Actos is in the news again with a study published in the British Medical Journal that showed a link between the diabetes drug and an increased risk of bladder cancer among type 2 diabetics. These data piggyback on previous trials spawned by the FDA that also found a slight increase in risk. Risk doubled when patients were exposed to pioglitazone for more than two years.
This is not the first time this class of drug—thiazolidinediones or TZDs—has been in the hot seat. In fact, GlaxoSmithKline’s Avandia (rosiglitazone) also received flak when it was found to be associated with cardiovascular risk. But Actos may not be far behind, as a recent study showed that rosiglitazone and pioglitazone (Actos, Takeda) had similar risk of MI, heart failure or death.
Now, Laurent Azoulay, associate professor at the Jewish General Hospital in Montreal, and colleagues have found pioglitazone to be associated with an increased risk of bladder cancer in type 2 diabetics after they conducted a retrospective cohort study of more than 600 practices in the U.K.
The study included 115,727 type 2 diabetic patients who were treated with oral hypoglycemic agents between Jan. 1, 1988, and Dec. 31, 2009. Of the patient cohort, 67 percent received metformin monotherapy, 30 percent received sulfonylurea monotherapy and 0.5 percent received TZD monotherapy. The duration of pioglitazone use among the controls was 2.2 years and the duration for rosiglitazone was 2.3 years.
The researchers reported 470 patients with a diagnosis of bladder cancer during the 536,559 person-year follow-up; the overall rate for bladder cancer was 89.4 per 100,000 person years. The incidence rate of bladder cancer in the U.K. population was 73 per 100,000 person-years in 2008.
“The higher incidence rate observed in our cohort is consistent with data suggesting an association between type 2 diabetes and an increased risk of bladder cancer,” the authors wrote. They said that pioglitazone use was associated with an 83 percent increased rate of bladder cancer. “For cumulative dosage, a statistically significant association was observed in patients who received more than 28,000 mg,” the authors wrote.
The researchers did not find the same link for rosiglitazone, suggesting that this was a drug-specific effect. Additionally, the highest risk was found to be in patients who received pioglitazone for more than 24 months.
These findings are not surprising, as Actos made news in September 2010 when FDA cautioned that the drug could increase a patient's risk of bladder cancer after the agency received a 10-year observational study. The FDA added the warnings to the drug’s label, and made revisions to the Medication Guide.
An FDA expert review found that patients on pioglitazone for more than 12 consecutive months had a 40 percent increased risk for bladder cancer when compared to those never exposed to the drug. However, the current study showed an even higher risk, an 83 percent increased risk of bladder cancer for patients administered pioglitazone.
In an accompanying editorial, Dominique Hillaire-Buys and Jean-Luc Faillie, of Centre Hospitalier Regional Universitaire in Montpellier in France, wrote "Taking into account Azoulay and colleagues’ current findings and given the consistency of these results, the relative strength of the association, the dose-response effect, the known pharmacodynamic characteristics of pioglitazone, and evidence of a significant association in a meta-analysis of randomised trials, it can confidently be assumed that pioglitazone increases the risk of bladder cancer."
Additionally, the editorialists said that this association could have been predicted earlier. "Worldwide, exposure to pioglitazone is estimated to be more than 20 million patient years," they wrote. Lastly, they offered that the benefit in reducing cardiovascular events is "questionable." Hillaire-Buys and Faillie said that clinicians should be questioning the benefit-risk ratio of pioglitazone and whether it is still beneficial for their diabetic patients.
The authors noted that “while the magnitudes of the rate ratios were relatively high, the risks associated with pioglitazone are in absolute terms low.” Doctors, patients and regulatory agencies should be made aware of this association when looking at the overall risks and benefits of pioglitazone, the authors summed.