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Sabtu, 6 Julai 2013
A Lone Voice Raises Alarms on Lucrative Diabetes Drugs
A Lone Voice Raises Alarms on Lucrative Diabetes Drugs
LOS ANGELES — Dr. Peter C.
Butler initially declined a request by the drug maker Merck to test whether its
new diabetes drug, Januvia, could help stave off the disease in rats.
“I said, I’m not interested in your money, go
away,” Dr. Butler recalled.
Merck no doubt now wishes it had. When Dr.
Butler finally agreed to do the study, he found worrisome changes in the
pancreases of the rats that could lead to pancreatic cancer. The discovery, in
early 2008, turned Dr. Butler into a crusader whose follow-up studies now
threaten the future of not only Januvia but all the drugs in its class, which
have sales of more than $9 billion annually and are used by hundreds of
thousands of people with Type 2 diabetes.
“I knew some stuff that I thought was a worry
and I was obliged to pursue it,” said Dr. Butler, chief of the division of
endocrinology at the University of California, Los Angeles.
Dr. Butler faces powerful opponents in the
makers of the drugs and many diabetes specialists, who say his studies are
contradicted by other evidence.
“The data are inconclusive,” said Dr. Robert
Ratner, chief scientific and medical officer of the American Diabetes
Association. He said even if there were some excess risk, it would be
Nancy Thornberry, who heads diabetes drug
development at Merck, said that clinical trials, the gold standard of medical
evidence, had found no increased risk of pancreatic disease from Januvia, even
when results of trials were pooled
to achieve greater numbers. “In fact, my mother takes sitagliptin,” she added,
referring to Januvia by its generic name.
Questions about whether the drugs raise the
risk of pancreatitis, a painful and possibly lethal inflammation of the
pancreas, arose soon after the first one, Byetta, now sold by Bristol-Myers
Squibb and AstraZeneca, was approved in 2005. The drugs’ labels already contain
warnings about that. What is new and potentially more serious is a possible
risk of pancreatic cancer, which is virtually untreatable and kills most
victims within a year.
Many people in the field compare Dr. Butler
to Dr. Steven Nissen, the well-known Cleveland Clinic cardiologist whose
warnings about Avandia, a different type of diabetes drug, led to its being
banned in Europe and highly restricted in the United States.
Both men have faced criticism from those who
call them zealots. The F.D.A. is about to examine data suggesting that Avandia
might not be so dangerous after all. Some critics say Dr. Butler overstates his
conclusions and that his findings have not been replicated by others.
“Basically, no one in the entire world over
the last 10 years, with thousands of animals,” has found what Dr. Butler found,
said Dr. Daniel J. Drucker, a professor of medicine at the University of
Toronto and a consultant to many drug companies.
Still, Dr. Butler is not easy to write off.
He is a former editor of Diabetes, the flagship journal of the American
Diabetes Association. And he has some defenders.
“He should be an American hero, actually, a
rugged individualist who is not going to be browbeaten,” said Dr. Edwin Gale,
professor emeritus at the University of Bristol in Britain, who recently wrote a commentary with
Dr. Butler on the drugs.
Dr. Butler was born in Kenya to British
parents, though he has worked in the United States since 1987 and is an
American citizen. His wife, Dr. Alexandra E. Butler, a pathologist who occupies
the office next to his, has also worked on some of the studies.
In the last month, lawyers defending drug
companies against a lawsuit claiming that Byetta had caused a patient’s
pancreatitis, subpoenaed virtually all of Dr. Butler’s records.
“I think the message here is they want him
out of business,” said Brian Depew, a lawyer representing the plaintiff, Ross
Hubert of New Hampshire, who claims that Byetta caused him to get pancreatitis.
Dr. Butler said U.C.L.A. told him not to comment on the subpoena.
More than 100 lawsuits representing 575
plaintiffs around the country are claiming injury from Byetta, mostly
pancreatitis, according to the latest quarterly regulatory filing from
Bristol-Myers. Forty-three suits claim that Januvia caused pancreatic cancer,
according to Merck.
