Doubts raised over drugs for cholesterol

Side effects have included lost memory in some patients

By JOHN FAUBER, jfauber~journalsentinel.com

Posted: March 27, 2004

http://www.jsonline.com/alive/news/mar04/217976.asp

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.

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."

From the March 28, 2004 editions of the Milwaukee Journal Sentinel