Cholesterol, Other Lipids, and Lipoproteins

March 2002

WHAT ARE CHOLESTEROL, OTHER LIPIDS, AND LIPOPROTEINS?

Lipids

Lipids are the building blocks of any of the fats or fatty substances found in animals and plants. They are microscopic layered spheres of oil, which, in animals, are composed mainly of cholesterol, triglycerides, proteins (called lipoproteins), and phospholipids (molecules made up of phosphoric acid, fatty acids, and nitrogen). Lipids do not dissolve in water and are stored in the body to serve as sources of energy.

Cholesterol

Cholesterol is a white, powdery substance that is found in all animal cells and in animal-based foods (not in plants). In spite of its bad press, cholesterol is an essential nutrient necessary for many functions, including the following:

Repairing cell membranes.
Manufacturing vitamin D on the skin's surface.
Production of hormones, such as estrogen and testosterone.
Possibly helping cell connections in the brain that are important for learning and memory.

Regardless of these benefits, when cholesterol levels rise in the blood, they can have dangerous consequences, depending on the type of cholesterol. Although the body acquires some cholesterol through diet, about two-thirds is manufactured in the liver, its production stimulated by saturated fat. Saturated fats are those found in animal products, meat and dairy.

Triglycerides

Triglycerides are composed of fatty acid molecules and are the basic chemicals contained in fats in both animals and plants.

Lipoproteins

Lipoproteins are protein spheres that transport cholesterol, triglyceride, or other lipid molecules through the bloodstream. Most of the information about the effects of cholesterol and triglyceride actually concerns lipoproteins.

Lipoproteins are categorized into five types according to size and density. They can be further defined by whether they carry cholesterol (the two smaller lipoproteins) or triglycerides (the three largest lipoproteins).

Cholesterol-Carrying Lipoproteins. These are the lipoproteins commonly referred to as cholesterol.

Low density lipoproteins (LDL). (Often called the "bad" cholesterol.)
High-density lipoproteins (HDL), the smallest and most dense. (Referred to as the "good" cholesterol)

Triglyceride-Carrying Lipoproteins.

Intermediate density lipoproteins (IDL). They tend to carry triglycerides.
Very low density lipoproteins (VLDL). These tend to carry triglycerides.
Chylomicrons (largest in size and lowest in density).

Lipoprotein(a). Lipoprotein(a), or lp(a) has a size and density somewhere between LDL and HDL. The molecules carries a protein that may deter the body's ability to dissolve blood clots and is under investigation as either a marker or cause of heart disease.

Remnant Lipoproteins. Remnant lipoproteins are byproducts of chylomicrons, very low-density lipoproteins (VLDL), or both. Some research indicates that high levels may be an important risk factor for coronary artery disease, particularly in patients who have otherwise normal cholesterol levels.

Cholesterol Guidelines

A number of studies have now suggested that reducing LDL and total cholesterol levels and boosting HDL levels have improved survival and prevented heart attacks in people with or without heart disease. In general, blood tests can easily measure both HDL and overall cholesterol levels. It is very difficult to measure LDL levels by themselves, but LDL levels can be reliably calculated by subtracting HDL levels from total cholesterol. (LDL makes up the difference.) Reducing LDL is the primary goal of most cholesterol therapy. [ See Table Cholesterol Goals.]

Cholesterol Goals
Total Cholesterol Goals	LDL Goals	HDL Goals	Triglyceride Goals
Less than 200 mg/dL is desirable. Between 200 and 239 is borderline. Over 240 is very high.	Below 100 mg/dl is optimal for everyone. Should be the goal for people with existing heart disease or diabetes or who have multiple heart risk factors sufficient to make their long-term survival rates equal to having heart disease. 130 mg/dl or below for people with two or more risk factors. 160 mg/dl or less for people with one or zero risk factors. Anything over 160 is high with levels over 190 being very high.	Over 60 mg/dL is optimal. Below 40 mg/dL is too low.	Below 150 mg/dL is normal. 150-199 is borderline high. 200-499 is high. Over 500 is very high.
*Risk factors for heart disease include a family history of early heart problems before age 55 for men, before age 65 for women), smoking, high blood pressure, diabetes, being older (over 45 for men and 55 for women), and having HDL levels below 35 mg/dl. People with two or more of these risk factors may have a ten-year risk of heart attack that exceeds 20%, and may therefore need to aim for LDL levels of 100 mg/dL or below.

Although current guidelines as described in the table are extremely useful, they do have pitfalls. For example, the following cholesterol levels pose some dilemmas:

Low LDL levels (protective) accompanied by low HDL, high triglycerides, or both (harmful).
High total cholesterol (harmful) accompanied by high HDL (protective).

Would individuals with these cholesterol balances be at high risk or low risk for developing heart disease? To resolve this dilemma, experts have devised a calculation for a risk ratio simply by dividing the total cholesterol by either total HDL or LDL. It isn't clear at this point which ratio is a better predictor of heart disease, although the HDL ratio may be superior. Using this ratio, the following results indicate better to worse outlook:

The ideal ratio is 3.5 or below.
A ratio of 4.5 carries an average risk.
Ratios of 5:1 or higher are potentially dangerous.

For example, if a person has a high, total cholesterol of 280 mg/dl but a high HDL level of 70 mg/dl, the risk ratio is 4, which actually carries a lower than average risk. The use of this ratio may predict coronary artery disease more accurately than total cholesterol levels.

HOW DO CHOLESTEROL, OTHER LIPIDS, AND LIPOPROTEINS AFFECT THE HEART?

Atherosclerosis and Danger to the Heart

Coronary artery disease, commonly known as heart disease, is the leading cause of death in the US and was responsible for nearly 530,000 deaths in 1999. As many as half of these deaths may be attributed to unhealthy cholesterol and lipid levels. Strong evidence points to LDL as the villain and HDL as a hero in the process. The role of other lipids, notably triglycerides, is not entirely clear.

Unhealthy cholesterol, particularly low-density lipoprotein (LDL), forms a fatty substance called plaque, which builds up on the arterial walls. Smaller plaques remain soft, but older, larger plaques tend to develop fibrous caps with calcium deposits.

The long-term result is atherosclerosis, commonly called hardening of the arteries. The heart is endangered in two ways by this process:

Eventually these calcified and inelastic arteries become narrower (a condition known as stenosis). As this process continues, blood flow slows and prevents sufficient oxygen-rich blood from reaching the heart. This condition leads to angina (chest pain) and, in severe, cases to heart attack.
Smaller unstable plaques may rupture, triggering the formation blood clots on their surface. The blood clots block the arteries and are important causes of heart attack.

This process is accelerated and enhanced by other risk factors, including high blood pressure, smoking, obesity, diabetes, and a sedentary life style. When more than one of these risk factors is present, a synergistic phenomenon occurs whereby the whole is more dangerous than the sum of its individual risk factors.

The effects of cholesterol on the heart may involve more than just one the arteries. There is some evidence unhealthy levels may affect the heart muscles and increase the risk for heart failure. High cholesterol levels may even inhibit the protection that aspirin provides for people with heart disease.

