Regulators in the USA have begun a review of Takeda Pharmaceutical Co's diabetes blockbuster Actos amid fears of a link to bladder cancer.

The US Food and Drug Administration is reviewing Actos (pioglitazone), after receiving preliminary results from a long-term observational study designed to evaluate the risk of bladder cancer associated with use of the $4 billion-a-year drug. Those findings are based on five-year data from an ongoing, 10-year observational study being carried out by the Japanese firm's Noth Amercian division.

The FDA noted that these early results "showed no overall association" but there was an increased risk of bladder cancer in patients with the longest exposure to Actos "and in those with the highest cumulative dose of the drug". The agency stresses that patients should not stop taking the drug unless told to do so by their doctors.

In preclinical carcinogenicity studies of pioglitazone, bladder tumours were observed in male rats receiving Actos that produced blood drug levels equivalent to those resulting from a clinical dose. Additionally, results from two, three-year controlled trials (the PROactive study and a liver safety study) "demonstrated a higher percentage of bladder cancer cases in patients receiving Actos versus comparators," the agency added.

Takeda conducted a planned analysis of the study data at the five-year mark, which showed no statistically significant association between Actos  and bladder cancer risk and the company says it will complete the trial as planned.

The FDA also noted that GlaxoSmithKline's Avandia (rosiglitazone), which like Actos belongs to the thiazolidinedione class of drugs, has not been associated with bladder cancer. The latter disease occurs in an estimated 20 per 100,000 people per year in the United States and is thought to be higher in diabetics, the agency added.