Ongoing FDA safety review: pioglitazone and potential increased risk of bladder cancer

FDA, in conjunction with Takeda Pharmaceuticals and researchers from the University of Pennsylvania and Kaiser Permanente Northern California, reported 5-year interim results of an ongoing, 10-year epidemiological study designed to evaluate whether pioglitazone (Actos) is associated with an increased risk of bladder cancer.

Key Points

FDA, in conjunction with Takeda Pharmaceuticals and researchers from the University of Pennsylvania and Kaiser Permanente Northern California, reported 5-year interim results of an ongoing, 10-year epidemiological study designed to evaluate whether pioglitazone (Actos) is associated with an increased risk of bladder cancer.

Pioglitazone was approved by FDA in July 1999 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Across the approved doses, Actos reduced HbA1C compared to placebo by an average of 1.5%.

However, findings from early animal studies and 2 subsequent 3-year controlled clinical trials in humans suggested a potential increased risk of bladder cancer and the need for further evaluation.

The most notable of these trials was the randomized, PROspective pioglitAzone Clinical Trial In macroVascular Events (PROACTIVE) trial, published in the Lancet in 2005, which demonstrated a strong signal (P=.06) toward an increased risk with pioglitazone compared to placebo (14 out of 2,605 participants receiving pioglitazone vs 6 out of 2,633 participants receiving placebo developing bladder cancer). Although the risk of bladder cancer related to pioglitazone was found to be less after blinded expert review (6 cases in the pioglitazone group vs 3 cases in the placebo group; P=.31), a related warning currently exists in the pioglitazone prescribing information and medication guide.

Patients (n=193,099) selected for this current 10-year observational cohort study were identified from the Kaiser Permanente Northern California health plan database, had diabetes mellitus, and were at least 40 years of age at study entry. Patients with bladder cancer prior to study entry or within 6 months of joining the Kaiser Permanente Northern California health plan were excluded.

The planned 5-year interim analysis included data collected from January 1, 1997, through April 30, 2008. Patients treated with pioglitazone had a median follow up of 2 years (range, 0.2–8.5 years) and overall did not exhibit a statistically significant increased hazard for new-onset bladder cancer (HR=1.2, 95% CI, 0.9–1.5).

Of note, however, the risk of bladder cancer did appear to increase with increasing dose and duration of pioglitazone exposure, reaching statistical significance after 2 years of exposure.

Currently, FDA states that it is in the process of more thoroughly reviewing the results of this observational data set, but at this time the Agency "has not concluded that Actos increases the risk of bladder cancer." Until the time the Agency updates clinicians and patients, they are recommending patients continue taking pioglitazone unless told otherwise by their healthcare provider, and that providers continue to follow the recommendations in the drug label when prescribing pioglitzone. Current American Diabetes Association treatment guidelines recommend pioglitazone as a possible second-line treatment for hyperglycemia despite lifestyle modification and metformin therapy.

According to the National Cancer Institute, bladder cancer develops at a rate of about 21 cases per 100,000 persons per year in the United States and is more common in those diagnosed with diabetes.

SOURCES

FDA. FDA Drug Safety Communication: Ongoing Safety Review of Actos (pioglitazone) and Potential Increased Risk of Bladder Cancer After Two Years Exposure. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm226214.htm. Accessed November 30, 2010.

Dormandy JA, Charbonnel B, Eckland DJ, et al; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279–1289.

Actos (Pioglitazone Hydrochloride) Tablets Prescribing Information. Takeda Pharmaceuticals America, Inc., Deerfield, IL. August 2008. Available at: http://general.takedapharm.com/content/file/pi.pdf?applicationcode=8a9c4571-a123-4477-91de-b9cafe7d07e3&filetypecode=actospi. Accessed December 1, 2010.

Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association; European Association for Study of Diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203.

Seer Stat Fact Sheets: Urinary Bladder. National Cancer Institute Website. Bethesda, MD. Available at: http://seer.cancer.gov/statfacts/html/urinb.html. Accessed December 1, 2010.