On an encouraging note, however, mortality rates associated with coronary artery disease have dropped by over one-half during the past 30 years. Some experts estimate that about 30% of the decline is due to better cholesterol management. Only 40% of people with high cholesterol levels actually die of heart disease, however, and experts cannot yet define which people are most at risk from high cholesterol levels.

Effect of Total Cholesterol

Studies consistently report a higher risk for death from heart disease with high (200 and over) total cholesterol levels. The higher the cholesterol the greater the risk. So, for example, according to a 2000 study, men with cholesterol levels over 240 mg/dL have a risk that is 2.15 to 3.63 of those whose cholesterol is below 200. On average, every time a person's cholesterol level drops by a point, the risk of heart disease drops by 2%.

Low Density Lipoproteins (LDL), the "Bad Cholesterol"

The primary villain in the cholesterol story is low-density lipoprotein (LDL). In a major study, the lowest incidence in heart disease was found among people with lowest LDL levels. Low-density lipoprotein (LDL) transports about 75% of the blood's cholesterol to the body's cells. It is normally harmless. However, if it is exposed to a process called oxidation, it can penetrate and interact dangerously with the walls of the artery, producing a harmful inflammatory respons e.

Oxidation. Oxidation is a natural process in the body that occurs from chemical combinations with unstable molecules called oxygen-free radical , also called oxidants .

When LDL collects on arterial walls these oxidants are released from the wall membranes.
Oxidants are missing an electron and tend to bind with other molecules in the body, which is the process called oxidation.
When the oxidation process modifies LDL, it signals the immune system that a harmful molecule has appeared.

Inflammation and Plaque. In response to oxidized LDL, the body releases various immune factors aimed at protecting the damaged walls. Unfortunately, in excessive quantities they cause inflammation and promote further injury to the areas they target:

White blood cells and other factors gather and form the fatty substance called plaque. (Of interest in this process is an enzyme called lipoprotein-associated phospholipase A2, which binds to oxidized LDL. Studies are now reporting that it may play a major role in the release of the plaque-forming inflammatory factors.)
Other immune factors also cause inflammation and injure the endothelium, the layer of cells that line blood vessels.
Immune factors that increase the risk for blood clots are also mobilized.
Oxidized LDL plays another dangerous role by reducing levels of nitric oxide, a chemical that helps relax the blood vessels, allowing blood to flow freely.

Lowering LDL is the primary goal of cholesterol drug and lifestyle therapy.

High Density Lipoproteins (HDL), the "Good Cholesterol'

HDL appears to benefit the body in two ways:

It removes cholesterol from the walls of the arteries and returns it to the liver.
It helps prevent oxidation of LDL. In fact, it appears to have antioxidant properties on its own.

HDL then helps keep arteries open and reduces the risk for heart attack. High levels of high-density lipoprotein (HDL), above 60 mg/dl, may be as important for the heart as low levels of LDL. HDL levels below 40 mg/dl are considered to be harmful. In one study, for each 4 mg/dL decline in HDL levels there was a 10% increase in coronary artery disease.

Triglycerides

Evidence now suggests that triglycerides may be major troublemakers for the heart, possibly in the following ways:

Triglyceride appears to interact with HDL cholesterol in such a way that HDL levels fall as triglyceride levels rise. Low HDL is known to be harmful to the heart.
The harmful imbalance of high triglycerides with low HDL levels is also associated with obesity (particularly around the abdomen), insulin resistance, and diabetes. Insulin is a hormone essential for regulating the storage and use of glucose (sugar) and amino acids (proteins) in the body. Insulin resistance occurs when there are normal insulin levels but the body cannot use it. It is the mechanism responsible for type 2 diabetes and occurs in common forms of diabetes, and with or without diabetes, is now believed to be a major risk factor for heart disease regardless of the presence of diabetes.
Some evidence also suggests that high triglycerides are risk factors for heart disease on their own regardless of cholesterol levels. Triglycerides, for example, may be responsible for blood clots that form and block the arteries.

Still, some experts believe there is not sufficient proof of an independent risk to warrant separate tests for triglycerides.

Lipoprotein(a)

Studies are finding an elevated risk for angina and first heart attacks in people with elevated levels of lipoprotein(a), or lp(a). This lipoprotein falls somewhere in density between HDL and LDL and may have some properties that increase the risk for blood clots. Some experts suggest, however, that high levels of lp(a) may merely be markers of late-stage atherosclerosis, not a cause.) Because concentrations of lipoprotein(a) are usually inherited, they do not respond to dietary or lifestyle changes. At this time, however, few experts are recommending drug treatments to reduce lp(a) levels. Older women, but not men, appear to be at greater risk for high lp(a) levels and their consequences. (Men may be protected by the male hormone testosterone.) High levels are almost nonexistent in Asians, while they have been observed in half of African American. Caucasians carry medium risk.

WHAT ARE THE EFFECTS OF CHOLESTEROL ON THE BRAIN?

The effect of cholesterol on the brain is complex. High cholesterol has been linked to Alzheimer's disease and a greater risk for certain strokes. Low cholesterol, however, may have some negative effects on the brain. [See Box Consequences of Low Cholesterol Levels.]

High Cholesterol and Ischemic Stroke

Having adequate levels of HDL may be the most important lipid-related factor for preventing ischemic stroke, which is a type of stroke caused by blockage of the carotid arteries, those carrying blood to the brain. The effects of high total cholesterol and LDL levels on ischemic stroke are less clear. One study suggested that the risk for ischemic stroke increases when total cholesterol is above 280 mg/dl.

HDL may even reduce the risk for hemorrhagic stroke, which is a less common stroke caused by bleeding in the brain and associated with low overall cholesterol levels. [See Box Consequences of Low Cholesterol Levels.]

High Cholesterol and Late-Onset Alzheimer's Disease (AD)

There has been research suggesting an association between high cholesterol levels and Alzheimer's disease (AD) in some people. The major target in genetic research on late-onset AD has been apolipoprotein E (ApoE), which plays a role in the movement and distribution of cholesterol for repairing nerve cells during development and after injury. People who carry a variant of this gene (ApoE4) are at significantly higher risk for AD. (Other variants may even reduce the risk.) High cholesterol may pose a risk for Alzheimer's regardless of this genetic factor, however. A number of recent studies support the link between Alzheimer's disease and cholesterol by suggesting that certain cholesterol-lowing drugs statin drugs known as statins may be protective against AD. (Of interest are studies reporting that cholesterol is important within the brain for cell communication and memory, but such benefits do not apply to high cholesterol levels in the blood.)

Consequences of Low Cholesterol Levels

The negative consequences of low cholesterol levels, whether actively lowered or naturally low, are the subject of ongoing debate. In one study, men with the lowest cholesterol levels had the highest mortality rate, generally due to cancer and other, non-heart related diseases. An analysis of this study along with additional research suggests strongly, however, that this higher death rate is almost totally due to lung cancer in smokers with low cholesterol.

