Drug Treatments for High Cholesterol

If lifestyle changes don't lower your cholesterol enough or your doctor feels your cholesterol levels are so high that you need medication right away, the best approach is diet and exercise plus medication. However, even taking cholesterol-lowering medication doesn't give you license to make daily trips to the ice cream store and forget about exercise. On the contrary, the people who reduce their heart risk the most are those who diet, exercise, and take medication.

At the University of Texas Medical School, researchers followed more than 400 men and women with angina or other forms of coronary artery disease. Some of them did little to control their cholesterol levels. Others gave cholesterol control a decent try by taking a statin and following a standard heart-healthy diet, or by following a very strict diet. Those in a third group went all out — they adopted a strict diet, exercised, and took a statin. The all-out approach was the clear champion. During the five-year study, only 1 in 20 of the people in this group had a heart attack, underwent a procedure to open or bypass cholesterol-narrowed arteries, or died of heart disease. Rates of such cardiovascular problems ballooned in the medium-effort and do-nothing groups.

A number of cholesterol-lowering drugs are available. Which ones a physician prescribes depends on your individual lipid profile, other risk factors, other medications you take, and your general health.

Reductase Inhibitors (statins)

Reductase inhibitors, more commonly known as statins, were first introduced clinically in 1987 and today are the most widely used class of cholesterol-lowering drugs. They work by fundamentally changing the way the liver handles cholesterol. By blocking a key liver enzyme involved in cholesterol production (3-hydroxy-3-methylglutaryl coenzyme A reductase), they decrease the amount of cholesterol that can be dumped into the blood and increase the amount of LDL the liver can remove from the blood (see Figure 7). Six statins are currently on the market: atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor), pravastatin (Pravachol), rosuvastatin (Crestor), and simvastatin (Zocor). Three of these drugs — lovastatin, pravastatin, and simvastatin — are also available in generic form. Clinical studies show that statins can lower LDL cholesterol by 20%–60% and raise HDL by 2%–10%. Large, randomized clinical trials of statins show that the use of these drugs is associated with a 20%–30% reduction in death and in the incidence of major cardiovascular events such as heart attacks, strokes, and angina.

Figure 7: How statins work   How statins work   Most of the cholesterol circulating in your blood has been made by your liver, not digested from the food you eat. An enzyme called HMG CoA reductase plays a key role in deciding how much cholesterol the liver makes.

Statins have few known side effects. They are capable of damaging the liver and muscles, but such problems are rare. However, one statin drug, cerivastatin (Baycol), was voluntarily removed from the market in 2001 because it was associated with multiple occurrences of rhabdomyolysis, a condition characterized by muscle cell damage that can lead to kidney failure and, very rarely, death. Rosuvastatin (Crestor) came under fire in 2004 when critics charged that it was more likely than other statins to cause rhabdomyolysis and kidney failure. After reviewing the data, however, the FDA concluded that Crestor was safe, but also warned that to reduce risk, the lowest doses should be prescribed in people older than 65, those who have hypothyroidism or kidney disease, and Asian Americans. Statins can also make people drowsy, constipated, or nauseous, but these side effects are relatively uncommon.

Although statins have been in use since the 1980s and are used by millions of people, it's still important to conduct long-term studies because people will probably take these drugs for many years. The first such analysis offers some reassurance: A decade-long study from Sweden showed that the side effects of therapy with simvastatin were limited to minor, temporary changes in liver enzymes circulating in the bloodstream.

Most clinicians recommend that, to be safe, anyone using a statin have his or her liver function checked periodically. Initially, doctors tended not to prescribe statins to people with existing liver disease or to heavy drinkers, whose livers may be under stress. However, several studies have found that most people with liver abnormalities can take statins safely without further damage to the liver. If you have liver problems, the decision of whether to take a statin should be based on your individual needs and medical history. If you do go on a statin, you should have regular liver-function tests.

