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Bladder Cancer Link Seen Again With A Diabetes Drug

While the risk remains low overall, a new large study showed a greater risk for pioglitazone than other diabetes drugs.

Researchers looked at about 146,000 patients in the U.K. who had recently started taking an anti-diabetic drug; those on pioglitazone faced an increased risk of bladder cancer of 121.0 versus 88.9 per 100,000 person-years among those on other diabetes drugs (hazard ratio 1.63, 95% CI 1.22-2.19). Fifty-four patients receiving pioglitazone were diagnosed with cancer after a mean follow-up of 4.7 years.

According to lead author Marco Tuccori, PhD, at the Jewish General Hospital in Montreal, Canada, the increased risk was not a class effect. But those on rosiglitazone (Avandia) didn’t see an increased risk of bladder cancer (HR 1.10, 95% CI 0.83-1.47).

Last year, Actos manufacturer Takeda agreed to pay $2.4 billion to settle lawsuits alleging that it hid from patients bladder cancer risks associated with the drug.

Pioglitazone, an antidiabetic drug belonging to the thiazolidinedione class, has been shown to improve glycemic levels in people with type 2 diabetes. However, in 2005, the PROactive randomized controlled trial unexpectedly showed an imbalance in the number of cases of bladder cancer with pioglitazone compared with placebo. In contrast, this imbalance was never observed in randomized controlled trials of rosiglitazone, the other approved drug belonging to the thiazolidinedione class.

The findings of the PROactive trial were subsequently corroborated in some, but not all, observational studies. Indeed, in the five-year interim analysis of a large observational study using the Kaiser Permanente Northern California database, the use of pioglitazone for 24 months or more was associated with an increased risk of bladder cancer (hazard ratio 1.4, 95% confidence interval 1.03 to 2.0). However, in the final analysis of the Kaiser Permanente Northern California study, which used the same cohort with follow-up extended to 10 years, the use of pioglitazone was no longer significantly associated with an increased risk of bladder cancer in a duration-response fashion. These null findings are also consistent with those of another large multicohort study. The apparent heterogeneity in this literature may be due to methodological limitations.

Given these discrepant findings, the methodological shortcoming of previous studies examining this association, and the apparent loss of an association in studies with longer follow-up, additional studies are needed to investigate further the association between pioglitazone and bladder cancer. In a large, population-based study, the associations was assessed between the use of pioglitazone and bladder cancer in people with type 2 diabetes.

The new study is the latest in a long-running seesaw drama, with one study identifying an increased bladder cancer risk with the drug, only to be followed by another showing no link.

The latest results support findings from a 2005 trial that found a heightened risk of bladder cancer for those on pioglitazone versus placebo. But last year, a study published in the Journal of the American Medical Association found no association between the two, for example.

Silvio Inzucchi, MD, at the Yale School of Medicine, said he still considers that JAMA study to be the definitive one in this area.  He added that, “It’s interesting to note that the sum total of bladder cancer events in the pioglitazone-treated patients was only 54 [in the BMJ study and,] given such small numbers, any modest changes in the underlying risk for bladder cancer could have a big impact on measured incidence rates.”

The JAMA study, on the other hand, analyzed a larger number of cases (n=1,261) and had a longer duration of follow-up (with a median of 7.3 years), he pointed out.

Inzucchi also noted that in the BMJ study, pioglitazone patients “tended to be older, had worse diabetes control, had a greater likelihood of previous bladder conditions, and had more urine testing.” He added that those factors, rather than the drug itself, could have been determining factors in bladder cancer diagnosis. (Tuccori and colleagues adjusted for age, HbA1c, and presence of bladder conditions, as well as certain other factors, in their statistical analyses.)

But there’s still a “substantial and fairly consistent body of evidence” that supports the link between bladder cancer and pioglitazone, according to Victor Montori, MD, at the Mayo Clinic in Rochester, Minn. “By some accounts, the association between pioglitazone and bladder cancer should be added to the long list of suppressed information about harm that would have affected the informed use of a drug during its patent protected life,” he wrote in an accompanying editorial.

In conclusion, the results of this large population-based study indicate that pioglitazone is 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.

Practice Pearls:

  • Out of 146,000 patients, 54 receiving pioglitazone were diagnosed with cancer after a mean follow-up of 4.7 years.
  • Patients should be educated as to the possible risk of bladder cancer, even though it is thought to be low.
  • There is a substantial and fairly consistent body of evidence that supports the link between bladder cancer and pioglitazone.

Researched and prepared by Steve Freed, BPharm, Diabetes Educator, Publisher and reviewed by Dave Joffe, BSPharm, CDE

 

Tuccori, M “Pioglitazone use and risk of bladder cancer: population based cohort study” BMJ 2016; DOI: 10.1136/bmj.i1541.

Montori, V “Selecting the right drug treatment for adults with type 2 diabetes” BMJ 2016; DOI: 10.1136/bmj.i1663.