Cognitive Function and Depression

Effects of Natural Low Cholesterol Levels. Some studies have found that cholesterol is important for the production of serotonin, a chemical in the brain that at low levels is associated with depression. Men with naturally low cholesterol levels also have low serotonin levels.

Some evidence has reported a link between natural low natural cholesterol levels and negative emotional states:

One study found that male psychiatric patients with cholesterol below 160 mg/dl had twice the normal rate of suicide and that elderly men with low cholesterol levels had three times the normal risk of depression.
Another 2000 study supported earlier work on an association between depression and chronically low cholesterol levels.
In a large 2001 Swedish study, violent behavior was linked with naturally low cholesterol levels.
A 2000 study of patients with depression and bipolar disorders found lower cholesterol levels during specific manic or depressive episodes. The study suggested that mood states might produce low cholesterol levels, not vice versa.

Some researchers have observed that people with low cholesterol levels due to medical conditions or alcoholism are often also deficient in dietary fats known as omega-3 fatty acids. Low levels of omega-3s, which are found in oily fish, are linked with depression and aggression. In fact, some studies in which cholesterol was lowered using diets that included omega-3 fatty acids reported less depression. Clearly, any link between low cholesterol levels and emotional disorders is uncertain.

Effects of Medication-Induced Low Cholesterol Levels. Importantly, numerous studies have reported no association between the use of cholesterol-lowering drugs and depression or rates of suicide, accidents, or violent death.

Hemorrhagic Stroke

People with overall cholesterol levels below 180 mg/dl may be at risk for hemorrhagic stroke (which is bleeding in the brain), particularly if they also have high blood pressure. It should be noted, however, that this type of stroke is much less common than ischemic stroke (which is caused by artery blockage and may be related to low HDL cholesterol).

WHO IS AT RISK FOR UNHEALTHY LIPID LEVELS?

Western Lifestyle and Obesity

About half of all American adults, regardless of ethnicity, have total cholesterol levels over 200. Over 25% have been told by doctors that they have unhealthy levels. The major risk factor for these high rates may be the Western lifestyle. The typical high-fat low-fiber American diet coupled with sedentary habits is largely responsible for this unfortunate trend.

Risk by Gender

Men. Heart disease is the major cause of death in men. On average, men develop coronary artery disease ten to 15 years earlier than women do and their risk for dying of heart disease at younger ages than women is higher.

Women. Coronary artery disease is still the number one killer of women as well. Women between the ages of 20 and 34 and after menopause, around age 55, have higher cholesterol levels than men do. Some evidence suggests HDL levels might have more significance in women than in men. In one study, at total cholesterol levels above 200, women with HDL levels below 50 had a higher death rate than those with levels above 50, regardless of their LDL cholesterol levels. Women also appear to be more susceptible to the high-triglyceride low-HDL syndrome, which may be a particular risk factor for heart disease.

Risk by Age

Children and Adolescents. It is not clear what constitutes normal cholesterol levels in children. According to one study, the current adult guidelines are accurate only for Caucasian adolescent males at age 16. They do not take into account changes in cholesterol levels that occur between the ages of 8 and 18, which, furthermore, may vary between genders and population groups. In general, cholesterol levels tend to naturally rise sharply until puberty, then decrease sharply, and then rise again.

It is increasingly clear, however, that children who are overweight are at higher risk for high triglycerides and low HDL, which many experts now believe may be directly related to later unhealthy cholesterol levels. One 2000 study reported evidence of injuries in the arteries in children aged nine to 11 with high cholesterol levels.

As in adults, primary source of unhealthy cholesterol levels in children is most likely from diets high in unhealthy fats, saturated fats (found mainly in animal and dairy products) and trans-fatty acids (found in commercial food products). One study reported that five out of six American young people consume too many fats. A certain amount of fat is important for growth, but over-consumption is a major factor in the obesity epidemic occurring in American children as it is in adults. Simply lowering fat intake in their diets may safely reduce cholesterol in young children, according to one long-term study.

Less common causes of unhealthy cholesterol levels in children are the following:

Low-birth weight (associated with low HDL levels).
Hypothyroidism.
Kidney or liver diseases.
Homozygous familial hypercholesterolemia. This is an uncommon inherited condition that, in European studies, occurs in about one in 400 people. It causes severe cholesterol imbalances and can result in very early heart disease.
Certain medications, such as specific antiseizure agents, corticosteroids, isotretinoin (Accutane).

Young and Middle-Aged Adults. The strongest evidence of unhealthy cholesterol levels and heart disease is in middle-aged adults over 40. Research, however, is now strongly suggesting that the younger a person is unhealthy cholesterol levels develop, the greater the chance for serious heart and blood vessel problems in the future. In one important 2000 study, young men (ages 16 through 34) who had cholesterol levels at or above 240mg/dL had two to four times the risk of dying from heart attack or other cardiac problems than did men whose cholesterol was lower than 200mg/dL. Young men without cholesterol problems also had higher life expectancy, by up to eight years. Other studies have suggested similar risks from unhealthy cholesterol in young women as well.

Elderly Adults. The effects of high cholesterol in people over 70 and how to treat them have been controversial issues. A number of studies report that in older adults, high cholesterol levels pose a significant risk for death from coronary artery disease, while some others have suggested that lowering cholesterol levels in the elderly may increase the risk for stroke or heart attack. (For example, a 2001 study reported that statin therapy reduces mortality rates in people over 65 with heart disease.) According to 2000 data, men over 70 years old with levels under 160 or over 240 were at significant risk for serious heart events. Some experts, then, now suggest that the ideal cholesterol range for older adults may be between 200 and 219 mg/dl.

Obesity

In American obesity is at epidemic levels in all age groups. The effect of obesity on cholesterol levels is complex. Although obesity does not appear to be strongly associated with overall cholesterol levels, among obese individuals triglyceride levels are usually high while HDL (beneficial cholesterol) levels tend to be low, both risk factors for heart disease. Obesity, in any case, has other effects (hypertension, increase in inflammation) that pose major risks to the heart.

Hypothyroidism

According to one 2000 study, hypothyroidism (thyroid hormone deficiency) may be the second most common cause of high cholesterol, after poor diet. Between a quarter and a half of all people with hypothyroidism may develop high cholesterol, particularly high levels of LDL and lipoprotein (a). Symptoms of hypothyroidism include slowed metabolic rate, weight gain, fatigue, and sensitivity to cold. Even those with subclinical (without symptoms) hypothyroidism may be at risk. The association is so strong between these two problems that experts recommend that people with high cholesterol also be tested for hypothyroidism. [ See the Well-Connected report Hypothyroidism.]

Type 2 Diabetes and Syndrome X

Type 2 diabetes is a risk factor of heart disease. It is by far the more common form of diabetes, accounting for 90% of diabetes cases. About 16 million Americans have type 2 diabetes and half are unaware they have it. Type 2 diabetes is a particularly hazard when it is one of the components the metabolic syndrome, also called syndrome X. This condition is a group of disorders that also includes insulin resistance, cholesterol and lipid disorders, obesity, high blood pressure, a high risk for blood clotting, and disturbed blood flow to many organs.

