Treatment

In 2004, the National Cholesterol Education Program issued its latest recommendations for cholesterol control and management. These guidelines increase the number of Americans who should be taking LDL-lowering medication.

Starting Medications. Even modest lowering of high cholesterol levels, whether through drug therapy or lifestyle changes, reduces the risk of disability and death from heart disease. Most experts now focus on lowering LDL cholesterol, the "bad" kind. Reducing LDL levels is particularly critical for patients with diabetes.

The doctor will start or consider medication when:

• LDL cholesterol is 190 mg/dL or higher.
• LDL cholesterol is 160 mg/dL or higher AND patient has one risk factor for heart disease.
• LDL cholesterol is 130 mg/dL or higher AND patient has either diabetes or two other risk factors for heart disease.
• LDL cholesterol is 100 mg/dL or higher AND patient has heart disease. (If patient has diabetes, even without heart disease, medication may be considered for an LDL cholesterol of 100 mg/dL)
• LDL cholesterol is greater than 70 mg/dL AND patient has had a recent heart attack or has known heart disease along with diabetes, current cigarette smoking, poorly controlled high blood pressure, or the metabolic syndrome (high triglycerides, low HDL, and obesity).

Risk factors for heart disease include:

• Having a first-degree female relative diagnosed with heart disease before age 65 or a first-degree male relative diagnosed before age 55
• Being male and over age 45 or female and over age 55
• Cigarette smoking
• Diabetes
• High blood pressure
• Metabolic syndrome (risk factors associated with obesity such as low HDL levels and high triglycerides)

Recent studies have found that aggressive lipid lowering with high-dose statin therapy is more beneficial than standard statin therapy in patients with existing heart disease. The Pravastatin or Atorvastatin Evaluation and Infection Trial (PROVE-IT) and the Reversal of Atherosclerosis with Aggressive Lipid-Lowering trial (REVERSAL) compared the benefits of standard statin therapy (pravastatin, 40 mg) with intensive statin therapy (atorvastatin, 80 mg) in treating patients with heart disease.

Results from PROVE-IT demonstrated that for high-risk patients, intensive statin therapy is more effective than standard therapy in lowering LDL cholesterol and C-reactive protein (CRP) levels, and that CRP levels predict risk even when LDL cholesterol has been lowered substantially. The REVERSAL data suggest that intensive statin therapy produces greater reductions in LDL and CRP levels, and that the more that statins can lower LDL, the more effective they are in reducing the progression of atherosclerosis.

An important 2006 study found that aggressive treatment with rosuvastatin (Crestor):

• Helped lower LDL to below guideline levels
• Moderately increased HDL levels
• Reduced fatty plaque in the arteries

These results suggest that statin therapy might have the potential to reverse coronary atherosclerosis. Future studies will explore whether other statins have a similar positive effect on coronary artery disease. Rosuvastatin lowers LDL more than other statins, but it also carries greater risks for more serious side effects (see Adverse Effects section.) Many experts believe that the more that LDL is reduced through statin therapy, the greater the reduction in risk for heart disease, heart attack, and stroke.

Evidence indicates that cholesterol-lowering drugs improve survival in heart attack patients. However, a 2001 study reported that only about a fourth of patients have their cholesterol checked after a heart attack, and only about 30% with unhealthy cholesterol levels are prescribed cholesterol-lowering drugs. In addition, research presented at the 2004 annual scientific sessions of the American Heart Association demonstrated ethnic disparities in cholesterol management. According to the data from the Multi-Ethnic Study of Atherosclerosis (MESA), Hispanics and non-Hispanic blacks were less likely to receive adequate drug treatment than non-Hispanic whites.

It is important to emphasize that cholesterol-lowering medications are used along with healthy lifestyle habits, not in place of them. In spite of these guidelines, fewer than half of people who would presumably benefit from cholesterol-lowering drugs are taking them.

