50–56]. Hospital-based design was applied in a Japanese report [57] and in a Korean study [58]. A report using the Adverse Event Reporting System of the US Food and Drug Administration (FDA) [59] and a case series report from India [60] are also available. The findings of these observational studies are summarized in Table 2 and discussed next according to study regions and countries. The administrative databases are briefly described when they are first referred to.

North America USA: Lewis and Colleagues (KPNC Prospective Cohort Study) The KPNC database includes information from cancer registries, pharmacy records, laboratory records, and inpatient and outpatient medical diagnoses. The KPNC outpatient pharmacy database covers 3.2 million members, representing approximately 30% of the population of the area; approximately 95% of the members have their prescriptions filled at KPNC pharmacies. Various sources of longitudinal electronic medical records and clinical data are gathered for patients with diabetes in the KPNC diabetes registry. The KPNC study is a 10-year ongoing prospective observational study aimed at evaluating the risk of various cancers, especially bladder cancer,

5

6

Asia Tseng [2012]

Tseng [2013]

50

51

Azoulay et al. [2012]

49

Taiwan

Taiwan

UK

Wei et al. [2013] UK

48

47

USA

USA

USA

Location

Europe Neumann et al. France [2012] Mamtani et al. UK [2012]

Piccinni et al. [2011]

59

10

Lewis et al. [2012]∗

45

9

Pioglitazone North America Lewis et al. [2011]∗

Authors [Year Reference Published]

Cohort

Cohort

Casecontrol

Cohort

Cohort

Cohort

AERS

Cohort

Cohort

Study Design

Pioglitazone vs. other glucose-lowering drugs

4.30 (2.82–6.52)∗∗∗

1.02 (0.75–1.39)∗∗∗∗

1.31 (0.66–2.58)

1.83 (1.10–3.05)

1.16 (0.83–1.62)

1.14 (0.79–1.66)

Yes (ever smoking)

No

No

Yes (current smoking)

Yes (current smoking)

Adjusted for Smoking

Yes (p-trend not reported) Yes (p-trend < 0.001 for time since initiation)

Yes (p-trend 0.03 for duration of therapy) Yes (p-trend 0.24 for duration of therapy) No

Dose-response Analysis

Ever-users vs. never-users


(Continued on next page)

No (COPD as Yes (p-trend 0.71 surrogate) for cumulative dose) No (COPD as No surrogate)

No Yes (current and ex-smokers) Yes (p-trend 0.03 Exclusive ever use of Yes (ever smoking) for cumulative pioglitazone vs. dose) never use of any TZD

Ever-users vs. never-users New use of pigliatazone vs. new use of rosiglitazone Ever-users vs. never-users


1.07 (0.87–1.03)∗∗∗

1.22 (1.05–1.43)∗∗∗


Comparison

1.2 (0.9–1.5)∗∗∗

RR (95% CI)

Table 2: Summary of Observational Studies Investigating Thiazolidinediones and Bladder Cancer


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Asia Tseng [2013]

Tseng [2013]

Chang et al. [2012]

51

54

Azoulay et al. [2012]

52

49

47

10

59

60

58

USA

India

Korea

Japan

Taiwan

Taiwan

Taiwan

Taiwan

Taiwan

UK

Europe Neumann et al. France [2012] Mamtani et al. UK [2012]

Fujimoto et al. [2012] Song et al. [2012] Unnikrishnan et al. [2012] Rosiglitazone Piccinni et al. [2011]

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55

Chang et al. [2012] Hsiao et al. [2013]

54

Casecontrol

Cohort

Cohort

Casecontrol

Cohort

Cohort

AERS

1.12 (0.92–1.37)∗∗∗∗ 1.05 (0.81–1.36)

0.98 (0.87–1.10)

1.14 (0.78–1.68)

1.51 (0.62–3.67)

1.08 (0.92–1.26)∗∗∗

0.38 (0.12–1.05)

No

Ever-users vs. never-users Ever-users vs. never-users


(Continued on next page)

No (COPD as Yes (p-trend surrogate) 0.6914 for cumulative dose) No (COPD as No surrogate) No No

Yes (p-trend 0.13 for duration of therapy) Yes (p-trend 0.49 for cumulative dose)

No

No

Yes (p-trend not reported) No (COPD as Yes (p-trend 0.03 surrogate) for duration of therapy) Not No mentioned Yes (ever No smoking) NA NA

No

Ever-users vs. No never-users Yes (ever Rosiglitazone use smoking) ≥5 years vs. 36 months), duration of therapy (< 12, 12–24, and > 24 months), and cumulative dose (1–10,500, 10,501–28,000 and > 28,000). The overall hazard ratio (95% CI) [1.2 (0.9–1.5)] for bladder cancer was not significant for ever-users versus never-users. When analyzed in separate sexes, the hazard ratios (95% CI) for men and women were 1.1 (0.9–1.5) and 1.4 (0.8–2.6), respectively. In the doseresponse analyses, the p-values for the trend of the previous three parameters were 0.07, 0.03, and 0.08. Patients who used pioglitazone for > 24 months showed a significant risk with adjusted hazard ratio (95% CI) of 1.4 (1.03–2.0), while analyses in the other categories of the three dose-response parameters were not significant [9]. A nested case-control study was also performed, and it suggested absence of residual confounding (data not reported in the article). Adjustment for smoking is a strength, but only current smoking was considered, which may not fully control confounding. In the recently released eight-year follow-up analysis of the KPNC database, the adjusted hazard ratio (95% CI) for bladder cancer was 1.07 (0.87–1.30) for ever-users versus never-users of pioglitazone [45]. Unlike the midpoint interim analysis, none of the categories of the three dose-response parameters were significant in this analysis [45]. Analyses were also conducted for separate sexes and for smoking status, but none of the hazard ratios were significant. However, in the dose-response analyses for men, a significantly higher risk was observed for the highest cumulative dose of > 35,000 mg [hazard ratio (95% CI): 1.43 (1.03–1.99)]. A further analysis suggested a potential detection bias due to more frequent urinary monitoring for albuminuria, thus resulting in an increased detection of subclinical hematuria and bladder cancer among the pioglitazone users, because the risk estimate shifted to the null after adjustment for proteinuria and diabetic nephropathy [45,61]. However, the possibility of such detection bias remains to be confirmed [45].

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USA: Piccinni and Colleagues (Adverse Event Reporting System) Piccinni and colleagues used the Adverse Event Reporting System of the FDA to evaluate the risk of bladder cancer associated with various glucoselowering drugs [59]. Reporting data between 2004 and 2009 were retrieved and bladder cancer cases were compared to all other reports of adverse effects within the system. Reporting odds ratios were calculated by using the case/noncase methodology with comparison of the ratio of case/noncase of bladder cancer for the drug of interest (e.g., pioglitazone, rosiglitazone, gliclazide, and acarbose, respectively) to the ratio for all other glucose-lowering drugs. A reporting odds ratio (95% CI) for bladder cancer of 4.30 (2.82–6.52) was estimated for pioglitazone use while compared to other diabetes drugs. The elevated risk could be shown in each sex, with reporting odds ratios (95% CI) of 3.86 (2.37–6.26) and 5.19 (2.15–12.11) for men and women, respectively [59]. It is worth noting that the reporting odds ratios for gliclazide and acarbose were also significantly > 1 [59]. Because the adverse drug reports may not be a representative sample of the population and the population at risk is unknown, it is hard to interpret the disproportionate results as a true risk. Notoriety bias leading to over-reporting can also be a problem in the reporting system. Confounders like smoking and occupational exposure to bladder carcinogens cannot be adjusted for in the study.

Europe France: Neumann and Colleagues (CNAMTs Retrospective Cohort Study) The CNAMTs study is a retrospective cohort analysis using the French national health insurance information system (Système National d’Information Inter-régimes de l’Assurance Maladie; SNIIRAM) linked with the French hospital discharge database (Programme de Médicalization des Systèmes d’Information; PMSI). The databases cover all French employees (approximately 75% of the total population), and contain all reimbursement data for health expenditure including medications and outpatient medical and nursing care. To evaluate the association between the use of pioglitazone or rosiglitazone and the risk of various cancers, a cohort of 1,491,060 patients with diabetes, who were aged 40 to 79 years and had been prescribed at least one dose of glucose-lowering drugs in 2006, were followed for four years up to 2009 for the incidence of cancer. Bladder cancer was diagnosed based on hospital discharge diagnosis with a specific surgical procedure or on hospital discharge diagnosis in an additional analysis. After adjustment for age, sex, and exposure to other glucose-lowering drugs, the estimated hazard ratio (95% CI) for bladder cancer for pioglitazone use was 1.22 (1.05–1.43) [10]. Dose–response analyses showed increasing



