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Posted by paradigm9 on April 12, 2003, at 16:51:03
HEADLINE: Drug Debate: New Antipsychotics Pose a Quandary For FDA, Doctors
--- Eli Lilly's Big Seller, Zyprexa, Can Help Schizophrenics; Is It Linked
to Diabetes? --- Warnings Abroad, Not in U.S.
By Geeta Anand and Thomas M. Burton
11 April 2003 -- The Wall Street Journal
For more than four years, the U.S. Food and Drug Administration has been
mulling a mystery: Is a new generation of big-selling drugs for severe
mental illness causing diabetes and, in rare cases, killing patients?
Among the most widely prescribed versions of these medications, Zyprexa,
made by Eli Lilly & Co., is the one most frequently associated with serious
side effects. Of the millions of patients who took the drug over an
eight-year period that ended in 2002, 288 are reported to have developed
diabetes. Seventy-five of those people became severely ill, and 23 died.
Some researchers see these statistics as significant because in some cases
diabetes symptoms came on suddenly after patients began taking Zyprexa,
eased after they went off the drug and returned when they tried the
The company says there isn't conclusive evidence that Zyprexa caused the
dire side effects. But pointing to some reports of complications with rival
drugs, Lilly also says that if there is a problem, it affects the entire
class of medications, known as atypical antipsychotics.
It is up to the FDA to decide whether Zyprexa or any competing drugs are
responsible for the illnesses and deaths -- and what to do about it. The
stakes are huge for the patients taking the drugs and for the companies
making them. In the U.S., sales of antipsychotic drugs, used to treat
schizophrenia and other severe mental illnesses, topped $5 billion last
year. The market is expanding as doctors try the medicines with patients who
have other problems, such as depression, as well as with children. Lilly
took in $2.5 billion last year -- 39% of its U.S. sales -- from Zyprexa
The FDA says it hasn't arrived at a definitive answer on whether Zyprexa or
any other atypical antipsychotics harm some patients. The resulting quandary
illustrates a difficult challenge the agency, manufacturers and physicians
regularly face: what to do with otherwise effective drugs that may cause
serious side effects.
A big part of that challenge concerns labeling. Japan and the European Union
have required Lilly to provide a prominent warning about diabetes-related
complications. The safety message must be included in the
product-information sheets -- known in the industry as the "label" -- that
doctors and patients are supposed to read. Zyprexa's main rival, Risperdal,
which is made by a unit of Johnson & Johnson, so far hasn't been hit with
Lilly has resisted such precautions in the U.S., pointing to the
inconclusive evidence. The company contends that people with schizophrenia
-- a mental illness whose symptoms can include delusions, hallucinations and
social withdrawal -- are more likely to get diabetes anyway. Some research
psychiatrists agree. They say there is some evidence that schizophrenia
patients have high blood-sugar levels -- the condition underlying diabetes
-- because of bad eating habits and inactivity. Including a safety message
could put Lilly at a commercial disadvantage, causing doctors to prefer
Meanwhile, many doctors continue to prescribe Zyprexa and rival
antipsychotics, unaware of the debate. Thomas Johnson, a general
practitioner in Colorado Springs, Colo., says a 25-year-old patient nearly
died last October, two months after she started taking Zyprexa prescribed by
her psychiatrist. She arrived in Dr. Johnson's office leaning heavily on her
mother, unable to talk, he says. The patient was taken to a hospital, where
her blood sugar was recorded at 15 times the normal level -- a
life-threatening diabetic state.
The young woman was hospitalized for a week and released, still taking
Zyprexa, in addition to insulin, which controls blood-sugar levels. Dr.
Johnson says that neither he nor doctors at the hospital initially
considered any potential connection between Zyprexa and the patient's
blood-sugar problem because the drug's label lacks any alert on the topic.
After he found reports on the Internet about the drug and diabetes, he took
the patient off Zyprexa. Her blood sugar returned to normal, he says.
Asked about this case, Marni Lemons, a Lilly spokeswoman, says that "there
are stories like this on all of the [atypical antipsychosis] drugs." She
adds that many patients take multiple medications, making it difficult to
attribute side effects to just one drug. "And we know Zyprexa and the other
drugs cause people to crave carbohydrates. We often hear of people drinking
two-liter bottles of Coca-Cola or juice, and that can drive the blood sugar
up," she says. Overall, Ms. Lemons says that "one or two anecdotal reports
out of 11 million patients can raise fear among patients and drive them off"
Nearly all drugs have some side effects, and doctors are encouraged to
report possible side effects to the FDA, whether or not they can link the
problems to the drug. Especially in the early years of a drug's life, it can
be hard to tell whether a drug has caused a given side effect. The FDA
doesn't have hard-and-fast rules on when to require warnings or bar a
Since 1997, a dozen drugs approved for marketing have been withdrawn, in
some cases several years after initial reports of sickness and death. These
include cholesterol-lowering Baycol, the diabetes drug Rezulin and the
heartburn medicine Propulsid. Waves of lawsuits followed, accusing the
companies that made them of dragging their feet in the face of growing
evidence the drugs were dangerous.
