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Help for your cholesterol when the statins won’t do

(This article was first printed in the March 2005 issue of the Harvard Men’s Health Watch. For more information or to order, please go to

If you are one of the many, but also one of the few…

After a routine check-up, your doctor says that you are one of the many, the 100 million Americans with an unhealthy cholesterol level. Since you are already pretty careful about your diet and you walk every day, medication is the next step. Like most physicians, your doctor prescribes one of the statin drugs. It’s a good choice; these widely popular drugs can lower LDL (“bad”) cholesterol levels by 20%–60%, thus reducing the risk of cardiac events (unstable angina, heart attacks, and cardiac deaths) by 24%–37%. If that’s not enough reason to start therapy with a statin drug, consider that it appears to reduce the risk of stroke by 24%–31% — and it may even protect you against osteoporosis (“thin bones”) and dementia.

Unfortunately, you also turn out to be one of the few, one of the 3%–4% of people who don’t do well with a statin drug. In a few cases, the drugs simply don’t work, but more often the reason is a side effect. The most common statin toxicity is liver inflammation. Most patients with the problem don’t even know they have it, but some develop abdominal distress, loss of appetite, or other symptoms. Even without these complaints, liver enzyme abnormalities, such as high aminotransferase levels, show up in the blood tests of 1%–2% of people taking a statin drug. The other major side effect is muscle inflammation, which can be silent or cause cramps, fatigue, or heavy, aching muscles. Like liver inflammation, muscle damage can often be detected with a simple blood test; in this case, it’s an abnormally high level of creatine phosphokinase (CPK). It’s the reason the statin drug cerivastatin (Baycol) was withdrawn from the market on August 8, 2001, because of 31 cases of fatal rhabdomyolysis (muscle damage). Fortunately, the other statins have proved much safer. Other possible side effects include loss of concentration, sleep disturbance, nerve inflammation, nausea, diarrhea, and rash. A few men may also develop breast enlargement or impotence.

Table 1: Cholesterol goals for healthy adults



Total cholesterol

Below 200 mg/dL


200–239 mg/dL

Borderline high

240 mg/dL or above


LDL (“bad”) cholesterol

Below 100 mg/dL


100–129 mg/dL

Near or above optimal

130–159 mg/dL

Borderline high

160–189 mg/dL


190 mg/dL or above

Very high

HDL (“good”) cholesterol

Below 40 mg/dL


40–59 mg/dL


60 mg/dL or above


It’s a long list of side effects, but it shouldn’t stop doctors from turning to a statin first when medication is needed to bring cholesterol into range. Fortunately, most side effects are mild and disappear promptly when the statin is stopped. In some cases, the problems will resolve simply by reducing the dose or switching to another statin, but care is required. Still, all in all, the statins are the safest and best tolerated of all cholesterol-lowering medications.

Although most patients respond well to statin therapy, some don’t. But don’t reserve a bed in the Coronary Care Unit just because a statin is not right for you. In fact, many other helpful medications are available, and they can even be more effective than the statins for some cholesterol problems, particularly low levels of HDL, the “good” cholesterol.

Who should be treated?

In a sense, everyone. That’s because no cholesterol level is too good. But people with unhealthy levels should work hard to improve, while those with ideal results can afford to relax a bit. Table 1 (see above) shows the goals established by the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults.

Cholesterol is a crucial determinant of cardiovascular health, but it’s only one. In fact, smoking is even more dangerous than unhealthy cholesterol levels, and high blood pressure, diabetes, and lack of exercise are nearly as harmful. Because each risk factor adds to the harm of others, people with the most risk need the most vigorous treatment. Table 2 (see below) shows how an individual’s risk profile influences the choice of therapy.

Lifestyle therapy: The first step

With so many people in need and so many medications available, it’s understandable that both doctors and their patients are tempted to rely on medications to improve unhealthy cholesterol levels. That’s a mistake. Instead, lifestyle therapy is the place to start. That means avoiding tobacco in all its forms. It also means choosing foods low in saturated fat, trans-fatty acids, and cholesterol while favoring foods that provide heart-healthy omega-3 and monounsaturated fats and large amounts of dietary fiber. It also requires regular exercise, which can be as simple as walking at a moderate pace for at least 30 minutes nearly every day. And the combination of a good diet and regular exercise should help men achieve another important goal, weight control.

Lifestyle therapy can improve cholesterol levels, and certain foods can provide extra help (see “Foods that lower cholesterol” below). But even with clean living, many people need medication to achieve optimal cholesterol levels, particularly when they have to reduce their LDL levels to 100 mg/dL or less. It’s important to keep up a good diet and exercise program even if you take medication. And if you can’t take a statin, here is a rundown of other medications that can help; Table 3 (see below) summarizes their effects on blood lipids and compares them to the statins.

Foods that lower cholesterol

A heart-healthy diet means more than simply avoiding harmful fats, simple sugars, and excess calories; it also means eating lots of whole grains, fruits, vegetables, nuts, and fish that provide vitamins, fiber, and omega-3 fats. But some foods can provide extra help by actually lowering LDL (“bad”) cholesterol levels — and they work best in people with high cholesterol levels.