Other drugs in the class, called incretin
mimetics, are Bydureon and Onglyza, which are also sold by Bristol-Myers Squibb
and AstraZeneca; Victoza from Novo Nordisk; Tradjenta from Eli Lilly and
Boehringer Ingelheim; and Nesina from Takeda. By far the biggest, though, is
Merck’s Januvia and the related Janumet, which had global sales of $5.7 billion
Dr. Butler said that after his group
presented its rat findings to Merck, “I never heard from them again,” except
from company lawyers asking when the study would be published.
He said that studies done by the drug
companies that led to the drugs’ approval by the F.D.A. tended to use young
healthy animals that would not be expected to get pancreatic cancer.
The concern, he said, was that the drugs work
essentially by increasing levels of a hormone called glucagonlike peptide-1.
That hormone might accelerate precancerous conditions already present in
middle-aged people, much as the hormone estrogen might promote growth of
nascent breast tumors.
Three other pieces of evidence raise possible
One is the side effects reported to the
F.D.A., typically by doctors or companies, after a drug is on the market. Dr.
Butler and colleagues found far more cases of pancreatitis and pancreatic
cancer reported for the incretin drugs than for Avandia.
Public Citizen and the Institute for Safe
Medication Practices, two watchdog groups, have since separately found the same
thing. Public Citizen has already asked the F.D.A. to remove Victoza from the
But these reports are voluntary and can be
unreliable. Also, when there is publicity about a safety risk, reports of that
side effect can spike.
Several groups have looked at medical records
of thousands of patients held by insurance companies. At least three of these
studies have found no increased incidence of pancreatitis or pancreatic cancer.
But a recent study found
roughly a doubling of the risk of acute pancreatitis among users of the drugs.
But what has prompted the reviews by
regulatory agencies has been Dr. Butler’s study of human
pancreases obtained from 34 organ donors who had died for reasons
unrelated to pancreatic disease. Seven of the donors happened to have taken
Januvia and one had taken Byetta.
The pancreases of those eight people tended
to have more precancerous lesions than the organs of the diabetics who had not
taken those drugs, or those of the nondiabetics. There was also one case of a
neuroendocrine tumor, a type of pancreatic cancer.
Also, the pancreases of the incretin drug
users were heavier, with faster growth of certain cells. “There were strange
growths” that “you’d never see in a normal human pancreas,” Dr. Alexandra
Critics point out that the incretin users were
much older than the other diabetics and had been sick longer than other
diabetics. That, not the drugs, could have accounted for the findings, they
“There are enormous problems with this
paper,” said Dr. Ratner of the diabetes association.
Dr. Fred Gorelick, professor of medicine and
cell biology at Yale, said the precancerous lesions found were early-stage
ones. Many middle-age people have these and they often do not lead to cancer.
Still, he said, the study “raised several red flags.”
More information could come out in June when
the National Institutes of Health will hold a two-day meeting on possible links
between diabetes, diabetes drugs and pancreatic cancer. Dr. Butler will be one
of the speakers.
And starting this summer, results will be
coming from large randomized clinical trials meant to assess whether the drugs
raise the risk of heart attacks. Those trials should also be able to pick up an
increased risk of pancreatic cancer that might have been missed by the smaller
trials used to win approval of the drugs.
So far the safety concerns have not
substantially reduced use of the drugs, though there are signs of “possible
softness” recently, said Mark Schoenebaum, a pharmaceutical analyst at ISI
Group. He said the evidence of a risk was weak and that the F.D.A. would
probably take no action.
Dr. Butler said he was not calling for the
drugs to be removed from the market, though he does not prescribe them to his
own patients. Rather, he said, studies should be done using M.R.I. scans to see
if use of the drugs is enlarging the pancreases of patients.
“We have all these people out there taking
these drugs,” Dr. Butler said, “and the problem is: What is happening to their
This article has been revised to reflect the following correction:
Correction: June 3, 2013
An article on Friday about the concerns Dr. Peter C.
Butler has raised about some diabetes drugs referred imprecisely to Dr.
Butler’s position of at the University of California, Los Angeles. He is the
chief of the division of endocrinology at the university — not chairman, which
the school uses for the head of the department of medicine.
A version of this article appeared
in print on May 31, 2013, on page B1 of the New York edition with the headline:
A Lone Voice Raising Alarms.