Pioglitazone once again linked to bladder-cancer risk

Laurie Barclay

June 01, 2012

Montreal, QC - Pioglitazone (Actos, Takeda) is associated with an increased risk of incident bladder cancer among those with type 2 diabetes, according to the results of a nested case-control study published online yesterday in BMJ[1] . The risk doubled in patients treated with pioglitazone for two years or more.

"The safety of pioglitazone, an oral antidiabetic agent in the thiazolidinedione class, is controversial," write Dr Laurent Azoulay (Jewish General Hospital, Montreal, QC) and colleagues. "Although pioglitazone is effective at reducing glycated hemoglobin . . . and may decrease the risk of cardiovascular events, it has also been associated with weight gain and an increased risk of congestive heart failure. Although available data are limited, there is now some evidence suggesting that pioglitazone may be associated with an increased risk of bladder cancer."

In August 2011, the US Food and Drug Administration updated the label to warn against starting pioglitazone in patients who have active bladder cancer and to use caution if starting pioglitazone in patients with a prior history of the cancer. The European Medicines Agency issued similar warnings.

Using data from the General Practice Research Database, including more than 600 general practices in the UK, investigators of the present study identified 115 727 people with type 2 diabetes who were newly treated with oral hypoglycemic agents between January 1, 1988 and December 31, 2009. Incident cases of bladder cancer during follow-up were each matched to as many as 20 control patients.

During an average of 4.6 years of follow-up, 470 patients were diagnosed with bladder cancer (89.4 per 100 000 person-years). Of these, 376 cases of bladder cancer diagnosed beyond one year of follow-up were matched with 6699 controls.

Exposure to pioglitazone was associated with an increased rate of bladder cancer (rate ratio [RR] 1.83, 95% CI 1.10-3.05). The rate of bladder cancer increased with dosage and duration of use and was highest in patients treated with pioglitazone for more than 24 months (RR 1.99, 95% CI 1.14-3.45; p=0.05 for trend) and in those with a cumulative dosage exceeding 28 000 mg (RR 2.54, 95% CI 1.05-6.14; p=0.03 for trend).

These findings remained consistent in several sensitivity analyses. Absolute risks for bladder cancer associated with pioglitazone were low, at up to 137 extra cases per 100 000 person-years (95% CI 4-271). In contrast, use of rosiglitazone was not associated with an increased risk of bladder cancer.

"[T]he results of this study provide evidence that pioglitazone is associated with an increased risk of bladder cancer, whereas no increased risk was observed with the thiazolidinedione rosiglitazone," the study authors write. "The increased risk associated with pioglitazone became apparent after use for at least 24 months and [in those] receiving cumulative dosages greater than 28 g. Such associations may have been underestimated in the previous observational studies that included prevalent users."

In an accompanying editorial[2], Drs Dominique Hillaire-Buys and Jean-Luc Faillie (Centre Hospitalier Regional Universitaire de Montpellier, France) suggest that the risks of treatment with pioglitazone seem to outweigh the benefits.

"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 randomized trials, it can confidently be assumed that pioglitazone increases the risk of bladder cancer," they write. "It also seems that this association could have been predicted earlier. Worldwide, exposure to pioglitazone is estimated to be more than 20 million patient-years. Considering that the benefit of pioglitazone in reducing cardiovascular events is questionable, 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."

This study was supported by the Canadian Institutes of Health Research and Canadian Foundation for Innovation . One of the study authors served as a c onsultant for Novo Nordisk and Sanofi and received research funding from Novo Nordisk. Hillaire-Buys and Faillie disclosed no relevant financial relationships.

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