June 18, 2012
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Diabetes drug linked to increased risk for bladder cancer

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The use of the type 2 diabetes drug pioglitazone was associated with an increased risk for bladder cancer, according to results of a retrospective study.

Those who used pioglitazone (Actos, Takeda) daily for more than 2 years doubled their risk for the malignancy. Still, the absolute risk is low, with up to 137 additional cases of bladder cancer developing per 100,000 person-years, the researchers wrote.

The researchers did not identify an increased risk between bladder cancer risk and use of a similar type 2 diabetes drug, rosiglitazone (Avandia, GlaxoSmithKline).

Pioglitazone and rosiglitazone are thiazolidinediones, which help patients with type 2 diabetes control their blood sugar levels. Some evidence suggested the use of pioglitazone may be linked to higher risk for bladder cancer, according to background information in the study.

To further investigate that potential association, Laurent Azoulay, PhD, an assistant professor in the department of oncology at McGill University in Montreal, and colleagues reviewed data from the General Practice Research Database, which contains patient records from more than 600 general practices in the United Kingdom.

The researchers evaluated 115,727 patients with type 2 diabetes (mean age, 64.1 years) who were newly treated with oral antidiabetic agents between 1988 and 2009.

The mean duration of follow-up was 4.6 years, and each case of bladder cancer was matched with up to 20 controls.

During the follow-up period, 470 of the study patients developed bladder cancer. The bladder cancer rate in the study population was 89.4 cases per 100,000 person-years, compared with 73 per 100,000 person-years in the general UK population aged at least 65 years, the researchers wrote.

“The higher incidence rate in our cohort is consistent with data suggesting an association between type 2 diabetes and an increased risk of bladder cancer,” Azoulay and colleagues wrote in the study.

The primary analyses included 376 bladder cancer cases and 6,699 controls.

Patients who had ever taken pioglitazone were at an 83% increased risk of developing bladder cancer (adjusted rate ratio=1.83; 95% CI, 1.1-3.05), which corresponds to an absolute adjusted rate difference of 74 per 100,000 person-years, the researchers said.

The rate increased to 88 per 100,000 person-years for patients who had taken pioglitazone daily for more than 2 years (adjusted rate ratio=1.99; 95% CI, 1.14-3.45), and 137 per 100,000 person-years for patients who had taken a cumulative dosage of more than 28,000 mg (adjusted rate ratio=2.54; 95% CI, 1.05-6.14).

The findings remained consistent during several secondary analyses determined to verify results, the researchers said.

“The results of the study provide evidence that pioglitazone is associated with an increased risk of bladder cancer,” Azoulay and colleagues wrote.

Although the risks in absolute terms are low, the researchers advised doctors, practitioners and regulatory agencies to “be aware of this association when assessing the overall risks and benefits” of pioglitazone therapy.

In an accompanying editorial, Dominique Hillaire-Buys, MD, PhD, and Jean-Luc Faillie, MD, of the department of medical pharmacology and toxicology at Le Centre Hospitalier Universitaire de Montpellier in France, said the study findings suggest the association between pioglitazone and bladder cancer could have been predicted earlier. The drug’s ability to reduce cardiovascular events is also “questionable,” Hillaire-Buys and Faillie wrote.

“Prescribers who are ultimately responsible for therapeutic choices can legitimately question whether the benefit-risk ratio of pioglitazone is still acceptable for their patients with diabetes,” they concluded.

For more information:

Azoulay L. BMJ. 2012;doi:10.1136/bmj.e3645.

Disclosure: Dr. Azoulay reports no relevant financial disclosures. Other researchers involved with the study report serving as consultants for Novo Nordisk and Sanofi-Aventis, and receiving research funding from Novo Nordisk.