Doubts raised over drugs for cholesterol Side effects have
included lost memory in some patients By JOHN FAUBER
[email hidden] Posted: March 27, 2004
It was hot on the golf course, and, with every hole, the
mysterious pain that vibrated through Jeff Bryden's body
worsened, finally forcing him into the locker room.
Statins And Memory
In one study, 308 men were given a placebo or two different
doses of the statin Zocor for six months. In memory tests
and a test involving a complex maze, the statin users did
not perform as well as those on the placebo. The difference
was subtle but significant, said the study's lead author,
Matthew Muldoon, an associate professor of medicine at the
University of Pittsburgh School of Medicine. Horror Stories
Jeff Bryden of Brookfield still has the sensation that his
muscles are vibrating, almost three years after
discontinuing statin use. Duane Graveline forgot that he had
a family and had been a NASA astronaut.
He drank some Gatorade and took a shower, but the pain only
intensified, seeming to engulf every muscle in his body.
"I literally couldn't move," he said. "It looked like the
exorcist had gotten ahold of me. It was excruciating pain."
As he lay on a bench, a fellow club member who is a doctor
saw him and immediately suspected he was suffering a
reaction to a drug.
Bryden, 48, of Brookfield, had been taking the cholesterol-
lowering drug Lipitor,which he and his doctor now believe
may have caused extensive damage to his muscle cells, a
condition that could linger for years.
Bryden's case is unusual, maybe even rare. But a growing
number of researchers, doctors and patients are wondering
whether so-called statin drugs are associated with
significantly more side effects, both minor and more
serious, than previously thought.
Those complications include muscle pain, kidney and liver
conditions, and cognitive problems.
It's a complex and dicey issue, being raised at a time when
36 million Americans are being told they should take the
drugs, although currently only 11 million are following
that advice.
Four years ago, the makers of the statins Pravachol and
Mevacor asked the Food and Drug Administration to allow lower-
dose versions of those drugs to be sold over-the-counter. An
FDA advisory committee voted against the application.
"But it will come back again," said physician Sidney Wolfe
of the advocacy group Public Citizen. "People want to put it
in the drinking water."
Although many doctors don't think statins should be sold over-the-
counter, some, including cardiologist James Stein, say the
statin guidelines should be broadened to include more
patients. Stein, an associate professor of medicine at the
University of Wisconsin-Madison, said he believes that most
of the complications reported by patients are overstated.
For many patients, especially those with heart disease or
high-risk conditions such as diabetes, statins can be
lifesavers. Numerous clinical trials have showed that the
drugs can significantly reduce heart attacks, strokes and
the need for bypass surgery or angioplasty.
Measuring side effects As more people take statins, the
number of side effects has grown. Some doctors now say they
suspect the incidence of side effects is much higher than
what has been shown in various clinical trials, including
several funded by the drug makers.
"If you believe the clinical trial data, the problems occur
at very modest rates," said Beatrice Golomb, an assistant
professor of family medicine at the University of
California, San Diego, who is conducting two studies on
statin side effects.
Those trials generally report side effects in less than 1%
to 2% of patients. And many of those complications are
minor and disappear if the drug is discontinued or the
dose lowered.
But, "there are clinicians whose personal experience is
substantially different than what is reported in the
trials," Golomb said.
She said that based on her experience and that of
other doctors, 20% or more of patients encounter some
side effects.
People may be excluded from a trial for a variety of
reasons, including medical conditions. Others may be sought
out for inclusion because of their ability to tolerate
drugs, for example. In addition, people in trials often are
paid and receive free care and medication. That may create a
disincentive to report side effects for fear of losing those
benefits, Stein said.
"People in clinical trials aren't like the rest of the
world," he said.
Weighing a drug's risks against its benefits is crucial for
people who may have a risk factor or two for heart disease
but aren't in the high-risk groups for which statin therapy
clearly is recommended.
Group pushes FDA The issue took on more urgency this month
when Public Citizen asked the FDA to remove the statin
Crestor, which came on the market in September.
The group cited four cases of kidney failure, five
additional cases of kidney damage, six cases of abnormal
bleeding, and seven cases of life-threatening rhabdomyolysis
in patients taking the blood-thinning drug coumadin, which
can interact with Crestor.
Otherwise considered rare, rhabdomyolysis is one of the most
serious statin side effects. It's a condition in which
muscle tissue is destroyed and released into the blood.
In 2001, Bayer Corp. was forced to remove its statin,
Baycol, from the market after it was linked to more than 52
deaths, including 31 in the United States. Most of the
deaths involved rhabdomyolysis.