Choosing the Correct Lipid-Lowering Medication. Experts now recommend that drug treatments be tailored for raising or lowering specific lipids, depending on the patient's blood lipid picture:

• Statins are now the standard drugs for most people who require LDL-lowering therapy. Bile-acid binding resins or niacin may be considered. If LDL goals are not achieved, combinations of a statin with a bile-acid resin or niacin should be considered.
• Fibrates or niacin are beneficial for people who need to lower triglycerides and increase HDL.

Considerations for Children and Adolescents. Children and adolescents with high cholesterol levels should first change any lifestyle risk factors (obesity, high-fat diet, sedentary habits) that might responsible. Young people over 7 or 8 years old with evidence of inherited unhealthy cholesterol levels (LDL over 190 mg/dL) may benefit from the following medications:

• Statins are effective for children with genetic conditions that cause early elevations in cholesterol and may help reduce long-term dangers.
• Bile-acid binding resins may be an alternative choice, assuming the child has normal triglyceride levels. A multiple vitamin with folic acid and iron supplements may be needed in such cases.
• Nicotinic acid (niacin) may be an option for young people with high triglycerides.

Cholesterol-lowering drugs are also prescribed for some children who have high cholesterol levels without evidence of genetic causes. It should be noted that there is no evidence on the long-term safety of statins or any cholesterol-lowering drugs in children. Parents should discuss medications very carefully with their doctors and, in any case, always focus on lifestyle factors.

Considerations for People with Diabetes. At this time, statins are recommended as the best drugs for improving cholesterol and lipid levels in people with diabetes. Studies suggest that they can reduce the risk for adverse heart events in people with diabetes, even if their cholesterol levels are normal or if their diabetes is mild. Furthermore, in one study, a statin was shown to reduce the risk of developing diabetes by 30% in people with high cholesterol. Fibrates may also be useful for people with type 2 diabetes. Niacin (nicotinic acid) has the best effect on the cholesterol profile of people with diabetes but it also increases blood sugar levels. One well-controlled study, however, found that people with diabetes who used niacin had little trouble with glucose control, and some experts believe it now may be used as an alternative to or in combination with statins.

Statins

Statins are the most effective drugs for the treatment of high cholesterol, and may even prove important drugs for many people at risk for heart disease who have normal cholesterol levels. Statins inhibit the liver enzyme hMG-CoA reductase, which is used in the manufacturing of cholesterol. These drugs effectively reduce the risk of major coronary events, including first and second heart attacks, in both adult women and men of any age with unhealthy cholesterol levels. Experts estimate a 25 - 30% reduction in mortality rates when patients take statins after a heart attack. (Some believe the decrease may even be greater.) These drugs may also help improve the outcome in patients with heart disease who have had angioplasty.

Important studies have reported lower rates of heart attack, stroke, and mortality rates from all causes in statin users who were at high risk for heart disease, even if they had normal or low cholesterol levels. Benefits were similar in these people regardless of gender, age, or the presence of specific heart risk factors, such as diabetes or peripheral artery disease.

Brands. Statins are currently categorized into four groups:

• So-called natural statins, including lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). These are the most studied statins and have proven effectiveness and good safety record.
• Synthetic statins include fluvastatin (Lescol) and atorvastatin (Lipitor). Studies using atorvastatin suggest they may reduce LDL more effectively than natural statins. Lipitor is also approved for children.
• The newer statins, called "superstatins" by their manufacturers, include rosuvastatin (Crestor), which was approved in 2003. Trial results have suggested that rosuvastatin is more effective in improving lipid profiles than atorvastatin, simvastatin, or pravastatin. However, like all statin drugs, rovustatin can cause serious side effects (see the Adverse Effects section in this report). The risks may be higher for Asian patients; this population should be started on the lowest rosuvastatin dose (5 mg).
• Fixed-dose combination statins, which combine two drugs in one pill, first appeared on the market in 2004. Ezetimibe/simvastatin (Vytorin) combines two cholesterol medications that work in different ways. Simvastatin blocks cholesterol production in the liver, while ezetimibe (a non-statin cholesterol medication) blocks cholesterol absorption in the digestive tract. A 2005 study found that Vytorin was more effective than atorvastatin in lowering LDL and increasing HDL levels. Amlodipine/atorvastatin (Caduet) is a dual-therapy medication that combines the antihypertensive calcium channel blocker amlodipine with atorvastatin. It is used to treat simultaneously high blood pressure and high cholesterol.

