In a new, large, population-based study, the antidiabetic thiazolidinedione pioglitazone (Actos, Takeda) was associated with a 63% increased risk of bladder cancer in as many as 14.5 years of follow-up, and, moreover, the risk increased with longer treatment and higher doses.
In contrast, the thiazolidinedione rosiglitazone did not have this effect, which suggests that the risk of bladder cancer is specific for pioglitazone and is not a drug class effect, Dr Marco Tuccori, from McGill University, in Montreal, Quebec, and colleagues report in an article published online March 30, 2016, in the BMJ.
Since the PROactive randomized controlled trial unexpectedly showed an imbalance in the number of cases of bladder cancer with pioglitazone compared with placebo, the link between pioglitazone and this outcome has been controversial, senior author Dr Laurent Azoulay, from McGill University, explained.
Studies have shown an increased risk at 5 years and a "surprising" lack of signal at 10 years, he noted, but this may have been due to shortcomings in the methods used. "We used robust methodology to try to address the potential biases and observed quite consistent results," he said.
Importantly, they also showed that in a head-to-head comparison, pioglitazone was associated with a 50% increased risk of bladder cancer compared with rosiglitazone — which might be explained by different biological mechanisms of action.
"A substantial and fairly consistent body of evidence supports the notion that pioglitazone use is associated with an increased risk of bladder cancer," and now this study "confirms these results," Dr Victor M Montori, from the Mayo Clinic, in Rochester, Minnesota, writes in an accompanying editorial. "Controlling for the effect of the duration and severity of diabetes by exploring the same link with rosiglitazone strengthened their findings," he added.
Newer second- and third-line antidiabetic agents might have a better risk/benefit profile, Dr Azoulay suggested. Together with clinicians, "patients can identify the agent that is best for them given their context, both clinical and personal," Dr Montori adds.
The findings from the PROactive trial were corroborated by some but not all observational studies, Azoulay explained. In 2011, researchers published the 5-year interim results from an FDA-mandated study that was based on data from the Kaiser Permanente Northern California database, which showed that there was a 40% increased risk of bladder cancer after 2 years of use of pioglitazone.
But in the analysis of the final 10-year data, which was published in July 2015, "it was quite surprising to see that the signal that they had observed completely disappeared," although the researchers did acknowledge that "they couldn't exclude a small, increased risk" of bladder cancer with pioglitazone use, he added.
To investigate this risk, Tuccori et al conducted a population-based cohort study using data from the United Kingdom Practice Research Datalink. They identified 145,806 patients age 40 or older who received a first-ever prescription for a noninsulin antidiabetic drug between January 1, 2000 (after pioglitazone and rosiglitazone were introduced into the UK market) and July 31, 2013. Patients who started or added a new antidiabetic drug or switched to a new drug were included, and patients with bladder cancer were excluded.
During a follow-up to 14.5 years, 622 patients were diagnosed with bladder cancer, which developed after a median of 4.4 years.
The researchers developed risk models that were adjusted for multiple confounders including age, sex, year of study entry, body mass index, alcohol-related disorders, HbA1c levels, duration of treated diabetes, and previous bladder conditions.
Compared with other antidiabetic drugs, pioglitazone was associated with a 63% increased risk of bladder cancer (121 cases per 100,000 person-years vs 89 cases per 100,000 person-years; hazard ratio [HR], 1.63; 95% confidence interval [CI], 1.22–2.19).
However, the use of rosiglitazone was not associated with an increased risk of bladder cancer (86 cases per 100,000 person-years vs 89 cases per 100,000 person-years; HR, 1.10; 95% CI, 0.83–1.47)
The risk of bladder cancer was increased after 1.8 years of pioglitazone use and continued to increase with longer duration, but this did not achieve statistical significance due to a relatively small number of events in patients with longer use. Cumulative doses of less than 10,500 mg or more than 28,000 mg were also associated with increased risk of bladder cancer.
"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," Dr Montori writes.
According to Azoulay, the benefits of pioglitazone are unclear, whereas the drug has known potential risks of fractures, cardiovascular events, and now bladder cancer. "So it seems that the pendulum is tilting more toward risk than benefit." There are newer options for second- and third-line treatment for diabetes, such as the incretins, "which will have to go through the same scrutiny, but for now appear to be relatively safe," he noted.
This study was funded by the Canadian Institutes of Health Research. The authors and editorialist have no relevant financial relationships.