Possible link of pioglitazone with bladder cancer in Japanese patients with type 2 diabetes

doi:10.1016/j.diabres.2012.11.013

Diabetes Research and Clinical Practice

Volume 99, Issue 2, February 2013, Pages e21-e23

https://doi.org/10.1016/j.diabres.2012.11.013 Get rights and content

Abstract

We retrospectively examined the frequency of bladder cancer in Japanese patients with type 2 diabetes in relation to use of pioglitazone. Among a total of 663 patients identified to be taking pioglitazone, 9 had bladder cancer (1.36%). Overall the hazard ratio of 1.75 [95% CI: 0.89–3.45] for pioglitazone for bladder cancer was not significant.

However the prevalence of bladder cancer was 2.10% in patients taking pioglitazone for less than 24 months which was significant increased (HR 2.73 [95% CI: 1.11–6.72]).

Introduction

Recently, concern about a possible risk of bladder cancer associated with pioglitazone has emerged [1], [2]. This concern had been raised in an animal experiment in which a high dose of pioglitazone was associated with an increased risk of bladder cancer in male rats [3]. In addition, although it did not reach statistical significance, a slightly higher prevalence was observed in a large clinical study [4]. It has been reported that the prevalence of bladder cancer is relatively lower in Japan when compared to that in Western countries [5]. In the present study, we investigated whether pioglitazone treatment might be associated with an increase in the prevalence of bladder cancer in Japanese patients.

Section snippets

Materials and methods

We retrospectively examined the frequency of bladder cancer in patients with type 2 diabetes in relation to pioglitazone treatment using the database in our institute. The data were collected during a 12 years period from 2000 to 2011. The numbers of newly diagnosed bladder cancer during the period, patients with type 2 diabetes, and the occurrence of bladder cancer among type 2 diabetes patients were identified. Occurrence of bladder cancer was defined as incident cases after the initiation of

Results

The total number of subjects with type 2 diabetes was 21,335 and the number of bladder cancers was 682. In patients with diabetes, 170 were found to have bladder cancer, representing a prevalence of bladder cancer in type 2 diabetes of 0.80%. Among patients with diabetes, 663 patients were taking pioglitazone and bladder cancer was found in 9 (1.36%). The hazard ratio (HR) of pioglitazone for bladder cancer was 1.75 [95% CI: 0.89–3.45] which was not statistically different for patients taking

Discussion

Our study showed that bladder cancer was seen in 0.8% of patients with type 2 diabetes and the HR of 1.75 for pioglitazone for bladder cancer was not significant. An increased tendency for bladder cancer with pioglitazone treatment has been reported in large cohort studies (HR 1.2, 95% CI: 0.9–1.5 [1] and HR 1.22, 95% CI: 1.05–1.43 [2]) and a recent meta-analysis [6]. The US Food and Drug Administration (FDA) issued an alert that the prescription of pioglitazone with high doses for long periods

Conflict of interests

There are no conflicts of interest.

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Increased risk of bladder cancer with pioglitazone therapy in patients with diabetes: a meta-analysis
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Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study
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Cited by (30)

