The safety of pioglitazone, an oral anti-diabetic agent in the thiazolidinedione class, is controversial. Although pioglitazone is effective at reducing glycated hemoglobin (HbA1c) levels and may decrease the risk of cardiovascular events [1,2], it has also been associated with weight gain and an increased risk of congestive heart failure [1]. Although data are limited, there is now some evidence suggesting that pioglitazone may be associated with an increased risk of bladder cancer. A recent observational study [3] using the Kaiser Permanente Northern California diabetes registry data found that, among 193,099 diabetic patients who were ≥40 years old, use of pioglitazone at any time (n = 30,173) was not associated with the risk of bladder cancer (adjusted HR: 1.2; 95% CI: 0.9–1.5). However, long-term use of pioglitazone (>24 months of therapy) was associated with an increased risk of bladder cancer (adjusted HR: 1.4; 95% CI: 1.03–2.0). More recent data from observational studies show relative risks (RRs) ranging from 1.12 to 1.33 when diabetic patients receiving pioglitazone are compared with diabetic patients receiving other antidiabetic medicines but not exposed to pioglitazone [4]. Two studies have been reported from England: one suggested an association between pioglitazone and the risk of bladder cancer [5], while the other did not [6]. Two subsequently published Taiwanese studies and one Korean study found no significant association between pioglitazone and bladder cancer [7-9]. Thus, this relationship remains controversial.

Only one study in Japan investigated the risk of bladder cancer with pioglitazone use [10]. In our hospital, half of the patients with type 2 diabetes mellitus (T2DM) were treated by pioglitazone to prevent cardiac or cerebral vascular events. Most pioglitazone was prescribed by cardiologists. Therefore, it seems that this situation facilitated an assessment of the relationship between pioglitazone and bladder cancer. Therefore, the data of diabetic patients treated at Teikyo Chiba Medical Center were retrospectively analyzed.

The frequency of bladder cancer in patients with T2DM treated with any medication from February 2009 to October 2011 was retrospectively examined using the computerized medical records system in our hospital. This system was started from February 2009. A total of 720 patients had been treated with pioglitazone, and 742 patients had not during this period. We could access past use of pioglitazone before January 2009, only 248 patients. The numbers of newly diagnosed bladder cancers during the period up to December 2013 in these patients and the occurrence of bladder cancer in T2DM patients were identified. The occurrence of bladder cancer was defined as incident cases after the initiation of pioglitazone. The ratio of cases was calculated, and significance was analyzed using Fisher’s exact test. The risk of bladder cancer with several diabetes medicines was calculated by multivariate logistic regression analysis. The study was approved by the Hospital Ethics Committee.

The patients’ characteristics are shown in (Table 1). There were no differences in patients’ age and sex between those treated with pioglitazone and those not. A total of 720 patients (49.6%) were treated with pioglitazone. Most patients were treated with two or more drugs. Alpha-glycosidase inhibitors (AGIs), biguanides, meglitinides, D-phenylalanine derivatives, and sulfonylureas were used significantly more in the pioglitazone group than in the no pioglitazone group. However, insulin was used significantly more in the no pioglitazone group than in the pioglitazone group.

Table 1: Patients’characteristics. There are no differences in age, sex, and incidence of bladder cancer between patients treated with pioglitazone and patients treated with other antidiabetic drugs.

The incidence of bladder cancer was not different between the groups 15/720 [2.0%] in the pioglitazone group and 14/742 [1.9%] in the no pioglitazone group) (Figure 1). There is no difference in tumor characteristics between two groups. (pioglitazone group: G1 is 0, G2 is 8 and G3 is 7, no pioglitazone group, G1 is 1, G2 is 5 and G3 is 5, unknown is 3, p=0.2732, pioglitazone group: PT2 or more is 3, pT1 is 9, pTa is 3, no pioglitazone group:, pT2 or more is 4, pT1 is 5, pTa is 5, p=0.2505). However, a very high incidence of bladder cancer was seen in diabetic patients. Male sex was associated with a high risk of bladder cancer in diabetic patients (HR: 6.001; 95% CI: 1.397–43.06; p=0.0137) (Table 3).

Table 3: Bladder cancer risk and age, sex, smoking, and duration of diabetes.

Figure 1: Occurrence of bladder cancer in patients treated with pioglitazone and patients treated with other antidiabetic drugs.

