Cholesterol, Other Lipids, and Lipoproteins

Description

An in-depth report on the diagnosis, treatment, and prevention of high cholesterol.

Introduction

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 products.

Saturated fats are found predominantly in animal products such as meat and dairy products, and are strongly associated with higher cholesterol levels. Tropical oils such as palm, coconut, and coconut butter, are also high in saturated fats.

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 or triglycerides.

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.

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 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 using total cholesterol levels alone. Still, it is important to note that the primary goal of lipid-lowering therapy is reducing LDL-C levels.

Cholesterol's Effect on 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.

Atherosclerosis is a common disorder of the arteries. Fat, cholesterol, and other substances collect in the walls of arteries. Larger accumulations are called atheromas or plaque and can damage artery walls and block blood flow. Severely restricted blood flow in the heart muscle leads to symptoms such as chest pain.

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.

Click the icon to see an image of the developmental process of atherosclerosis.

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.

Click the icon to see an image of a 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 higher) total cholesterol levels. The higher the cholesterol the greater the risk. So, for example, according to a 2000 study, men with total cholesterol levels higher than 240 mg/dL have a risk that is 2.15 to 3.63 times that of those whose cholesterol is below 200 mg/dL. 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 response.

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 a 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 this enzyme 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.

Click the icon to see an image of the cut section of an artery.

• 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.

Click the icon to see an image of 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. Triglycerides appear 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 levels of insulin 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 further suggests that high triglycerides pose other dangers, regardless of cholesterol levels. Triglycerides, for example, may be responsible for blood clots that form and block the arteries. High triglyceride levels are also associated with the inflammatory response -- the harmful effect of an overactive immune system that can cause considerable damage to cells and tissues, including the arteries.

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 between HDL and LDL in density 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.

Cholesterol's Effect 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.

High Cholesterol and 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. 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.

The build-up of plaque in the internal carotid artery may lead to narrowing and irregularity of the artery's lumen, preventing proper blood flow to the brain. More commonly, as the narrowing worsens, pieces of plaque in the internal carotid artery can break free, travel to the brain and block blood vessels that supply blood to the brain. This leads to stroke, with possible paralysis or other deficits.

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. A 2002 study suggested that high cholesterol poses a risk for stroke only when specific proteins called ISPs associated with inflammation were present.

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

To date, evidence points to high cholesterol levels, along with hypertension and a family history of the disease, as independent risk factors for AD. A major research target in the investigator for common factors between cholesterol levels and 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. (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.)

Click the icon to see an image of omega-3 fatty acids.

Risk Factors

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. A 2003 study confirmed that childhood LDL-C level and body-mass index (BMI) are strongly associated with cardiovascular risk during adulthood.

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 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 240 mg/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 200 mg/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 older than 70 with levels under 160 mg/dL or more than 240 mg/dL 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, Metabolic Syndrome, and Type 2 Diabetes

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.

Obesity is a particularly hazard when it is one of the components of the metabolic syndrome, also called syndrome X. This syndrome consists of obesity marked by abdominal fat, unhealthy cholesterol levels, high blood pressure, and insulin resistance. Metabolic syndrome is a pre-diabetic condition that is significantly associated with heart disease and higher mortality rates from all causes. A 2002 study estimated that 24% of the population now has this condition.

Obesity is highly linked with type 2 diabetes, in any case. And diabetes itself poses a significant risk for high cholesterol levels and heart disease.

Hypothyroidism

Hypothyroidism is significantly associated with unhealthy lipid levels. (Lipids are fat molecules). Specifically, people with hypothyroidism and even subclinical hypothyroidism are at higher risk for high total and LDL -- the so-called bad -- cholesterol, triglycerides, and other lipids associated with heart disease. In fact, one 2000 study indicated that hypothyroidism is second only to poor dietary habits as a cause of high unhealthy cholesterol levels. Treating the thyroid condition can significantly reduce cholesterol levels. Among people with high cholesterol levels, between 1.3% and 2.8% have hypothyroidism and between 4.4% and 11.2% have subclinical hypothyroidism. Some experts are suggesting then that patients with high cholesterol should be assessed for thyroid function before they are given cholesterol-lowering agents. Research on whether the association between mild hypothyroidism and cholesterol levels has any significance is mixed, however.

Hypothyroidism is a decreased activity of the thyroid gland which may affect all body functions. The rate of metabolism slows causing mental and physical sluggishness. The most severe form of hypothyroidism is myxedema, which is a medical emergency.

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.

Click the icon to see an image of a polycystic ovary.

• Kidney disease.

