Clarified on 2/11/07: An earlier version of this article implied that the elevation of liver enzymes is a cause of severe muscle deterioration and kidney malfunction when it's an additional effect of statin use.
Until a few weeks ago, Larry Cohen believed he'd finally figured out how to beat his high cholesterol and stave off heart disease. Zocor, a statin that works by blocking the production of cholesterol in the liver, had brought his levels of "bad" LDL cholesterol down from a whopping 195 milligrams per deciliter to a still-disappointing 125. Next, on Vytorin, a combination of Zocor and a nonstatin drug that reduces the absorption of cholesterol in the gut, he dropped to a desirable 98 mg/dL. Then came word that Vytorin is no better at preventing plaque buildup in the arteries than Zocor. Suddenly, Cohen and millions of other people faced two big questions: How much protection were they getting from their cholesterol meds? And how much does lowering LDL even matter?
"After hearing the news, I have doubts, absolutely," says Cohen, 68, a retired math professor in Port Jefferson Station, N.Y. And doctors are hearing them: "My office is in an uproar. I've been in the past two Saturdays just returning calls," says Nieca Goldberg, medical director of New York University's Women's Heart Program and author of Dr. Nieca Goldberg's Complete Guide to Women's Health. Not surprisingly, refills for Vytorin have fallen nearly 25 percent since the news broke; new prescriptions are off by 40 percent.
Heart experts like Goldberg are seriously concerned that the media uproar about Vytorin may be causing even patients who have had heart attacks to conclude that they no longer have to worry about treating their high cholesterol. Bottom line, the experts say: There are two types of medication users—those who definitely need them and those who don't but are taking them anyway (thanks in no small part to effective drug marketing). The first group is made up of people with known heart disease: They've had heart-related chest pain, a previous heart attack or stroke, or angioplasty or bypass surgery. These folks, according to a large body of research, will lower their 10-year risk of a cardiac event by about 25 percent and their risk of dying from heart disease by 15 to 20 percent if they stay on a statin for the rest of their lives. The second group may have cholesterol levels that make their doctors frown but otherwise are fine.
Better drugs. Until two decades ago, doctors had few effective, safe medications at their disposal to treat high cholesterol. Now, the six powerful statins on the market (Zocor, Lipitor, Crestor, Pravachol, Lescol, Mevacor) and the non-statin Zetia—the other component of Vytorin—are so good at what they do that lowering cholesterol has taken on prime importance. In 2001, the government's National Cholesterol Education Program tightened the definition of a healthy total cholesterol level to under 200 mg/dL—previously, it was 300 mg/dL—and recommended that people at high risk keep their LDL levels below 100. "Good" HDL cholesterol levels should be kept above 40 mg/dL and preferably above 60. Result: Doctors began treating millions more people with drugs—including plenty with no signs of heart disease—even though statins are approved only for high-risk people.
"Some of the lowest-risk people are given statins," says Terry Jacobson, a cardiologist who heads the office of health promotion and disease prevention at Emory University in Atlanta. Given that the drugs can sometimes elevate liver enzymes and cause muscle aches, he says, "I've taken a lot of young women with high LDL levels and no risk factors off of them."
So what should people who are offered a drug take into account as they decide? Far more than just their cholesterol levels. The decision is almost a no-brainer for those who have had a cardiovascular event or clear evidence of clogged arteries—though the drugs aren't advised for those who are pregnant, nursing, or have liver disease. The NCEP issued new guidelines in 2004 that make clear distinctions between when medications should and should not be used in those who haven't yet developed heart disease. An LDL level of, say, 120 mg/dL—which would warrant drug therapy in a heart patient—is not considered worrisome in someone without symptoms or major risks.
On the other hand, diabetics are now automatically in the high-risk camp, considered to be as likely to have a heart attack, stroke, or other cardiac event within 10 years as someone who's already had one—about a 1-in-5 chance. "Diabetes causes multiple risks to the arteries, like high levels of inflammation and more blood clots," says cardiologist Melissa Walton-Shirley, who moderates a forum at theheart.org, a cardiologists' website, and is codirector of the cardiovascular lab at TJ Samson Community Hospital in Glasgow, Ky. Plus, elevated blood sugar levels make proteins and fats "stickier" and more likely to accumulate as plaque on the arteries.
In diabetics, like heart patients, explains Jacobson, "we can prevent one heart attack for every 30 high-risk people that we treat for five years." According to the guidelines, anyone with established heart disease or diabetes should follow a low-fat diet and exercise program and take medication to lower LDL levels above 100 mg/dL; doctors are also given the option of aiming for a more aggressive goal of 70.
