You Want Statins With That?

Life was treating Harry Barninka just fine. In the mid- 1990s, the Sao Paulo insurance broker was in his mid-50s, prospering and reasonably fit, carrying 80 judiciously arranged kilos on his 1.8-meter frame. He exercised regularly, consulted a physician yearly and, except for a stinky-cigar habit and a soft spot for churrasco (fatty barbecued meat so popular in Brazil), managed to keep mostly to a sensible diet. So in 1996, when he called on his doctor for a checkup before a planned trip to Israel, he had good reason to expect it would be a routine in-and-outer. It wasn't. Barninka didn't make the flight. In fact, "I never left the hospital," he says. "My doctor told me my arteries were all clogged up. I said, 'Are you sure you have the right patient?' " Barninka underwent a quintuple-coronary-bypass operation and vowed he would never again take his health for granted.

Barninka was willing to change. He cut back on the churrasco, upped his workout on the treadmill and gave up the stogies. But that alone wasn't going to be enough to trim his cholesterol, which had soared to 270, and there wasn't much more he could do to make his lifestyle more healthful. His job still required him to work 11-hour days planted mostly in his chair. Is it stressful? "Are you kidding?" he says, "Stress plus!" His doctor, though, started prescribing 20 milligrams of Lipitor daily. After five years on the pills, Barninka, 60, has dropped five kilos and his cholesterol is down to 180.

Welcome to the age of statins. If you aren't taking a cholesterol-lowering drug yourself, chances are you know someone who is. And it's not necessarily an overweight, out-of-shape sports fan in his 50s who ventures off the couch only in search of chips and beer. Millions of high-cholesterol sufferers of every age and description--from Gen-Xers to their octogenarian grandparents--depend on prescription drugs to scour their bloodstreams of LDL cholesterol, the waxy goo that can block arteries and cause heart attacks and strokes. And, according to health experts, millions more should be taking statins to help ward off cardiovascular disease. Statins have become so critical in the war against cholesterol that a leading statin researcher compares them to the ultimate miracle med. Says Dr. Rory Collins of Oxford University: "Statins are the new aspirin."

His bold words could be an understatement. Promising new research is underway to investigate statins as a treatment for a number of other disorders, including Alzheimer's disease, multiple sclerosis, osteoporosis and even cancer. "I'm very, very hopeful," says Alzheimer's researcher Dr. Larry Sparks of Sun Health Research Institute in Sun City, Arizona, who is nearing the end of a yearlong clinical trial of statins.

High cholesterol was first recognized as a major risk factor for heart disease more than 40 years ago, but no one really --started worrying about it until the 1980s, when tests for it became common. In the past few years the concern has taken on new urgency, as health experts have raised their estimates of the number of people who should take cholesterol-lowering drugs. In May 2001, the U.S. National Institutes of Health (NIH) issued aggressive new cholesterol guidelines that nearly tripled overnight the number of people in the United States who should be using statins, from 13 million to 36 million. According to an independent analysis of the NIH guidelines, the number of people under 45 who ought to be on cholesterol-lowering drugs jumped 201 percent, to 12 million, while the pool of drug candidates 65 and older increased 131 percent, to 10 million. In France, home of such heart-stopping delicacies as sauce bearnaise and quiche lorraine, 12 million people have high cholesterol, but fewer than 3 million take statins. After studying 81,000 people, the Brazilian Society of Cardiology concluded recently that 40 percent of Brazilian adults suffer from high cholesterol, up 10 percent from a decade ago. Even in Japan, where traditional sushi is easy on the arteries, 20 million people have high cholesterol, but only 4 million take statins. Statins got another boost in late 2001, when Collins and his team released the world's largest randomized study of statins (they followed 20,000 patients for up to eight years), which showed that cholesterol-lowering drugs reduced the risk of heart attack and stroke by at least one quarter for those at highest risk.