Statins are generally administered once a day, typically in the evening because most cholesterol synthesis occurs between midnight and 3 A.M. Statins are often prescribed along with other cholesterol-lowering drugs such as bile acid-binding resins, nicotinic acid (niacin), and fibrates.

Beneficial Effects on the Heart and Circulation.

Statins are particularly effective for lowering LDL levels. They also reduce triglycerides, apparently in direct proportion to their LDL-lowering effects. Statins also raise HDL levels, but to a lesser extent than other anti-cholesterol drugs. (The newer "superstatins" appear to produce more significant increases in HDL.) Evidence now strongly suggests that statins may offer other health benefits beyond lowering cholesterol:

• Statins may improve the function of the endothelium (the lining of blood vessels), thereby improving blood flow. (This benefit apparently does not extend to people with diabetes.)
• Statins appear to reduce inflammation in the arteries, which is now believed to be a major factor in blood vessel injury.
• Some evidence suggests that statins may help prevent blood clotting, a major factor in heart attacks.

Beneficial Effects Outside the Heart. Studies also suggest that the benefits of statins go beyond the heart. At this time, nearly all studies on the following conditions have used natural statins:

• Stroke. Statins may reduce the risk for ischemic stroke in high-risk patients with a wide range of cholesterol and lipid levels. (Ischemic strokes occur from blockage in the blood vessels that lead to the brain.) In 2003, statin therapy was shown to reduce both fatal and non-fatal stroke in patients with hypertension and at least three additional cardiovascular risk factors. A 2004 study of stroke patients found that those who were receiving statin therapy at the time of their stroke had more favorable long-term outcomes than patients who were not on statin therapy, suggesting that statin therapy may provide additional benefits to patients who develop stroke.
• Diabetes. Statins may have a number of effects that are helpful for patients with diabetes, and may even prevent diabetes in some people with high cholesterol. Statins, however, do not appear to have any effect on blood vessel inflexibility in diabetes, which is an important risk factor for heart disease in these patients. A major 2003 study found that statin therapy helped prevent cardiovascular events including coronary death, heart attack, stroke, and the need for revascularization therapy in patients with diabetes, even in those who did not have high cholesterol levels or established coronary disease.
• High Blood Pressure. In an important 2002 study, patients with high blood pressure but norhMG-CoA reductasemal or slightly high cholesterol levels had fewer heart attacks and strokes when they took the statin atorvastatin. The study was stopped so all subjects could take statins. An earlier study showed similar benefits with the statin simvastatin.
• Alzheimer's Disease. A number of studies have reported a significantly lower risk for Alzheimer's disease in people who take specific statins. Some evidence suggests they may even improve mental function in people without unhealthy cholesterol levels. Statis showing the greatest promise include lovastatin (Mevacor), pravastatin (Pravachol), and atorvastatin (Lipitor.) These statins appear to reduce levels of beta-amyloid. Other statins have not been associated with a lower risk for Alzheimer's. In fact, some researchers are concerned that certain statins that cross the blood-brain barrier may actually worsen Alzheimer's in people who already have it.
• Osteoporosis. Some preliminary reports have suggested that statins may protect against bone loss in older women. It is not clear, however, if the statins themselves have properties that prevent osteoporosis or if any cholesterol-lowering drug would work equally well.
• Kidney Disease. Statins may prove to protect against heart disease development in patients with mild kidney disorders. According to a 2004 study, statins may also help slow the progression of existing kidney disease.
• Eye Disease. Studies are investigating whether statins can help prevent macular degeneration, an age-related eye disease that can lead to blindness. Research is still preliminary, and results have been mixed.