Genetic Factors and Family History

Genetics play a major role in determining a person's blood cholesterol levels, and children from families with a history of premature heart disease should be tested for cholesterol levels after age two. Genes may influence whether one has low HDL levels, high LDL levels, triglycerides, or high levels of other lipoproteins, such as lipoprotein(a).

Some inherited disorders and genetic abnormalities have been identified:

Familial hypercholesterolemia causes hazardous elevations of cholesterol. It may be more common than thought; one European study reported familial hypercholesterolemia in one out of 400 people.
Familial lipoprotein lipase deficiency is a very rare disorder that causes depletion of lipoprotein lipase. This is an enzyme that appears to be important in the removal of lipoproteins that are rich in triglycerides. People who are deficient in it have high levels of cholesterol and fat in their blood. A very low-fat diet is essential and is an effective treatment for these individuals.
Two studies have found a genetic mutation affecting neuropeptide Y in people with high total cholesterol and LDL levels. Neuropeptide Y is a compound in the brain that regulates appetite.
Researchers have identified a gene called APOAV, which may help detect patients at risk for elevated levels of triglycerides.

Other Medical Conditions

Other medical conditions strongly associated with unhealthy cholesterol levels are the following:

Polycystic ovarian syndrome. Women with this disorder, particularly those who are obese, appear to be at increased risk for high triglyceride and low HDL levels. This risk may be due to higher levels of the male hormone testosterone in these women.
Kidney disease.

WHAT ARE THE SYMPTOMS OF UNHEALTHY LEVELS OF CHOLESTEROL?

There are no warning signs for high LDL-cholesterol levels. When symptoms finally occur, they usually take the form of angina or heart attack in response to the buildup of atherosclerotic plaque in the patient's arteries. This is definitely an affliction where it pays to invest in preventive medicine before dangerous complications occur.

HOW ARE CHOLESTEROL LEVELS DIAGNOSED AND WHO SHOULD BE SCREENED FOR THEM?

Blood Tests for Cholesterol

A blood test for cholesterol should now include the entire lipoprotein profile: LDL, total cholesterol, HDL, and triglycerides. (It is very difficult to measure LDL levels by themselves, but LDL levels can be reliably calculated using total cholesterol and HDL levels.) [For current guidelines on who should be tested see Box Screening Guidelines.]

To obtain a reliable cholesterol reading, experts advise the following:

Avoid strenuous exercise 24 hours before the test.
Do not eat or drink anything but water for 12 hours beforehand.
If the test results are abnormal, a second test should be performed between one week and two months after the first test.

Tests are available for home use and in public locations, such as shopping malls and pharmacies, but they only measure total cholesterol. A laboratory test is still needed to measure individual lipid and lipoprotein levels.

Tests for Markers of Heart Disease in People with Unhealthy Lipid Levels

Eventually, blood tests for factors with inflammation in the arteries may be useful in demonstrating a higher risk for heart disease in people with unhealthy lipids:

A high white-blood cell count.
Elevated fibrinogen (a factor responsible for blood clotting).
C-reactive protein. This protein is regulated by a very potent immune factor called interleukin-6 and elevated levels have been strongly associated with the inflammatory response and a higher risk for heart attack, even in people with normal cholesterol levels. It is also associated with high blood pressure, insulin resistance (the primary action in diabetes), and obesity.
Lipoprotein-associated phospholipase A2 may be prove to be another marker for inflammation and heart disease. In fact, studies suggest that it may play some causal role in coronary artery disease.

Skin Test

A test that measures cholesterol levels in the skin is in development. (High skin levels appear to be an indicator of a high risk for serious heart disease.)

Screening Guidelines

General Screening Recommendations. In 2001, the government-sponsored National Cholesterol Education Program (NCEP) issued major new guidelines for managing and screening for cholesterol. While expert groups differ slightly on when screening should start, the following are the current recommendations by the NCEP expert panel:

Periodic cholesterol testing in all adults starting at age 20. An adult with normal cholesterol levels does not need to have the test repeated for five years unless changes occur in his or her lifestyle, including weight gain and changes in medication or diet.
Selective screening of children who are at risk for high cholesterol and heart disease or familial hypercholesterolemia, which is genetically elevated cholesterol. (Risk factors include having parents with total cholesterol levels greater than 240, or having a parent or grandparent who had overt heart disease at age 55 or younger.
Patients already being treated for high cholesterol should be checked every two to six months.

Early screening is important for the following reasons:

Evidence is accumulating on the dangers of early unhealthy cholesterol levels in both young people and older adults.
Screening of young people will encourage them to make important lifestyle changes, possibly early enough to make significant differences.
The obesity epidemic is increasing the numbers of young people with unhealthy cholesterol levels. One study reported that one-third of all young adult men have cholesterol levels over 200 mg/dL.
Late screening would miss the one out of every 500 individuals with inherited familial hypercholesterolemia, for whom early treatment could be life saving.

The panel also recommends testing for the total lipoprotein profile (which includes HDL, LDL, and triglycerides) instead of merely measuring total cholesterol. Testing only for the overall cholesterol level misses specific lipids and blood proteins that are becoming increasingly important in determining an individual's particular risk for heart disease.

WHAT LIFESTYLE MODIFICATIONS IMPROVE CHOLESTEROL LEVELS?

Although most studies that prove that lowering cholesterol saves lives are done using drug therapy, the absolute mandate for improving cholesterol levels is to first make changes in life style (both diet and exercise). And, even when drugs are used healthy diet and physical activity are critical companions.

As in hypertension, people with unhealthy cholesterol levels do not experience symptoms until dangerous heart disease develops. So, changing their daily patterns is like breaking through a wall. It seems impenetrable at first, but once the patient has broken through, the rewards of these good, new habits are a sense of energy and physical freedom that few will want to relinquish.

Heart Healthy Diets

Currently, there is much controversy over the best balance of carbohydrates, fats, and protein. A number of dietary approaches for improving the heart are available, which all have benefits depending on specific risk factors. Although all the major dietary approaches differ in important aspects, they have some recommendations in common:

Choose fiber-rich food (whole grains, legumes).
Choose fresh fruits and vegetables.
Choose unsaturated fats over saturated fats (found mostly in animal products) and transfatty acids (found in hydrogenated fats and many commercial products and fast foods).
In selecting proteins, choose soy protein, poultry, and fish over meat.
Weight control and exercise are essential companions of any diet program.

After embarking on any heart healthy diet, it generally takes an average of three to six months before any noticeable reduction in cholesterol occurs, although some people have reported better levels in as few as four weeks. [For detailed information see the Well-Connected Report #43 Heart Healthy Diet .]