Pioglitazone and risk of bladder cancer in type 2 diabetes mellitus patients: A systematic literature review and meta-analysis of observational studies using real-world data
2018, Clinical Epidemiology and Global Health
Citation Excerpt :
The general characteristics of each study are reported in Table 1. Among the 16 studies, 2 were conducted in USA,12,34 5 in Taiwan29,32,37–39, 3 in Korea33,40,41, 1 in Japan,31 4 in UK28,30,35,36, and 1 in France.14 2 studies reported two drugs pairs, pioglitazone vs. no pioglitazone use and pioglitazone vs. rosiglitazone use.35,36
Patients with type 2 diabetes mellitus (T2DM) have a higher incidence of bladder cancer (BC); however, the evidence underlining the association between pioglitazone use and BC risk remains inconclusive. We conducted a systematic review and meta-analysis of observational studies to investigate the effect of pioglitazone on risk of BC in T2DM patients.
We searched all publications regarding risk of BC with pioglitazone use through PubMed, Web of Science and Cochrane library databases from inception to March, 2017. Pooled hazard ratio (HR) and 95% confidence interval (CI) were calculated using a random-effect, generic inverse variance method.
Total 15 observational (9 cohort and 6 case-control) studies were meta-analyzed. The pooled results showed a significant association between risk of BC and pioglitazone use (HR 1.20, 95%CI 1.09–1.31; P < 0.0001; I² = 4%). In subgroup analysis, cumulative dose of pioglitazone (− and >mg) showed a significant association with risk of BC (HR 1.27; 95%CI 1.05–1.54; P = 0.01; I² = 0% and HR 1.68, 95%CI 1.36–2.08; P < 0 I² = 0% respectively). In addition, a significant association was seen with risk of BC and pioglitazone treatment duration (12–24 months and >24 months) (HR 1.43; 95%CI 1.19–1.71; P = 0.0001; I² = 0% and HR 1.58; 95%CI 1.27–1.97; P < 0.0001; I² = 29% respectively). Meta-analysis of pioglitazone vs. rosiglitazone use, showed a significant association (HR 1.34; 95%CI 1.05–1.71; P = 0.02; I² = 0%) with BC risk and pioglitazone use.
Pioglitazone use is associated with risk of BC in T2DM patients. Risk of bladder cancer appears to be associated with higher dose and longer duration of pioglitazone use.
An updated meta-analysis of pioglitazone exposure and bladder cancer and comparison to the drug's effect on cardiovascular disease and non-alcoholic steatohepatitis
2018, Diabetes Research and Clinical Practice
We performed a meta-analysis of epidemiological studies evaluating exposure to pioglitazone and the risk for bladder cancer and compared these results to the drug’s effects on cardiovascular disease (CVD) and non-alcoholic steatohepatitis (NASH).
Pubmed and Embase were searched for cohort and case control studies for all years through 2016.
Data from 17 papers were analyzed. In cohort studies, 822 of 357,888 pioglitazone-exposed patients (0.23%) developed bladder cancer while 7691 of 2,898,682 unexposed (0.26%) did. In case control studies, 3219 of 1,146,916 patients (0.28%) developed bladder cancer. A random effects model showed no significant association between ever vs never use or with cumulative doses of pioglitazone. However, there was a significant association with 1–2 years (HR = 1.28 [1.08–1.55]) and >2 years (HR = 1.42 [1.14–1.77]) of exposure. The numbers needed to treat for one additional case of bladder cancer ranged from 899 to 6380 while to benefit CVD and NASH, 4–256 and 2–12, respectively.
Given the very small prevalence of bladder cancer in diabetic patients exposed (or not) to pioglitazone (<0.3%) and the much greater beneficial effects of the drug on CVD and NASH, the use of pioglitazone should be resurrected.
Pioglitazone (Actos) and bladder cancer: Legal system triumphs over the evidence
2016, Journal of Diabetes and its Complications
In preclinical studies, pioglitazone was associated with bladder cancer in male rats (but not in female rats, mice dogs or monkeys). Because of this association, the Federal Drug Administration requested a large 10 year epidemiological study to evaluate whether there was an association between bladder cancer and exposure to pioglitazone in patients. A 5-year interim report published in 2011 showed no significant association between ever vs never exposure to the drug but a significant association in patients exposed to pioglitazone for > 2 years. Importantly, the final 10 year report did not confirm the 5 year interim report finding no association between bladder cancer and pioglitazone, even after > 4 years of exposure to the drug. However, as would be expected, following the 5-year interim report, many epidemiological studies were carried out and civil litigation lawsuits began to be filed.
Of the 23 epidemiological studies that have been published to date, 18 showed no association between bladder cancer and pioglitazone (5 with a combination of rosiglitazone and pioglitazone). Of the five that did show a significant association with pioglitazone, three could not be confirmed in the same population and in one of them there were significantly more risk factors for bladder cancer in the patients exposed to pioglitazone. In the fourth one, a significant association became non-significant when patients > 79 years were included. In the fifth one, detection bias was a major flaw. Currently, > 11,000 legal cases have been filed, many of which claim emotional distress due to the fear of bladder cancer. To limit their legal costs, the pharmaceutical company has established a 2.4 billion dollar settlement pool. So much for evidence-based medicine.
Positive and negative effects of glitazones in carcinogenesis: Experimental models vs. clinical practice
2014, Pathology Research and Practice
Citation Excerpt :
Another study from Taiwan found no significant association between pioglitazone use and bladder cancer, even in long-term and high-cumulative doses users [135]. A small retrospective Japanese study did not find increased risk of bladder cancer among pioglitazone users (9 cases of bladder cancer among a total of 663, HR 1.75, 95% CI 0.89–3.45), the risk was increased in patients taking pioglitazone for less than 24 months (5 cases of bladder cancer among a total of 425, HR 2.73, 95% CI 1.11–6.72), but all of these patients were long-term smokers or ex-smokers [57]. On the whole, even if pioglitazone was associated with higher bladder cancer incidence when administered at higher doses for longer periods, other risk factors (such as smoking or exposure to chemicals that might alter the risk) were not properly investigated in most studies and, therefore, clear link cannot be confirmed.
Diabetes increases cancer risk, which may be modulated by careful choice of treatment. Experimental reports showed efficacy of glitazones in various in vitro and in vivo models of carcinogenesis, but procarcinogenic effects in some models were reported too, and, similarly, data on cancer incidence in glitazone users are inconsistent. This review summarizes oncostatic effects of glitazones in preclinical and clinical studies and brings a brief summary of their impact on cancer risk in diabetic patients, with a focus on the association between pioglitazone use and bladder cancer.
Cancer biology in diabetes update: Focusing on antidiabetic drugs
2024, Journal of Diabetes Investigation
Pioglitazone, Bladder Cancer, and the Presumption of Innocence
2022, Current Drug Safety

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Brief reportPossible link of pioglitazone with bladder cancer in Japanese patients with type 2 diabetes

Abstract

Introduction

Section snippets

Materials and methods

Results

Discussion

Conflict of interests

Lancet

Diabetes Res Clin Pract

Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study

Diabetes Care

Pioglitazone and risk of bladder cancer among diabetic patients in France: a population-based cohort study

Diabetologia

Actos (Pioglitazone Hydrochloride) Tablets: Full Prescribing Information

Brief report
Possible link of pioglitazone with bladder cancer in Japanese patients with type 2 diabetes