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New lowdown on cholesterol

(This article was first printed in the October, 2004 issue of the Harvard Heart Letter. For more information or to order, please go to http://health.harvard.edu/heart.)

Advisory ratchets down targets for LDL (bad) cholesterol for some people, not others; no one-size-fits-all recommendation yet.

Advice on cholesterol tackles a contentious question in heart disease: How low should cholesterol levels go? For people who have had heart attacks or are at very high risk of having one, the answer is: Lower than before and almost as low as possible.

The same thing doesn't necessarily apply to everyone else. The target set for your LDL (bad) cholesterol depends on your cardiovascular health and the odds of your having a heart attack in the next 5 or 10 years. Levels range from an astonishing 70 or lower for those most likely to have heart attacks to 160 for healthy people (see LDL targets, below).

If a low, low LDL is good for one group, wouldn't it be just as good for everyone else? Maybe, maybe not (more about that later). There isn't good science, at least not yet, to support such a one-size-fits-all recommendation. Equally important, the cost of driving down cholesterol to basement levels - in terms of money, effort, and side effects - might not be worth the payoff for relatively healthy people.

LDL targets Aim for 70 mg/dL or lower if this describes you: You have been diagnosed with cardiovascular disease - meaning you have narrowed or partially blocked arteries in your heart, neck, legs, or elsewhere; or have chest pain (angina); or had a heart attack, stroke, or mini-stroke in the past; or have undergone bypass surgery or angioplasty - and one or more of the following also applies to you: You have diabetes or kidney disease. You smoke, your blood pressure isn't in the healthy range (below 130/85), or you have other uncontrolled risk factors for heart disease. You have several elements of the metabolic syndrome: a large waist (over 40 inches for men or 35 inches for women), triglyceride level above 150 mg/dL, low HDL (under 40 mg/dL for men or 50 mg/dL for women), high blood pressure (above 130/85), and high blood sugar (above 110 mg/dL) after a fast. You have recently had a heart attack or been hospitalized for unstable angina. Aim for 100 mg/dL or lower if just one of the following applies to you: You have had a heart attack, stroke, or mini-stroke. You have chest pain (angina). You have peripheral artery disease or narrowed carotid arteries. You have had bypass surgery, angioplasty, or a procedure to open a narrowed artery in your neck. You have diabetes or kidney disease. You have two or more major risk factors for heart disease, such as smoking, high blood pressure, or a family history of heart disease before age 60. Aim for 130 mg/dL or lower - with an emphasis on "lower" - if your odds of having a heart attack in the next five years are between 10% and 20%.* Aim for 130 mg/dL or lower if your odds of having a heart attack in the next five years are under 10%.* Aim for 160 mg/dL or lower if your odds of having a heart attack are low (you have no more than one risk factor). *To calculate your risk, talk with your doctor or visit http://hin.nhlbi.nih.gov/atpiii/calculator.asp

Here are the main changes in the advice on cholesterol from the National Cholesterol Education Program (NCEP), endorsed by the American Heart Association, the American College of Cardiology, and the National Heart, Lung, and Blood Institute. The panel that wrote the guidelines included Heart Letter associate editor Richard Pasternak. The guidelines, which appeared in the July 13, 2004 issue of Circulation, recommend:

• an LDL of 70 or below (down from 100) for people at very high risk of having a heart attack
• an LDL of 100 or below for people at moderately high risk
• a lower threshold for starting drug therapy to reduce LDL levels in people at high and modest risk
• cholesterol-lowering therapy even for some people with so-called optimal LDL levels
• that drug doses be strong enough to cause a 30%-40% drop in LDL, regardless of starting level.

Why now?

In 2001, the NCEP overhauled the standards for diagnosing and treating high cholesterol. It emphasized LDL as the troublemaker to watch and defined three risk groups with different LDL cutoffs at which to start cholesterol-lowering therapy.

Since then, a half-dozen trials have indicated that cholesterol-lowering statin drugs may be good for a wider range of people than previously believed, that LDL levels as low as 70 (or even lower) are good for people likely to have heart attacks in the near future, and that aggressively lowering LDL can even benefit some people with so-called optimal cholesterol levels.

Defining benefits

Statins work by blocking the liver from making cholesterol, a substance the body needs for building cells, forming hormones, and a host of other essential functions. When the liver can't make cholesterol, it draws LDL cholesterol from the blood to use as raw material. The less LDL in the bloodstream, the less there is available to trigger or promote the artery-clogging process known as atherosclerosis. Statins also appear to stabilize cholesterol-filled deposits in artery walls, promote the growth of new blood vessels, and calm inflammation. All of these actions can help steer you away from a heart attack or other forms of cardiovascular trouble.

