When Statins Cause Problems
Side effects of cholesterol-fighting drugs get attention in wake of concern about CrestorAug 9, 2004 | Newsday Eileen Mulvey is a spry 70-year-old who's usually up and down the steps to her second floor co-op a dozen times a day. But in February, two weeks after she started taking Crestor to lower her cholesterol, she couldn't make it up the stairs.
"My legs were throbbing and I would have to stop midway, and I'd have to sit down," said Mulvey, of Oakdale, who stopped taking the medication even before her doctor ran a blood test showing she had suffered muscle damage from the statin. "This wasn't normal for me. I wasn't short of breath - my muscles were screaming.
"And I'm a very vigorous person," Mulvey added. "For me to be complaining about something is unusual."
Harvey Gardner, a 73-year- old from Huntington, started taking a different statin, Zocor, March 10. After just a few doses, he said, he started feeling "lousy."
"The symptoms were dramatic," Gardner said. "I had pain in my arms and my legs. I felt like I had arthritis all over my body."
The pain subsided when he quit taking the drug, but now he wonders whether the numbness he's had in his toes for several years might be a side effect of another statin, Mevacor, that he took several years ago. Doctors have diagnosed the numbness as peripheral neuropathy, which is listed as one of the potential side effects of statins.
Millions of Americans now take statins, a class of medications whose remarkable ability to lower blood cholesterol levels has endowed them with virtual miracle drug status. But many who take the drugs worry about the effects they may have on their kidneys, liver and muscles, and a consumer advocacy group's call in June to ban Crestor, the newest statin, has reawakened concerns about the potential side effects. Officials for AstraZeneca, which makes Crestor, have dismissed the consumer group's allegations as inaccurate and misleading. "Statins overall are remarkably safe," said Gary Bruell, a spokesman for AstraZeneca. "Every drug ever invented has adverse effects."
A rare side effect
Rhabdomyolysis, a breakdown of muscle fibers that can cause kidney damage and may be fatal, is an extremely rare side effect, occurring in one in 10,000 patients, drug manufacturers say. But up to 5 percent of statin patients suffer non-life-threatening muscle pain disorders that can nevertheless be debilitating, according to doctors who have studied statin-related muscle syndromes. And, they say, certain patients smaller people, women, the elderly, and athletes and people who exercise a lot may be more vulnerable. People of Japanese descent also are at higher risk, as are patients with some other medical complications.
"I think the muscle part of the statins is underappreciated," said Dr. Paul Thompson, director of preventive cardiology at Hartford Hospital and author of a paper on statin-associated muscle disease published in the Journal of the American Medical Association in April 2003. "Some people not everybody, but a fair number of people get a mild myalgia [muscle pain] on the drug. With some of these patients, it can be extreme."
Public Citizen Health Research Group, a consumer organization, called on the Food and Drug Administration in 2001 to add a new warning, known as a black box warning, to the labels on statins, emphasizing that patients must notify their doctors if they experience muscle pain, tenderness and weakness, the symptoms that may precede rhabdomyolysis. The FDA has not taken any action, and an FDA official, Dr. Mary Parks, would not comment on the issue last week. At the time Public Citizen made its request, 72 deaths during a three-year period had been linked to statin use; 20 of those were linked to Baycol, which the FDA withdrew from the market the same year.
Dr. Robert Rosenson, director of preventative cardiology at Northwestern's Feinberg School of Medicine in Chicago, whose review of statin-induced myopathy was published in the American Journal of Medicine in March, said 3 percent to 5 percent of statin patients experience muscle problems. He often tries switching drugs or lowering the dose, he said, but "some people can't tolerate any dose of a statin."
Still, not all physicians recognize the link between the drugs and the muscle syndromes, Thompson said, and some of his colleagues dismiss it as insignificant. "A lot of lipid experts say: 'The myalgia stuff you talk about doesn't exist,'" he said. "I say, 'You're not taking care of enough patients.'"
Jeanne Bruderman is one patient whose physicians did not recognize a link: After going through surgery to treat back problems, she experienced pain, weakness and cramps in her arms and legs and tingling in her fingers. She sought help from a rheumatologist, a neurosurgeon and a pain-management doctor. Finally, a physician's assistant mentioned the symptoms could be related to statins and ordered a blood test to measure levels of the enzyme creatine kinase, an indication of muscle damage. "I nearly fell off my chair," said Bruderman, who lives in Bellport, is only 39 and had been put on Lipitor 19 months earlier. She quit the drugs and says the tingling in her fingers has subsided.
Many cardiologists consider statins to be wonder drugs - especially for people who are at high risk for cardiovascular disease. "You can't go to a cardiology meeting and ask who's on the drug without everyone's hand going up," Thompson said. He takes a statin himself, and acknowledged that he serves as a consultant to several pharmaceutical companies that make them. But, he said, "they do have nagging side effects in some people."
That description doesn't quite capture the experience of Rena Sweeney, a physical education teacher in upstate Kinderhook who was raised in Yonkers and now lives in what she calls "a whirlwind of pain." Sweeney, who is 53, started taking a low dose of Lipitor around the end of October, after blood tests showed her total cholesterol was 239. By the time her family came to visit around Thanksgiving, she said she couldn't even enjoy their company.
