Diabetes drug pioglitazone increases risk for bladder cancer

Patients taking pioglitazone for type 2 diabetes demonstrated an increased risk for bladder cancer, according to results of a population-based cohort study.

However, researchers observed no correlation between bladder cancer risk and rosiglitazone use, despite that both drugs are in the thiazolidinedione class.

In 2005, results of the PROactive trial showed an imbalance in the incidence of bladder cancer between patients assigned pioglitazone and placebo. However, these results were replicated in some, but not all, observational studies.

“Given these discrepant findings, the methodological shortcoming of previous studies examining this association and the apparent loss of an association in studies with longer follow-up, additional studies are needed to investigator further the association between pioglitazone and bladder cancer,” Marco Tuccori, PhD, postdoctoral fellow in the center for clinical epidemiology at the Lady Davis Institute of Jewish General Hospital in Quebec, Canada and in the department of epidemiology, biostatistics and occupational health at McGill University, and colleagues wrote.

Tuccori and colleagues used general practice data from the United Kingdom Clinical Practice Research Datalink to identify 145,806 patients (mean age, 63.7 years; 56.8% men) newly treated for type 2 diabetes. Researchers excluded patients prescribed insulin prior to their noninsulin antidiabetic drug prescription.

At baseline, 921 patients used pioglitazone whereas 142,758 patients used no thiazolidinedione drug.

Mean follow-up was 4.7 years, or 689,616 person-years.

Overall, 622 patients received a bladder cancer diagnosis during follow-up for an incidence rate of 90.2 (95% CI, 83.2-97.6) per 100,000 person-years. Median time between study entry and bladder cancer diagnosis was 4.4 years (interquartile range, 2.5-6.5).

Results showed pioglitazone increased risk for incident bladder cancer (121 vs. 88.9 per 100,000 person-years; adjusted HR = 1.63, 95% CI, 1.22-2.19). Researchers observed a duration–response relationship, where pioglitazone use for more than 2 years increased bladder cancer risk (adjusted HR = 1.78; 95% CI, 1.21-2.64).

Further, there appeared to be a dose–response relation, where cumulative doses of less than 10,500 mg (adjusted HR = 1.63, 95% CI, 1.02-2.6) and more than 28,000 mg (adjusted HR = 1.7; 95% CI, 1.04-2.78) increased risk for bladder cancer.

Researchers conducted a secondary analysis that included a subcohort of patients who initiated pioglitazone (n = 10, 591) or rosiglitazone (n = 13,946) at any time from January 2000 to July 2013.

In this analysis, the association with pioglitazone and bladder cancer persisted (adjusted HR = 1.64; 95% CI, 1.23-2.2). By comparison, the use of rosiglitazone did not appear to increase risk for bladder cancer (86.2 vs. 88.9 per 100,000 person-years; adjusted HR = 1.1, 95% CI, 0.83-1.47).

The researchers acknowledged that the study did not account for some variables associated with cancer risk including diet, physical activity, occupational exposure, pelvic radiation, family history of cancer and race or ethnicity.

“These results may have implications for prescribing, and suggest doctors and patients should be aware when assessing the overall risks and benefits of diabetes drugs,” researchers wrote.

More data are needed to determine how to incorporate these findings into clinical practice, Victor M. Montori, MD, professor of medicine at Mayo Clinic in Rochester, Minnesota, wrote in an accompanying editorial

“The problem now is whether the increased likelihood and undesirability of bladder cancer (which remains rare) justify withholding pioglitazone from adults with type 2 diabetes given the benefits (such as stroke prevention) and potential harms (such as weight gain, heart failure, bone fractures) associated with its use, and the relative efficacy and safety of alternatives,” he wrote. “This is the kind of consideration that complicates the treatment of diabetes and demands reliable evidence of comparative effectiveness and safety.” – by Nick Andrews

Disclosure: The researchers report no relevant financial disclosures.