Antipsychotics block or moderate the level of dopamine, a chemical found in
the brain that in excessive amounts is believed to cause abnormal thinking
and hallucinations. Atypical antipsychotics -- which include Zyprexa,
Risperdal and Clozaril, made by Novartis AG -- have been widely prescribed
since coming on the market in the early 1990s. They relieve some psychotic
symptoms without causing as much of the stiffness and jerky movement
frequently associated with older psychosis drugs. Last year, doctors wrote
7.3 million prescriptions for Zyprexa and 7.6 million for the less expensive
Risperdal, the market leaders, according to the information service NDC
In the case of Zyprexa, FDA officials say they are very much aware that
requiring a warning could influence doctors to prescribe it less often. They
say they don't want to act in a way that might divert patients to other
drugs, when it could turn out the rival medications cause the same problems.
The FDA has approved Zyprexa to treat schizophrenia and bipolar disorder.
But in December 2000, Frank Olenick's doctors prescribed the drug to help
him with sleeplessness and confusion he suffered while withdrawing from
painkillers, says his wife, Christine, who lives in Wintersville, Ohio. Such
"off label" prescriptions are legal and not unusual with some drugs.
Although she is a nurse, Ms. Olenick says she didn't recognize warning signs
two months later -- including excessive thirst -- that might have signaled
her 40-year-old husband's blood-sugar level was elevated.
After Mr. Olenick complained of feeling sick, his wife took him to a nearby
hospital in Weirton, W.Va. Doctors recorded his blood-sugar level at 20
times the normal level, according to hospital records. He had no history of
diabetes, his wife says. After suffering two cardiac arrests, Mr. Olenick
died two days later. "Nobody told us to watch for glucose levels, or I would
have," his wife says.
In January, Ms. Olenick sued Lilly in a West Virginia state court. Her law
firm, Hersh & Hersh, says in court papers that the company "fraudulently
withheld relevant information from potential users of Zyprexa." The company
says it hasn't yet been served with court papers and so declines to comment
in detail. It stresses, though, that Zyprexa hasn't received government
approval for treating withdrawal symptoms.
Individual cases aren't sufficient evidence that a medication is causing a
side effect, "but they're often the first signal of a link," says P. Murali
Doraiswamy, chief of biological psychiatry at Duke University and co-author
of several studies on possible side effects of atypical antipsychotics.
The FDA in 1999 launched a broad review of atypical antipsychotic drugs then
on the market, after a number of academic studies and individual reports of
problems had accumulated. The agency's neuropharmacological division does
about 10 such extensive reviews annually, drawn from a much larger number of
suggestions it receives of possible side-effect problems. The division also
asked manufacturers to check their records for evidence of blood-sugar
elevation during clinical trials of antipsychotics.
Officials with the division say that in recent years, they have gradually
moved away from requiring manufacturers to warn about "possible" side
effects. The division now aims, instead, to define risks with more
certainty, the officials say. The idea is that it's better to avoid
tentative precautions that later have to be adjusted, because revisions tend
to encourage doctors to ignore warnings. This shift doesn't reflect any
formal change of policy and hasn't affected the FDA as a whole, the
By mid-2000, the FDA had gathered some information on the possible link
between atypical antipsychotics and diabetes, but making even rudimentary
findings proved difficult, agency officials say.
For example, researchers often compare the frequency of a drug's possible
bad side effect to the frequency of the malady in the general population.
This can provide helpful information if, as is typical, the disorder is
relatively rare among people generally. But diabetes is relatively common,
so comparing the general-population rate to that of medicated psychosis
patients doesn't prove or disprove whether antipsychotic drugs cause
Separately, company records of clinical trials weren't of much use because
researchers hadn't focused on blood-sugar levels. The medical literature
didn't offer conclusive answers either, the FDA officials say.
A team of researchers, led by Elizabeth Koller, a former FDA official, and
Dr. Doraiswamy of Duke, catalogued the number of diabetes-related
complications reported to the FDA in patients taking Zyprexa and Risperdal,
the drug made by Johnson & Johnson unit Janssen Pharmaceutica. The
researchers reported the possible Zyprexa side-effect cases last July in the
journal Pharmacotherapy: Over an eight-year period, 288 diabetes cases, of
which 75 resulted in severe illness and 23 in death. Of the millions who had
taken Risperdal over an overlapping nine-year period, Dr. Koller's group
found 132 diabetes cases, 31 of which involved life-threatening
complications and five that ended in death. The findings were based on
voluntary reports to the FDA, which scientists estimate reflect between 1%
and 10% of actual cases.
