Statins: beyond cholesterol
When his doctor first suggested he start taking one of the cholesterol-lowering drugs called statins, Steven Peterson hesitated. “If it meant taking a pill every day for the rest of my life, I wanted to make sure it was safe,” said the Petaluma, Calif., business consultant. He remembers exactly what his doctor told him. “If it was up to him, he said, they’d put this stuff in the water supply.”
Indeed, doctors have been prescribing statins to millions of Americans because of the drugs’ remarkable success at cutting a type of cholesterol that has been linked to heart disease. Now, a host of studies suggest that statins may have other significant benefits, from strengthening bones to lowering the risk of Alzheimer’s disease.
Though almost everyone, from doctors to patients, agrees that statins are saving many lives, some experts caution that the drugs’ benefits are being overblown and that serious side effects are being largely overlooked.
Statins, for example, don’t lower cholesterol in every patient who tries them. As for side effects, about 5% of patients experience muscle aches and pains. In rare cases, a more severe condition occurs, one called rhabdomyolysis, in which muscle cells die and are sloughed off. Rhabdomyolysis can lead to kidney failure and death.
One of the newer statins, Baycol, was pulled from the market after reports of 52 deaths linked to the drug. And a consumer watchdog group has called for tough warnings on the labels of statins because of these potential risks.
But circumstances surrounding Baycol, a particularly potent version of statins, were an exception, many researchers say. “Statins have been in use for 15 years, we have millions of people taking them, and we’ve seen remarkably few problems associated with these drugs,” said Dr. P.K. Shah, director of the cardiology department at Cedars-Sinai Medical Center in Los Angeles. “Are we likely to see risks show up when people take them for 20 or 25 years? There’s no way to know.”
One thing doctors do know: Statins save lives. Studies show they reduce the risk of death from heart attacks and other causes by 30% to 40% in people with elevated cholesterol levels. “The fact is, the risks of not taking statins are far greater than the potential side effects,” said Dr. Gregg C. Fonarow, professor of cardiology at UCLA. In randomized studies of more than 100,000 patients taking statins, there have been no deaths attributed to the medication. (The deaths associated with Baycol occurred outside clinical trials in patients taking drugs but not closely monitored, as they would be in a research study.)
According to Fonarow, statins have been associated with less serious adverse events than has aspirin, a medication that is sold over the counter.
Statins, formally known as HMG CoA reductase inhibitors, were first approved because of their ability to interrupt a biochemical pathway by which the liver produces cholesterol, thus lowering lipid levels in the bloodstream. Since then, they’ve been found to do a lot more.
Indeed the real surprise, many experts say, is the range of their benefits. “These are wonderfully interesting and powerful drugs that are turning out to have multiple effects,” said David A. Drachman, professor of neurology at the University of Massachusetts Medical School. Statins have been shown to reduce the risk of heart attacks and strokes, two major killers. Cardiologists have been surprised to discover that they also improve the survival of patients suffering from heart failure and heart transplant patients. Taking statins also reduces the need for coronary bypass surgery.
“The amazing thing about statins is that they have many benefits that don’t have anything to do with lowering cholesterol,” Fonarow said. And not just benefits for the heart. Several observational studies suggest that people on statins may lower their risk of Alzheimer’s disease by as much as 70%. By maintaining blood flow through the tiniest capillaries that supply blood to brain cells, statin drugs could even reduce the risk of garden-variety age-related memory loss, experts speculate. Some neurologists, Drachman said, have even begun to call statins “Viagra for the brain.”
The same drugs may help keep bones strong as people age, reducing the incidence of fractures that plague older people. There’s also preliminary evidence that they may help treat diseases associated with abnormal immune function, such as multiple sclerosis, lupus and rheumatoid arthritis, researchers say. Diabetics, too, may benefit.
Statins also boost certain levels of nitric oxide, a substance that helps keep blood vessel walls flexible enough to fully open and allow ample blood flow. This could well be one of their most important effects, Drachman believes. “The cells that line blood vessel walls, called endothelial cells, are turning out to have many other functions,” he explained. “Keeping them healthy could promote the health of organs throughout the body.”
Healthier blood vessels may be one reason statins lower the risk of stroke, even in people with normal cholesterol levels. Healthy vessels are especially important in the brain, where a vast network of capillaries delivers oxygen and nutrients to brain cells. Simply by lowering cholesterol levels, the drugs may do a brain good.
