# Therapeutic Potential and Challenges of Pioglitazone in Cancer Treatment
## 4 Discussion  
Concerns have been raised regarding the elevated risk of bladder cancer, which has been reported since 2012. This can be attributed to overexpression of PPAR\(\gamma\), which is present in the urinary bladder and several other tissues. This adverse event is prevalent, especially in cases of prolonged pioglitazone administration, indicating a time-dependent and dose-dependent pharmacological profile. However, analysis does not suggest a strong dose-dependence relationship, since bladder cancer risk can be attributed to comorbidities and administration of antidiabetic drugs, such as metformin. Existing studies suggest a slightly, but significantly, elevated risk of bladder cancer associated with pioglitazone administration in a time- and dose-dependent manner [41]. This suggestion is confirmed by the cohort study conducted by [PERSON] et al. (2012), who initiated TZD or SU treatment in 18,459 and 41,396 T2 DM patients, respectively. Out of the 59,855 patients, 33,730 were males and 26,125 were females. Regarding bladder cancer incidence, 60 cases were reported in the TZD group and 137 cases were reported in the SU group. No difference was found between the two groups. Interestingly, in the TZD group long-term treatment (\(\geq\)5 years) was associated with an increased risk of bladder cancer, but not among those with shorter duration of exposure to TZDs. This observation was not limited only to pioglitazone, but may apply to other TZDs [159].  
Another cohort study which gathered data from the French national health insurance information system, indicates the time- and dose-dependent pharmacological profile of pioglitazone. The study included 155,535 T2 DM patients, out of whom 83,755 were males and 71,780 were females. The risk was increased by 75% for cumulative doses \(\geq\)28,000 mg over the span of \(\geq\)24 months. Analysis by sex revealed a significant association between pioglitazone and bladder cancer for males, but not for females [160]. This was contradicted by the meta-analysis of [PERSON] et al. (2018), who found no gender difference, though they did indicate a higher bladder cancer risk for Europeans versus US or Asian populations, which could be attributed to dissimilar genetic backgrounds or socioeconomic factors [161]. Lastly, it is important to acknowledge that T2 DM patients have an increased risk of bladder cancer at baseline. Other confounding factors, such as cigarette smoking, exposure to arylamines, and schistosomiasisonal infection, should be taken into consideration. Thus, it is plausible that the TZDs may exacerbate a pre-existing high-risk state of T2 DM patients [162].  
Due to the structure of these studies, there is no conclusive data regarding the risk-benefit ratio of pioglitazone. To date, there is no study that proves the direct cause-effect relationship between pioglitazone and bladder cancer [41].  
Similar concerns have been raised regarding the association of metformin with risk of bladder cancer. While metformin does not decrease bladder cancer risk, it improves clinical parameters such as recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS) [121]. Although no effect was reported between overall survival (OS) and bladder cancer, studies show a positive outlook [122]. Another meta-analysis conducted in bladder cancer patients showed neither a protective nor a harmful effect of metformin exposure [123]. Few reports indicate decreased bladder cancer risk in metformin users versus never-users. However, the link between metformin and bladder cancer risk is not clear due to co-administration of other drugs and small proportion of metformin users versus never-users [124]. Overall, meta-analyses show no association of metformin with bladder cancer risk. Considering that these studies are limited to T2 DM or bladder cancer patients, a consensus cannot be drawn regarding the risk of bladder cancer in the general population.