hazard ratios with increasing duration of therapy and cumulative dose. While compared to never-users, the hazard ratios (95% CI) were 1.05 (0.82–1.36), 1.34 (1.02–1.75), and 1.36 (1.04–1.79) for duration of exposure < 360, 360–719 and ≥ 720 days, respectively. The hazard ratios (95% CI) for users with cumulative dose of < 10,500, 10,500–27,999 and ≥ 28,000 mg were 1.12 (0.89–1.40), 1.20 (0.93–1.53), and 1.75 (1.22–2.50), respectively [10]. The p-values for the trend of the dose-response parameters were not reported. Sex-specific analyses suggested that the association between pioglitazone and bladder cancer was only observed in men but not in women, with respective hazard ratios (95% CI) of 1.28 (1.09–1.51) and 0.78 (0.44–1.37). However, because there were only 13 cases of bladder cancer in women with pioglitazone exposure, the study might not have sufficient power to detect the risk of bladder cancer in women. This French study has been challenged by some investigators for a potential selection bias (channeling bias: a form of allocation bias in which prescription of a drug is related to prognosis or outcome [62]) and its inability to adjust for major confounders for bladder cancer, like smoking, diabetes duration, and comorbid conditions [63] (authors’ response can be seen in [64]). Because pioglitazone is usually used as a second- or third-line glucose-lowering drug, users of pioglitazone may have longer diabetes duration, poorer glycemic control, and higher rates of chronic diabetic complications and comorbidities. All of these characteristics may affect the risk of bladder cancer [2,63], but they are not controlled in the study. UK: Description of the General Practice Research Database The THIN (since 2003) database is similar to the GPRD (1994–2002) in structure and content, which provides the electronic medical records of approximately 10 million patients living in the United Kingdom. It is currently managed by the United Kingdom Medicines and Healthcare products Regulatory Agency. Data available include demographic information, lifestyle, medical diagnoses (using Read codes, a standard classification system used in the UK primary care settings), and measures taken during clinical practice. The database is regularly updated and practitioners contributing data receive training for consistency in data recording. The database has provided an important and inexpensive resource in researches related to epidemiology, drug safety, and health outcomes. Two cohort [47,48] studies and one nested case-control [49] study used this database to evaluate the risk of bladder cancer associated with the use of TZDs. All three studies evaluated pioglitazone, and two of them also evaluated rosiglitazone [47,49]. These three studies are described next. Mamtani and Colleagues (retrospective Cohort Study) Mamtani and colleagues analyzed the THIN database to determine the risk of bladder cancer in new use of TZDs versus new use of sulfonylureas, and

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in new use of pioglitazone versus new use of rosiglitazone [47]. The respective hazard ratios (95% CI) were 0.93 (0.68–1.29) and 1.14 (0.79–1.66). Doseresponse analyses were also conducted by using the parameters of “time since initiation” and “duration of therapy” with the same cutoffs of < 1, 1 to < 2, 2 to < 3, 3 to < 4, 4 to < 5, and ≥ 5 years for the following drugs in comparisons: TZDs, sulfonylureas, TZDs versus sulfonylureas, pioglitazone, rosiglitazone, and pioglitazone versus rosiglitazone. In dose-response analyses for TZDs versus sulfonylureas, the hazard ratios (95% CI) were significant for the longest duration (≥ 5 years) of therapy [3.25 (1.08–9.71)], and for the longest time (≥ 5 years) since initiation of therapy [2.53 (1.12–5.77)], but the p-trend was significant for the time since initiation (p = 0.03) and not significant for the duration of therapy (p = 0.20). In dose-response analyses for pioglitazone, the time since initiation was significant (p < 0.001) but the duration of therapy was not (p = 0.13). In dose-response analyses for pioglitazone versus rosiglitazone, neither time since initiation nor duration of therapy was significant. The authors concluded that long-term use of TZDs (≥ 5 years) may be associated with an increased risk of bladder cancer, irrespective of pioglitazone or rosiglitazone. Adjustment for age, sex, smoking, and hemoglobin A1C is considered a strength of the study, but smoking was classified as ever and never smokers without detailed information of current or ex-smokers or duration/cumulative exposure to smoking. Furthermore, residual confounding and misclassification could not be completely excluded in the study. Wei and Colleagues (Retrospective Cohort Study Plus Subgroup Analysis with Propensity Score Matched Cohort) Wei and colleagues used the GPRD to analyze the risk of bladder cancer associated with pioglitazone in patients with type 2 diabetes [48]. They conducted a retrospective cohort analysis (main analysis) and a propensity score matched analysis (propensity matched analysis, in order to minimize confounding by indication) in a subgroup of patients without missing data of baseline characteristics of age, sex, smoking, body mass index, and diabetes duration. Between 2001 and 2010, 207,714 patients aged ≥ 40 years were studied in the main analysis; 23,548 pioglitazone users and 184,166 patients on other glucose-lowering medications. Follow-up started at the date of first prescription for pioglitazone or other oral glucose-lowering drugs during the study period and ended in December 2010. Patients with a cancer diagnosis before the entry date or less than 90 days of follow-up time were excluded. Incident cases of bladder cancer were obtained from the records during follow-up. During the study period, 66 new bladder cancer cases (mean follow-up time, 3.5 years) occurred in the pioglitazone group and 803 in the other oral glucose-lowering drugs treatment group (mean follow-up time, 5.3 years), with an adjusted hazard ratio (95% CI) of 1.16 (0.83–1.62) for pioglitazone versus the other oral



glucose-lowering drugs. In the propensity matched analysis, 34,498 patients were included with 17,249 patients in each group. During follow-up 38 and 48 new cases of bladder cancer were found in the pioglitazone group and the group using other glucose-lowering drugs, respectively. The adjusted hazard ratio (95% CI) was 1.22 (0.80–1.84) [48]. The investigators also conducted sensitivity analyses by repeating the main analysis and the propensity matched analysis by using only practices that could be linked to the Hospital Episode Statistics. The findings were consistent with the GPRD analyses, with adjusted hazard ratios (95% CI) of 1.12 (0.50–2.53) and 1.59 (0.55–4.61), respectively [48]. This study suggested a lack of significant association between pioglitazone use and bladder cancer risk. The strengths of this study include the adjustment for smoking, the use of propensity score matched analysis for minimizing confounding by indication and the consistency in different analyses. However, there is a concern of potential overlapping of study population with the other groups using the GPRD, and the conflicting findings with the nested case-control study by Azoulay and associates (discussed next) [49].

Azoulay and Associates (Nested Case-Control Study) By using the GPRD, Azoulay and associates conducted a nested casecontrol analysis within a cohort of 115,727 patients with type 2 diabetes who were newly treated with oral glucose-lowering drugs between January 1, 1988 and December 31, 2009 [49]. All incident cases of bladder cancer occurring during follow-up (n = 470) were identified, and 376 cases were matched to up to 20 controls (n = 6699) on year of birth, year of cohort entry, sex, and duration of follow-up. Exposure was defined as ever use of pioglitazone and/or rosiglitazone (defined by the presence of at least one prescription between cohort entry and the year before the index date), along with measures of duration and cumulative dosage. In this study, never use of any TZDs was the referent group, and the risk for bladder cancer was estimated for exclusive ever use of pioglitazone, exclusive use of rosiglitazone and ever use of both pioglitazone and rosiglitazone. Overall, exclusive use of pioglitazone was associated with an increased risk of bladder cancer, with an adjusted rate ratio (95% CI) of 1.83 (1.10–3.05). Dose-response analysis was also performed for cumulative duration and cumulative dose of pioglitazone, and a positive exposure–response trend was observed. While compared to never use of any TZDs, the adjusted hazard ratios (95% CI) for cumulative duration of pioglitazone ≤ 12 months, 13–24 months, and > 24 months were 0.56 (0.07–4.42), 3.03 (0.63–14.52), and 1.99 (1.14–3.45), respectively (p-trend = 0.050). The respective hazard ratios (95% CI) for cumulative dose of pioglitazone of ≤ 10,500 mg, 10,501–28,000 mg, and > 28,000 mg were 1.58 (0.69–3.62), 1.66 (0.70–3.94), and 2.54 (1.05–6.14) (p-trend = 0.030). This study suggested a significantly higher risk of bladder

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cancer associated with pioglitazone, but not with rosiglitazone (discussed later under the heading of “Rosiglitazone”). This study has the strengths of enrolling new drug users who may have less severe disease, and having smoking adjusted for. However, the findings are conflicting with the other study by Wei and colleagues using the same database but with a different approach (discussed previously) [48].