Soluble fiber can lower cholesterol levels substantially. Oat bran is the best-known example; 1–2 ounces a day should reduce your cholesterol by 10%–15%. Other excellent sources include beans, barley, prunes, citrus fruits, apples, Brussels sprouts, broccoli, and apricots. Psyllium, a natural grain from India, is also rich in soluble fiber. It is not part of the American diet, but you can get it in supplements such as Metamucil or Perdiem Fiber. On average, 3 teaspoons a day will drop cholesterol levels by 15% within 4 months.

Soy protein has a similar effect, but it takes quite a lot of soy to do the job; 1–2 ounces a day will lower LDL cholesterol levels by about 12%. Soy may have other health benefits as well. Try tofu, soy milk, soy flour, or soy-based meat substitutes to see if soy is right for you.

Plant stanols sound exotic, but they are widely available in margarines such as Benecol and Take Control. They are more expensive than traditional spreads, but people who consume about 2 tablespoons a day can lower their LDL levels by up to 14%.

Several other foods may also help. Health nuts will be glad to know that nuts may help lower cholesterol levels, but it takes quite a lot of nuts to have an impact, and that means a lot of calories. Despite wide popularity, garlic has had mixed results in clinical trials. And although none of these foods will boost HDL cholesterol levels, one liquid food will do just that. It’s alcohol — but like cholesterol-lowering drugs, it can have major side effects. Think over the risks and benefits of alcohol, and if you choose to drink, do so responsibly and keep your dose low. For men, that means 1–2 drinks a day, counting 5 ounces of wine, 12 ounces of beer, or 1 1/2 ounces of spirits as one drink.

When it comes to lower cholesterol, foods may not rival medications — but they cost less, taste better, and are safer. Best of all, people who eat right may not need drugs at all.


Doctors often prescribe a fibrate for patients who can’t take a statin. Like the statins, fibrates reduce the body’s cholesterol production, but they are less effective in lowering LDL cholesterol levels. In other areas, though, fibrates actually have the edge. They are substantially better at boosting HDL levels, and only two statins, atorvastatin (Lipitor) and rosuvastatin (Crestor), can match their ability to reduce triglyceride levels.

Gemfibrozil (Lopid) and fenofibrate (TriCor) appear equally safe and effective. Fenofibrate is more convenient, since it is taken once rather than twice a day, but generic gemfibrozil is substantially less expensive. The fibrates are particularly effective in patients with high triglycerides, low HDL, or diabetes. However, some patients with high triglyceride levels may experience a paradoxical rise in LDL levels. Side effects are uncommon but can include liver inflammation, muscle damage, abdominal pain, gallstones, dizziness, and interactions with the anticoagulant (“blood thinner”) warfarin (Coumadin).

Fibrates should not be taken by patients with advanced liver or kidney disease, and they should not be combined with a statin except under very strict medical supervision, including careful monitoring for muscle damage. While the risk of muscle damage from either statins or fibrates alone is small, a Harvard study found that the combination of a statin and a fibrate increases that risk more than sixfold.

Table 2: Goals for LDL cholesterol

Risk category

LDL goal

Optional LDL goal

Very high risk

Acute coronary artery syndrome

Below 70 mg/dL

High risk

Stable coronary artery disease




Multiple cardiac risk factors*

Below 100 mg/dL

Below 70 mg/dL

Moderate risk

Two or more cardiac risk factors*

Below 130 mg/dL

Below 100 mg/dL

Low risk

0–1 cardiac risk factor*

Below 160 mg/dL

Below 130 mg/dL

*Risk factors include cigarette smoking, high blood pressure (over 140/90 mm Hg or on treatment), low HDL cholesterol (under 40 mg/dL), a family history of premature coronary artery disease in a parent or sibling (below age 55 in a male, 65 in a female), and age (over 45 in men, 55 in women).

All individuals who are above their LDL goals should follow a therapeutic lifestyle that includes diet, exercise, weight control, and tobacco avoidance. Drug therapy may be needed to achieve these goals; medication is usually needed to reduce LDL cholesterol to 100 mg/dL and is almost always needed to reduce it to 70 mg/dL. Most patients will benefit from a statin, with additional drugs if necessary; a fibrate or nicotinic acid may be used to raise HDL cholesterol or lower triglyceride levels.

Developed from updated recommendations of the National Cholesterol Education Program. Circulation, July 2004; 110: 227–239.


Unlike other cholesterol-lowering medications, which are absorbed into the body, resins remain in the intestinal tract, where they latch onto bile acids, preventing them from being absorbed into the bloodstream. Because the liver uses bile acids to produce cholesterol, the net effect is to lower LDL levels, but in a few patients, triglyceride levels may rise.