Macular degeneration is a disease of the retina that affects the macula in the back of the eye. The macula is important for clear central vision, allowing an individual to see fine details. There are two types of macular degeneration, dry and wet. Dry macular degeneration is more common and is characterized by the thinning of the retina and drusen, small white deposits that form within the retina. The dry form of macular degeneration is usually mild. Wet macular degeneration can happen more quickly and be more serious. It occurs when vessels under the retinal layer hemorrhage and cause the retinal cells to die, creating blind spots or distorted vision in the central vision. The disease becomes increasingly common among people in each succeeding decade over 50.

Adverse Effects. The statins tend to be better tolerated than other cholesterol-lowering drugs. In many studies the side effects reported were nearly the same as those taking placebo. Side effects may include gastrointestinal discomfort, headaches, skin rashes, muscle aches, sexual dysfunction, drowsiness, dizziness, nausea, constipation, and peripheral neuropathy (numbness or tingling in the hands and feet).

The primary safety concern with statins has involved an uncommon condition called myopathy, which can cause muscle damage and in some cases, muscle and joint pain. A specific myopathy, called rhabdomyolysis, can lead to kidney failure. Reports of rhabdomyolysis prompted the recall of cerivastatin (Baycol) in 2001. The risk for myopathy/rhabdomyolysis is highest at higher doses and in older people (over 65 years), those with hyperthyroidism, and those with renal insufficiency (kidney disease). Both statins and fibrates carry a risk for myopathy. The combination of the two drugs increases this side effect. Some people who use a statin-fibrate combination withdraw from the regimen because of muscle discomfort.

In 2005, the FDA issued a public health advisory for rosuvastatin (Crestor), noting that this drug, like other statins, increased the risk for myopathy and rhabdomyolysis. The risks were greatest at the highest dose level (40 mg). The FDA advises that patients should not start therapy at this dose. In addition, the FDA reported the results of a post-marketing study that found that people of Asian heritage had twice the blood levels of the drug as Caucasians who had taken the same dose. Because of this difference in drug metabolism, the FDA advises that Asian Americans should start treatment at the lowest rosuvastatin dose (5 mg). In general, all statin therapy should start at a lower dose and be raised incrementally until healthy cholesterol levels are maintained. Patients should immediately tell their doctor about any unusual muscle discomfort or weakness, fever, nausea or vomiting, or darkening of urine color.

Statins can also affect the liver, particularly at higher doses, so patients should have periodic liver function tests. Statins should not be taken by anyone with liver problems or by women during pregnancy or breast-feeding. Similarly, high statin doses increase the risk for kidney failure, particularly for patients with other existing risk factors (diabetes, hypertension, atherosclerosis, history of heart failure).

Interactions with Drugs and Food. Statins may have some adverse interactions with other drugs, including other cholesterol-lowering medications. Among the drugs that increase the risk for adverse effects are cyclosporine, macrolide antibiotics, and certain antifungals. Patients should tell their doctors about any other medications they are taking. Grapefruit juice and Seville oranges may increase statin potency.

Nicotinic Acid (Niacin)

Brands. Nicotinic acid is the active compound found in niacin, or vitamin B3. It is the first choice for patients with low HDL levels. Brands include Niacor, Nicolar, and Slo-Niacin. An extended-release form (Niaspan), administered at bedtime, may have fewer side effects, including headaches and flushing, than rapidly-acting niacin drugs. Although niacin is available over the counter, the active form used for cholesterol is given in much higher doses and is available only by prescription. It is important to take this medication under a doctor's direction in order to ensure its safety and effectiveness.

Benefits. When used in high doses, it has the following benefits:

• Raises HDL levels higher than other anti-cholesterol drugs
• Reducing triglyceride levels very effectively
• Lowers LDL-cholesterol and lipoprotein(a).
• Costs less than other anti-cholesterol drugs

Combinations with other drugs, particularly statins, may add significant benefits.

Side Effects. Many patients find nicotinic acid's side effects intolerable. About a quarter of patients who use rapid-acting forms of nicotinic acid stop taking them. The most common side effects are flushing of the face and neck, itching, headache, blurred vision, and dizziness. They usually occur between 5 minutes to hours after taking the drug and can last for minutes to, uncommonly, hours. The body does eventually become tolerant to these effects, and they generally subside.