Statins do not appear to interfere with most of the other medications that people with heart disease often take. Another advantage is that they require only a single daily dose. The drawback is their expense — a month's worth of statins runs about $35–$120, depending on the type and the daily dose needed. Although prices vary, the generic statins (lovastatin, pravastatin, and simvastatin) cost about half to two-thirds what the prescription statins cost. If money is an issue, talk with your doctor about whether you should switch from a brand-name statin to a generic one.

With six statins available, physicians, insurers, and patients want to know, "Is one statin the best, or do they work equally well?" Most experts agree that all six work well; however, potency and side effects of the statins can vary from person to person and from one drug or dosage to another, particularly at higher dosages. Work with your physician to find the right choice for you.

If cost is a factor, it's good to know that research has shown that most people can reach their LDL target with any statin. In other words, the specific drug doesn't matter as much as a person's persistence and a close working relationship with his or her physician.

Ezetimibe

Another drug on the cholesterol-lowering block is ezetimibe (Zetia). Like a statin, ezetimibe reduces total cholesterol, LDL cholesterol, and apolipoprotein B, a protein constituent of LDL cholesterol. It works in a different way than statins, though. Instead of interfering with the body's mechanism for making cholesterol, ezetimibe interferes with the body's absorption of dietary cholesterol from the small intestine. Taking ezetimibe along with a statin puts two different mechanisms to work, so it's more effective than taking either drug alone. Ezetimibe can also be used as an alternative for people who can't tolerate statins or other cholesterol-lowering agents, but it is not as effective in lowering LDL as any of the statins.

Long-term information is not yet available on ezetimibe's side effects, but, so far, they are few. Some people experience fatigue, stomach pain, or diarrhea.

Fibric Acid Derivatives (fibrates)

Drugs in this family block the production and activity of proteins that transport cholesterol (see Table 8). The two most commonly prescribed fibric acid derivatives are gemfibrozil (Lopid) and fenofibrate (TriCor). Fibric acid derivatives reduce triglyceride levels by 20%–50% and raise HDL levels by 10%–15%, but they have only a modest effect on LDL. They are mainly prescribed for people with high triglyceride levels and are rarely used for people whose sole problem is high LDL.

Gemfibrozil and fenofibrate, which come in pill form, are generally taken once or twice a day with meals. Most people don't experience side effects, although a few develop dyspepsia (feelings of fullness, bloating, or heartburn after eating), dizziness, or changes in sensations such as touch and taste. Gemfibrozil and fenofibrate also can increase the risk for gallbladder disease. When used with a statin, fibric acid derivatives can cause rare cases of significant muscle breakdown. However, evidence suggests that fenofibrate may be less likely to do this than gemfibrozil when used with moderate doses of statins. Fibrates can also boost the action of blood thinners such as warfarin (Coumadin). Because of these uncommon but real side effects, everyone taking a fibric acid derivative should have liver-function and blood count tests before and during therapy. And those on blood-thinning medications should have their prothrombin time (a measure of clotting ability) monitored closely.

Niacin

The B vitamin niacin, also called nicotinic acid, is an essential part of a healthy diet. Too little niacin leads to a disease called pellagra, which was once common in the southern United States and is still a major problem in parts of Asia and Africa. At doses way above the Recommended Dietary Allowance — say, 1,000–2,500 mg (1–2.5 grams) a day — crystalline nicotinic acid acts as a drug instead of a vitamin (see Table 9). It can reduce total cholesterol levels by up to 25%, lowering LDL and raising HDL levels, and can rapidly lower the blood level of triglycerides. It does so by reducing the liver's production of VLDL, which is ordinarily converted into LDL.