Asia Taiwan: Description of the National Health Insurance databases Since March 1995 a compulsory and universal system of health insurance (the so-called NHI) was implemented in Taiwan. All contracted medical institutes must submit computerized and standard claim documents for reimbursement. More than 99% of the 23-million population are enrolled in the insurance, and > 98% of the hospitals nationwide are under contract with the insurance in recent years. The average number of annual physician visits in Taiwan is one of the highest around the world, at approximately 15 visits per year per capita in 2009. The National Health Research Institutes is the only organization approved, as per local regulations, for handling these reimbursement databases for academic research. The databases contain detailed records on every visit for each patient, including outpatient visits, emergency department visits, and hospital admissions. The databases also include principal and secondary diagnostic codes, prescription orders, and claimed expenses. Certain computerized databases including a database from the national cancer registry (with a high level of completeness) are also available for data linkage. Several independent groups used the NHI databases for evaluating the association between the use of TZDs and risk of various cancers. Those related to bladder cancer are described next. Taiwan: Tseng (Retrospective Cohort Study in a Random Sample) In a retrospective cohort analysis of the NHI reimbursement databases, a random sample of 54,928 patients with type 2 diabetes was followed for a period of four years from January 1, 2006 to December 31, 2009 [50]. A total of 165 incident cases of bladder cancer were identified, and among them 10 (0.39%) were ever-users and 155 (0.30%) were never-users of pioglitazone, with respective incidence of 1 and 0.8 per thousand population. The hazard ratio (95% CI) for ever-users versus never-users of pioglitazone was 1.305 (0.661–2.576) after adjustment for age, sex, diabetes duration, various comorbidities, and medications. In this study, smoking was not available for analyses, but chronic obstructive pulmonary disease was used as a surrogate for smoking. Dose–response relationship was also evaluated, but no significant trend was observed. It is noteworthy that the case number of bladder cancer in the



pioglitazone group was small. Furthermore, 4 of the 10 cases of bladder cancer in the pioglitazone users were diagnosed within 18 months since starting the use of the drug; and 8 of the 10 cases were diagnosed with a duration of therapy with pioglitazone < 12 months and with a cumulative dose of < 10,500 mg [50]. Such a short time of pioglitazone use when bladder cancer was diagnosed may imply an early effect of pioglitazone on bladder cancer development, or preclude a cause–effect relationship because of the confounding by indication, differential detection, or late pioglitazone use in patients with a high risk of bladder cancer [50]. Taiwan: Tseng (Retrospective Cohort Study in Diabetic Men with Benign Prostatic Hyperplasia) In a second study drawn from the entire national database, the association between benign prostatic hyperplasia and bladder cancer risk was evaluated in patients with type 2 diabetes, which showed an adjusted hazard ratio (95% CI) of 1.794 (1.572–2.047) for a diagnosis of benign prostatic hyperplasia [51]. In a subgroup analysis of 85,152 men with type 2 diabetes and having benign prostatic hyperplasia, the adjusted hazard ratios (95% CI) for bladder cancer in ever-users of pioglitazone and rosiglitazone were 1.023 (0.752–1.393) and 1.124 (0.923–1.369), respectively, while compared to never-users of the respective drugs. Because this study was not aimed primarily at analyzing the risk of bladder cancer associated with pioglitazone or rosiglitazone, no dose–response relationship was assessed. Smoking and body mass index could not be controlled because of lack of information, but chronic obstructive pulmonary disease and a clinical diagnosis of obesity were used as surrogates. Potential overlapping of study population with other studies using the NHI database is a concern. Taiwan: Chang and Colleagues (Case-Control Study) A case-control study was conducted by Chang and colleagues to evaluate the risk of several malignancies in diabetic patients who received TZDs (pioglitazone or rosiglitazone) [54]. A total of 606,583 patients with type 2 diabetes, aged ≥ 30 years and without a history of cancer were identified from the NHI database between January 1, 2000 and December 31, 2000. As of December 31, 2007, patients with incident cancer of liver, colorectal, lung, and urinary bladder were included as cases and up to four age- and sex-matched controls were selected by risk-set sampling. Approximately 26.1% of the patients received rosiglitazone and 14.1% received pioglitazone. Using 1583 bladder cancer cases and 70,559 diabetic controls, the overall hazard ratio (95% CI) comparing everusers to never-users of pioglitazone was not significant: 0.95 (0.70–1.29). In dose-response analyses, cumulative dosage (< 120 and ≥ 120 defined daily dose), cumulative duration (≤ 1, and 1–2, 2–3, and ≥ 3 years) and cumulative dose duration (high, intermediate, and low) were estimated. While compared

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to never-users of pioglitazone, none of the categories in the dose-response parameters were significant, but a nonsignificantly increased risk for bladder cancer could be seen in patients with ≥ 3 years of pioglitazone use [adjusted hazard ratio (95% CI): 1.56 (0.51–4.74)] and in the highest category of cumulative dose duration [adjusted hazard ratio (95% CI): 1.13 (0.69–1.83)] (p-trend not available in this study). It is worthy to note that the evaluated drugs of pioglitazone and rosiglitazone did not become available in Taiwan until after follow-up began for a certain period. Therefore, bladder cancer cases identified before the availability of these drugs or shortly after the initiation of these drugs cannot be related to the drugs. Furthermore, the methods in calculating the cumulative dose were not clearly described. The investigators considered chronic kidney disease and various drugs in the models, but smoking could not be adjusted for. There is also a concern of overlapping population with other studies using the same NHI database.

Taiwan: Hsiao and Colleagues (Nested Case-Control Study) Hsiao and colleagues used the NHI database to set up a cohort of diabetic patients based on an outpatient diagnosis of type 2 diabetes between January 1, 1997 and December 31, 2008 [55]. They used a nested case-control design to analyze the association between pioglitazone and rosiglitazone use and bladder cancer. A total of 3412 cases of bladder cancer were identified from the hospitalization database with a first hospitalized primary diagnosis of bladder cancer. Each case of bladder cancer was then matched with five controls without bladder cancer from the cohort based on age (± 1 year), sex, and entry date (defined as the date of first diagnosis of diabetes, ± 90 days). Exposure to pioglitazone and rosiglitazone, respectively, was classified as nonusers, current users [prescription period covered 90 days on and before (but including) the index date], recent users (prescription period ended within 91 to 180 days before index date), and past users (prescription period did not overlap the last 180 days before the index date). Cumulative days of exposure were also calculated and classified as < 1 year, 1–2 years, and ≥ 2 years. Conditional logistic regression was used to estimate the odds ratios after adjustment for duration of diabetes, comorbidities [chronic renal failure and bladder conditions (calculus of the kidney, ureter, lower urinary tract, cystitis and urinary tract infection)], and concomitant medications (sulfonylureas, biguanides, alpha-glucosidase inhibitors, and insulin). While compared with nonusers, the respective adjusted odds ratios (95% CI) for current users, recent users, and past users were 2.39 (1.75–3.25), 1.62 (0.79–3.33), and 1.10 (0.79–1.52) for pioglitazone. The adjusted odds ratios (95% CI) were 1.45 (1.12–1.87), 1.74 (1.05–2.90), and 2.93 (1.59–5.38), respectively, for pioglitazone use < 1 year, 1–2 years, and ≥ 2 years while compared to nonusers. The findings for rosiglitazone were very similar to those observed for



pioglitazone and will be discussed later under the heading of “Rosiglitazone.” This study suggested that long-term exposure to either pioglitazone or rosiglitazone was associated with higher odds of bladder cancer, especially when exposure was ≥ 2 years. This is the first observational study showing a significantly higher risk of bladder cancer associated with both pioglitazone and rosiglitazone in Taiwan. However, potential confounding could not be excluded and some biases may possibly exist as a result of the selection of cases and controls and the analytical methods. First, the comparability between the cases and controls is questionable because the cases were identified from hospitalization database and the controls were matched from the whole national random cohort of diabetic patients. Furthermore, the use of primary diagnosis of bladder cancer at hospitalization might have neglected the cases of bladder cancer who were hospitalized with other primary diagnoses. Because both pioglitazone and rosiglitazone may cause congestive heart failure leading to hospitalization, extensive laboratory examinations including urinalysis during admission in these patients might subsequently lead to a higher detection rate of subclinical cases of bladder cancer. The longer the patients used these drugs, the higher the probability of hospitalization would be, and therefore a spurious dose-response relationship between exposure to TZDs and bladder cancer risk could be observed. Second, smoking is a risk factor for ischemic heart disease, and patients with ischemic heart disease may have a higher probability of using pioglitazone because of its potential macrovascular benefits observed in the PROactive study [3]. Therefore, smoking rate may be higher in patients who were prescribed pioglitazone. Lack of adjustment for smoking or the surrogate of ischemic heart disease could be a detrimental limitation of the study. Third, the investigators divided the use of TZDs into pioglitazone use and rosiglitazone use. However, they neglected the impact of the high possibility of subsequent use of one and the other between these two TZDs. For example, rosiglitazone was marketed in Taiwan earlier than pioglitazone, while estimating the odds ratio for current users of pioglitazone, the influence of recent and past use of rosiglitazone was not considered. Fourth, the study period started from January 1, 1997, but TZDs were not available until after 2001 in Taiwan. Therefore, the cause of bladder cancer in cases identified before the availability of TZDs could not be ascribed to these drugs. Japan: Fujimoto and Colleagues (Single Hospital-Based Retrospective Cohort Study) In a retrospective cohort analysis of 21,335 patients with type 2 diabetes recruited from a single Japanese hospital during a 12-year period from 2000 to 2011, Fujimoto and colleagues identified a total of 170 cases of bladder cancer in the patients with diabetes (0.8%) [57]. Among them, nine cases of bladder cancer were seen in 663 patients (1.36%) who had been taking pioglitazone. The authors reported a hazard ratio (95% CI) of 1.75 (0.89–3.45) for