The following may reduce flushing and itching:

• Starting with low doses taken at mealtime and gradually working up to the prescribed dose.
• Taking low-dose aspirin about 30 minutes before taking nicotinic acid. This may help prevent flushing.
• Avoiding hot drinks.
• Choosing an extended release form. (Even with this form, it is wise to gradually increase the bedtime dose over time and take a low-dose aspirin a half-hour beforehand.)

Stomach problems are common. Other side effects include dry skin and mucous membranes and darkening of the skin.

About 30% of patients who take niacin experience elevated levels in blood glucose, which can be a problem for people with diabetes. Niacin's effects on HDL and triglycerides, however, are especially suited for the lipid imbalances that are common in diabetes. And, some studies report that people with diabetes who use niacin have little trouble with blood sugar control.

Potentially Serious Complications. About 3 - 5% of people taking nicotinic acid develop liver problems, which disappear after the medication is discontinued. The extended form (Niaspan) appears to be safe for the liver, but people with chronic liver disease should not use any form of nicotinic acid. People with gout should also avoid nicotinic acid because it elevates uric acid.

Bile-Acid Binding Resins

Bile-acid binding resins work, as their name suggests, by binding to bile in the digestive tract. This reduces cholesterol in the following way:

• Bile is made in the liver and is used as one of the body's primary manufacturing components.

Click the icon to see an image of the gallbladder.

• Once the resins bind to bile in the digestive tract, the bile is excreted in feces.
• As the resins eliminate bile from the body, the liver takes more cholesterol from the bloodstream in order to produce more bile.
• As cholesterol is taken out of the bloodstream, LDL levels drop.

When used in combination with dietary control, LDL levels are reduced by 15 - 20%. Combinations with nicotinic acid are even more effective, with reductions of 40 - 60% observed.

Brands. The bile-acid binding resins and similar drugs include cholestyramine (Questran, Questran Light) and colestipol (Colestid). They are commonly used either in a powder that is dissolved in liquid or as a chewable bar (Cholybar). Colesevelam (Cholestagelm, Welchol) is available in tablet form.

Side Effects. None of these drugs poses major risks. Most, however, cause constipation, heartburn, gas, and other gastrointestinal problems, side effects that many people cannot tolerate. One study found that only half the standard dose of colestipol was needed when psyllium, (a soluble fiber supplement found in Metamucil, Fiberall, and Perdiem), was added to the drink. In addition, bloating and constipation were reduced. Colesevelam, a newer resin, appears to have significantly fewer of these side effects.

Bile-acting drugs may contribute to calcium loss and therefore increase the risk for osteoporosis. Over time, deficiencies of vitamins A, D, E, and K may occur, and vitamin supplements may be necessary.

Rarely, toxic effects on the liver have been reported. Patients with liver disorders should be monitored.

Drug Interactions. Bile-acid binding resins may also interfere with other medications, including digoxin (Lanoxin), warfarin, beta-blocker drugs, and a number of medications used to treat low blood sugar. In order to prevent drug interactions, other drugs should be taken 1 hour before or 4 to 6 hours after taking the bile acid-binding resins.

Fibrates

Brands. Fibrates (sometimes called fibric acid derivatives) break down the particles that make triglycerides. Gemfibrozil (Lopid) is the standard fibrate. It is usually taken twice a day, 30 minutes before breakfast and before the evening meal. Newer fibrates, including fenofibrate (Tricor) and bezafibrate (Bezalip), may be more effective in lowering cholesterol than gemfibrozil. Clofibrate (Atromid-S) was the first fibrate used but is now rarely prescribed because of its serious side effects.

