Patients who take the diabetes drug pioglitazone are at increased risk of bladder cancer, according to the findings of a large population-based study. The risk rises with longer duration of use and increasing cumulative dose.

In a large population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink, the incidence of bladder cancer was significantly higher among users of pioglitazone—a thiazolidinedione drug—rather than diabetes drugs other than thiazolidinediones (121 vs. 88.9 cases per 100,000 person-years), a difference that translated into a 63% increased risk of bladder cancer associated with pioglitazone use.

Use of pioglitazone for 1 year or less, 1–2 years, and more than 2 years was associated with a 33%, 66%, and 78% increased risk of bladder cancer, respectively. A cumulative dose of 10,500 mg or less, 10,500–28,000, and more than 28,000 mg was associated with a 63%, 58%, and 70% increased risk of bladder cancer, respectively.

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Rosiglitazone, another thiazolidinedione drug, was not associated with an increased risk of bladder cancer. “The absence of an association with rosiglitazone suggests that the increased risk is drug specific and not a class effect,” Marco Tuccori, MD, of Jewish General Hospital in Montreal, Canada, and colleagues concluded in a paper published online in the British Medical Journal.

In addition, compared with rosiglitazone, pioglitazone was associated with a 48% increased risk of bladder cancer in adjusted analyses.

The study included a cohort of 145,806 patients newly treated with antidiabetes drugs from January 1, 2000 to July 31, 2013. During a mean follow-up of 4.7 years (689,616 person-years of follow-up), 622 patients received a diagnosis of bladder cancer (crude incidence rate of 90.2 per 100,000 person-years).

Given the similarities between pioglitazone and rosiglitazone, the authors noted, “it is unlikely that confounding by indication or detection bias can explain the association observed with pioglitazone.”

Although the biological mechanism by which pioglitazone might increase bladder cancer is not clear, “this imbalance in the risk of bladder cancer between these two thiazolidinediones could likely be explained by pharmacological differences,” they wrote.

Rosiglitazone is selective for the peroxisome proliferator activated receptor (PPAR) gamma, whereas piogliazone has dual PPAR-alpha and PPAR-gamma activity, which in rats has been shown to increase expression of carcinogenic biomarkers in the bladder, the authors explained. This has not been seen with selective activation of PPAR-gamma.

Studies of the association between pioglitazone and bladder cancer have been contradictory. The IRIS [Insulin Resistance Intervention after Stroke] trial, published recently in the New England Journal of Medicine (2016;374:1321-1331), which randomized 3,895 individuals without diabetes to either pioglitazone or placebo, found an increased number of new bladder cancers in the pioglitazone group compared with the placebo group—12 (0.6%) vs. 8 (0.4%)—but the difference was not statistically significant. A 10-year observational follow-up study of patients who completed the PROactive trial found that pioglitazone users had a 35% decreased risk of bladder cancer and a 47% increased risk of prostate cancer (PCa) compared with placebo recipients, according to a report in Diabetes, Obesity & Metabolism (2016;18:266-273). The researchers noted, however, that “these imbalances should be interpreted with caution because of the limitations of the observational study design.”

In the Journal of the American Medical Association (2015;314:265-277), researchers reported on a study of 193,099 patients with diabetes showing no significantly increased risk of bladder cancer associated with pioglitazone use, although pioglitazone use was associated with an increased risk of PCa and pancreatic cancer. The study included 34,181 patients who received pioglitazone for a median duration of 2.8 years.

Commenting on the study by Dr. Tuccori and colleagues, Connie M. Rhee, MD, a nephrologist at the University of California Irvine who has studied the adverse effects of antigylcemic agents, stated that the study findings were robust across an extensive number of sensitivity analyses. Other strengths, she pointed out, included incorporation of a lag period between pioglitazone initiation to the commencement of at-risk time, as short-term pioglitazone use is unlikely to cause incident bladder cancer. In addition, the study excluded prevalent pioglitazone users (given that the study did not capture patients who died or had adverse effects from pioglitazone), which could bias towards a protective association, she said.

She noted that potential limitations, which the authors acknowledged, include residual confounding and misclassification of pioglitazone exposure and bladder events in the clinical database.