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bladder cancer for pioglitazone users versus all patients with diabetes [57]. A significantly higher risk was observed in 425 patients who had been taking pioglitazone for < 24 months, with an estimated hazard ratio (95% CI) of 2.73 (1.11–6.72). It should be pointed out that seven of the nine cases of bladder cancer who had been taking pioglitazone were either current smokers or ex-smokers; and five of the nine cases had a duration of pioglitazone use < 24 months. This study reported incident cases of bladder cancer after pioglitazone use, but no information on follow-up time was available. The duration and dose of pioglitazone and smoking status were only given in the nine identified cases with incident bladder cancer and pioglitazone use. The analytical methods are not clear in this study and the reported hazard ratios were probably estimated as odds ratios without adjustment for confounders. The occurrence of bladder cancer within a short time of pioglitazone exposure in this Japanese study was similar to the observation in the previously mentioned study by Tseng in Taiwan [50]. This may indicate a detection bias associated with the use of pioglitazone especially during the first one to two years of its use. Korea: Song and Colleagues (Single Hospital-Based Case-Control Study) A case-control study was conducted in a single-center in Korea by including diabetic patients with bladder cancer (n = 329) from November 2005 to June 2011 [58]. A control group was created by matching by sex and age (with a 1:2 ratio of cases and controls) to 658 patients without bladder cancer who were listed on the diabetes registry of the hospital. The prevalence of pioglitazone use in the case group and the control group was 6.4% and 15%, respectively (p < 0.001). The odds ratio (95% CI) for bladder cancer associated with a history of pioglitazone use was 2.09 (0.26–16.81) after adjusting for smoking and other factors including alcohol, coexisting cancer, hemoglobin, and albumin. It is noted that the description of the methods was not clear and opposing association with pioglitazone was observed in univariate and multivariate analyses. Some elements of the design are also of concern: cases and controls enrolled in a single tertiary hospital may not be appropriate, history of pioglitazone or other medications prescribed before visiting this tertiary hospital was not available, and recall bias may be associated with the collection of information of confounders. The distributions on the use of other glucose-lowering drugs were remarkably different between the case group and the control group, but this information had not been considered in the analyses. India: Unnikrishnan and Colleagues (Case Series Report) Unnikrishnan and colleagues reported eight cases of bladder cancer in patients with type 2 diabetes who were on pioglitazone therapy [60]. The patients were aged 43 to 76 years, had been treated with pioglitazone at a dose



of 15–30 mg per day for two to nine years. Among them seven were males, and seven had transitional cell carcinoma on biopsy; the pathology in the other one was not clear. This case series report brought up the clinical caution of a possible link between pioglitazone and bladder cancer risk at a relatively lower daily dose in the Indian population than the up to 45 mg per day in the white populations. This could probably be due to the small body build or different ethnic/genetic susceptibility. However, no causal inference can be made because no referent group, no estimated risk ratio, no confounding factors, and no other background information had been provided.

ROSIGLITAZONE Clinical Trials Table 3 summarizes the findings of six available meta-analysis studies on TZDs and bladder cancer risk (to be discussed in detail later under the heading of “Meta-analysis of Clinical Trials and Observational Studies”). In the meta-analysis by Colmers and associates the bladder cancer risk associated with rosiglitazone was assessed for two RCTs—ADOPT and RECORD—with respective relative risk (95% CI) of 0.50 (0.11–2.34) and 1.20 (0.37–3.94) (Table 1) [38]. The combined meta-relative risk from these two trials was 0.87 (0.34–2.23) (Table 3). However, the case numbers of bladder cancer are too small and the overall risk of bias was rated as “high” by the investigators for both studies. In another meta-analysis by Monami and colleagues the Mantel-Haenszel odds ratio estimated from RCTs for bladder cancer for rosiglitazone was 0.91 (0.62–1.33) (Table 3) [65].

Observational Studies USA Piccinni and Colleagues (Adverse Event Reporting System) In the study by Piccinni and colleagues using the Adverse Event Reporting System of FDA, the reporting odds ratios (95% CI) for rosiglitazone was 0.38 (0.12–1.05) (Table 2) [59].

Europe France: Neumann and Colleagues (CNAMTs Retrospective Cohort Study) The French CNAMTs population-based retrospective cohort study evaluated the risk of bladder cancer associated with pioglitazone and rosiglitazone

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Bosetti et al. [2013] Ferwana et al. [2013] Monami et al. [2013] He et al. [2013]

66

67

1.50 (1.14–1.98)∗

2.05 (0.84–5.02)

1.23 (1.09–1.39)∗

1.20 (1.07–1.34)∗

1.17 (1.03–1.32)∗

1.22 (1.07–1.39)

Meta-RR (95% CI)

1 RCT, 5 cohort, 2 case-control, 1 AERS

1 RCT, 3 cohort, 1 case-control 4 cohort, 2 case–control 1 RCT, 4 cohort, 1 case-control 4 RCT

3 cohort

Studies included

NR

0.91 (0.62–1.33)

NR

1.08 (0.95–1.23)

NR

0.87 (0.34–2.23)

Meta-RR (95% CI)

3 RCT

1 cohort, 2 case-control

2 RCT

Studies included

Rosiglitazone

NR

NR

NR

1.13 (1.05–1.23)

1.15 (1.04–1.26) NR

1.45 (0.75–2.83)

Meta-RR (95% CI)

5 cohort, 2 case-control

6 cohort

4 RCT∗∗

Studies included

Thiazolidinediones

RR, risk ratio; CI, confidence interval; NR, not reported; RCT, randomized controlled trial; AERS, FDA Adverse Event Reporting System. ∗ Dose-response analysis shows significantly higher risk associated with higher cumulative dose and longer duration of exposure. ∗∗ Respective findings of these four RCTs are shown in Table 1.

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Colmers et al. [2012]

Authors [Year Published]

38

Reference

Pioglitazone

Table 3: Findings of Six Meta-analyses Evaluating Thiazolidinediones and Bladder Cancer




in the same paper. Findings from the study suggested a possible link with pioglitazone (discussed earlier) but not with rosiglitazone. The estimated hazard rate ratio (95% CI) for rosiglitazone was 1.08 (0.92–1.26) after adjustment for age, sex, and exposure to glucose-lowering drugs [10]. The major limitation of this study may be related to its inability to adjust for smoking and the possible confounding by indication. UK: Mamtani and Colleagues (Retrospective Cohort Study) The cohort study by Mamtani and colleagues also evaluated the risk of bladder cancer in patients using pioglitazone and rosiglitazone in the same paper [47]. For rosiglitazone, dose-response analyses were conducted using the parameters of “time since initiation” and “duration of therapy” with the same cutoffs of < 1, 1 to < 2, 2 to < 3, 3 to < 4, 4 to < 5, and ≥ 5 years. The p–trend for the time since initiation was significant, but only the category of ≥ 5 years of this parameter was significant with an adjusted hazard ratio (95% CI) of 2.91 (1.34–6.36) while compared to the first category of < 1 year. For the duration of therapy, neither the p–trend nor any of the categories was significant [adjusted hazard ratio (95% CI) for ≥ 5 years versus < 1 year of rosiglitazone use: 1.51 (0.62–3.67)]. The authors concluded that long-term use of TZDs (≥ 5 years) may be associated with an increased risk of bladder cancer, irrespective of pioglitazone or rosiglitazone, but some limitations of the study have been discussed earlier. UK: Azoulay and Colleagues (Nested Case-Control Study) The nested case-control study by Azoulay and colleagues described earlier for pioglitazone did not suggest a risk of bladder cancer associated with rosiglitazone use either in overall analysis or in dose-response analysis [49]. The hazard ratio (95% CI) for exclusive use of rosiglitazone versus never use of any TZDs was 1.14 (0.78–1.68). Neither the p–trend nor any of the categories of cumulative duration (p–trend = 0.32) and cumulative dose (p–trend = 0.49) of rosiglitazone use was significant [49]. This study did not suggest an association between rosiglitazone and bladder cancer, but an increased risk was observed for pioglitazone (discussed earlier).

Asia Taiwan: Tseng (Retrospective Cohort Study using Whole Nation NHI Database) In a separate study drawn from the entire database of the Taiwanese NHI, Tseng evaluated the association between rosiglitazone use and bladder cancer risk after excluding patients who had ever been exposed to pioglitazone. A total of 885,236 patients with type 2 diabetes and under oral glucose-lowering drugs (except pioglitazone) and/or insulin were studied for bladder cancer incidence from January 1, 2006 to December 31, 2009. Among them, 102,926 were

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ever-users and 782,310 were never-users of rosiglitazone, with 356 (0.35%) and 2753 (0.35%) incident cases of bladder cancer, respectively. Adjusted hazard ratios for ever-users versus never-users, and for the tertile cutoffs of “time since starting rosiglitazone,” “cumulative duration of therapy,” and “cumulative dose” were estimated. The hazard ratio (95% CI) for bladder cancer for ever- versus never-users of rosiglitazone was 0.980 (0.870–1.104) after adjustment for age, sex, diabetes duration, various comorbidities, and medications. In the dose-response analyses, neither the p-values for the hazard ratios of the categories nor their p-trends were significant [52]. The author concluded a null association between rosiglitazone use and bladder cancer. This study used the NHI database covering the whole nation and the whole period since the inception of rosiglitazone in Taiwan. This avoided any error in sampling procedure. The exclusion of pioglitazone users avoided the potential residual confounding from pioglitazone. Lack of information of smoking may be a limitation, but chronic obstructive pulmonary disease was used as a surrogate. There is a concern of overlapping population with other studies using the same NHI database. In addition, the four-–year follow-up duration may be too short.

Taiwan: Tseng (Retrospective Cohort Study in Diabetic Men with Benign Prostatic Hyperplasia) In the cohort analysis conducted in a subgroup of patients with type 2 diabetes and benign prostatic hyperplasia, neither use of pioglitazone nor rosiglitazone was associated with an increased risk of bladder cancer. The adjusted hazard ratio (95% CI) for bladder cancer for ever-users versus never-users of rosiglitazone was 1.124 (0.923–1.369) [51]. The hazard ratio for pioglitazone and the limitations of the study have been discussed previously.