No oral diabetes medication was related to the risk of bladder cancer, but insulin use was significantly related to bladder cancer risk (HR: 2.83; 95% CI: 1.15–6.84; p=0.0246) (Table 2).

Table 2: Bladder cancer risk and antidiabetic drugs. Pioglitazone use is not related to bladder cancer.

Duration of diabetes and history of smoking were not associated with bladder cancer risk. However, the duration of diabetes was known in only 248 patients, and history of smoking was known in only 271 patients.

Bladder cancer is the 5th most common cancer in the United States [11], the 7th most common cancer worldwide [12], and the 9th most common cancer in Japan [13]. Known risk factors include age, sex (male), ethnicity/race (white), smoking, and several occupations, particularly those involving exposure to aromatic amines [14]. Evidence is accumulating that diabetes may be related to the risk of several cancers, including a reduced risk for prostate cancer [14] and increased risks for cancers of the pancreas, liver, colon, and breast [15,16], but the evidence is not as clear for bladder cancer. A meta-analysis published in 2006 suggested that diabetic patients had a slightly elevated risk of bladder cancer relative to non-diabetic patients [17]. One metaanalysis in 2013 found that diabetic patients had a slightly elevated risk of bladder cancer (HR: 1.11; 95% CI: 0.95–1.31; p<0.001) [18], and another meta-analysis indicated a relationship between bladder cancer and diabetes (HR: 1.29; 95% CI: 1.08–1.54; p=0.0000) [19]. In the present study, the risk of bladder cancer was high in diabetic patients, especially in males. About 2% of diabetic patients had a bladder cancer.

Thus, diabetes is associated with bladder cancer. It is important to investigate the relationship between anti-diabetic drugs and bladder cancer. The present study found a relationship between insulin use and bladder cancer. The elevation of insulin and insulin-like growth factor-1 and their role as mitogens is the mechanism cited most often to explain the association between diabetes and cancer risk [20,21]. A single case-control study has found higher circulating levels of these factors in bladder cancer cases than in controls [22].

Newton et al. reported that there were no associations between T2DM and the overall risk of bladder cancer (RR =1.01; 95% CI: 0.87– 1.17), noninvasive disease (RR = 0.93; 95% CI: 0.76–1.14), or invasive disease (RR = 1.13; 95% CI: 0.91–1.40). Compared to participants without T2DM, the risk of invasive bladder cancer was higher among participants who had had T2DM for >15 years (RR = 1.63; 95% CI: 1.09–2.43) and among those using insulin (RR 5 1.64; 95% CI: 1.18– 2.27) [23]. It is, therefore, important to investigate the relationship between insulin use and the risk of bladder cancer.

In the present study, there was no relationship between pioglitazone use and bladder cancer risk, despite the fact that half of the patients were treated with pioglitazone. All Asian studies reported that pioglitazone was not associated with bladder cancer risk [7-10], possibly because the incidence of bladder cancer in East Asian countries is lower than that in Western Europe and North America [12]. An 8-year long observational study [24] using the Kaiser Permanente Northern California diabetes registry data found that use of pioglitazone at any time (n= 30,173) was not associated with the risk of bladder cancer (adjusted HR: 1.07; 95% CI: 0.87–1.3), and long-term use of pioglitazone (>48 months of therapy) was not associated with an increased risk of bladder cancer (adjusted HR: 1.30; 95% CI: 0.91–1.86). However, that was an 8-year interim analysis. Any formal conclusions of the KPNC study should be reserved until the study is fully completed.

Morgan et al. reported that metformin with pioglitazone reduced cardiovascular events [25]. There is an abundance of evidence from randomized, controlled trials demonstrating the cardiovascular protective effects of pioglitazone [2,26,27], especially in patients who have already had a myocardial infarction or stroke [26]. In our hospital, many patients with T2DM had cardiovascular disease, and they took pioglitazone to prevent further cardiovascular events.

The limitation of this study is that it was a small, retrospective study. The duration of diabetes was known in only 248 patients, and history of smoking was known in only 271 patients. Because we access the computed medical record system from 2009 February. In almost cases, we could not access the data before 2009 February. Thus we could not clarify the duration of treatment for diabetes. However, this study showed that insulin use might be related to bladder cancer risk in T2DM patients, and pioglitazone was not related to bladder cancer. Further study is necessary to investigate the relationship between pioglitazone and bladder cancer risk.