That was supersize news in the land of the double bacon-cheeseburger: in the United States, statin sales jumped a whopping 32.5 percent in the two years ending in March 2003. Of course, the billions of dollars the drug makers spent marketing and advertising statins ($1.4 billion in 2002) certainly helped. Last year alone, global sales reached $21.7 billion as doctors wrote more than 118 million statin prescriptions, according to IMS Health. All those pills mean big profits for Big Pharma, but there's no denying that statins prevent a lot of pain and suffering. Heart disease remains the leading cause of death in the developed world, taking more than 3.5 million lives each year. With people less inclined than ever to do the things--like eating less saturated fat and exercising--that are known to lower cholesterol and reduce the risk of heart attack, statins have emerged as perhaps our most reliable weapon against a relentless killer. While experts recommend lifestyle changes as the primary treatment for high cholesterol, not everyone can reach his target LDL level that way. "For those that can't, the drugs are crucially important because they will provide a degree of LDL lowering that lifestyle alone won't, in most cases, achieve," says Dr. James Cleeman, head of the NIH's National Cholesterol Education Program.

Critics of drug therapy say the NIH guidelines and Collins's study are flawed by an implicit assumption that people can't or won't change their behavior. They say statins can reinforce bad habits and actually serve as a disincentive to get up and move. "Most people can accomplish comparable reductions in LDL [the bad cholesterol] by diet and lifestyle alone, if the changes are comprehensive enough," says Dr. Dean Ornish, head of the Preventive Medicine Research Institute in Sausalito, California. In a 1998 study, Ornish reported a 40 percent reduction in LDL after one year among a group of patients with heart disease who followed a rigorous program, including 30 minutes of moderate exercise daily, and a low-fat, vegetarian diet. (Statins have been shown to reduce LDL by 25 to 60 percent.) Ornish also notes that taking pills isn't necessarily easy, citing one study that found 65 percent of statin users stopped taking their medicines after a year. Dr. Donald Fedder of the University of Maryland-Baltimore, who wrote an analysis of the new NIH guidelines in which he expressed some concern about over prescribing statins, says physicians need to present their patients with all the options. "You've got to give the intelligent patient a [chance]," says Fedder. "I wouldn't want to be on the Ornish diet because I'm a carnivore. But if you follow his diet you will not have to take any pills."

While the doctors in the front lines of the war against heart disease agree that lifestyle changes should be the cornerstone of cholesterol-lowering therapy, they also say their --fast-food-loving patients simply aren't up to the task. "There is a great deal of truth in what Ornish is doing," says Dr. Sidney Smith, professor of medicine at the University of North Carolina-Chapel Hill and former president of the American Heart Association. "The problem is that the changes needed are frequently very difficult. For some it's an inability to break habits, but for many the reality is it's just not palatable."

That's certainly true for statin user Cao Huiliang. Twenty years ago, in his late 40s, he was having some health problems, including trouble sleeping. His doctor told him he had a total cholesterol count of 400 and prescribed some medicine, but he soon stopped taking it because it made him nauseous. "I didn't feel anything," he says, "so I didn't pay attention." For years afterward, Cao suffered from chest pains, for which he took traditional Chinese remedies--he still keeps a little red plastic bottle of pills in his pocket. Two months ago, though, the pains got so bad that he checked into Anzehn Hospital in Beijing. Cao, now a trim 67-year-old with thick white hair, sits around in his pajamas while doctors try to gauge the extent of his illness. Meanwhile, his doctor has prescribed statins.

The rising popularity of statins, first introduced in 1987, has been accompanied by twin epidemics of obesity, which now includes 300 million adults worldwide, up from 200 million in 1995, and diabetes, which is expected to climb from 176 million at present to 370 million by 2030. Both conditions are preventable, and their rise is due in large part to what might be called couch-potato syndrome. Although experts recommend at least 30 minutes of exercise daily, fewer than half of U.S. adults (more than 60 percent of whom are overweight or obese) get any regular exercise at all, and other developing countries can't be far behind.

While statins help control high cholesterol, that's just one of the many risk factors for heart attack. Others--including high blood pressure, smoking and obesity--are not affected by statins. "So you have an enormously greater benefit if you fix the obesity, if you exercise, if you eat the low-saturated-fat and low-cholesterol diet" in addition to using the drugs, Cleeman says. "It's a one-two punch: lifestyle and drugs."