Taiwan: Chang and Colleagues (Case-Control Study) Chang and colleagues analyzed the risk of bladder cancer and pioglitazone and rosiglitazone separately in their case-control study [54]. Approximately 26.1% of the patients received rosiglitazone and the mean cumulative duration was 522 days and the mean daily dosage was 0.14 defined daily dose for rosiglitazone. The overall hazard ratio (95% CI) comparing ever- to never-users of rosiglitazone was 1.05 (0.81–1.36). In dose-response analyses, neither the pvalues for the hazard ratios of the categories of cumulative dosage, cumulative duration, and cumulative dose duration nor their p-trends were significant. Therefore a null association between rosiglitazone use and bladder cancer risk was observed. Lack of adjustment for smoking may be a limitation of the study, and overlapping population with other studies using NHI database may be a concern.



Taiwan: Hsiao and Colleagues (Nested Case-Control Study) The nested case-control study by Hsiao and colleagues using the NHI databases as discussion previously for pioglitazone also suggested a significantly higher risk of bladder cancer associated with the use of rosiglitazone [55]. While compared with nonusers, the respective adjusted odds ratios (95% CI) for current users, recent users, and past users of rosiglitazone were 1.89 (1.51–2.38), 0.78 (0.46–1.35), and 0.95 (0.78–1.14). The adjusted odds ratios (95% CI) were 0.98 (0.82–1.17), 1.78 (1.31–2.39), and 2.00 (1.37–2.92) for rosiglitazone use < 1 year, 1–2 years, and ≥ 2 years while compared to nonusers [55]. Contrary to the population-based cohort study by Tseng using the NHI database with a different approach and excluding patients who had been exposed to pioglitazone in the analysis [52], the findings of this study by Hsiao and colleagues [55] suggested that long-term exposure to rosiglitazone, like the exposure to pioglitazone, was also associated with a higher odds of bladder cancer, especially when exposure was ≥ 2 years [55]. Besides the limitations discussed in the section under “PIOGLITAZONE,” a potential contamination of pioglitazone use is possible in this study because patients might have switched from pioglitazone to rosiglitazone use or have alternatively used both TZDs during different periods of time.

ANY THIAZOLIDINEDIONES Studies not specifying pioglitazone and rosiglitazone are not informative, and it may be difficult to interpret the results because these two drugs may have different effects on cancer outcomes. However, these studies are also briefly described next.

Clinical Trials A meta-analysis by Colmers and colleagues included the records of a terminated RCT sponsored by Sanofi-Aventis, which calculated the risk ratio for bladder cancer between users versus nonusers of TZDs as 2.55 (0.12–52.70) [38]. The findings may not be reliable because only two cases of bladder cancer were observed and the mean follow-up time was not reported. Furthermore, the risk of bias was rated as “high” (Table 1).

Observational Studies Five observational studies evaluated the risk of bladder cancer associated with the use of any TZDs (Table 2). Two of them evaluated any TZDs in addition to specifying on pioglitazone and rosiglitazone [47,49] and the other three evaluated any TZDs without specifying the drugs [46,53,56]. These five studies are discussed next.

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USA: Oliveria and Colleagues (Retrospective Cohort Study) This study using the US pharmacy claims database did not find any association between TZDs (not specified) and the risk of bladder cancer [46]. After adjustment for age, sex, schistosomiasis, and pelvic radiation, the relative risk was 0.94 (0.66–1.34) for ever-users of TZDs (either monotherapy or combination therapy) versus never-users; and was 1.05 (0.71–1.54) for ever-users of TZDs versus ever-users of other oral glucose-lowering drugs (no TZDs or insulin). However, this study has limitations of being unable to discern among the various drugs in the class of TZDs, a small number of bladder cancer cases (n = 178), failure to consider important risk factors for bladder cancer such as smoking, some occupational exposure, renal function and urolithiasis, and not considering the cumulative dose and duration of exposure. Furthermore, the ascertainment and confirmation of the bladder cancer cases and the completeness of case identification by using administrative databases are not certain. UK: Mamtani and Colleagues (Retrospective Cohort Study) Mamtani and colleagues analyzed the UK THIN database on the risk of bladder cancer in new use of TZDs versus new use of sulfonylureas, and in new use of pioglitazone versus new use of rosiglitazone [47]. The hazard ratio (95% CI) for new use of TZDs versus new use of sulfonylureas was 0.93 (0.68–1.29). In dose-response analyses, the hazard ratios (95% CI) was significant for the longest duration (≥ 5 years) of therapy with TZDs versus sulfonylureas [3.25 (1.08–9.71)], and for the longest time (≥ 5 years) since initiation of therapy [2.53 (1.12–5.77)]. The p-trend was significant for time since initiation of therapy but not significant for duration of therapy in the TZDs versus sulfonylureas analysis. The p-trend for pioglitazone versus rosiglitazone was not significant for either time since initiation of therapy or duration of therapy [47]. No significantly increased risk was observed in each of the categories of duration of therapy for either pioglitazone or rosiglitazone [47]. UK: Azoulay and Colleagues (Nested Case-Control Study) In the nested case-control study by Azoulay and colleagues, never use of any TZDs was the referent group, and the risk for bladder cancer for exclusive ever-use of pioglitazone, exclusive use of rosiglitazone and ever-use of both pioglitazone and rosiglitazone was estimated. The hazard ratio (95% CI) for ever use of both pioglitazone and rosiglitazone was 0.78 (0.18–3.29) [49]. Taiwan: Tseng (Retrospective Cohort Study) Tseng used the NHI database of a sample of one-million people randomly selected from the 23-million population of Taiwan in year 2005 to investigate the risk of bladder cancer in patients with diabetes compared to the general



population without diabetes. The adjusted hazard ratio (95% CI) for users versus nonusers of TZDs (pioglitazone and/or rosiglitazone) was 0.80 (0.34–1.90) [53]. It should be pointed out that the referent group of nonusers of TZDs included individuals without diabetes in this study. Because individuals without diabetes (men: 442,764, women: 440,452) outnumbered the patients with diabetes (men: 52,435, women: 63,296), the referent group mainly represented the individuals without diabetes. It is interesting that after adjusting for diabetes status, various medications, comorbidities, living region, and occupation, the use of TZDs in patients with diabetes is associated with a lower risk (although not significant) of bladder cancer while compared to the referent group composed mainly of individuals without diabetes. This study may suggest a preventive role of TZDs on bladder cancer in the diabetic patients while compared to the general population. However, smoking could not be adjusted for in the study, and the findings need to be confirmed. Taiwan: Kao and Colleagues (Matched Retrospective Cohort Study) Kao and colleagues also used the Taiwanese NHI database for their study. They reported a lack of significant risk for bladder cancer for TZDs users versus nondiabetic controls, and versus nonusers of TZDs in the diabetic patients. The respective hazard ratios (95% CI) were 0.74 (0.27–1.99); 1.48 (0.56–3.92) [56]. It is interesting that the hazard ratio (95% CI) of 0.74 (0.27–1.99) for TZDs users versus nondiabetic controls in this study is very similar to the estimated 0.80 (0.34–1.90) in the previous study by Tseng comparing users versus nonusers of TZDs (mainly composed of non-diabetic individuals) [53]. This may further suggest a preventive role of TZDs on bladder cancer in the diabetic patients while compared to the general population.

META-ANALYSIS OF CLINICAL TRIALS AND OBSERVATIONAL STUDIES As shown in Table 3, a total of six meta-analysis studies evaluating the association between the use of TZDs (specified or unspecified) and bladder cancer have been published, two in 2012 [38,66] and the other four in 2013 [65,67–69]. Most of the previously mentioned clinical trials and observational studies were covered by these meta-analysis studies. All of the six studies reported metarisk ratio for pioglitazone, three for rosiglitazone [38,65,67], and two for any TZDs [38,67] (Table 3). These meta-analysis studies will be briefly described in the following paragraphs under the names of the first authors. It is difficult to compare the different meta-analysis studies as they included different but partially overlapping studies, some of which were unpublished; and some of them included RCTs and observational studies in the meta-analysis. Furthermore, new sources of bias may be introduced in the meta-analysis if biases and flaws of individual studies are pooled together [70–72].

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Colmers and Colleagues (2012) The first meta-analysis by Colmers and colleagues estimated the risk for bladder cancer associated with pioglitazone, rosiglitazone, and any TZDs. The meta-risk ratio (95% CI) for pioglitazone was 1.22 (1.07–1.39) derived from three cohort studies, for rosiglitazone 0.87 (0.34–2.23) from two RCTs, and for any TZDs 1.45 (0.75–2.83) from four RCTs, and 1.15 (1.04–1.26) from six cohort studies [38]. The information derived from the four RCTs included in the meta-analysis for any TZDs can be seen in Table 1. The overall risk of bias was assessed and was denoted as “unclear” for the PROactive and as “high” for the other three trials (Table 1) [38].