Based on this and other research, Johnson & Johnson says Risperdal has a
lower risk of diabetes than Zyprexa. But Lilly says its research undercuts
this contention. A study led by a Lilly consultant looked at prescription
records of AdvancePCS, the giant pharmacy-benefits manager. Published in the
February 2003 issue of the Journal of Epidemiology, the study found that
patients on a selection of antipsychotics were two to three times as likely
as the general population to have diabetes. But the study found no
difference in the rate of diabetes among patients taking the various drugs.
Robert W. Baker, a senior clinical research scientist at Lilly, says the
company has spent millions of dollars on research evaluating the diabetes
question. Roughly a quarter of Zyprexa patients gain more than 25 pounds
while on the medication, Lilly researchers say, and obesity is linked with
diabetes. But Dr. Baker says the evidence suggests Zyprexa itself doesn't
cause diabetes-related problems. He says the research suggests that the
Zyprexa patients who developed diabetes probably had elevated blood-sugar
levels before taking the medication.
He says, however, it is still possible that antipsychotic drugs in rare
cases cause some health problems. Lilly continues to evaluate evidence and
discuss research with the FDA, Dr. Baker says.
As some researchers themselves concede, each of the studies of
antipsychotics has had limitations precluding firm conclusions. Some had too
few subjects; others lacked a scientifically proper comparison, or
Even so, Novartis, the maker of Clozaril, agreed to alert doctors to
possible diabetes-related complications, beginning in 1997. Novartis says it
agreed to this step to make sure physicians and their patients were aware of
the potential side effect. The precaution isn't thought to have affected
sales very much, however. Since Clozaril came on the market in 1990, the FDA
has required that its label carry other warnings and that patients get
weekly blood tests in early treatment. Those safety steps probably had
already lessened Clozaril sales.
Dr. Koller, the former FDA official, has reported 384 diabetes cases among
Clozaril patients. Fifty-five were life-threatening, and 25 were fatal. The
drug is prescribed far less often than the big two, but Novartis says its
side effects may be recognized more often since patients are monitored
weekly for the other potential medical problems.
Some psychiatrists say the FDA's approach on Zyprexa and other leading
antipsychotics is understandable, given the many confounding factors. "The
short answer is, we just don't know yet," says Paul Keck, a professor of
psychiatry at the University of Cincinnati.
Others think FDA action is long overdue. These doctors typically don't
believe Zyprexa and similar drugs ought to be pulled from the market but say
some sort of precaution is warranted because of cases such as that of
The 31-year-old Fort Worth, Texas, rock musician was rushed to the emergency
room in February 2002, the day before he was to see a doctor for a range of
symptoms. His family found a note in his handwriting, listing excessive
thirst, frequent urination and other symptoms associated with high
blood-sugar levels, his brother, Matt Ferguson, says. Douglas had been
taking Zyprexa for four months, his brother says. "We didn't know these were
symptoms of something life threatening," adds Matt, a physics graduate
Doctors at Fort Worth's John Peter Smith Hospital recorded Douglas's blood
sugar at about 10 times the normal level, his brother says. The patient's
organs progressively failed, and he died days later, his brother says.
Nobody at the hospital raised any potential connection with Zyprexa, Matt
Ferguson says. But his mother, a reference librarian, found studies and
cases describing a possible link on the Internet.
Ms. Lemons, the Lilly spokeswoman, reiterates that cases such as this one
aren't unique to Zyprexa. There are similar accounts involving patients on
other psychosis drugs, she says. She adds that many patients take more than
one drug and that making too much of such cases may encourage other patients
to stop taking medication that drastically improves their lives.
Dr. Doraiswamy of Duke University favors label language that would caution
doctors about diabetes-related complications in patients taking Zyprexa. "No
one is denying the benefit of these drugs," he says. "The real issue is
trying to avoid unnecessary harm."
Peter Landers contributed to this article.
Posted by missliz on April 14, 2003, at 1:25:37
In reply to News Article: Zyprexa causing diabetes?, posted by paradigm9 on April 12, 2003, at 16:51:03
Kinda old news- but keep spreading the word. Zyprexa has more bad side effects than diabetes, and Patients need to know how badly it can mess you up.
Posted by denise528 on April 14, 2003, at 8:52:35
In reply to Re: News Article: Zyprexa causing diabetes?, posted by missliz on April 14, 2003, at 1:25:37
Would you only get diabetes with Zyprexa if you have a weight problem. I asked my psychiatrist about this and he said I wouldn't have any problems because I wastn't overweight, is this true?
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