Six statins are available in the United States: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor, generic), pravastatin, (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor).

There's no question that statins are one of the most important advances in drug therapy in the last 25 years. But they don't work miracles. Let's put their benefits into perspective, using information from two of the trials cited in a NCEP report.

The Heart Protection Study compared a daily dose of 40 milligrams (mg) of simvastatin against a placebo in more than 20,000 men and women with heart disease or diabetes, some of whom had cholesterol levels in the normal range. After five years, simvastatin therapy reduced the relative risk of heart disease by 24%.

That doesn't mean only one-fourth as many people taking the drug were stricken. Rather, 19.8% of those taking simvastatin had had a heart attack or stroke, needed a procedure to bypass a clogged heart artery, or died of heart-related causes, compared with 25.2% of those taking placebo. Put another way, if 1,000 people with heart disease or diabetes took simvastatin every day for five years, it would prevent 70-100 heart attacks, strokes, heart procedures, or deaths.

The Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial compared two different intensities of cholesterol-lowering therapy in people just hospitalized for a heart attack or chest pain at rest. Two years of treatment with standard-dose pravastatin (Pravachol, 40 mg) lowered LDL below the then-current target to a very respectable 95, while high-dose atorvastatin (Lipitor, 80 mg) dropped LDL levels into the 60s. Those with the lower LDL levels were 16% less likely to have had a repeat heart attack, needed bypass surgery or angioplasty, or died of heart disease. In absolute terms, the high-dose approach improved the chances of avoiding a heart-related problem from 73.7% to 77.6%.

Don't jump the gun

If it was a snap to substantially lower LDL, maybe we'd all be urged to do it. But it isn't always a simple matter. Eating a healthier diet, losing weight if needed, exercising more, and reducing stress can shave LDL levels by 5%-10%. That's absolutely worth doing, and these steps yield widespread benefits that go far beyond heart disease. But a 30%-40% reduction requires either the kind of intensive lifestyle changes promoted by Dr. Dean Ornish or lifestyle changes plus medication. All medications, including the ones used to lower LDL, cost money (see drug comparison table) and sometimes cause side effects.

If you are at high risk of having a heart attack, the benefits of getting serious about cholesterol far outweigh the costs and risks of medication. Things are much more murky if you don't have signs of heart disease or are at low risk for it. Uncertainty over the balance of benefits and risks for people in the low-risk category is reflected in the guidelines, which leave LDL targets for healthy people at 160 or below.

Here's one way to think about it. Take 100 very-high-risk people. In this case, very high risk means 40% will have a heart attack, need bypass surgery or angioplasty, or die of heart disease over a 10-year period. If all of them faithfully take a statin for 15 years, somewhere between half and all of them will derive some benefit from the drug. Now take 100 people at moderate (10%) risk who take a statin for 15 years. Only 10 or so would benefit from 15 years' worth of statin therapy. For people at even lower risk, the costs and risks of drug therapy further counterbalance the benefits.

Beyond statins

The latest guidelines emphasize statins, mostly because these are the most carefully studied of the cholesterol-lowering drugs. Although they work without side effects for most people, they don't work that well for some, and they cause side effects in others. Several other drugs can boost the LDL-lowering effect of statins or can be used in place of them.

The runaway best "drug" to use with a statin is exercise and healthy eating. This approach improves all types of cholesterol and blood fats, is a proven way to prevent or treat diabetes and osteoporosis, and helps virtually all of the body's systems.

If you have high triglycerides - the main fat-carrying particle in the blood - in addition to high LDL, the class of drugs known as fibrates may help. These include fenofibrate (Tricor, generic) and gemfibrozil (Lopid, generic).

If you have low HDL (good) cholesterol, niacin is an option. Niacin alone lowers LDL by 15% or so, triglycerides even more, and boosts HDL by as much as 20%. With a statin, niacin drops LDL an extra 10%.

Colesevelam (WelChol) latches onto cholesterol and bile acids in the intestine and locks them into a gooey, watery mess that is excreted in the stool. Like niacin, it lowers LDL about 15%-20% by itself, and adds an extra reduction of 6%-10% when combined with a statin.

Ezetimibe (Zetia) blocks cholesterol in food from crossing the intestinal wall and getting into the bloodstream. It, too, reduces LDL levels by 20% or so alone, or by an extra 15-20% when combined with a statin. In mid-July of 2004, the FDA approved a drug named Vytorin that combines Zetia and Zocor in a single pill.