Therapeutic Lifestyle Changes (TLC) from the National Cholesterol Education Program. New guidelines in 2001 from the National Cholesterol Education Program have now supplanted older guidelines from the American Heart Association Diet. They are more rigorous than previous standards and include the following for preventing and managing high cholesterol levels in adults:

Choose fiber-rich whole grains, legumes, and fresh fruits and vegetables. Soluble fiber is preferred (from cereal grains, beans, peas, legumes, and many fruits and vegetables).
Fats can be up to 35% of daily calories, but no more than 7% should be from saturated fat. (People with high triglycerides or low HDL or both may need a higher fat intake.) Choose fats containing unsaturated fatty acids (from vegetables, fish, legumes, and nuts). Choose margarines containing sterols or stanols (e.g., (Benecol, Take Control). Dairy products should be low- or no-fat.
Limit cholesterol intake to less than 200 mg per day.
Maintain healthy body weight and a healthy level of physical fitness.

Mediterranean Diet. The Mediterranean diet is rich in heart-healthy fiber and nutrients, including omega-3 fatty acids and antioxidants. The diet recommends the following:

A relatively high fat intake (about 35% to 45% of daily calories, mostly in monounsaturated and polyunsaturated fats.) The Mediterranean diet is known for its use of olive oil, but the greatest benefits found in a major study of this diet appeared to be derived from the use of canola oil, which is rich in omega-3 fatty acids. Olive oil, in fact, does not contain omega-3 fatty acids. On the other hand, olive oil, may have beneficial effects independent from those on lipids, such as improving insulin and blood glucose levels and reducing blood pressure.
Daily glass or two of wine.
The same protein intake as the AHA, although fish is the primary source. (It avoids high-fat dairy and meat products.) In fact, one 2001 study suggested that fish-consumption, not wine, that is the heart-protective ingredient in this diet.
Lower carbohydrate intake than AHA. Emphasizes not only fresh fruits and vegetables, but also higher amounts of nuts, legumes, beans, and whole grains.
Foods seasoned with garlic, onions, and herbs.

The Ornish Program and Severely Fat-Restricted Diets. The Ornish program limits saturated fats as much as possible, reduces total fat to 10%, and increases carbohydrates to 75% of calories. It is a very effective but demanding regimen:

It excludes all oils and animal products except nonfat yogurt, nonfat milk, and egg whites.
Foods stressed are whole grains, legumes, and fresh fruits and vegetables.
People in the program exercise 90 minutes at least three times a week.
Stress reduction techniques are employed.
People do not smoke nor do they drink more than two ounces of alcohol per day.

Everyone on low fat diets should consume a wide variety of foods and take a multivitamin if appropriate.

The DASH Diet. A diet known as Dietary Approaches to Stop Hypertension (DASH) is now recommended as an important step in managing blood pressure. Evidence now also suggests that it may be a good diet for lowering LDL levels (although HDL levels also decline). This diet is not only rich in important nutrients and fiber but also includes foods that contain two and half times the amounts of electrolytes, potassium, calcium, and magnesium, as are found in the average American diet. It makes the following recommendations:

Avoid saturated fat (although include calcium-rich dairy products that are no- or low-fat).

When choosing fats, select monounsaturated oils, such as olive or canola oils. (One study reported a reduced need for anti-hypertension medication in people with a high intake of virgin olive oil, but no sunflower oil, a polyunsaturated fat.)

Choose whole grains over white flour or pasta products.
Choose fresh fruits and vegetables every day. Important foods include most fruits (especially potassium-rich fruits including bananas, oranges, prunes, and cantaloupes) and vegetables (especially carrots, spinach, celery, alfalfa, mushrooms, lima beans, potatoes, avocados, broccoli). Note: Grapefruit boosts the effects of calcium channel blocking drugs, which are often used for hypertension. (Regular oranges do not appear to pose any hazard, but one study suggested that Seville oranges, also called bitter oranges, may be similar to grapefruit in their effect.)
Include nuts, seeds, or legumes (dried beans or peas) daily.
Choose modest amounts of protein (preferably fish, poultry, or soy products). Oily fish may be particularly beneficial.

In one study, after eight weeks on the diet, subjects from a broad range of backgrounds experienced a significant reduction in blood pressure. A 2000 study reported that a combination of the DASH diet and salt restriction is very effective in reducing blood pressure. (Each approach has positive benefits, but the combination is best.) Some individuals should take particular measures to restrict salt. [For more information see the Well-Connected Report #14 High Blood Pressure .]

Calorie Restriction. Calorie restriction has been the cornerstone of weight-loss programs. Restricting calories also appears to have beneficial effects on cholesterol levels, including reducing LDL and triglycerides and increasing HDL levels. In fact, in a study of an African community, inhabitants had very-low calorie diets and favorable cholesterol levels in spite of a high intake of saturated fat.

The standard dietary recommendations for losing weight are the following:

As a rough rule of thumb, one pound of fat equals about 3,500 calories, so one could lose a pound a week by reducing daily caloric intake by about 500 calories a day. Naturally, the more severe the daily calorie restriction, the faster the weight loss.
To determine the daily calories requirements for specific individuals, multiply the number of pounds of ideal weight by 12 to 15 calories. The number of calories per pound depends on gender, age, and activity levels. For instance a 50-year old woman who wants to maintain a weight of 135 pounds and is mildly active might require only 12 calories per pound (1,620 calories a day). A 25-year old female athlete who wants to maintain the same weight might require 15 calories per pound 2,025 (calories a day).

Fat intake should be no more than 30% of total calories. Most fats should be in the form of monounsaturated fats (such as olive oil) and saturated fats (found in animal products) should be avoided.

Diets for Children. As in adults, obesity and unhealthy cholesterol levels in children appear to be due most often to diets high in unhealthy fats. Furthermore, a major study has reported that a low-fat diet is safe and effective for treating high cholesterol in adolescent children. In the study, fat restriction had no adverse effect on mental or physical development. It should be strongly noted, however, that certain amount of fat is essential in infancy and important for growth in children. Parents should always seek professional help in developing a diet plan for their children.

Exercise

Inactivity is one of the four major risk factors for coronary artery disease, on par with smoking, unhealthy cholesterol, and high blood pressure. In fact, studies suggest that people who change their diet in order to control cholesterol are successful in actually lowering their risk for heart disease only when they also follow a regular aerobic exercise program.

The following are some observations on the effects of exercise on coronary artery disease and cholesterol:

People who maintain an active lifestyle have a 45% lower risk of developing heart disease than do sedentary people. Even moderate exercise reduces the risk of heart attack. One 2001 study of women found that just one hour of walking a week was associated with a lower risk for heart disease. The effects were similar even in women at high risk for developing heart disease.
People who are on a cholesterol-lowering diet are successful in actually lowering their risk for heart disease only if they also follow a regular aerobic exercise program.
Some studies suggest that for the greatest heart protection, it is not the duration of a single exercise session that counts but the total daily amount of energy expended. Therefore, the best way to exercise may be in multiple short bouts of intense exercise.
Burning at least 250 calories a day (the equivalent of about 45 minutes of brisk walking or 25 minutes of jogging) seems to confer the greatest protection against coronary artery disease, most likely because it raises HDL levels-the so-called good cholesterol. (Note, however, moderate exercise has little effect on HDL, and it may take up to a year of sustained exercise to make any significant difference on HDL levels.)
Aerobic exercise appears to open up the blood vessels and, in combination with a healthy diet, may improve blood-clotting factors.
Resistance (weight) training offers a complementary benefit to aerobics by reducing LDL levels (the so-called bad cholesterol).
Exercises that train and strengthen the chest muscles may prove to be very important for patients with angina.