Though it has developed a rather ugly reputation, cholesterol is essential for the formation of cell membranes and hormones. Our bodies make all the cholesterol we need; it's synthesized in the liver. The problem is, the food we eat, particularly the saturated fat in it, can elevate LDL. There is --also a genetic condition in which the body makes too much LDL. An excess of LDL cholesterol can accumulate in arteries that feed the heart and brain and lead to a heart attack. HDL cholesterol, the "good" kind, takes away excess cholesterol.

Statins work by inhibiting an enzyme (HMG-CoA reductase, a name only a scientist could love) in the liver, thereby blocking production of cholesterol. This triggers a vacuuming effect in which the liver sucks up the LDL cholesterol in the bloodstream. Recent studies have found that statins also reduce the level of C-reactive protein (CRP), a marker for inflammation of blood vessels. Elevated levels of CRP have been associated with increased risk of heart attack. In addition, a new drug, Zetia, from Merck/Schering-Plough, inhibits the absorption of cholesterol in the intestine; it's used alone and in combination with statins to lower cholesterol. Statins do carry risks. The two main complications are liver problems, which occur in about 1 percent of patients, and myopathy, a painful muscle condition, which affects about one patient in a thousand. (Quitting the drugs stops both side effects.)

Popular as statins are, it could be that we ain't seen nothin' yet if they turn out to be effective against Alzheimer's disease, multiple sclerosis and other disorders. Researchers are cautious, to say the least. "We tell people not to take drugs for things that aren't proven," says Dr. Robert Green, associate professor of neurology at Boston University School of Medicine. But some of the early results are intriguing. Green authored a study that showed a 39 percent reduction in Alzheimer's risk in people who had been taking statins at least six months.

Though not everyone agrees on the underlying causes of Alzheimer's, many believe that a protein called beta amyloid, or A-beta, plays an important role. A-beta can form a plaque that is always found in the brains of Alzheimer's patients. Sparks thinks that elevated cholesterol may "augment the production" of A-beta plaque in the brain. "It may not be the only thing that induces it," he says, "but it certainly helps it along. And if I can get rid of this agent that's helping production of this toxin, maybe I can slow down the disease." Sparks is about to complete a clinical trial involving 65 mild- to moderate-Alzheimer's patients. The patients on statins received 80mg of Lipitor daily. (The research was funded in part by Pfizer, Lipitor's maker.)

The possibility that high cholesterol contributes to Alzheimer's disease is particularly frightening. "We've heard a lot about obesity and the coming epidemic in diabetes," says Harvard neurologist Rudy Tanzi, who --thinks other experimental cholesterol drugs may fight Alzheimer's better than statins. "I worry about the coming epidemic of Alzheimer's, based on the clear molecular link of cholesterol and A-beta production."

Statins are also getting a serious look as a possible treatment for multiple sclerosis, which afflicts about 2.5 million people worldwide. MS is an autoimmune disorder that destroys myelin, the fatty sheath around nerve cells. This fall, Dr. Scott Zamvil, a neurologist at the University of California, San Francisco, will launch the first placebo-controlled clinical study of MS patients taking statins. Because the object of the study is to test the effectiveness of statins in suppressing the development of the disease, the 152 subjects will be people who have had only their very first attack of MS. The research is an extension of work Zamvil and colleagues did on mice. That study, published last fall in Nature, showed that statins reversed paralysis in mice with MS and prevented relapse of the disease. While it's not known exactly how statins work against MS, Zamvil, who has received a competitive research grant from Pfizer, says the drugs prompt the cells that attack the nervous system in MS to instead secrete molecules that protect it.

Statins also show potential for protecting against aortic-valve disease, a hardening of the valve between the heart and the aorta, and osteoporosis, the age-related deterioration of bone that leads to fractures. And a Dutch study released last month found that people who had been using statins for four years or more had a 20 percent reduction in their cancer risk, especially prostate and liver cancer. There are a few caveats, however. It was only an association study based on analysis of existing data, not a placebo-controlled clinical study, the gold standard of medical research. And there have been other statin-cancer studies with neutral or negative findings.

It will be years before we know whether statins will work against these other conditions. But there's little mystery about their effectiveness in preventing heart disease. We may be lazy and we may be fat and we may feel guilty about taking the darn things. But we're better off with them than without them.