The diabetes medications pioglitazone (Actos) and rosiglitazone (Avandia) do not appear to be associated with bladder cancer, according to a study of more than one million people published in Diabetologia.
Bladder tumors overexpress a transcription factor called peroxisome proliferator-activated receptor gamma (PPAR-gamma) found in the lining of the urinary tract. Pioglitazone and rosiglitazone are both thiazolidinediones (TZDs), a class of drugs that act as PPAR-gamma agonists.
Preclinical studies, however, have shown that male rats overexposed to pioglitazone had an increased risk for bladder cancer. Further, observational studies have suggested an increased bladder cancer risk in patients taking pioglitazone, according to information in the background article.
These data subsequently led to the withdrawal of the drug from the market in France and Germany. In the same vein, the FDA and European Medicines Agency (EMA) advised against pioglitazone’s use in people with current or previous bladder cancer.
“The evidence on the association between pioglitazone use and bladder cancer is contradictory, with many studies subject to allocation bias,” the researchers wrote. “The aim of our study was to examine the effect of exposure to pioglitazone on bladder cancer risk internationally across several cohorts.”
The potential for allocation bias in this study was minimized by “focusing on the cumulative effect of pioglitazone as the primary endpoint using a time-dependent approach,” according to the researchers.
For the study, Samira Bell, MD, of Ninewells Hospital and Medical School in the United Kingdom, and colleagues evaluated prescription, cancer and mortality data on people with type 2 diabetes from six populations worldwide: British Columbia, Canada; Finland; Manchester, United Kingdom; Rotterdam, Netherlands; Scotland; and the U.K. Clinical Practice Research Datalink.
The researchers then modeled the effect of cumulative drug exposure on bladder cancer incidence using data from each center. Data were collated on 1.01 million people over 5.9 million person-years.
During a median follow-up of 4.0 to 7.4 years, a total of 3,248 cases of incident bladder cancer occurred, with only 117 cases in patients exposed to pioglitazone, according to the study results.
After adjustment for age, calendar year, diabetes duration, smoking and any use of pioglitazone, the researchers found no evidence of an association between cumulative exposure to pioglitazone and bladder cancer in men (rate ratio per 100 days of cumulative exposure [RR]=1.01; 95% CI, 0.97-1.06) or women (RR=1.04; 95% CI, 0.97-1.11).
Similarly, no association between rosiglitazone exposure and bladder cancer was found in men (RR=1.01; 95% CI, 0.98-1.03) or women (RR=1.00; 95% CI, 0.94-1.07).
When evaluating a potential dose–response relationship, the researchers found that bladder cancer risk did not increase with longer exposure to pioglitazone.
“In summary, our large international analysis did not support a causal effect of pioglitazone on bladder cancer, thus contradicting previous studies deemed to have proven this relationship,” the researchers wrote. “To fully resolve this controversy, future analyses are needed, involving longer follow-up of exposed persons and using methods to minimize allocation bias.”