Niacin is safe — except in people with chronic liver disease or certain other conditions, including diabetes and peptic ulcer. It is also inexpensive. However, it has numerous side effects. It can cause rashes and aggravate gout, diabetes, or peptic ulcers. Early in therapy, it can cause facial flushing for several minutes soon after a dose, although this response often stops after about two weeks of therapy and can be reduced by taking aspirin or ibuprofen half an hour before taking the niacin. A sustained-release preparation of niacin (Niaspan) appears to have fewer side effects, but may cause more liver-function abnormalities, especially when combined with a statin.

Many people begin treatment at low doses (250 mg twice a day, for example) and, over six weeks or so, gradually build up to an amount that lowers lipid levels, anywhere from 1,000 to 2,500 mg split between two doses during the day. This gradual approach may help build tolerance to side effects such as facial flushing. Although niacin is available over the counter, you should not use it in quantities sufficient to lower cholesterol without a physician's supervision. It is important to test liver function and levels of blood sugar and uric acid before beginning niacin therapy and during the course of treatment.

Niacin's cousin, niacinamide (nicotinamide), cannot be used in place of niacin to lower cholesterol. Although niacinamide closely resembles niacin and is equivalent as a vitamin, it has no effect at all on blood cholesterol. This is unfortunate, because large doses of niacinamide do not have the side effects that can make large doses of niacin unpleasant.

Bile Acid Binders

Bile acid binders are synthetic resins that bind chemically with cholesterol-rich bile acids in the intestine, preventing their reabsorption (see Table 10). To replace the bile acids lost in this way, the body draws upon its store of cholesterol, thus lowering cholesterol levels in the blood. Medications in this class include cholestyramine (Questran), colesevelam (WelChol), and colestipol (Colestid). Typically, they lower LDL cholesterol by 15%–30%, depending on the daily dose. Larger amounts produce greater reductions, but also more pronounced side effects.

Because of the many unpleasant side effects of bile acid binders, their use is waning. Since ezetimibe has come along, anyone who would've taken bile acid binders in the past will probably get ezetimibe instead. Side effects of bile acid binders include constipation, heartburn, and a bloated feeling. Bile acid resins can bind with substances other than bile acids and may interfere with the body's ability to absorb some medications, particularly digitalis preparations, beta blockers, warfarin, thiazide diuretics, anticonvulsants, and thyroid hormone supplements. People with high triglyceride levels should not take bile acid binders because they tend to elevate triglycerides. Otherwise, the resins are quite safe.

Drug Combinations

There are sometimes advantages to pairing cholesterol-lowering medications. Such combinations can be more beneficial than either medication alone. Equally important, multidrug regimens may cause fewer side effects, partly because they rely on lower doses of each medication.

For example, gemfibrozil and niacin are an oft-used and well-tolerated combination. Another example is Vytorin, a combination of the drugs ezetimibe and simvastatin. Although doctors had been prescribing this combination of drugs already, Vytorin allows patients to get the two medications in one pill, which can be cheaper and more convenient.

Not all cholesterol-drug combinations are safe. The combined use of any statin and a fibric acid derivative can lead to severe muscle damage, causing kidney failure and even death. While it is difficult to estimate the frequency of this risk, it is likely lower than 0.01%. Evidence suggests that fenofibrate may be safer than gemfibrozil when used in combination with a statin. With any multidrug regimen, routine exams and blood testing for signs of either muscle damage or liver dysfunction is prudent, both at the start and during the course of the therapy.

Selective Estrogen Receptor Modulators

Sometimes called "designer estrogens," selective estrogen receptor modulators block the effects of estrogen in some parts of the body, such as the breasts, but not in others. One of these drugs, raloxifene (Evista), reduces levels of both total and LDL cholesterol, but does not increase HDL. However, it is not clear whether this helps heart disease risk.

Substances That May Lower Cholesterol

When the recommended remedy for a medical condition or ailment involves substantial lifestyle changes, you can bet that people will be on the lookout for a quicker or simpler solution. That is certainly the case with high cholesterol. A number of specific foods or supplements have been touted as sure-fire ways to lower cholesterol. Some of these show promise; others don't. But none take the place of an overall effort to lower fat and cholesterol in your diet.

