The diabetes drug pioglitazone was associated with an increased risk for bladder cancer among patients with type 2 diabetes, according to the results of a new study. The increased risk seems to be specific to this drug and not associated with the drug class, as a similar drug, rosiglitazone, was not linked with any increased risk.
“Of note, although the biological mechanism for pioglitazone induced bladder cancer is not clear, this imbalance in the risk of bladder cancer between these two thiazolidinediones could likely be explained by pharmacological differences,” researchers led by Marco Tuccori, of Jewish General Hospital, Montreal, wrote in BMJ.
“Indeed, unlike rosiglitazone, which is selective for the peroxisome proliferator activated receptor (PPAR) Î³, pioglitazone has a dual PPARÎ±/Î³ activity. This is particularly important, as PPARÎ±/Î³ activation in rat models has been shown to increase the expression of carcinogenic biomarkers in the bladder, which has not been observed with the selective activation of PPARÎ³,” they wrote.
The large study looked at 145,806 patients newly treated with anti-diabetes drugs between 2000 and 2013. During the follow-up period, the researchers identified 622 patients with newly diagnosed bladder cancer.
Use of pioglitazone was associated with a 63% increased risk for developing bladder cancer compared with other diabetes drugs (hazard ratio [HR], 1.63 [95% CI, 1.22–21.9]). The incidence rate for bladder cancer in patients using pioglitazone was 121 per 100,000 person years compared with 88.9 per 100,000 person years among patients not taking a thiazolidinedione.
Tuccori and colleagues evaluated this association further and found a duration-response relationship with the use of pioglitazone for more than 2 years associated with increased risk for bladder cancer (HR, 1.78 [95% CI, 1.21–2.64]). An increased risk for bladder cancer emerged after 1.8 years use of pioglitazone, with the risk continuing to increase with longer duration of use. However, the researchers noted that this relationship “did not achieve statistical significance owing to a relatively small number of events among patients with longer duration of use.”
In addition, the researchers also found that cumulative doses less than 10,500 mg (HR, 1.63 [95% CI, 1.02–2.60]) and greater than 28,000 mg (HR, 1.70 [95% CI, 1.04–2.78]) were associated with an increased risk for bladder cancer.
In contrast, use of the thiazolidinedione rosiglitazone was not associated with any increased risk for bladder cancer. The incidence rate for bladder cancer was 86.2 per 100,000 person years compared with 88.9 per 100,000 person years for patients not taking a thiazolidinedione.
In an editorial that accompanied the article, Victor M. Montori, of Mayo Clinic, Rochester, Minnesota, wrote that this new data complicates the decision of whether or not to use pioglitazone in patients with type 2 diabetes.
“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.