To determine if the rest of the world is at high risk, moderately high risk, moderate risk, or low risk of developing heart disease, doctors are supposed to take into account five key factors: age, smoking history, blood pressure, HDL levels (lower than 40 mg/dL is a bad sign), and a family history of early heart disease (before age 55 for a male relative or age 65 in a female relative). Using a mathematical modeling tool such as the Framingham risk assessment calculator, they assign patients points for each factor and can calculate a 10-year likelihood of having a heart event. Those who have two or more of the five risk factors and 10-year odds of at least 1 in 5 are considered "high risk" and should aim to get below that LDL threshold of 100 mg/dL. High-risk folks who have low HDL, too, might benefit from adding a moderate dose of prescription niacin or a fibrate drug, such as TriCor or Gemcor, that raises HDL by altering fat metabolism.
Those who are at "moderately high risk" should aim for an LDL level of less than 130 mg/dL. This group includes anyone who has a somewhat lower Framingham score and two or more risk factors. If this is you, consider drugs if you can't get your cholesterol to a healthy level with lifestyle changes. If your likelihood of a heart attack is less than 1 in 10 over the next 10 years, the guidelines say medication isn't necessary unless LDL tops 160 mg/dL.
In people with just one risk factor or none at all, elevated cholesterol often shouldn't be treated with medication. The likelihood that the drugs will prevent a cardiac event is extremely slim, so any side effects are apt to be for naught. If LDL levels soar above 160 mg/dL, it's time for lifestyle changes; medication becomes more pressing if LDL levels hit 190 mg/dL.
The female factor. Whether women with high LDL and no heart disease derive any benefit from statins is questionable. Those who take the drugs are as likely to die of heart disease as those who do not, according to a 2004 review of 13 studies of women published in the Journal of the American Medical Association. The researchers did find that statins may reduce the likelihood of heart attacks, strokes, and heart surgery—but 140 women would need to be treated to prevent just one of these events. "We don't have a good idea of how the drug is metabolized in women compared to men," says Goldberg. "Do females need higher or lower doses?" Goldberg limits statins primarily to high-risk women. "If she has just one risk factor and her LDL is approaching where the guidelines say to medicate," she says, "I give her time to work things out with diet and exercise."
Like Larry Cohen, some people can't push low enough using statins alone; others simply can't tolerate the drugs. In Vytorin, they could get a lower dose statin plus the cholesterol-absorbing action of Zetia in the intestine. If, as it now appears, the combination's LDL-lowering benefit may not translate into a lower risk of heart disease, what does that mean for patients? Research suggests that statins offer bonus effects: They also raise HDL levels, reduce inflammation, and stabilize plaque so it's less likely to rupture. Zetia may not—and despite its LDL-lowering benefit, studies hint that it might also have some detrimental effect on the arteries, according to Allen Taylor, chief of cardiology at Walter Reed Army Medical Center in Washington. "These actions aren't intended and certainly weren't understood when the drug was approved [in 2002]," he says.
Stand fast. For now, the American Heart Association is telling doctors and patients to maintain the status quo, noting that none of the 720 participants in the study—who had extremely high cholesterol due to a genetic condition—were able to get their LDL levels down to a desirable level. What's more, the statement adds, the study simply looked at physical changes in artery walls, not at whether Vytorin did a better job of preventing heart attacks or deaths. That won't be known until a large study is completed in 2011. "I don't think there's significant information to direct change," says aha president Daniel Jones, dean of the University of Mississippi School of Medicine in Jackson. (The AHA received nearly $2 million in contributions from Vytorin maker Merck/Schering-Plough last year.)
Statins are, by and large, considered to be very safe drugs. But rarely, they elevate liver enzymes and can cause severe muscle deterioration and kidney malfunction. About 3 to 5 percent of users who participated in clinical trials developed muscle pains, though doctors say the true incidence may be 10 to 15 percent. One reason it's hard to know, according to a 2007 study from the University of California-San Diego, is that when statin users complain about muscle pain, half the time doctors tell them it has nothing to do with the drug. The same goes for memory loss. "If doctors don't acknowledge that these are real side effects, we can't expect them to report them to the FDA," says study author Beatrice Golomb.
But many of those who experience side effects from cholesterol drugs will tell you the pains are very real indeed—and quite different from everyday achiness. "It feels like that really, really sore feeling you get two days after going to the gym for the first time and using every machine to the max," says Walton-Shirley, who didn't realize what her patients were going through until she experienced these symptoms herself; she tried various statins until she finally found that she could tolerate a low dose—5 milligrams—of Crestor. Though still a firm believer, she notes that statins are not a magic bullet against heart disease. Her own prescription: Daily workouts on her elliptical trainer and treadmill, a nutritious diet, and a loss of 15 excess pounds.