May 31, 2012 — Pioglitazone is associated with an increased risk for incident bladder cancer among persons with type 2 diabetes, according to the results of a nested case-control study published online May 31 in the British Medical Journal. Risk doubled in patients treated with pioglitazone for 2 years or more.
"The safety of pioglitazone, an oral antidiabetic agent in the thiazolidinedione class, is controversial," write Laurent Azoulay, PhD, from the Centre for Clinical Epidemiology at Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada, and colleagues. "Although pioglitazone is effective at reducing glycated haemoglobin...levels 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."
As reported by Medscape Medical News in August 2011, the US Food and Drug Administration updated the pioglitazone label to warn against starting pioglitazone in patients with active bladder cancer and to use caution if starting pioglitazone in patients with a prior history of bladder cancer. The European Medicines Agency issued similar warnings.
Using data from the General Practice Research Database, including more than 600 general practices in the United Kingdom, the investigators in 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 up to 20 control patients based on birth year, cohort entry year, sex, and follow-up duration.
The primary study endpoint was risk for incident bladder cancer associated with pioglitazone exposure, defined as ever use of pioglitazone. The investigators also studied measures of duration of therapy and cumulative dosage. Average duration of follow-up was 4.6 years.
During follow-up, there were 470 patients diagnosed with bladder cancer (89.4 per 100,000 person-years; 95% confidence interval [CI], 81.4 - 97.7 per 100,000 person-years). Of these, 376 cases of bladder cancer diagnosed beyond 1 year of follow-up were matched to 6699 control patients.
Exposure to pioglitazone was associated with an increased rate of bladder cancer (rate ratio [RR], 1.83; 95% CI, 1.10 - 3.05). Rate of bladder cancer increased with dosage and with 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 = .05 for trend) and in those with a cumulative dosage exceeding 28,000 mg (RR, 2.54; 95% CI, 1.05 - 6.14; P = .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 per 100,000 person-years). In contrast, use of rosiglitazone was not associated with increased risk for 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 receiving cumulative dosages greater than 28,000 mg. Such associations may have been underestimated in the previous observational studies that included prevalent users."
Limitations of this study include a lack of information on certain risk factors for bladder cancer and an inability to determine whether prescriptions were actually filled and whether patients were fully adherent to prescribed treatment. In addition, the database did not include prescriptions written by specialists or during hospitalization; only prescriptions written by general practitioners were included in the database. Also, indications for pioglitazone include patients with diabetes who are either unable to take metformin or sulfonylureas or are poorly controlled on other oral hypoglycemic; however, patients prescribed rosiglitazone represent this same, typically advanced, disease population.
Pioglitazone Risks Outweigh Benefits
In an accompanying editorial, Dominique Hillaire-Buys, MD, PhD, and Jean-Luc Faillie, MD, from the Department of Medical Pharmacology and Toxicology at Centre Hospitalier Régional Universitaire de Montpellier, France, suggest that the risks for 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 randomised trials, it can confidently be assumed that pioglitazone increases the risk of bladder cancer," Dr. Hillaire-Buys and Dr. Faillie 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."
The Canadian Institutes of Health Research and the Canadian Foundation for Innovation supported this study. One of the study authors served as a consultant for Novo Nordisk and sanofi-aventis and received research funding from Novo Nordisk. Dr. Hillaire-Buys and Dr. Faillie have disclosed no relevant financial relationships.
BMJ. Published online May 31, 2012. Article full text, Editorial extract
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