[For complete information, see Well-Connected Report #29, Exercise.]

Quitting Smoking

Cigarette smoking lowers HDL-cholesterol levels and is directly responsible for approximately 20% of all deaths from heart disease. Once a person quits smoking, HDL cholesterol levels rise within weeks or months to levels that are equal to their nonsmoking peers. Passive smoking also reduces HDL levels in people highly exposed to smokers. The importance of breaking this habit cannot be emphasized enough. [For more information, see Well-Connected Report 41, Smoking.]

Alcohol

number of studies have suggested that light to moderate alcohol intake (one or two glasses a day) improve cholesterol levels and reduce the risk for heart disease in both men and women compared to not drinking. (Heavy drinking, however, is a major heart risk.) Red wine has plant chemicals called polyphenols that may have particular heart benefits, possibly by reducing the risk for blood clots. (For those who can't, or choose not to drink, purple grape juice seems to have similar positive effects.) A number of studies, however, have found heart protection from moderate intake of any type of alcohol. Some research suggests that alcohol has anti-inflammatory properties that protect arteries from injury.

On the negative side one 2001 study also found an association between alcohol and higher homocysteine levels. Another 2001 study found that middle aged men who take up moderate wine drinking for heart health had no more protection against heart disease than those who abstained. Further, they were more likely to develop other diseases, such as cancer. And, a Danish study suggested that the apparent heart protective properties in wine were due to a higher consumption of fish in wine drinkers. More studies are still needed. Pregnant women or those at risk for alcohol abuse in any case should not drink alcohol.

WHAT ARE DRUG THERAPIES AND OTHER TREATMENTS FOR UNHEALTHY LEVELS OF CHOLESTEROL?

General Guidelines for Drug Treatments

Starting Medications. Even modest lowering of cholesterol in those whose levels are high, whether through drug therapy or lifestyle changes, reduces the risk of disability and death from heart disease. Most expert clinicians now focus on lowering LDL cholesterol, the "bad" kind. Expert guidelines now recommend starting cholesterol-lowering drugs along with a diet and exercise regimen for the following groups:

People with LDL levels of 130 mg/dL or greater if they have existing heart disease or risk factors that place them in equivalent danger. Such factors include diabetes or other diseases that suggest atherosclerosis (such as peripheral artery disease or blockage in the carotid artery). Their goal is to achieve LDL of 100 mg/dL. (Some of these individuals may actually want to start medication at LDL levels as low as 100 mg/dL.)
People with LDL cholesterol levels of 160 mg/dL or greater who have no existing heart disease but have two or more risk factors. Their goal is an LDL of 130 mg/dL or less.
People whose LDL is 190 mg/dL or over and have one or no risk factors. They should strive for LDL levels of 160 mg/dL or less. (Some of these individuals might consider medications if they have LDL over 160 mg/dL.)

Evidence now strongly suggests that cholesterol-lowering drugs are improving survival in heart attack patients. Nevertheless, a 2001 study of Massachusetts residents reported that only 24% of patients were tested for high cholesterol levels after a heart attack and only about 30% who showed unhealthy cholesterol were actually given cholesterol-lowering drugs.

It is always 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 being given 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 agents for most people who require LDL-lowering therapy. Bile-acid binding resins are also effective in lowering LDL, but statins have additional advantages that make them the first choice. (Another LDL-lowering agent, probucol, is usually limited to people with genetic disorders that cause severely high cholesterol levels.)
Fibrates and nicotinic acid are important agents for people who need to lower triglycerides and increase HDL.

[For more information see Table Effects of Medications on Different Lipids.]

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 seven or eight years old with evidence of inherited unhealthy cholesterol levels (LDL over 190 mg dl) may benefit from the following medications.:

Statins are proving to be effective for children with genetic conditions that cause early elevations in cholesterol and is proving to be helpful in reducing long-term dangers.
Bile-acid binding resins may be an alternative option 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 agents are also being for some children with 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 agents in children. Parents should discuss medications very carefully with their physicians and, in any case, should always focus on lifestyle factors.

Considerations for People with Diabetes. At this time the best agents for improving cholesterol and lipid levels in people with diabetes are the statins. 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. Further, 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 diabetics 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.

Effects of Medications on Different Lipids
	Effect on High LDL	Effect on Low HDL	Effect on High Triglycerides	Effect on Lp(a)
Statins	Decrease (18% to 55%)	Modest increase (5% to 15%)	Decrease 7% to 30%	No change
Nicotinic acid (Niacin)	Modest decreases (5% to 25%). In combination with statins, may convert more dangerous LDL type to less dangerous.	Increase (15% to 35%) Drugs of choice for improving HDL levels.	Decrease (20% to 50%) Drug of choice for lowering triglycerides	Lower
Fibrates	Effect varies, but in general has little effect or modest decrease (5% to 20%).	Modest increase (6% to 20%)	Decrease (20% to 50%)	No change
Bile acid-binding resins	Decrease (15% to 30%)	Very modest increase (3% to 5%)	No change	No change

Statins

Statins are the most effective drugs for the treatment of high cholesterol and are becoming very important agents in general. They may benefit the heart by mechanisms beyond lowering cholesterol levels but these possible effects are not yet fully understood. Some studies suggest the following:

Statins inhibit the liver enzyme hMG-CoA reductase, which is used in the manufacturing of cholesterol. They 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.
Statins may further contribute to heart protection by increasing cells called endothelial progenitor cells (EPCs) that repair blood vessels.
Statins appear to reduce inflammation in the arteries, which is now believed to be a major factor in blood vessel injury.
Some early evidence suggests that statins may help curtail blood clotting, a major factor in heart attacks. More research is needed substantiate these findings.

In addition studies are suggesting they may have benefits for the bones and the brain.

Candidates. Statins are now strongly recommended as the first choice for most patients with high cholesterol levels, particularly the following:

Patients with diabetes, existing heart disease, or both.
Postmenopausal women with heart disease or risk factors for it. (Importantly, statins are now recommended over hormone-replacement therapy in this group.)
Statins may be safe children and adolescents with unhealthy cholesterol levels, but long-term studies are needed to confirm their value and safety in all children.