Plant sterols and stanols. Plant sterols, obtained from pine trees, soybeans, and other plants, are chemical cousins of cholesterol that, nevertheless, may help lower your own cholesterol level. Plant sterols (also known as phytosterols) and the related compounds called plant stanols (or phytostanols) prevent the body from absorbing cholesterol from food. Since the liver needs cholesterol to make bile acids for digestion, it grabs LDL cholesterol from the bloodstream, while leaving HDL cholesterol alone. As a result, both total and LDL cholesterol levels fall.

The first sterol- and stanol-enriched products sold in the United States were margarines, such as Benecol and Take Control. But these substances are now showing up in a variety of other products, including Minute Maid Heart Wise orange juice, Nature Valley Healthy Heart granola bars, Rice Dream Heartwise rice milk, Lifetime low-fat cheese, CocoaVia chocolates, and Vivola cooking oil.

It isn't clear who might benefit from the ability of plant sterols and stanols to lower cholesterol: Some people using these products see their LDL drop as much as 20%; others see little or no reduction. The effect appears to be more pronounced when plant sterols and stanols are used by people who consume an average (meaning relatively high-fat) diet. Whether these compounds are right for you also depends on your current cholesterol levels. If your cholesterol level is slightly elevated, consuming more plant sterols and stanols could be enough to rein it in. But if your cholesterol level is already substantially above where it should be, then a statin should be your first choice.

One group of people should stay away from these foods — those with the rare genetic disorder known as phytosterolemia or sitosterolemia, who absorb plant sterols and stanols at abnormally high rates. In such people, these substances accumulate and cause the same problems as too much cholesterol.

If you decide to try plant sterols or stanols, remember that persistence is key: You need to eat about two grams worth of added sterols or stanols every day to put a dent in your cholesterol. Doing it once in a while won't work. It's also important to keep track of total calories; two glasses of Heart Wise orange juice, for example, contribute 220 calories along with sterols. If you don't reduce calories elsewhere, you may gain weight — counteracting some of the benefit of the fortified foods. Another thing to think about is the impact on your wallet: Products enriched with sterols or stanols may cost much more than you'd pay for regular products.

Fiber. Fiber can slightly lower both total and LDL cholesterol. Perhaps more significantly, a number of studies show that fiber helps to prevent heart disease and reduce the risk of heart attack. For example, in the Harvard-based Nurses' Health Study, women who ate two to three servings of whole-grain products (mostly bread and breakfast cereals) each day were 30% less likely to have a heart attack or die from heart disease over a 10-year period than women who ate less than one serving per week.

The 2005 federal Dietary Guidelines for Americans recommend 14 grams of fiber for every 1,000 calories consumed — about 25 grams a day for many women and 30 grams a day for many men. The best way to get fiber is to eat a diet rich in whole grains, fresh fruits, and vegetables, which provides not only fiber but also other nutrients that may guard against heart disease, cancer, and other chronic diseases.

The main drawback to eating a high-fiber diet or taking a fiber-rich supplement is flatulence, especially if you go straight from low fiber consumption to high fiber consumption. The digestive system has trouble breaking down all the complex carbohydrates it receives and generates a higher than usual amount of gas. Slowly increasing the amount of dietary fiber can often prevent or at least minimize this effect. Constipation is another problem; it can be prevented by drinking extra water.

