Updated Review Confirms Potential Risk of Bladder Cancer with Pioglitazone

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Following an updated review of published studies, the Food and Drug Administration (FDA) has concluded that the drug pioglitazone (Actos)—also available in combination with metformin (Actoplus Met, Actoplus Met XR), the sulfonylurea glimepiride (Duetact), and the dipeptidyl peptidase-4 inhibitor alogliptin (Oseni)—may increase the risk of bladder cancer. The FDA first alerted the public to the potential risk of bladder cancer with pioglitzone in 2010 and 2011 based on interim results from a 10-year epidemiologic study.
Pioglitazone is an antihyper-glycemic drug from the class known as thiazolidinediones. It lowers blood sugar by reducing insulin resistance in the periphery and in the liver, thus lowering circulating levels of glucose and the release of glucose from the liver.
The clinical research evidence regarding the contribution of pioglitazone to bladder cancer is contradictory. The initial decisions by the FDA were based on preliminary, five-year findings from a 10-year prospective cohort study of patients in the Kaiser Permanente of Northern California database. While no significant increase in the risk of bladder cancer was found with pioglitazone use compared with no pioglitazone use, there appeared to be a trend of increasing risk of bladder cancer with increasing doses of pioglitazone and duration of pioglitazone use. In response to these five-year data, the FDA published a Drug Safety Communication and added a warning to pioglitazone's labeling stating that the drug may increase the risk of bladder cancer. The full 10-year study by Lewis and colleagues, published in the July 21, 2015, JAMA, found an even weaker relationship between the use of pioglitazone and the risk of bladder cancer. While the trend of an increased risk of bladder cancer with increased doses of pioglitazone continued, the 10-year findings were not statistically significant. The FDA also reviewed data from the 2005 Prospective Pioglitazone Clinical Trial in Macrovascular Events, a multinational European study, and its observational 10-year follow-up study by Erdmann and colleagues in the March 2016 Diabetes, Obesity and Metabolism. Long-term follow-up of patients did not find an increased risk of bladder cancer. The final study reviewed by the FDA, a retrospective cohort study of patients in the United Kingdom Clinical Practice Research Datalink, found a statistically significant trend of an increased risk of bladder cancer the longer a person received pioglitazone and the larger the cumulative pioglitazone dose.
The FDA's interpretation of these findings provides the rationale for its conclusion that pioglitazone may confer an increased risk of bladder cancer. The labeling for all products containing pioglitazone will be revised to include the data from these studies. No other labeling changes are being made at this time. To read the full summary of the data the FDA evaluated, go to http://bit.ly/2jHEe6U.

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