The Association of Pioglitazone and Urinary Tract Disease in Type 2 Diabetic Taiwanese: Bladder Cancer and Chronic Kidney Disease

Abstract

ObjectiveAlthough studies have shown an association between pioglitazone and bladder cancer, the associated factors have not been identified. The aim of this study was to investigate the factors that may link pioglitazone to bladder cancer.Materials and MethodsIn total, 34,970 study subjects were identified from the National Health Insurance Research Database in 2003 with follow-up from 2005 to 2009. The demographic characteristics of patients who had used and had never used pioglitazone, including age, sex, diabetes duration, urinary tract disease, nephropathy, bladder cancer, and cumulative dose and duration of pioglitazone therapy, were analyzed using the χ2 test. Cox proportional hazard regression models were used to determine the independent effects of pioglitazone on bladder cancer and newly developed chronic kidney disease.ResultsAmong 3,497 ever users and 31,473 never users of pioglitazone, the respective incident cases of bladder cancer were 12 (0.4%) and 72 (0.2%), and for newly developed chronic kidney disease 245 (8.1%) and 663 (2.3%), respectively. Ever use of pioglitazone [1.59(1.32–1.91)], cumulative dose of pioglitazone <10,500 mg [1.69 (1.37–2.01)] and >10,500 mg [1.34 (1.04–1.73)], and duration of therapy <12 months [1.68 (1.36–2.08)] and >12 months [1.39 (1.09–1.76)] were associated with the development of chronic kidney disease.ConclusionsThere was no association of pioglitazone use with bladder cancer development, however, there was an association with an increased risk of newly developed chronic kidney disease.

A systematic review of observational studies of the association between pioglitazone use and bladder cancer

“…Hence, such time is misclassified and is referred to as 'immortal time'. In two out of seven studies with potential for immortal time bias we reported significant risk of bladder cancer [26,31]. We found potential for this bias in seven of the 20 studies (35%) we reviewed [22,23,26,27,31,33,35].…”

“…The problem is that people prescribed with different lines of treatment are unlikely to be at the same stage of disease and this, by itself, may confound the relationship with the outcome. We found potential for this bias in six studies [23][24][25][26]31,33]. We found potential for this bias in six studies [23][24][25][26]31,33].…”

“…This misclassification typically leads to a systematic bias toward a 'protective effect' of exposure. While the direction of the bias is unpredictable in the study by Neumann et al [26], it should be protective in the study by Lee et al [31] because the authors used fixed cohort entry with unexposed participants as the reference group. In the case of comparison of two drugs (e.g.…”

“…Two papers reported the findings of international multi-population studies [32,37]. In the primary analysis, adjusted for the greatest number of putative confounders, a risk effect of pioglitazone was obtained in four out of 12 studies [24,26,31,34] (Table 1 and Fig. Nine studies considered the effect of differential cumulative exposure and six considered the effect of differential cumulative dose.…”

The Importance of Reverse Translation for Preclinical Off-Target Mitigation: Quantification and Mitigation of Biases in the FDA Adverse Event Reporting System

“…Conversely, this signal is significantly underrepresented in the rosiglitazone reports (RRR = 0.12; q-value < 10 -5 ; see Figure B). There is evidence that non-selective PPAR agonists (α + γ) such as pioglitazone could contribute to carcinogenesis 32 , and a recent study linked bladder cancer to the development of chronic kidney disease as an effect of long term use of pioglitazone 33 . Still, the mechanisms linking the less selective pioglitazone but not the selective PPAR-γ agonist rosiglitazone to bladder cancer are unclear, and this association must remain tentative.…”