Brands. The statins may currently be categorized into three groups:

So-called natural statins, including lovastatin (Mevacor), pravastatin (Pravachol), and simvastatin (Zocor). The natural statins are generally administered once a day; they should be taken in the evening because most cholesterol synthesis occurs between midnight and 3 AM. If more intensive treatment is required, a second, morning dose may be administered.
Newer statins include fluvastatin (Lescol) and atorvastatin (Lipitor). Atorvastatin reduces LDL more effectively at equal doses to the natural statins. Long-term studies are needed to demonstrate survival benefits that are comparable to the natural statins.
So-called "superstatins" (named by the manufacturers) are in late-trials but not yet approved. They include rosuvastatin (Crestor) and itavastatin. Manufacturer studies are suggesting that Crestor is more effective in lowering LDL than Lescol or Lipitor. Furthermore, in high doses, it may increase HDL (a weak effect with other statins). Itavastatin may be even more potent. Longer and more objective research is needed, however, to confirm any of these findings as well as any long-term adverse effects.
The longest studies have been conducted on the natural statins, including those reporting benefits not only on the heart but on other regions in the body. The comparable long-term complications and benefits of the newer statins are not yet entirely known. In one 2001 study, for example, fluvastatin, a newer statin, had only modest effects on blood flow in heart attack patients a year after the attack. Another reported a 16% reduction in mortality rates with fluvastatin, although the natural statins have shown higher survival rates. There are no long-term studies on the "superstatins."

Benefits on the Heart and Mortality Rates. Studies are reporting considerable benefits on the heart from statins:

Evidence has reported that the natural statins effectively reduce the risk of major coronary events, including first and second heart attacks, in both women and men and in older people with evidence of heart disease.

Experts estimate a 25% to 30% reduction in mortality rates when patients take statins after a heart attack. (Some believe the decrease may even be greater.) To date most subjects have had high cholesterol levels at the time of the attack, but evidence suggests that statins may improve survival rates even in heart attack patients with normal cholesterol levels by reducing harmful inflammation in the arteries.

Unfortunately, studies suggest that only about a third or less of appropriate patients are given statins, although as many as 90% may benefit from them. Most benefits in the studies have been obtained with the natural statins, although work on the newer ones is showing promise. Combinations with other agents may be particularly beneficial. [ See Box Combinations of Cholesterol-Lowering Agents.]
Benefits Outside the Heart. Studies are also suggesting that the benefits of statins go beyond the heart. At this time, nearly all these studies have been conducted with the natural statins:
Statins may protect against kidney deterioration in patients with mild kidney disorders.
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.)
Statins are particularly helpful for patients with diabetes. In one study, statins even appeared to prevent type 2 diabetes from developing in some men with high cholesterol.
Some studies are reporting up to 70% lower risk for Alzheimer's disease and dementia in people who take statins. (High cholesterol levels have been linked to a high risk for the disease.)
Some studies, including one in 2002, have reported a lower risk of hip and other fractures in women who take statins, although a 2001 study did not confirm any significant benefits. Few clinical trials have been published, to date, and more work is needed to confirm early data.
In one small 2002 study, statins appeared to help prevent macular degeneration, an age-related eye disease that can lead to blindness.

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 (inactive agents). Those reported 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). Statins can effect the liver, so periodic liver function tests should be administered. Statins should never be taken by anyone with liver problems or by women during pregnancy or breast-feeding.

Interactions with Drugs and Food. Statins may have some adverse interactions with other drugs, including other cholesterol-lowering agents. [ See Box Combinations of Cholesterol-Lowering Agents.] Patients should tell they physicians about any other medications they are taking. It should noted that one study suggested that antioxidant supplements, such as vitamin E and C, may blunt the effects of a statin-niacin combination. Grapefruit juice and sour oranges (found in marmalades and other condiments, not in juice) may increase their potency.

Combinations of Cholesterol-Lowering Agents

Benefits. Combinations of the cholesterol lowering agents may be beneficial, particularly for patients with specific lipid imbalances, such as those with the metabolic syndrome, and patients with inherited cholesterol abnormalities.

Statins, for example, can be used with bile acid-binding resins, nicotinic acid (niacin), and fibrates. Significant benefits have particularly been reported with combinations of statins and nicotinic acid. In a 2001 study, for example, patients with low HDL cholesterol and normal LDL cholesterol who took both simvastatin (Zocor) and niacin reported a significantly lower risk for stroke and heart attacks. Advicor, a single medication that combines niacin and lovastatin, has now been approved.

Complications. Combinations between statins and fibrates or niacin increase the risk for rhabdomyolysis, a serious condition that that causes muscle pain and, in rare cases, can lead to kidney failure. The only fatal events associated with rhabdomyolysis and statins have occurred with the cerivastatin (Baycol), particularly at high doses and in combination with fibrates. This statin has been withdrawn from the market.

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 agents. 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 physician's direction in order to ensure its safety and effectiveness.

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

It raises HDL levels higher than any other anti-cholesterol drug.
It is extremely effective in reducing triglyceride levels.
It lowers LDL-cholesterol and lipoprotein(a).
It is also the least expensive.
Combinations with other agents, particularly statins, may be add significant benefits. [ See Box Combinations of Cholesterol-Lowering Agents]

Side Effects. Many patients find its side effects intolerable, however. About a quarter of patients taking 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 five minutes to hours after taking the drug and can last for minutes to, uncommonly, hours. The body does become tolerant to these effects eventually, and they generally subside.

Flushing and itching may be reduced with the following measures:

Start with low doses taken at mealtime and gradually work up to the prescribed dose.
Consider taking low-dose aspirin about 30 minutes before taking nicotinic acid, which appears to help prevent flushing.
Avoid hot drinks.
Choose 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.)

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

Potentially Serious Complications. About 3% to 5% of people taking nicotinic acid develop liver abnormalities, 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 avoid nicotinic acid, since it elevates uric acid. The role of nicotinic acid in people with diabetes is less clear. About 30% of patients experience elevated levels in blood glucose. The agent has specifically good effects on lipid levels in diabetes, however. And one well-controlled study, found that diabetics who used niacin had little trouble with glucose control. Still, at this time most physicians avoid it for this population.

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 primary manufacturing components.
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 circulation in order to produce more bile.
As cholesterol is taken out of the blood stream, LDL levels drop.

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

Brands. The bile-acid binding resins and similar agents include cholestyramine (Questran, Questran Light) and colestipol (Colestid). They are generally used in powder form, which is dissolved in liquid, or as a chewable bar (Cholybar). Colesevelam (Cholestagelm, Welchol) is a newer agent available in tablet form. It is therefore easier to administered and is proving to lower LDL without as many side effects, such as constipation.

Side Effects. None of these drugs pose major risks, but most 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 (Metamucil, Fiberall, Perdiem), a soluble fiber supplement, was added to the drink. In addition, bloating and constipation were reduced. Colesevelam, the newer resin, appears to have significantly fewer of these side effects.

Bile-acting agents 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 hypoglycemia. In order to prevent drug interactions, other drugs should be taken one hour before or four to six hours after taking the bile acid-binding resins.

Fibric Acid Derivatives (Fibrates)

Brands. Fibrates 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. Others include fenofibrate (Tricor) and bezafibrate (Bezalip), which is in trials. Clofibrate (Atromid-S) was the first fibrate used but is rarely prescribed because of perceived serious side effects.