Resins were the first cholesterol-lowering drugs to reach the American market. Although they are effective and have few serious side effects, they have not been widely used. That’s because many patients find them unpalatable due to bloating, constipation, and nausea. But the resin, colesevelam (WelChol), appears to have fewer of these side effects, and it is proving particularly useful as add-on therapy for patients who do not respond fully to other drugs, including statins. Resins can interfere with the absorption of other medications, including digoxin, thyroid hormones, and some beta blockers, calcium-channel blockers, and diuretics. Always review your medications with your doctor or pharmacist before you start a resin.


A type of cholesterol-lowering drug, ezetimibe (Zetia), is assuming a significant clinical role. The drug acts by blocking the intestinal absorption of cholesterol in a different way than the resins do. On its own, a 10-mg dose can reduce LDL cholesterol levels by 17%–19%, a major benefit. When added to a statin drug, ezetimibe can produce additional LDL reductions of about 25% without boosting the risk of statin side effects. Ezetimibe can enable some patients who experience side effects from high-dose statins to reduce the dose to one that is tolerated. As a result, the FDA has approved a preparation combining simvastatin and ezetimibe in a single tablet (Vytorin).

Ezetimibe has remarkably few side effects; a few patients may develop mild diarrhea. It also has a very low potential to interact with other medications. Another advantage is the convenience of taking a single 10-mg tablet once a day. The only apparent disadvantages are the limited clinical experience and its expense.


Unlike statins, fibrates, resins, and ezetimibe, niacin (nicotinic acid) is available without a prescription. It’s a natural vitamin, vitamin B3. It also has the best effect on HDL cholesterol as well as an excellent ability to lower triglycerides and a good ability to reduce LDL levels. But that doesn’t mean niacin is right for you. To improve your cholesterol levels, you’ll need 20–200 times more niacin than the Dietary Reference Intake of 15 mg a day. At those doses, niacin has potentially serious side effects. Whether you get it with a doctor’s prescription or on your own, treat niacin as a serious drug. Use it only if you must, always under medical supervision.

The many niacin preparations fall into two categories, crystalline and controlled release. Crystalline niacin is quickly absorbed and rapidly metabolized, so it’s usually taken two or three times a day, ideally at the end of a meal (but not with hot foods or beverages). Many patients experience unpleasant itching, flushing, and headaches, particularly as the dose is slowly increased. This side effect can be minimized by taking an 81-mg aspirin tablet 30–60 minutes before taking niacin.

Table 3: Drugs for cholesterol


Effect on LDL (“bad”)cholesterol levels

Effect on HDL (“good”) cholesterol levels

Effect on triglycerides


Lovastatin (Mevacor)

Pravastatin (Pravachol)

Fluvastatin (Lescol)

Simvastatin (Zocor)

Rosuvastatin (Crestor)

Atorvastatin (Lipitor)

Down 20%–60%

Up 5%–15%

Little change,
except atorvastatin and rosuvastatin (down 40%)


Fenofibrate (TriCor)

Gemfibrozil (Lopid)

Down 10%–30%

Up 10%–35%

Down 20%–50%


(Questran, LoCholest)

Colestipol (Colestid)

Colesevelam (WelChol)

Down 15%–30%

Up 3%–5%

Little change;
may rise in
some patients

Absorption Blocker

Ezetimibe (Zetia)

Down 17%–19%

Little change

Down about 8%


Crystalline (many brands)

Controlled-release (Niaspan and others)

Down 10%–25%

Up 15%–35%

Down 20%–50%

Controlled-release preparations are much less likely to produce flushing and itching; however, they are more likely to produce liver inflammation, to raise blood sugar levels in diabetics, and to trigger gout by raising uric acid levels. Other side effects can include fatigue, blurred vision, nausea, peptic ulcers, and impotence. Niacin prescriptions vary widely in price; brand names are much more expensive than over-the-counter generics. But since over-the-counter preparations are sold as dietary supplements, not drugs, they are not regulated by the FDA and so vary widely in efficacy.

Despite these worries, niacin can be extremely helpful. The granddaddy of cholesterol-lowering drugs, it was the first medication to lower cholesterol levels (1955), the first to reduce heart attacks (1984), and the first to lower long-term mortality rates (1986). Because it is harder to take, niacin was quickly overshadowed by statins, but it is finding new uses in patients who cannot tolerate statins and in those with low HDL. Niacin is also effective in combination with other medications, including statins, sometimes in very low doses that have few side effects. The FDA has approved a combination drug that contains extended-release niacin and lovastatin (Advicor).


Statins are the undisputed stars of the cholesterol-lowering medications. It’s a lofty position that is well deserved, and it’s likely to endure even as scientists develop new and better medications, including a new generation of “super-statins.” But behind every star is a supporting cast, and in the case of cholesterol, the second- and third-choice drugs can have first-rate benefits, either alone or together.

Don’t despair if you can’t take a statin. Instead, work with your doctor to find a program that’s effective. Above all, remember that even statins finish second behind lifestyle therapy. Even if you can’t take a statin, you can enjoy the many benefits — and pleasures! — of a healthful diet and regular exercise.

(This article was first printed in the March 2005 issue of the Harvard Men’s Health Watch. For more information or to order, please go to

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