Fiber comes in two forms: water-soluble and insoluble. Soluble fiber in particular has been associated with improvements in lipid profiles. Oat bran, a good source of soluble fiber, was linked to a decline in cholesterol in the 1980s, prompting an unprecedented rush on the product, which quickly appeared in foods ranging from bread to beer. Studies of other foods high in soluble fiber, such as corn, beans, lentils, and peas, found much the same result. Soluble fiber helps reduce cholesterol levels in two ways: The high-bulk food crowds fat out of the diet, and — through a somewhat complicated chain of molecular events — it leaches LDL from the body, ultimately lowering the blood level of LDL. However, keep in mind that the impact of soluble fiber alone is relatively small. Researchers at the Harvard School of Public Health analyzed the results of 67 rigorous trials of soluble fiber and found that eating 3 grams of soluble fiber a day from oats (about 3 bowls of oatmeal) would decrease total and LDL cholesterol by about 5 mg/dL. A diet high in pectin, a soluble fiber found in such fruits as tart apples, citrus fruits, cranberries, and sour plums, can also reduce high cholesterol levels. Wheat bran, which is an insoluble fiber, has no direct effect on cholesterol.

Psyllium, a soluble fiber derived from the husk of a plant related to the common weed plantain (ribgrass), has earned a reputation for its cholesterol-lowering properties. According to the American Heart Association, in some studies, people eating a typical American diet who took fiber supplements with psyllium have had 15% drops in LDL levels, while people on a more restricted diet who took psyllium saw drops of 9%. Psyllium is safe and far less likely to cause bothersome side effects than some of the older cholesterol-lowering medications. You can buy psyllium in health food stores, grocery stores, and pharmacies. It is also the primary ingredient in fiber-based laxatives such as Metamucil and in breakfast cereals such as Kellogg's All-Bran Bran Buds.

Flaxseed has also been touted for its ability to prevent heart disease. These tiny brown seeds are rich in soluble fiber and in omega-3 fatty acids similar to those found in fish. The data on the benefits of flaxseed are rather sketchy. A review article that looked at numerous studies of flaxseed concluded that eating 1–5 tablespoons of flaxseed a day can modestly reduce total and LDL cholesterol levels, but doesn't affect triglycerides or HDL. Ground flaxseeds seem to work best and are easier to digest. They can be added to baked goods or sprinkled on cereal or salads.

Soy protein. Soy protein has garnered interest from those who are looking for solutions for high cholesterol. There has been interest in soy protein for years, based largely on the low rates of heart disease in East Asia and other regions with high average consumption of soy protein. Then a large study in the New England Journal of Medicine in 1995 really turned the spotlight on soy. This study re-examined the results of 38 controlled trials of soy protein in humans and reported that 47 grams of soy protein daily (just under 2 ounces) lowered total cholesterol levels by 9%, LDL by 13%, and triglycerides by 11%.

In most of these studies, participants replaced animal protein with soy protein. Thus, some of the drop in cholesterol may reflect the lower intake of meat and meat products rather than the actual consumption of soy protein. Some researchers believe that the beneficial effects also involve some of soy's other components, particularly substances known as isoflavones. Isoflavones are plant hormones that may prevent the oxidation of LDL and other processes that may lead to the buildup of cholesterol-rich plaque inside arteries. These hormones may also prevent blood-clot formation inside arteries by making platelets less likely to clump.

As part of a healthy diet, soy can be a great substitute for meats high in saturated fat or other unhealthy foods. What's more controversial is whether soy should be taken as a supplement. Early studies suggested soy supplements might lower LDL cholesterol, but other studies have cast doubt on this. So, for now, it's best to think of soy solely as a healthy protein source.

Antioxidants. While most cholesterol-fighting drugs are designed to lower cholesterol levels, another approach might be to limit the damage LDL can do once it is in the artery wall. Some researchers suggest preventing the conversion of circulating LDL to oxidized LDL. Drugs and vitamins called antioxidants have been able to do this — at least in test tubes — but whether they have a similar effect inside the body is still under investigation.

While some studies have shown that vitamins with antioxidant properties (such as beta carotene and vitamins C and E) can lower the risk for heart disease, the evidence is conflicting. One of the randomized studies found lower rates of heart attack and death from heart disease among people given 400 IU (the equivalent of 268 mg of vitamin E from food or 180 mg of synthetic E) or 800 IU of vitamin E rather than a placebo. However, in three other large-scale randomized studies, various doses of vitamin E didn't significantly reduce cardiovascular events. Because many of these studies involved high-risk populations or had other limitations, it's still possible that vitamin E could have protective effects, but hope has faded considerably.