Zhu and Colleagues (2012) Zhu and colleagues [66] conducted a meta-analysis on the association between pioglitazone and bladder cancer from five studies, including one RCT [3], three cohort studies [9,10,50], and one case-control study [54]. The metarisk ratio (95% CI) was 1.17 (1.03–1.32). After excluding the RCT with a small case number of bladder cancer and without considering confounders for bladder cancer, the estimated meta-risk ratio (95% CI) was still significant: 1.16 (1.03–1.32). Dose-response analysis was performed and the risk ratio was significant for a higher cumulative dose and longer exposure. In patients with a cumulative dose of > 28,000 mg the risk ratio was 1.58 (1.12–2.06) [1.20 (0.97–1.48) and 1.10 (0.91–1.33) for cumulative dose 10,501–28,000 mg and < 10,500 mg, respectively]. Patients with a cumulative exposure for > 24 months had a meta-risk ratio (95% CI) of 1.38 (1.12–1.70) [1.34 (1.08–1.66) and 0.96 (0.81–1.15) for exposure 12–24 months and < 12 months, respectively]. No heterogeneity was observed between studies [66].

Bosetti and Colleagues (2013) Bosetti and colleagues included 17 observational studies in their metaanalysis for the risk of a variety of cancers associated with TZDs [67]. They showed that the meta-risk ratio (95% CI) for pioglitazone was 1.20 (1.07–1.34) from six studies, 1.08 (0.95–1.23) from three studies for rosiglitazone; and 1.13 (1.05–1.23) from seven studies for any TZDs [67]. Longer duration (> 24 months) (1.42, 1.17–1.72) and higher cumulative dose (> 28,000 mg) of pioglitazone (1.64, 1.28–2.12) were associated with a significantly higher risk. In this study the risk of other cancers including colorectal, liver, pancreas, lung, breast, and prostate was also evaluated. The findings suggested a significantly reduced risk of colorectal cancer and liver cancer associated with TZDs, meta-relative risk (95% CI): 0.93 (0.90–0.97) and 0.65 (0.48–0.89), respectively [67].


Ferwana and Colleagues (2013) The meta-analysis by Ferwana and colleagues included six studies (one RCT, four cohort, and one case-control), and an estimated hazard ratio (95% CI) of 1.23 (1.09–1.39) for pioglitazone use was reported [68]. The risk ratios for rosiglitazone or any TZDs were not evaluated in this meta-analysis.


Monami and Colleagues (2013) The meta-analysis by Monami and colleagues included only RCTs to estimate the Mantel-Haenszel odds ratios for pioglitazone and rosiglitazone on the risk of a variety of cancers, including bladder cancer [65]. The meta-odds ratio for bladder cancer for pioglitazone was 2.05 (0.84–5.02) from four RCTs. The first trial was the PROactive study that compared the effect of pioglitazone to placebo on macrovascular outcomes [3]. The second trial was the CHICAGO (Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone) that compared the effect of pioglitazone to glimepiride on carotid intimamedia thickness in type 2 diabetes [73]. The third trial was the PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation) comparing pioglitazone to glimepiride on the progression of coronary atherosclerosis by intravascular ultrasonography [74]. The fourth trial was a one-year study comparing the efficacy of glycemic control between vildagliptin and pioglitazone [75]. The meta-odds ratio was 0.91 (0.62–1.33) for rosiglitazone. No detail information was provided in the paper for the case numbers of bladder cancer occurring in each of the trials. It should be recognized that all of the trials were not designed a priori to test the hypothesis for an association between the TZDs and bladder cancer risk. He and Colleagues (2013) The latest published meta-analysis by He and colleagues showed an overall meta-relative risk (95% CI) of 1.50 (1.14–1.98) for pioglitazone from one RCT, five cohort studies, two case-control studies, and one drug adverse-event reporting system [69]. Dose-response analysis showed a more significant risk associated with higher cumulative dose and longer duration. Meta-relative risk in subgroup analysis was 1.17 (1.04–1.31) from four cohort studies, 2.02 (0.84–4.89) from three case–control studies, and 1.64 (1.01–2.67) in men, and 1.69 (0.64–4.47) in women from three studies.

DISCUSSION Some concerns on the causal inference from the currently available studies and some comments on the clinical use of glucose-lowering drugs and future perspectives to clarify the association are summarized in Table 4 and discussed next.

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C.-H. Tseng Table 4: Some Comments and Concerns on Studies Evaluating Thiazolidinediones and Bladder Cancer Comments/concerns


1. Findings from animal studies may not be applied to humans 2. Different thiazolidinediones may show different effects 3. Sexual and ethnic comparison studies required

4. Effects of diabetes duration and glycemic control not sufficiently addressed 5. Effects of different daily doses

6. Lack of direct evidence from randomized controlled trials 7. Potential biases of observational studies

8. Lack of sufficient adjustment for smoking in most studies 9. Overlapping populations and contradictory findings from the same databases 10. Needs for comparison with other drugs and evaluation of their interactions

Explanations Preclinical animal studies suggest bladder carcinogenicity associated with pioglitazone. However, the findings in animal studies may not be applied to humans. Different effects on bladder cancer risk are observed for pioglitazone and rosiglitazone, suggesting a mechanism other than PPARγ activation. In general populations, bladder cancer incidence shows a 14-fold variation in different ethnicities, but men consistently have a higher risk than women in different ethnicities. Controversial findings on bladder cancer risk related to TZDs have been observed between different sexes and ethnicities, which requires further clarification. Diabetes duration and glycemic control may affect the development of cancer but these have not been fully addressed in studies on thiazolidinediones and bladder cancer. The daily dose of pioglitazone may be used at 45 mg in the white populations, but it is always used at 15-30 mg in the Asian populations. Whether the daily dose may affect the risk of bladder cancer in humans awaits further investigation. Cases of bladder cancer in clinical trials are usually too small because these trials were not primarily designed to address the cancer issue. Furthermore, a bias due to differential diagnosis could not be completely excluded. Available observational studies mainly depend on secondary administrative databases. Biases related to cohort or case/control selection, indication bias related to drug use, bias of cancer ascertainment, immortal time bias and prevalent user bias can not be fully addressed in most studies. Studies using adverse event reporting systems may suffer from notoriety bias. Not all studies have enough cases of bladder cancer for evaluating a dose-response relation. Residual confounding by smoking is possible in studies adjusted for smoking. Population-based studies in UK and Taiwan used similar databases with overlapping populations. Furthermore, opposing findings have been reported from the same databases. The risk of bladder cancer is similar in insulin users and pioglitazone users in one study in the US [100]. A 12-year follow-up study in Taiwan suggests that insulin use and smoking may jointly increase the risk of bladder cancer mortality [101]. Comparisons of bladder cancer risk between thiazolidinediones and other glucose-lowering drugs and evaluating their interactions with other drugs or environmental risk factors are required. (continued on next page)

Thiazolidinediones and Bladder Cancer Table 4: Some Comments and Concerns on Studies Evaluating Thiazolidinediones and Bladder Cancer (continued) Comments/concerns


11. Newer glucose-lowering drugs may not be risk-free

12. Balancing risks and benefits is important in clinical practice

Explanations A higher risk of acute pancreatitis, pancreatic cancer and thyroid cancer has been reported in incretin-based therapies. Bladder cancer and breast cancer have also been reported in association with sodium glucose cotransporter 2 inhibitors. Rosiglitazone is no more available in some countries and is of restricted use in others where it is still available because of the potential risk of myocardial infarction. Pioglitazone has potential benefits in macrovascular outcomes. Most commentaries recommends the continuous use of pioglitazone with caution or monitoring for bladder cancer.

Findings from Animal Studies May Not Be Applied to Humans Animal studies suggest that pioglitazone treatment may increase the risk of bladder cancer in rats (especially male rats), but probably not in other species including mice, rabbits, dogs, and monkeys [1]. On the other hand, rosiglitazone does not induce bladder cancer except in the presence of bladder carcinogen (4-hydroxybutyl(butyl)nitrosamine) [1]. The mechanisms of pioglitazone-related bladder cancer may not involve a direct effect of genotoxicity or cytotoxicity of the drug, but a receptor-mediated PPARγ effect cannot be excluded [1]. However, if this is the case, similar bladder carcinogenicity should be observed in animals treated with other PPARγ agonists. Some animal studies suggest a mechanism related to urolithiasis in pioglitazone-induced bladder cancer, but this may not have human relevance [1]. Bladder stones can remain symptomless in the ventral bladder for a long time in quadruped rodents, thus allowing the induction of bladder cancer. [1]. However, bladder stones in bipedal standing humans will easily obstruct the urinary outflow because of gravity’s effect and cause hematuria and pain on micturition. This would lead to the removal of the stones in the bladder in humans. Therefore, it seems difficult at this moment to apply the findings of the toxicity and mechanistic studies conducted in animals directly to humans for the interpretation of bladder carcinogenicity related to pioglitazone.

Different Thiazolidinediones May Show Different Effects The two different TZDs—pioglitazone and rosiglitazone—may have different effects on the risk of bladder cancer in either the animal studies [1] or in humans as reviewed in this article (Tables 2 and 3). While pioglitazone may

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show an increased risk, most studies do not suggest a higher risk for rosiglitazone (except for the nested case-control study by Hsiao and colleagues using the NHI database of Taiwan [55], Table 2). The two TZDs also show different effects in terms of cardiovascular outcomes. While rosiglitazone may increase the risk of myocardial infarction, pioglitazone on the other hand shows some protective effects on macrovascular disease [2]. These observations suggest that besides the common agonistic effects on PPARγ, different TZDs may also affect the expression of other different sets of genes. The discrepant effects on bladder cancer risk between the two different TZDs also strongly indicate a mechanism other than PPARγ activation in pioglitazone-related bladder cancer.

