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FDA Warns of Bladder Cancer Risk With Actos

By a Fiore, Staff Writer, MedPage Today

Published: June 15, 2011

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Patients taking pioglitazone (Actos) for more than a year may have an

increased risk of bladder cancer, according to an FDA interim review of

an ongoing epidemiological study.

The warning comes just days after two European countries banned use of

the drug. The European Medicines Agency (EMA) has yet to release any

guidance on use of Actos.

Five-year data show that although there's no overall increased risk of

bladder cancer, patients with the longest exposure to and the highest

cumulative dose of the drug were at greater risk, the agency said.

In a response to the FDA move, manufacturer Takeda stressed that the

interim data showed short-term use of the drug was not associated with

an increased risk of bladder cancer, and " use for more than two years

was weakly associated with increased risk. "

The company said it will continue to investigate potential safety

concerns, " is committed to supporting [the 10-year epidemiological study

begun in 2002] through its conclusion at the end of 2012, " and is

working with the FDA to " make appropriate updates " to the prescribing

information.

Pioglitazone is now the second medication in the thiazolidinedione (TZD)

class to be associated with serious side effects within the past year.

Last fall, the use of rosiglitazone (Avandia) was severely restricted in

the U.S. because of concerns about an increased risk of heart attack.

Some researchers suspect that this may prompt physicians to back away

from prescribing the class at all, moving toward newer therapies,

particularly the incretins, when metformin alone is no longer working

for type 2 diabetes patients.

" I will ask my patients on Actos to consider dropping it and give them

an alternative, " Albert Levy, MD, of Mount Sinai School of Medicine in

New York City, said in an email to MedPage Today.

Under the FDA's restrictions last fall, rosiglitazone is to be used only

in patients who have failed therapy with pioglitazone.

Researchers say the latest warning probably won't change that process,

but there doesn't appear to be much interest in choosing between what

some see as the lesser of two evils with the drug class.

Lee Green, MD, of the University of Michigan, said rosiglitazone has a

" solidly established association with heart disease. I wouldn't switch

someone from a drug that might turn out to be a problem [Actos] to one

that we know is a problem. "

, MD, of Massachusetts General Hospital, said he doubts that

rosiglitazone, " a potentially dangerous drug, will replace pioglitazone

-- another potentially harmful drug, if the bladder cancer risk proves

to be real -- given the numerous other choices to treat type 2 diabetes. "

Instead, many clinicians may move directly to incretin therapy if

metformin no longer does the trick.

Levy said he would jump to a GLP-1 agonist like liraglutide (Victoza) or

exenatide (Byetta) or DPP-4 inhibitors like sitagliptin (Januvia) for

patients who aren't well controlled on metformin.

Those drugs may pose problems, too. For example, on Tuesday, the FDA

issued a warning about the risks of thyroid cancer and pancreatitis

associated with liraglutide.

Sue Kirkman, MD, vice president of medical affairs for the American

Diabetes Association, said just prior to the FDA's recent decision that

the evidence of bladder cancer risk with pioglitazone has been

" conflicting, and it's hard to know whether this is a real problem or not. "

She said her organization's main concern is that patients might stop

taking their medication after hearing the news about the increased risk

rather than talking to their doctors first.

Still, Kirkman acknowledges that some of the clinicians her organization

represents have made the decision not to use the class, or have at least

given it serious consideration before prescribing.

" We already knew there were other issues with the class, aside from

those seen with rosiglitazone, " she said. " There are concerns about

fractures, fluid retention, and congestive heart failure. "

But not all clinicians were quick to decry use of pioglitazone or the

TZD class. Zonszein, MD, of Albert Einstein College of Medicine in

New York City, called the earlier European decision " precipitous and

premature " because it was based on a retrospective study and found only

a minor increase in cancer risk.

He added that triple therapy -- with metformin, a TZD, and incretins --

is an " excellent combination, particularly in the more aggressive type 2

diabetes we see nowadays. "

" During the last three decades, studies have shown that treating

diabetes early and aggressively results in much better outcomes, "

Zonszein said. " There is a need for medications such as Actos that can

slow down the devastating results of the diabetes epidemic. "

Green said that while the recent decisions in the U.S., France, and

Germany have made his " antennae go up, " they won't yet change his

prescribing. He said he also hears a greater public health message

within the controversy.

" I think the larger message is not about which drugs for diabetes, but

about the ultimate foolishness of trying to fix the problem with drugs, "

Green said. " As long as we keep supersizing ourselves, eating too much

and moving too little, we'll have this problem. "

The FDA began its review of pioglitazone and the potential risk of

bladder cancer last September and said it will continue to monitor data

until the full 10-year study is complete.

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