Benefits. Fibric acid derivatives, or fibrates, are useful in the following settings:

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. In fact, LDL may increase in patients with very high triglycerides who take these drugs. Though most fibrates have been shown to lower risk of heart attack, they may not have the ability to reduce mortality rates, as other cholesterol-lowering drugs do. More research is needed.
In a 2001 study, men with both low HDL and LDL levels had a slightly lower risk of stroke after taking gemfibrozil.
One study reported that fenofibrate may help reduce atherosclerosis in patients with diabetes.
Fenofibrate also seems to reduce certain clotting factors (another risk factor for heart disease) and uric acid (a risk factor for gout).

Side Effects. Side effects may include gastrointestinal discomfort, aching muscles, sensitivity to sunlight, and skin rashes. Impotence has been associated with fibrates in less than 1% of patients. Fibrates have been known to cause gallstones, so people with gallbladder problems should not use these drugs. The drugs may cause abnormal heart rhythms and can affect the liver and kidney. In one study, people who took gemfibrozil had higher rates of death from other causes, including cancer. Subsequent studies, however, have found no higher incidence of cancer, and a 1999 study found, in fact, a lower cancer rate.

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

Probucol

Probucol (Lorelco) lowers LDL-cholesterol levels by 10% to 15%. It is also an antioxidant. Unfortunately, it also lowers the beneficial HDL levels by 20% to 30%. It is generally used for certain genetic disorders that cause high cholesterol levels, or when other cholesterol-lowering drugs are ineffective or cannot be used. Common side effects include gastrointestinal discomforts such as diarrhea, bloating, nausea, and dizziness.

Hormone Replacement Therapy

In spite of estrogen's benefits on cholesterol levels and other factors that effect the heart, the most recent evidence suggests that hormone replacement therapy (HRT) may be harmful for women with existing heart disease, at least in the first few years. In July 2001, the American Heart Association sent out an advisory regarding the use of HRT in postmenopausal women. These guidelines state that women with heart disease, or women who have a heart attack while on HRT, should strongly consider stopping the therapy. In addition, they recommend that doctors stop telling women that hormone replacement therapy has any cardiovascular benefits. It is still not clear if HRT prevents heart disease in women without existing heart disease. If a woman's sole goal is to improve her cholesterol profile, statins are now the recommended first choice for most. See Well Connected Report on Menopause, Estrogen Loss, and Their Treatments. ]

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 it is particularly useful for patients with familial hypercholesterolemia. In such patients, plasmapheresis produced a significantly lower number of adverse heart events than other treatments. The process takes about three hours. If not performed regularly, its benefits last only about two weeks. People using this procedure are still advised to maintain a healthy diet and stay on any prescribed medications to control cholesterol.

Investigative Therapies

Ezetimibe. Ezetimibe (Zetia) inhibits the absorption of cholesterol in the intestines and may turn out to be a useful adjunct to statins. In fact, manufacturers are hoping to get FDA approval for a combination pill that includes both ezetimibe and 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 the heart are still unclear. They have some minor benefits for cholesterol level s but they also increase the risk for deep-vein blood clots. Droloxifene may lower blood pressure. Of course, SERMs are used most frequently in women, but in an interesting study of the SERM tamoxifen (a drug used to treat and prevent breast cancer), men who took the drug had improved cholesterol levels after two months.

Cholestin. Cholestin is a red yeast used in traditional Chinese medicine, which may have some ability to reduce cholesterol levels. One of the primary actions of the yeast is to produce lovastatin, one of the major statin agents. It is an herbal supplement, however, not a prescription drug, so the FDA has not been allowed to regulate it. Side effects are said to include mild digestive problems. It appears to be safe, but more studies are needed. Experts warn that any substance that has such strong effects on cholesterol may also have strong adverse effects, and, like all so-called natural remedies, no official standards have been developed to control its quality.

Avasimibe. This unique agent inhibits cholesterol storage and so may reduce atherosclerosis. Small early studies report reductions in triglycerides and very low density (VLDL) cholesterol but no changes in LDL or HDL.

SCAP Ligands. These drugs have been shown to reduce greatly LDL cholesterol and triglycerides in laboratory animals. Trials in humans are needed to verify their usefulness.

WHERE ELSE CAN INFORMATION ABOUT CHOLESTEROL BE OBTAINED?

National Cholesterol Education Program, Information Center, PO Box 30105, Bethesda, MD 20824-0105. Call (301-251-1222) or (http://rover.nhlbi.nih.gov/chd/)

American Dietetic Association. 216 W. Jackson Boulevard, Chicago, Illinois 60606. Call (312-899-0040 or 800-366-1655) or (fax 312- 899-1979) or (http://www.eatright.org/)
The organization offers a hot-line (900-225-5267) that allows people to speak to a licensed dietitian and also provides names of licensed dietitians for specific locations. Cost is $1.95 for first minute and. 95 for every additional minute. Its web site is excellent and highly recommended. It offers good, recent information on nutrition and an excellent, searchable database for dietitians within a particular locality in a desired specialty, including eating disorders and weight control.

American College of Cardiology, Heart House, 9111 Old Georgetown Rd., Bethesda, MD 20814-1699. Call (800-253-4636) or (301-897-540) or (http://www.acc.org/)

American Heart Association, 7272 Greenville Ave., Dallas, Texas 75231-4596. Call (214-373-6300 or 800-242-8721) or (http://www.americanheart.org).
This is a primary source of information for heart problems. They are very responsive and will send free pamphlets and reading material, including useful diet information and locations of local representatives

Offers a useful heart risk evaluation test. (http://www.heartriskevaluations.com/)

Government link for calculating ten-year risk. http://hin.nhlbi.nih.gov/atpiii/calculator.asp?usertype=pub.

An extremely informative site on the heart. (http://www.heartinfo.org)

Web site for registering and treating people with familial hypercholesterolemia (FH) (http://www.medped.org/)

RECENT LITERATURE

Review Date: March 2002

This Report Reviewed by:

Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

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Harvey Simon, MD, Editor-in-Chief, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital

Stephen A. Cannistra, MD, Oncology, Associate Professor of Medicine, Harvard Medical School; Director, Gynecologic Medical Oncology, Beth Israel Deaconess Medical Center

John E. Godine, MD, PhD, Metabolism, Harvard Medical School; Associate Physician, Massachusetts General Hospital

Edwin Huang, MD, Gynecology, Harvard Medical School; Physician, Massachusetts General Hospital

Daniel Heller, MD, Pediatrics, Harvard Medical School; Associate Pediatrician, Massachusetts General Hospital; Active Staff, Children's Hospital

Paul C. Shellito, MD, Surgery, Harvard Medical School; Associate Visiting Surgeon, Massachusetts General Hospital

Theodore A. Stern, MD, Psychiatry, Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital

Theodore A. Stern, MD, Psychiatry, Harvard Medical School; Psychiatrist and Chief, Psychiatric Consultation Service, Massachusetts General Hospital

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