Wolfe, of Public Citizen, said there is even more reason
to be concerned about Crestor. He noted that Crestor,
unlike Baycol, was linked to rhabdomyolysis cases before
it was approved.
The FDA is looking into the status of Crestor and hopes to
respond within 180 days, said Mary Parks, a physician and
deputy director of the FDA's metabolic and endocrine drug
products division.
Gary Bruell, a spokesman for AstraZeneca, the maker of
Crestor, said the drug was tested in more than 10,000
patients and "is the most-scrutinized statin ever."
Statin problems ongoing However, for patients such as
Bryden, those assurances are not convincing.
Bryden said he had been suffering muscle cramps and
fatigue for more than a year before the incident on the
golf course in July 2001. He also had switched statins -
from Zocor to Lipitor.
He saw a neuromuscular specialist at the Medical College of
Wisconsin, who diagnosed his condition as a disease in his
muscle cells brought on by statin toxicity, he said. His
muscles are still sore, despite the fact that he has been
off statins for nearly three years.
"I still have that constant feeling that my muscles are
vibrating," he said.
Wendy Peltier, the associate professor of neurology at the
Medical College who diagnosed Bryden, said she and other
specialists at the college have seen between 30 and 50
patients with statin-related muscle problems in the past
few years.
The drugs seem to cause a variety of muscle problems in some
people, she said. Most of the time, the problems disappear
when the drug is discontinued or the patient is given a
supplement. Cases such as Bryden's are rare, she said.
Still, she estimated that about 10% of statin users
encounter some kind of muscle problem.
In addition, there have been numerous accounts of statin
users experiencing mental problems.
For Duane Graveline, a retired doctor and astronaut, the
memory problem was so bad that he wrote a book about it:
"Lipitor, Thief of Memory," which was published in February.
Graveline began using Lipitor four years ago after his
annual NASA physical showed an elevated cholesterol level.
He was put on a low dose of the drug. About six weeks later
his wife found him wandering in their front yard. He could
not remember recent events, he said.
"I didn't know who she was," Graveline said.
Within about six hours, his memory returned. A neurologist
determined that he had had a bout of transient global
amnesia. Graveline said he suspected it might be related to
Lipitor, so he stopped taking it.
A year later, NASA doctors again told him he needed to
get his cholesterol down and persuaded him to go back
on Lipitor.
Six weeks later, he said, he had another bout of
amnesia, only this time he lost memory of everything
after high school.
When he was told that he was a former astronaut and that he
was married and had children, "I laughed," he said. "I
thought that was absurd."
It took about 12 hours for his memory to return to normal,
Graveline said.
Weighing risks, benefits Barbara LePetri, a cardiologist
with Pfizer, the maker of Lipitor, said the company is
sponsoring two studies examining whether the drug actually
improves cognitive function. Although there may be a very
small number of patients who report memory problems, that
has to be weighed against the substantial reduction in the
risk of heart disease and stroke, she said.
Parks, of the FDA, said the agency is aware of reports of
cognitive problems among statin users and is monitoring the
situation. She noted that many of the people who take the
drugs are older and may have other conditions that cause
memory problems.
Studies, however, have raised concern that statins may cause
cognitive problems and irritability.
One study looked at 308 men who were given a placebo or the
statin Zocor for six months. In memory tests and a test
involving a complex maze, the statin users did not perform
as well as those on the placebo. The difference was subtle
but significant, said the study's lead author, Matthew
Muldoon, an associate professor of medicine at the
University of Pittsburgh School of Medicine.
"We don't know why it's happening," he said.
Muldoon said one theory is that along with cholesterol,
statins may lower levels of omega-3 fat, which is vital to a
healthy brain. Another possibility is that the drugs also
lower levels of a substance known as Coenzyme Q10, an anti-
oxidant and essential nutrient for cells.
In addition, cholesterol itself is needed for the basic
metabolism of every cell in the body. When the level is
lowered too much, problems can arise, Muldoon said.
"They are powerful drugs," he said. "We are obligated to do
more extensive research because we are asking millions of
people to take these drugs for the rest of their lives."
However, some research also suggests that statins may
actually lower the risk of Alzheimer's disease.
For now, scientists say that for some people statins
may be beneficial and for a select group the drugs may
cause problems.
Golomb, of the University of California, soon will complete
a large five-year study on statins' effects on cognition,
behavior and the brain chemical serotonin. With funding
from the National Institutes of Health, she has been
studying both detrimental and beneficial effects of statins
in 1,000 people.
"What motivated us to do this was all the calls we were
getting from people saying, 'I've got this problem,' "
Golomb said. "It may turn out that we are able to
distinguish groups of people who are more likely to
experience risk or benefit."