WASHINGTON -- The FDA is investigating a possible link between pioglitazone (Actos) and bladder cancer, and, as a result, both of the available thiazolidinediones -- pioglitazone and rosiglitazone (Avandia) -- are undergoing safety reviews.
The FDA said it initiated the pioglitazone review after it received preliminary data from a 10-year epidemiological study sponsored by Takeda.
An interim analysis of data from the study, which includes more than 193,000 patients with type 2 diabetes, revealed no statistically significant increase in bladder cancer among pioglitazone users compared with nonusers (hazard ratio 1.2, 95% CI 0.9 to 1.5), but "the risk of bladder cancer increased with increasing dose and duration of [pioglitazone] use, reaching statistical significance after 24 months of exposure."
Moreover, "results from two, three-year controlled clinical studies of Actos (the PROactive study and a liver safety study) demonstrated a higher percentage of bladder cancer cases in patients receiving Actos versus comparators," the FDA wrote in its announcement of the safety review.
The findings from PROactive are included in the current pioglitazone label in the "Precautions -- Carcinogenesis, Mutagenesis, Impairment of Fertility" section.
Robert Spanheimer, MD, Takeda's medical director for pioglitazone, told ľֱ that the FDA announcement and the data from the epidemiological study need to be "interpreted in the context of being interim results from a 10-year study."
Moreover, he pointed out, the data did not reach statistical significance for the primary endpoint of increased risk of bladder cancer.
The "investigators did a post-hoc analysis (of these preliminary data) that showed duration [of treatment] had an effect on the association," Spanheimer noted, leaving unsaid the fact that results of a post-hoc analysis should be considered no more than hypothesis-generating.
When asked if he thought today's FDA announcement was justified based on the data, he said Takeda "is interested in safety, as is the FDA." He declined to offer comment on the appropriateness of the announcement.
Spanheimer made his comments in a phone interview that was monitored by a Takeda public relations spokesperson.
The FDA said the safety review should not impact clinical care and advised that physicians continue to prescribe pioglitazone according to approved marketing indications and label directions. Patients using pioglitazone should continue to take the drug unless they are told to stop by their physician.
Over the last few years, pioglitazone has enjoyed a reputation as the "safer" TZD because, unlike rosiglitazone, it has not been linked to excess risk of cardiovascular events -- even though both drugs carry warnings about increased risk of congestive heart failure.
Rosiglitazone has twice been the subject of special hearings, and the FDA is still digesting results of the latest round of hearings at which advisers again recommended that the drug stay on the market, but with even tougher boxed warnings.
Rosiglitazone has also been the subject of congressional hearings about the way in which its maker, GlaxoSmithKline, controlled findings from clinical trials, and more such hearings are expected.
Through more than two years of controversy, pioglitazone was, by comparison, racking up published data that burnished its reputation: for slowing atherosclerosis, for treating psoriasis, for providing cardiovascular safety, and even -- in a phase I study -- for treating Alzheimer's disease.
The flurry of data -- good, bad, and equivocal -- for both of the TZDs have at best created confusion for physicians treating patients with diabetes mellitus -- confusion that continued through this year's American Diabetes Association meeting at which Leo Green, MD, MPH, of the University of Michigan, in Ann Arbor, summed up the debate this way for ľֱ: "The first question is not whether to switch someone from Avandia to Actos, but whether they should be on either one at all."