Sexual and Ethnic Comparison Studies Required Bladder cancer is more commonly seen in males than in females. This is not only observed in humans but also in most species of animals [1]. In humans the sexual differences of bladder cancer incidence are similarly demonstrated in different ethnicities, including the white, black, and Asian populations [76,77]. In addition, the incidence of bladder cancer differs remarkably in different ethnicities in humans, with a 14-fold variation in incidence [78]. Smoking, exposure to arsenic or aromatic amines, and chronic infection with Schistosoma hematobium in some countries are important risk factors [78–80]. Metabolism of bladder carcinogens involves liver enzymes [81]. Therefore, the sexual disparity in bladder cancer risk may indicate interplays among androgen, estrogen, and liver enzymes, through which androgen and estrogen may exert opposing effects on bladder carcinogenicity [81]. Besides, both androgen and estrogen receptors are expressed on the epithelium of bladder [81]. It has been shown that androgen may sensitize the bladder to carcinogens by suppressing the detoxification of bladder carcinogens in the urinary bladder [81]. The knockout of androgen receptor prevents the development of bladder cancer induced by N-butyl-N-(4-hydroxybutyl)nitrosamine in both male and female mice, suggesting a critical role of androgen receptor signaling in the induction of bladder cancer [81]. An ethnic comparison study conducted in the United States suggested that white people have the highest incidence of and mortality from bladder cancer than black people and people of other ethnicities [77]. Such an ethnic difference may indicate a different genetic susceptibility, different environmental exposure, or different distribution of important risk factors. Because of the controversial findings in a few studies evaluating sexspecific risk (Table 2), it is too early to tell whether the association between pioglitazone and bladder cancer may differ with regards to different sexes or ethnicities. Except for the KPNC study [9,45], the French population-based cohort study [10] and the study using the FDA Adverse Event Reporting System



[59], most studies did not report the risk in different sexes. The KPNC reported a lack of overall association in either men or women [9,45]. The French study showed a significantly higher risk of bladder cancer associated with pioglitazone use in men but not in women [10], but the study using the FDA Adverse Event Reporting System reported a significantly higher risk in both men and women [59] (Table 2). The KPNC study is ongoing and the final report of the 10-year follow-up will not be available one or two years later. The lack of statistical power because of the small number of bladder cancer cases in women with exposure to pioglitazone (n = 13) may lead to the null association in the French study [10]. On the other hand, bias may exist in the study using the adverse event reporting system as described previously. Future studies are required to clarify the issue of bladder cancer risk related to TZDs with regards to sexual and ethnic disparities.

Effects of Diabetes Duration and Glycemic Control Not Sufficiently Addressed Diabetes may increase the risk of bladder cancer [53,82–85], with varying risk ratios across different duration of diabetes [53]. Furthermore, glycemic control may also have an impact on the development of cancer through mechanisms related to metabolic changes, accumulation of advanced glycation end-products, and increased oxidative stress [86,87]. Poorly controlled hyperglycemia always predisposes urinary tract infection, which is also a significant risk factor for bladder cancer [53]. Fasting hyperglycemia has been identified as a risk factor for many cancers including bladder cancer in women [88,89], who may also have a higher risk of urinary tract infection than men. Pioglitazone and rosiglitazone are always considered as second- or third-line drugs for glycemic control when hyperglycemia cannot be adequately managed by other oral glucose-lowering therapies. Therefore, the use of these late-line medications may indicate a poor glycemic condition for a long duration before their use. Many of the previous observational studies could not sufficiently address the potential confounding effects of diabetes duration and glycemic control in data collection and analyses.

Effects of Different Daily Doses The daily dose of pioglitazone may be as high as 45 mg in white populations [3,90], but it is always used at a dose of 15–30 mg in Asian populations [57,60]. Whether this prescription difference may present different risk of bladder cancer associated with the use of pioglitazone in different studies is not known. At least if bladder cancer development requires a certain threshold of cumulative dose, patients treated with a higher daily dose will surely reach the threshold sooner than those who receive a lower daily dose.

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Evidence from animal studies provides some clue to the possibility of differential effects with regards to different daily doses, but future studies are required for confirmation in humans. A dose-response relationship has been demonstrated between daily exposure dose to pioglitazone and urothelial changes and bladder cancer occurrence in rats [1]. It has also been shown that rats exposed to pioglitazone at 1 mg/kg/day, a dose below the maximum human daily dose of 45 mg, do not develop bladder cancer [1].

Lack of Direct Evidence from Randomized Controlled Trials RCT is considered the most powerful study design for controlling confounders (either known or unknown) in order to clarify the cause–effect relationship between use of TZDs and bladder cancer risk. However, there has been no single RCT aimed primarily at such issue. In the foreseeable future, an expectation to obtain direct evidence from RCTs is impossible for reasons of medical ethics because RCTs are usually designed to evaluate an efficacy or benefit of an intervention rather than a potential harm. The incidence of bladder cancer in patients with type 2 diabetes in different ethnicities is generally below 1 per 1000 patients per year [50,69]. The long latency required for cancer development along with the very high cost to deploy such a trial may also hinder the conduction of RCTs. Most information derived from clinical trials discussed in this article was based on studies evaluating the risk of cardiovascular outcomes but not cancer risk associated with the use of TZDs (Table 1). Therefore, the case numbers of incident bladder cancer observed during the trial periods are usually too small to allow sufficient power in statistical analyses. Furthermore, all clinical trials were conducted mainly in white populations, and they may not be completely free of the risk of bias (Table 1).

Potential Biases of Observational Studies There are some potential biases in the observational studies currently available in the investigation of the risk of bladder cancer associated with the use of TZDs, especially pioglitazone. First, most studies used secondary administrative databases. These may have limitations including a lack of systematic collection of research information of exposure, outcomes and confounders, residual confounding by indication, and unknown potential impact of detection bias. Dose-response and subgroup analyses had not been conducted in many studies; and for those analyzing a dose-response relationship the finding of a significant association is not consistent (Table 2). The case numbers of bladder cancer may also be too small to allow subgroup analysis. It is not clear whether the differences in the findings reported in the United States and Europe versus Asian countries, and the contradictory findings from different



studies using the same databases are due to study quality, genetic susceptibility, geographical differences related to risk factors for diabetes or bladder cancer, concomitant use of other drugs, or comorbidities [2]. Second, studies using an adverse event reporting system like that by Piccinni and colleagues [59] may suffer from a notoriety bias because a suspected or known adverse effect of a drug may be excessively reported. Third, there is a potential concern of ascertainment bias because most studies did not consider the differences in the intensity and frequency of ascertainment between the pioglitazone and control groups. Pioglitazone is associated with an increased risk of edema and congestive heart failure; therefore, patients on pioglitazone are more likely to undergo frequent urinalysis with early detection of microscopic hematuria, which can lead to a subsequent cystoscopic examination and diagnosis of subclinical bladder cancer. This can be demonstrated in the KPNC study suggesting a shift of the risk estimate to the null after adjustment for proteinuria and diabetic nephropathy [45,61]. Fourth, inadequate selection of a control group in a case-control study may also result in a biased estimate. For example, it is believed that the control group selected from a population-based cohort of diabetic patients in an outpatient basis and a case group from the hospitalization database in the study by Hsiao and colleagues may not be adequate [55]. Furthermore, an inclusion of cases and controls within a long period before the marketing of the TZDs in the studies by Chang and colleagues [54] and Hsiao and associates [55] may not be appropriate. Fifth, a lack of considering the possible contamination of alternative use of pioglitazone and rosiglitazone may also lead to a significantly higher risk related to current users of one drug (e.g., rosiglitazone) while the past use of the other (e.g., pioglitazone) is not taken into account. For example, the significantly higher risk of bladder cancer observed with rosiglitazone use may probably have been due to an effect of past use of pioglitazone in the study by Hsiao and colleagues [55]. Sixth, it is well recognized that patients with type 2 diabetes at different clinical stages may use different kinds of glucose-lowering drugs according to their indications, thus leading to a confounding by indication [91]. Furthermore, inclusion of prevalent users of drugs may result in a “prevalent user bias” because prevalent users are survivors of early pharmacotherapy and risk may vary with time [92–94]. A new-user design has been recommended to reduce the prevalent user bias [94]. In data analysis, “immortal time bias” can be introduced if the follow-up time and treatment status are not appropriately considered [95,96], although the effect of immortal time bias is considered to be small in nontrials by some investigators [94]. To reduce the immortal time bias, the following methods have been advocated: (1) use a time-dependent approach in data analysis; (2) start of follow-up at the end of the immortal time period among drug users with an assignment of a corresponding date for start

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of follow-up in the nonuser cohort; and (3) use a time-matched, nested casecontrol design [94,95]. To overcome confounding by indications, use of propensity score for matching in case-control study design or for adjustment as a covariate in statistical analysis has been recommended [94]. Sensitivity analysis is also suggested for confirmation of research findings [94]. It is noted that no single observational study meets all of the previously noted requirements in either study design or statistical analysis.