"I was feeling old and shriveled up, fatigued," she said. Until then, Sweeney said, she had been the kind of person who rarely even suffered a cold. "I'm a P.E. teacher, and I am in very, very good shape; I work out all the time."
Her leg muscles had started twitching, and her legs had started feeling weak, "like rubber." A blood test showed she had elevated creatine kinase levels, an indication of muscle damage, but the level was not high enough to convince her doctor that it was related to the medication. Her doctor thought she was having panic attacks.
Once an avid skier, Sweeney was barely able to complete two runs down the mountain last winter. The pain in her legs was so intense at times, she said, "I was crying, the fronts of my calves, my shins, were killing me. I felt poisoned." She feared she may have developed lupus or a neurological illness, and saw several specialists to rule out connective-tissue diseases.
An acquaintance who is an orthopedic surgeon was the first to ask whether she had started taking any new medications - and advised her to quit the drug immediately.
Sweeney stopped taking Lipitor on New Year's Eve and said her weakness and the "shriveled-up feeling" are gone, though she still has muscle pain after exertion, even gardening.
A spokeswoman for Pfizer, maker of Lipitor, declined to comment on the product's safety. In clinical trials, 5.6 percent of patients taking a 20-milligram dose of Lipitor reported myalgia or muscle pain, compared to 1.1 percent of subjects taking a placebo, according to the prescribing information. At a 40-milligram dose, 5.1 percent of patients taking Lipitor reported arthralgia or joint pain, compared to 1.5 percent on placebo.
Sweeney said doctors have been unable to give her a definitive answer about what triggered her symptoms. Such myalgia can occur without the elevated enzyme levels that mean muscle damage has resulted in protein leaking out of the muscle cells into the blood. Doctors who followed four patients at Scripps Mercy Hospital Clinical Research Center in San Diego found the patients were able to guess correctly whether they were given statins or placebos, based on their muscle pain and performance on strength tests, even though they had normal creatine kinase levels in their blood.
A number of other small studies have shown statins may exacerbate muscle injury during exercise. A study of 58 healthy men at the University of Pittsburgh in 1997, for example, found that those taking Mevacor (lovastatin) had much higher creatine kinase levels after 45 minutes of downhill walking on a treadmill than a group taking a placebo.
Jim Baggett, a housing inspector in Wilmington, N.C., said he started taking Zocor in July 2002 and became unable to do yardwork, couldn't get through his usual 2 1/2-hour weekend workouts and developed a cough, numbness in his feet, joint aches, weakness and tremors.
Baggett, who is 58, underwent thousands of dollars' worth of tests to rule out Lyme disease, chronic fatigue syndrome, tuberculosis and amyotrophic lateral sclerosis, among other diseases. All of the test results were negative. Since quitting the drug, Baggett said, his health has improved, but he is not yet symptom-free.
"I'm not one to say, 'Don't take it' I'm not a doctor," Baggett said. "But at least be aware of what the problems are."
Tony Plohoros, a spokesman for Merck, which makes Zocor and Mevacor, said side effects from both drugs are rare. "Both Mevacor and Zocor have excellent safety profiles," he said, adding that Merck is seeking FDA permission to sell Mevacor without a prescription. "The 20 milligram dose has shown in clinical trials to have roughly the same side effects as a placebo."
Risks and benefits
The risk-to-benefit ratio of taking a statin must be evaluated for each patient individually, said Dr. Sidney Wolfe, director of Public Citizen.
"There are millions of people getting statins who shouldn't be getting statins," Wolfe said. "These drugs have been especially useful for people when they are used for secondary prevention," in patients with established heart disease who are at risk for another heart attack, he said - and for them, "the benefits outweigh the risks."
For people who don't have heart disease and who have no other risk factors, he said, "the risks outweigh the benefits."
Dr. Mary Parks, deputy director of the FDA's division of metabolic and endocrine drug products, said she could not comment on the consumer group's 2001 petition to the agency to strengthen warnings on statins. She said the labels contain warnings already, and doctors need to convey the information to their patients.
"People need to be aware that with any drug, there are going to be side effects," Parks said. "If you're taking this product and having aches and pains and it is in some way affecting daily activity, you need to contact your physician and talk about it. You may need to do a trial and go off the medicine. It may go away. It may also not be the medication.
"Even in milder cases, it's worth people paying attention to it and not ignoring it," she said. In some cases of rhabdomyolysis, "if you can stop it early on, it may be of benefit to the patient."
1) This wasn't normal for me. My muscles were screaming.' - Eileen Mulvey, right, who was unable to climb stairs for two weeks after she started taking Crestor 2) 'The symptoms were dramatic. I had pain in my arms and my legs I felt like I had arthritis all over my body.' Harvey Gardner, who began having symptoms after taking a few does of Zocar 3) 'A lot of lipid experts say: "The myalgia (pain) stuff you talk about doesn't exist." I say: "You're not taking care of enough patients.'' Dr. Paul Thompson, director of preventive cardiology at Hartford Hospital 4) 'With any drug, there are going to be side effects. If you're taking this product and having aches and pains and it is in some way affecting daily activity, you need to contact your physician and talk about it It may also not be the medication.' Dr. Mary Parks of the FDA's division of metabolic and endocrine drug products.