A large study known as the Heart Protection Study also dampened hope about vitamin C and beta carotene. This study involved more than 20,000 adults with diabetes, coronary artery disease, or other artery disease. Half the people were randomly assigned to receive high-dose supplements of vitamin E, vitamin C, and beta carotene, the other half a placebo. At the end of five years, a similar number of people in each group had had coronary events, stroke, or death.

Green tea has been shown to lower cholesterol in animals, and with its high level of antioxidants known as flavonoids, it would be logical to assume that green tea might help decrease LDL's damage. Human trials have had mixed results. However, a study published in 2003 in the Archives of Internal Medicine fueled hope for this traditional Asian drink. In this study, 114 Chinese adults who took a pill extract of green tea in addition to following a low-fat diet improved their cholesterol profile more than 106 adults who ate similarly but took a placebo.

Even though moderate amounts of vitamin supplements seem reasonably safe for most people, the data don't support a blanket recommendation that everyone take antioxidants to prevent heart disease. The best advice is simply to eat a diet rich in the fruits and vegetables that provide these vitamins, such as citrus fruits, broccoli, and tomatoes.

Policosanol alcohol. This dietary supplement, made from alcohols extracted from sugar cane, shows promise as a cholesterol-lowering agent. Although it's not clear exactly how it works, policosanol alcohol seems to block the production of cholesterol. Trials have shown it to lower LDL cholesterol levels moderately in people with diabetes, postmenopausal women, the elderly, and those with familial hypercholesterolemia, a genetic disorder that causes high cholesterol. That said, most of the trials have been done by one group of scientists, and there haven't been enough long-term, independent clinical trials on policosanol alcohol to recommend it. And more importantly, no one knows if policosanol's beneficial effects actually translate to lower rates of heart attacks and strokes.

The substance does appear to be safe and not to interact with most medications used to treat heart disease, although a trial focused on this question needs to be done, particularly on how it interacts with aspirin. One noteworthy side effect is that it increases the effects of medications that decrease clotting (aspirin, warfarin). Policosanol alcohol can make platelets less sticky, making you prone to bleed more than usual. It should not be used with statins until the mechanism of action is better understood. Pregnant and breast-feeding women should also avoid it.

Garlic. Garlic is a popular folk remedy for many diseases, and some studies have shown that it can lower cholesterol slightly. In 2000, researchers did an analysis of the studies published on garlic and cholesterol. They found that garlic slightly reduces cholesterol compared with placebo. This lowering isn't much compared with other interventions, like a healthy diet's impact of a 5%–10% decrease. Also, not all of the trials showed that garlic improved cholesterol, and the study authors did not endorse garlic as a means of controlling cholesterol. If you like garlic, there's no reason not to add it to your favorite dishes. No one knows what component of garlic might affect cholesterol metabolism, so it's difficult to design rigorous empirical tests. It's also unclear whether cooking garlic, or processing it into tablets or extracts, inactivates any potential cholesterol-lowering activity.

Guggul. This extract from a tree native to Asia was used medicinally as early as 600 B.C. to fight obesity and muscle stiffness, among other things. It's been used in Asia with the intent of lowering cholesterol, and it's now making its way into the medicine cabinets of Westerners as well. There are few randomized, controlled trials of this substance, and one shows that guggul doesn't live up to its hype. In this 2003 study, 103 American adults with high cholesterol were assigned to take either a placebo, 1,000 mg of guggul extract, or 2,000 mg of the extract, three times a day. Surprisingly, researchers found that the extract actually increased LDL and decreased HDL. Researchers noted that the higher-fat American diet may have made a difference in how guggul worked, since other trials that focused on Asians — who typically eat a diet lower in fat — had encouraging results.