Lack of Sufficient Adjustment for Smoking in Most Studies Smoking has been recognized as the most common and important risk factor for bladder cancer [78,79]. However, this cannot be adequately controlled in many of the observational studies reporting a higher risk of bladder cancer associated with pioglitazone (Table 2). For example, in the KPNC study, only current smoking is available for adjustment [45]. In two UK studies using the GPRD with conflicting conclusions, information on smoking can only be classified as yes or no, and no detailed data are available for dose adjustment or evaluation of the effects of current versus ex-smokers [47,49]. Information on current and ex-smokers was available in another analysis using the GPRD, but this study did not conclude with a significantly higher risk of bladder cancer associated with pioglitazone use in either the main analysis or the propensity matched analysis [48]. It is also evident that most cases (seven of nine) of pioglitazone-related bladder cancer are also smokers, either current or past, in the Japanese study [57]. Therefore, the residual confounding effect of smoking cannot be excluded from currently available studies that show a significantly higher risk of bladder cancer associated with pioglitazone. The confounding effect of smoking may also differ between different sexes and ethnicities because of the different rates of smoking between sexes and the hormonal or genetic interaction in the metabolism of toxic chemicals found in tobacco. Smoking is always considered as an important risk factor for bladder cancer in white people [79], but it is not identified as a major risk factor in Taiwanese women, probably because of the very low smoking rate in the Taiwanese female population [97].

Overlapping Populations and Contradictory Findings from the Same Databases It should be noticed that different groups of investigators have used the same databases in their analyses on the risk of bladder cancer associated with either pioglitazone or rosiglitazone. For example, the UK GPRD was used in the studies by Mamtani and colleagues [47], Wei and associates [48] and Azoulay and coauthors [49]. On the other hand, Tseng [50–53], Chang and colleagues [54], Hsiao and associates [55] and Kao and coauthors [56] have used



the Taiwanese NHI database for their studies. Some of the investigators used a retrospective cohort study design and some used a case-control design from the same databases (Table 2). It is interesting that contradictory findings are observed among the different studies using the same databases in either the United Kingdom or Taiwan (Table 2). Such discrepant findings strongly suggest that the study designs, sample selections, confounding consideration, and analytical methods may affect the conclusions of the study. Inclusion of studies with overlapping populations in meta-analysis may also lead to biased results.

Needs for Comparison with Other Drugs and Evaluation of Their Interactions A higher risk of cancer has been reported with the conventionally used glucose-lowering drugs including insulin and sulfonylureas [98,99]. On the other hand, metformin may be associated with a lower risk of cancer [99,100]. Whether these medications may have an effect on bladder cancer risk or may interact with each other has not been extensively studied, but some recent reports suggest such a possible effect. A recent retrospective cohort study compared pioglitazone to insulin with respect to a variety of clinical outcomes including cancer, cardiovascular disease, and bone fracture by extracting the data from the i3 InVision Data Mart database within the period from May 1, 2000 until June 30, 2010 [101]. The database covers health care information of approximately 47-million people under United Healthcare insurance in the United States. Incidences of bladder cancer and a composite of nine other cancers (prostate, female breast, lung, pancreatic, endometrial, non-Hodgkin’s lymphoma, colorectal, kidney, and malignant melanoma) in new users of pioglitazone (n = 38,588) versus insulin (n = 17,948), both mainly used as third-line therapies, were calculated and the risk was compared between pioglitazone and insulin. Based on 63 and 32 confirmed incident cases of bladder cancer, the incidence rate was 85 per 100,000 person-years in the pioglitazone group and 111 per 100,000 person-years in the insulin group. The adjusted hazard ratio (95% CI) for pioglitazone versus insulin was 0.93 (0.61–1.44). In addition, the risk of cardiovascular disease, bone fracture, and other cancers may be significantly lower in the pioglitazone than in the insulin treatment group [101]. This study suggested that the risk of bladder cancer associated with pioglitazone may not be higher than the risk associated with insulin. Therefore, it may be important to compare the risk of bladder cancer associated with the use of TZDs to the other commonly used glucose-lowering drugs including insulin, metformin, and sulfonylureas. A recent study from Taiwan does not support an impact of insulin on the risk of bladder cancer incidence in patients with type 2 diabetes [51]. However, in another 12-year follow-up study of a national cohort of 86,939 patients with type 2 diabetes in Taiwan, insulin users had significantly higher risk of

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bladder cancer mortality than nonusers with hazard ratios ranging from 1.877 to 2.502 in different analyses [102]. Furthermore, insulin use and smoking may jointly increase the risk three-fold [102]. These two Taiwanese studies suggested that risk factors for incidence and mortality may not be the same. Therefore, studies including bladder cancer incidence and mortality should be interpreted carefully, and the interaction between medications or interaction with bladder cancer risk factors like smoking should be explored in future studies. TZDs were not marketed until late 1990s and were not available in Taiwan or some other countries until the early 2000s. If the conventionally used glucose-lowering drugs may influence bladder cancer risk, the effect of these medications should not be neglected while evaluating bladder cancer risk related to TZDs, especially in studies evaluating prevalent users. The use of these medications before the initiation of TZDs or concomitantly with TZDs may have greater influence on the risk of bladder cancer because they may have been used in the patients long before the inception of TZDs to allow sufficient time for the development or prevention of bladder cancer.

Newer Glucose-Lowering Drugs May Not Be Risk-Free The cancer risk of many newer classes of glucose-lowering drugs has not been extensively studied. Incretin-based therapy (in clinical use for less than 10 years) has become a mainstream in the treatment of hyperglycemia in patients with type 2 diabetes in recent years, but concern of a higher risk of acute pancreatitis, pancreatic cancer, and medullary thyroid cancer has been raised [103–106]. A potentially higher risk of breast cancer and bladder cancer is also observed with the use of sodium glucose cotransporter 2 inhibitors (two drugs in this class have just been approved for clinical use: dapagliflozin approved in Europe on November 14, 2012, and canagliflozin approved by the US FDA on March 29, 2013) [107]. Insulin glargine, an insulin analog marketed since 2000, has also been warned on its potential risk of cancer [108]. The potential cancer risk associated with these newer classes of glucose-lowering drugs may not be easily confirmed until after their widespread use for a longer time. Therefore it should be emphasized that the cancer safety issue of these newer classes of glucose-lowering drugs should be closely monitored with more extensive studies.

Balancing Risks and Benefits is Important in Clinical Practice As discussed previously, evidence supporting an increased risk of bladder cancer associated with the use of pioglitazone may be limited, and evidence for rosiglitazone is insufficient. Most commentary papers suggested that pioglitazone may still remain an important therapy in selected patients with type 2



diabetes [109–112], although some argued about the continuous use of pioglitazone [113], some suggested a urinary screening in patients who have been using pioglitazone for more than one year or with a cumulative dose of more than 28,000 mg [114], and some reiterated the importance of “primum non nocere” (first do no harm) in the treatment of our patients [115]. A significantly lower risk of liver cancer is associated with the use of either rosiglitazone or pioglitazone in Taiwan [54,56], and a significantly lower risk of breast cancer in pioglitazone users than insulin users has been reported by using the i3 InVision Data Mart database in the United States [101]. Another recent retrospective cohort study using the UK GPRD even suggested that after failure of metformin monotherapy, addition of pioglitazone provides a better combined outcome including all-cause mortality, major adverse cardiovascular events, and cancer than other glucose-lowering agents [116]. Although not significant, studies from Taiwan even suggested that the hazard ratio for bladder cancer may be < 1 when users of TZDs were compared to a referent group including individuals without diabetes [53,56]. Therefore, balancing the risks and benefits of each of the glucose-lowering drugs is important in clinical practice in order to comply with the concept of “primum non nocere.” Before in-depth investigation on the risk of all major clinical outcomes including mortality, cardiovascular disease and cancer associated with each of the glucose-lowering drugs, and evaluation of the medical conditions of each individual patient, we are not in a proper position to give an appropriate recommendation for the priority of the use of the drugs. A withdrawal of a drug with a controversial risk of bladder cancer may put the patients at a greater risk of developing cardiovascular disease or even cancer while exposing them to other medications without extensive study.

CONCLUSIONS There is a signal of higher risk of bladder cancer associated with the use of pioglitazone, but a weaker signal or null association is observed with rosiglitazone. Currently available observational studies are based on population-based administrative databases, single-hospital records, drug adverse event reporting system, or case series report. However, the findings are mainly based on analyses of existing health care databases, and except for the KPNC study that is prospective in design, all others are retrospective. Evidence from currently available RCTs may not be informative or conclusive because none of them were designed for answering a cancer risk associated with TZDs, and the small case numbers of incident bladder cancer did not allow sufficient power for statistical analysis. With regards to the studies using secondary administrative databases, there are inherent limitations and various degrees of biases related to sampling problems, differential detection, and medication indications may exist. Lack of control for smoking or residual confounding by smoking can be

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a major concern in many studies. The contradictory findings from studies using the same databases suggest unseen flaws hidden in the study design and statistical analysis. Therefore, future international comparison studies using well-designed and uniform methodology to clarify the risk in specific sexes, ethnicities, and other subgroups will be helpful to identify patients at risk.


ACKNOWLEDGMENTS The author thanks the National Science Council (NSC102-2314-B-002-067) of Taiwan for continuous support on the epidemiological issues relating diabetes and cancer.

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