They are miracle drugs of the modern age. Statins, sold under names such as Lipitor and Zocor, rack up sales of $19 billion annually and are the top-selling medicines in the world. Why? Study after study shows that for people at high risk for heart disease, they cut the number of fatal heart attacks. Evidence suggests statins may reduce the risk of Alzheimer's disease and slow the course of multiple sclerosis. It's no surprise, then, that many doctors say -- only half-jokingly -- that statins should be put in the drinking water.
Yet while the benefits of statins are well established, some doctors argue that their side effects have not received adequate scrutiny. A subset of patients reports muscle pain, but it's unclear how widespread these symptoms may be or if they could be a sign of long-term muscle injury. In addition, some scientists are concerned that the drugs could be having a negative impact on cognitive function in certain patients. If that's the case, is the effect permanent? And who is most at risk? The pharmaceutical industry has spent millions of dollars promoting the merits of statins and searching for new uses. Much less energy has been directed at answering the nagging questions.
At this stage hardly anyone predicts that statins could suffer a fall from grace such as that of Merck & Co.'s (MRK) painkiller Vioxx, which may have harmed thousands of patients and may engender some of the world's costliest drug-related class actions. But as the Vioxx debacle shows, there are worrisome gaps in the U.S. regulatory system when it comes to spotting side effects of prescription drugs over the long term. Even some proselytizers for statins concede that further studies are needed. And if research helps single out who is at greatest risk of damage from side effects, those most likely to benefit from statins may be more likely to take them.
The need for that sort of assessment will only grow more urgent. National health guidelines indicate that some 36 million Americans need cholesterol-lowering therapy. And with studies showing patients can benefit from bringing LDL, or "bad" cholesterol, even below what are considered normal levels, some experts worry that statins may be prescribed to more and more people at lower risk of heart attacks. Prescribing such potent, lifelong drugs to a healthy population is an uncharted voyage. "Do we know everything about statins?" says Dr. Mary H. Parks, a deputy director at the Food & Drug Administration unit that regulates these drugs. "No, we do not."
HOW THEY WORK
Parks is not in the alarmist camp on statins. The problems so far, she says, have been "overwhelmingly small." What's well known is that the drugs work by blocking an enzyme called HMG-CoA reductase, which plays a key role in the production of cholesterol, especially LDL. When the liver slows production of LDL, the body pulls more of it from the bloodstream to meet its biological needs -- leaving less to build up as plaque in the arteries of the heart and other blood vessels. The result is fewer heart attacks in some at-risk patients. "There aren't too many drugs out there that have so much clinical data that establish a benefit," says Parks.
Even in the case of known side effects, many outside experts contend that the story is reassuring. Some patients have suffered a rare but sometimes deadly side effect called rhabdomyolysis, in which muscle in the body is broken down. Others suffer less serious muscle aches and weakness. But in total, most statin trials have shown that muscle problems have occurred in fewer than 1% of patients, says Dr. Gary Palmer, vice-president for cardiovascular medicine at Pfizer (PFE). Cleveland Clinic cardiologist Steven E. Nissen says the side effects of statins "are rarely life-threatening and relatively manageable."
Nonetheless, troubling uncertainties remain. Take the issue of muscle pains. In clinical trials they seemed to be rare. But physicians such as Dr. James K. Liao, director of vascular medicine research at Brigham & Women's Hospital in Boston and a big supporter of statins, believes muscle pains are much more common, occurring in 15% to 20% of his patients. Doctors often rely on a blood test for an enzyme called creatine kinase CK to determine if patients are suffering from statin-related muscle pain. If the CK level is elevated, physicians may change the statin dose or try a different drug. If it's normal, some doctors may assume the muscle pains are not caused by the drug and won't alter the medication.
Problem is, some research shows patients can have normal CK levels and still suffer muscle damage. In addition, in 2002, Dr. Helmut Sinzinger, a professor in the Nuclear Medicine Dept. at the University of Vienna, published a paper showing that in 111 patients taking a variety of statins who did not have elevated enzyme levels or suffer any muscle pain, almost 10% did show a rise in a marker in the blood for possible muscle injury. He says that means some patients could be suffering subtle and undetected muscle injury. One theory: Statins may deplete an antioxidant called coenzyme Q10, used by mitochondria, the cells' energy factories. Merck says it did animal studies on this issue and found no link between COQ10 levels and muscle disorders.
While statin makers concede they don't know exactly what leads to muscle woes, Pfizer's Palmer says there's no evidence the drugs cause undetected, long-term muscle damage.
If there are still unknowns about how statins interact with muscle tissue, there are even more questions about how the drugs affect the brain. Epidemiological studies show a link between high cholesterol and a raised risk of Alzheimer's. And Pfizer, after getting positive results from a small study looking at whether its best-selling Lipitor might slow the progression of Alzheimer's, has embarked on a larger, 600-patient trial.
In a seeming paradox, though, statins may also have negative effects on the brain. Dr. Matthew F. Muldoon, associate professor of medicine at University of Pittsburgh School of Medicine, published a study in 2000 looking at the effect of Merck's statin Mevacor on cognitive function. He compared the performance of 209 patients before getting any medication and six months after taking either Mevacor or a sugar pill. The results: Statin users did worse on tests of attention and psychomotor speed. Muldoon says this may be a temporary impact that dissipates as the body adjusts to the drug. But it's also possible that statin users suffer longer-term negative cognitive impact.
Dr. Beatrice A. Golomb, a researcher at University of California at San Diego, hopes to answer some of those questions. Funded by the National Institutes of Health, she is leading a study looking at the effects of statins on the central nervous system. The 1,000-patient trial will study patients receiving Merck's Zocor, Bristol-Myers Squibb's (BMY) Pravachol, or a placebo for six months and measure any positive or negative changes in cognition, irritability, aggression, and serotonin levels. Golomb says she has been in touch with many patients and families reporting problems with statins ranging from memory lapses to changes in personality.
Pfizer, Merck, Bristol-Myers, and AstraZeneca, maker of Crestor, (AZN) say no cognition issues surfaced in clinical trials of their statins, with no sign of a problem among millions of patients filling prescriptions for them. Dr. Yale Mitchel, executive director for clinical research at Merck, says it repeated Muldoon's experiments and didn't get the worrisome results. Statin supporters dismiss the questions as needless scaremongering at a time when many people at high risk for heart disease go untreated.
Without more studies, though, manufacturers will have a hard time putting the concerns to rest. "The enzyme these drugs block is critical for lots of activities in the body," says Dr. James M. Wright, professor of medicine at the University of British Columbia. "So to think that it is going to be all for the good is very naïve." Given the swelling ranks of people taking statins, drugmakers would be wise to investigate their risks as closely as they do their benefits.
By Amy Barrett in Philadelphia and John Carey in Washington