“In animal models, high levels of cholesterol lead to greater amounts of amyloid plaque, one of the signs of Alzheimer’s,” said Dr. Lon S. Schneider, professor of psychiatry, neurology and gerontology at USC. “When you lower cholesterol, you reverse the process.” In addition, statins block a small molecule called Abeta peptide, found principally in the brain, preventing it from constricting blood vessels, according to Daniel Paris, a scientist at the nonprofit Roskamp Institute in Sarasota, Fla.
Researchers still are trying to determine if, indeed, statins really can lower the risk of Alzheimer’s the way they can the danger of heart disease and stroke. But there’s reason to think they will. In a study of 1,364 people age 50 and older, Drachman and colleagues from Boston University School of Medicine observed that people taking statin drugs were 70% less likely than those not on the drugs to have signs of Alzheimer’s and other forms of dementia.
More recently, Dr. Robert C. Green, a neurologist at Boston University, reported that taking statin drugs was associated with a 79% reduction in risk of developing Alzheimer’s. These studies gauged the role statins may play in preventing Alzheimer’s and possibly other forms of age-related dementia. A large nationwide study, involving both USC and UCLA, is underway to test whether giving statins to patients with early signs of Alzheimer’s could slow or prevent the disease.
Some scientists, however, are skeptical about statins’ possible role in improving cognitive function. Dr. Beatrice A. Golomb, a researcher at UC San Diego, says that other scientifically rigorous studies have found that, after six months, middle-aged people who took statins scored lower on tests of thinking and memory than did people who got a dummy pill. It is possible, Golomb said, “that statins will have benefits to cognitive function in some people and harm to cognitive function in others.”
Another unexpected discovery is that statins reduce inflammation, which could have important implications. Inflammation of blood vessels is now believed to be a factor in cardiovascular disease. The anti-inflammatory effect of statins may explain why they help even heart patients with normal cholesterol levels. Inflammation also has been implicated in a host of other diseases, from arthritis and lupus to multiple sclerosis. Studies are underway to see whether the drugs may help treat such conditions.
Soon after statins were approved for lowering cholesterol, researchers turned up its role in building strong bones. Biochemically, the drugs act similarly to Fosamax, a drug widely used to treat osteoporosis.
Whether people on statins will have stronger bones as they age remains controversial. In a study published in 2002, researchers at Virginia Commonwealth University in Richmond reported that men taking statins for more than two years were half as likely to develop osteoporosis, in which bones become brittle and prone to fracture. Other studies, however, have found no benefit.
The good news from research studies has translated into a healthy bottom line for pharmaceutical companies. Statins have quickly become one of the biggest-selling classes of prescription drugs on the market. Just one, Lipitor, accounted for almost $6.1 billion in U.S. sales last year and was the country’s top-selling drug.
That number is likely to continue climbing. For now, statins are officially recommended for people whose level of low-density lipoproteins, or “bad” cholesterol, is 130 or higher and who have risk factors for cardiovascular disease. They also are recommended for people with no risk factors but LDL levels of 190 or higher. According to the American Heart Assn., 36 million Americans meet those guidelines, but only about one-third currently are on statins.
Some experts say the number of people who could benefit is far higher. Cedars-Sinai’s Shah believes everyone with diabetes or early signs of insulin resistance should be on statins. Diabetics are at greatly increased risk of cardiovascular disease, Shah says. “We’re seeing a 40% to 50% reduction in cardiovascular disease among diabetics who are on statins.” Because insulin resistance syndrome is closely linked to obesity, as the nation’s waistlines expand, the number of people suffering from the syndrome will expand -- swelling the pool of people who might benefit from being on statins.
The prospect of putting so many people on statins worries some health experts. Dr. Sidney Wolfe, director of Public Citizen’s Health Research Group, says doctors aren’t doing enough to inform patients about side effects. “Sometimes all it takes is reducing the dosage to eliminate the problem.”
Two years ago, Public Citizen petitioned the Food and Drug Administration to include a “black box” warning -- the most serious warning a prescription drug can carry -- and a package insert for patients that describes the potential risks of statins. The FDA has yet to act on the request.
Wolfe worries, too, that the drugs are being prescribed to patients who should be encouraged instead to eat a healthier diet and get more exercise.
“Instead of encouraging people to make these healthy changes, doctors are pushing pills.”
Given the choice between dieting and popping a pill, many Americans would opt for the pill. “Yes, we should be counseling patients to exercise and eat better diets,” Shah said. “But as long as we have a medication that reduces cardiovascular risk, we should also make sure patients who need it get it.”
And Shah suspects that most patients won’t remain on statins long enough to face the risks that might result from decades of use. New drugs are being developed that promise to be more effective than statins, he said.
“For now, statins are one of the best things we’ve got, but they’re far from perfect,” he said. “I suspect it won’t be long before we have something better.”
