Pioglitazone and Bladder Cancer

CONCLUSIONS

An insignificant 30% increase in overall risk was observed in the full model (Table 1), which is a result similar to those of the KPNC study (4); however, the HR was attenuated in the model adjusting only for previously identified risk factors (6), which suggests overfitting in the full model.

Although not significant, an increase in risk was observed for time since starting pioglitazone <36 months, duration of therapy <12 months, and cumulative dose <10,500 mg (Table 1). Interestingly, 80% of incident bladder cancers occurred among patients who had <1 year of pioglitazone at baseline and no cancers occurred among those with >2 years at baseline. Unclear is whether this increased risk during the first year at baseline was the result of an early pioglitazone effect on bladder cancer or its late use in patients at high risk for bladder cancer. The lower risk with prolonged use (i.e., time since starting pioglitazone >36 months or duration of therapy >12 months) and cumulative dose >10,500 mg (Table 1) might be a chance effect, as the number of events was very small.

Pioglitazone is a third-line oral antidiabetes medication in Taiwan indicated for treatment of patients with longer diabetes duration or more comorbidities/complications. All of these factors could predispose patients to bladder cancer (6). Because metformin may prevent but insulin might promote some cancers (11,12), their interactions with pioglitazone require investigation.

These results differ from those in whites (4), possibly because of differences in genetic background, diet, socioeconomic status, or cultural background or because the present analysis was underpowered.

We did not analyze time-dependent pioglitazone use because it might have caused bias (13). Furthermore, the 2007 report of an association between rosiglitazone and acute myocardial infarction (14) might have markedly changed prescription practices of physicians, and patients might not have taken thiazolidinediones, including pioglitazone, even when they were prescribed. However, the present findings were unchanged when patients who started pioglitazone after the entry date were excluded from the analyses or when their follow-up was censored at pioglitazone initiation (data not shown).

This study has several strengths. It is population based, with a large, nationally representative sample. Cancer is considered a severe morbidity by the NHI, and most copayments are waived. Therefore, the detection rate is not likely to differ by socioeconomic class. The use of medical records reduced self-report bias.

Study limitations include the lack of actual measurements for confounders such as biochemical data, obesity, smoking, lifestyle, diet, occupational exposure, and genetic parameters. In addition, the underpowered analyses require confirmation.

In summary, there was an insignificant 30% overall increase in bladder cancer risk among pioglitazone users. However, all bladder cancer occurred within 2 years of the start of therapy and no patients with a cumulative dose >28,000 mg developed bladder cancer, which suggests an early effect of pioglitazone on bladder cancer or late pioglitazone use in patients with a high risk of bladder cancer.