Benefits. Most fibrates have been shown to lower the risk of heart attack. In a 2001 study, men with both low HDL and LDL levels had a slightly lower risk of stroke after taking gemfibrozil. Fibric acid derivatives, or fibrates, have the following effects on cholesterol, lipids, and other factors:

• They are good choices for many patients who need to lower triglyceride levels and increase HDL but who cannot take drugs ordinarily used for these purposes, such as nicotinic acid. In one study gemfibrozil, the standard fibrate, reduced the risk for adverse heart events by 22%.
• Fibrates can produce modest reductions in LDL levels, although not as effectively as statins or other drugs. LDL may actually increase in patients with very high triglycerides who take these drugs. (The newer fibrates are much more effective in lowering LDL than gemfibrozil.)
• A study on bezafibrate suggested it might have anti-inflammatory effects in patients with high triglyceride levels. Inflammation in the blood vessels is now recognized as a major contributor to the disease process leading to heart disease. However, according to a 2004 study, patients with diabetes or impaired fasting glucose levels were less likely to benefit from bezafibrate.
• A study on fenofibrate further suggested that it reduced certain clotting factors (another risk factor for heart disease) and also uric acid (a risk factor for gout). Another study, published in 2004, demonstrated that like bezafibrate, fenofibrate has significant anti-inflammatory properties in patients with high triglyceride levels.

Concerns. Fibrates do not appear to reduce mortality rates. In one study, people who took gemfibrozil had higher rates of death from other causes, including cancer. Some evidence suggests that fibrates may affect receptors involved in cancer development. However, a number of studies have found no higher incidence of cancer.

Side Effects. Side effects may include gastrointestinal discomfort, aching muscles, sensitivity to sunlight, and skin rashes. Fibrates have been known to cause gallstones, so people with gallbladder problems should not use these drugs.

Click the icon to see an image of gallstones in the gallbladder.

The drugs may cause abnormal heart rhythms and can affect the liver and kidney.

Drug Interactions. Fibrates interact with a number of drugs and substances including warfarin, some oral drugs used for diabetes, certain antibiotics, and grapefruit juice.

Plasmapheresis and Familial Hypercholesterolemia

Plasmapheresis is a blood-filtering procedure that is used to dramatically reduce triglycerides and may also be used to remove LDL. The procedure may be beneficial for patients with severe hereditary forms of high cholesterol that do not respond to other therapies. Studies suggest, for example, that plasmapheresis is particularly useful for patients with familial hypercholesterolemia. The process takes about 3 hours. If not performed regularly, its benefits last only about 2 weeks. People using this procedure are still advised to maintain a healthy diet and continue to take any prescribed medications to control cholesterol.

Ezetimibe

Ezetimibe (Zetia) inhibits the absorption of cholesterol in the intestines and is proving to be very effective when used in combination with statins. In one study, a combination of ezetimibe and simvastatin (Zocor) reduced LDL cholesterol levels by 57% compared to 18% with ezetimibe alone and 44% with simvastatin alone. A 2004 study demonstrated that ezetimibe might be particularly useful for patients who cannot achieve their cholesterol goals with statins alone.

Investigative Therapies

CETP Inhibitors. Cholesteryl ester transfer protein (CETP) inhibitors, such as the experimental drug torcetrapib, are being investigated for their effect on raising HDL ("good" cholesterol) levels while lowering LDL ("bad" cholesterol) levels. Torcetrapib, both alone and in combination with statin therapy, is being studied in several clinical trials. A small trial published in 2004 in the New England Journal of Medicine indicated promising results, particularly when torcetrapib was administered along with a statin.

Selective Estrogen-Receptor Modulators(SERMs). Selective estrogen-receptor modulators (SERMs) have been designed to produce the benefits of estrogen without its risks. They are thought to act like estrogen in some tissues but behave like estrogen blockers (antiestrogens) in others. They include tamoxifen (Nolvadex), raloxifene (Evista), and droloxifene. Any beneficial effects of the SERMs on cholesterol and the heart are still unclear. SERMs pose a risk for deep vein blood clots, which may have implications for people with heart problems. Longer studies are needed on possible risks and benefits.

Recombinant ApoA-I Milano. ApoA-I Milano is a type of HDL protein that is found in people with very low levels of HDL. A 2003 study showed that treating patients with a synthetic form of HDL, derived from ApoA-I Milano, caused a significant regression of atherosclerosis. Ongoing trials will evaluate whether this drug can prevent cardiovascular events such as heart attack or death.

---

Review Date: 4/12/2006
Reviewed By: Harvey Simon, M.D., Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital.