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Pioglitazone and bladder cancer risk: Examining the evidence
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In 2011, accumulating evidence on a possible link between pioglitazone and bladder cancer led to an FDA warning.
Around the same time, several European countries withdrew pioglitazone (Actos, Takeda Pharmaceuticals) from the market. The US package insert now states that data suggest an increased risk for bladder cancer in pioglitazone users. Data also suggest that the risk increases with duration of use. Other warnings state: Do not use pioglitazone in patients with active bladder cancer; use caution when using in patients with a prior history of bladder cancer; and tell patients to promptly report any sign of hematuria or other symptoms such as dysuria or urinary urgency, as these may be due to bladder cancer.
Concern about bladder cancer from pioglitazone first appeared in the PROactive study. In this study, bladder cancer developed more frequently in the pioglitazone group as compared with placebo (11 vs. six cases; P=.069). Eleven of the 20 patients developed bladder cancer within 1 year of beginning the study. After excluding these patients and those with known risk factors, researchers determined that pioglitazone did not increase the risk for bladder cancer.
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A retrospective study of US pharmacy claims by Oliveria and colleagues did not find any association between thiazolidinediones and colorectal, liver, bladder or pancreas cancers. The estimated RR for bladder cancer in this study was 1.05 (95% CI, 0.71-1.54). However, there were several limitations of the study because it was retrospective, could not discriminate between different thiazolidinediones, the number of documented bladder cancer cases was relatively small and other risk factors were unaccounted for.
A review of the FDA Adverse Event Reporting System (AERS) showed a high risk for bladder cancer in pioglitazone users (OR=4.3; 95% CI, 2.82-6.52). However, because there are potential biases associated with reporting, these data can be misleading.
Kaiser Permanente Northern California is conducting an observational study on pioglitazone and bladder cancer rates. An interim analysis showed an increased risk for bladder cancer with pioglitazone, with an HR of 1.2 (95% CI, 0.9-1.5). However, when looking at only those receiving pioglitazone for more than 24 months, the risk was increased by 40% with pioglitazone use (HR=1.4; 95% CI, 1.03-2.0). Concern over the time-dependent use design of this and the Oliveria study has been raised, as this may introduce a bias and thus make the results unreliable.
A study by Tseng and colleagues, published in Diabetes Care, reviewed insurance database information in Taiwan and found no significant increase in bladder cancer associated with the use of pioglitazone. There were, however, a relatively small number of cases.
Tseng also discussed some other confounding issues that must be considered. For example, diabetes itself may increase the risk for cancer. Also, pioglitazone is often used as a second- or third-line agent, and thus, the patient has likely had diabetes for a longer time, continues to have hypoglycemia and has been on other medications, all of which may increase the risk for bladder cancer.
Given the information to date, it is difficult to determine whether there is an association between pioglitazone use and bladder cancer. If such an association exists, further clarification on factors such as duration of use, ethnicity and concomitant bladder cancer risk factors must be clarified. Of course, when taking this information into consideration before prescribing pioglitazone, one should also consider the potential benefits of this agent such as reduced cardiovascular disease and improved glucose and lipids. Until better data are available, the FDA’s current precaution seems appropriate.
James R. Taylor, PharmD, CDE, is a clinical associate professor in the department of pharmacy practice at the University of Florida, Gainesville.
For more information:
- Lewis JD. Diabetes Care. 2011;34:916-922.
- Oliveria SA. Diabetes & Metabolic Syndrome: Clinical Research & Reviews. 2008;2:47-57.
- Piccinni C. Diabetes Care. 2011;34:1369-1371.
- Tseng CH. Diabetes Care. 2012;35:278-280.
- Tseng CH. J Formos Med Assoc. 2012;111:123-131.
- Yang X. Diabetes Care. 2011;34:e136.
Disclosure: Dr. Taylor reports no relevant financial disclosures.