Symptoms

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 a condition where it pays to invest in preventive medicine before dangerous complications occur.

Atherosclerosis is a disease of the arteries in which fatty material is deposited in the vessel wall, resulting in narrowing and eventual impairment of blood flow. Severely restricted blood flow in the arteries to the heart muscle leads to symptoms such as chest pain. Atherosclerosis shows no symptoms until a complication occurs.

Diagnosis

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.)

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

• Avoid strenuous exercise for 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.

Home Tests. Tests are available for home use and in public locations, such as shopping malls and pharmacies. For example, the CholesTrak Test can be taken at home with results in 10 minutes, but it measures only total cholesterol. The BioSafe Cholesterol Panel Test is also a home test, but it needs to be sent to a laboratory. This test, however, is very accurate and provides a full lipid profile -- total cholesterol, HDL, LDL, and triglycerides.

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

Certain blood tests for factors suggesting inflammation in the arteries are proving to demonstrate a higher risk for heart disease, some even in people without unhealthy lipids:

• C-reactive protein (C-RP). C-RP 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. In fact, some evidence suggests that it may prove to a more important marker than LDL cholesterol itself. It is also associated with high blood pressure, insulin resistance (the primary problem in type 2 diabetes), and obesity.
• A high white-blood cell count.
• Elevated fibrinogen (a factor responsible for blood clotting).
• 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.)

Lifestyle Changes

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

Although there are many major dietary approaches for protecting health, experts generally agree on the following recommendations for heart protection:

• Choose fiber-rich food (whole grains, legumes, nuts) as the main source of carbohydrates, along with a high intake of fresh fruits and vegetables.
• Avoid saturated fats (found mostly in animal products) and transfatty acids (found in hydrogenated fats and many commercial products and fast foods). Choose unsaturated fats (particularly omega-3 fatty acids found in vegetable and fish oils).
• In selecting proteins, choose soy protein, poultry, and fish over meat.
• Weight control, quitting smoking, 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. An intensive program may be necessary to achieve any significant improvements in cholesterol levels and to reduce heart risk factors.

Therapeutic Lifestyle Changes (TLC) from the National Cholesterol Education Program. Guidelines in 2001 from the National Cholesterol Education Program include the following for preventing and managing high cholesterol levels in adults:

• Choose five or more servings of fresh fruits and vegetables and six or more servings of whole grains, legumes. 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). Avoid trans fatty acids found in commercial products as much as possible.
• Proteins choices should be limited in general to fat-free and low-fat milk products, fish, legumes, skinless poultry, and lean means.
• 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 a low-fat diet should consume a wide variety of foods and take a multivitamin, if appropriate.

The DASH Diet. The DASH diet (Dietary Approaches to Stop Hypertension) is proving to help lower blood pressure after eight weeks. Restricting sodium improves results. The diet appears to have antioxidant effects and may even prove to be a good diet for lowering LDL cholesterol levels -- although the beneficial HDL levels also decline.

This diet is not only rich in important nutrients and fiber but also includes foods that contain far more electrolytes, potassium, calcium, and magnesium, than are found in the average American diet.

A diet that is effective in lowering blood pressure is called Dietary Approaches to Stop Hypertension (DASH).

The dietary recommendations are as follows:

• 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 not sunflower oil, a polyunsaturated fat.)
• Choose whole grains over white flour or pasta products.
• Choose fresh fruits and vegetables every day. In one 2002 study people who increased their intake of fruits and vegetables experienced a drop in blood pressure after six months. Many of these foods are rich in potassium, fiber, or both which may help lower blood pressure.
• Include nuts, seeds, or legumes (dried beans or peas) daily.
• Choose modest amounts of protein (preferably fish, poultry, or soy products). Soy in combination with fiber-rich foods or supplements may have specific benefits. Oily fish may also be particularly beneficial. They contain omega-3 fatty acids, which have been associated with heart and nerve protection.

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 moderately active woman who wants to maintain a weight of 135 pounds 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 25 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). Saturated fats (found in animal products) should be avoided.

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, that 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.

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.

Alcohol

A number of studies have found heart protection from moderate intake of alcohol (defined as one or two glasses a day). The benefits reported have been higher HDL levels, blood clot prevention, and anti-inflammatory properties. Although red wine is most often cited for healthful properties, any type of alcoholic beverage appears to have similar benefit. On the negative side, an estimated 10% of hypertension cases are caused by alcohol abuse. Men with hypertension should limit their intake to an average of no more than one or two drinks a day. Women -- especially those at risk for breast cancer -- and lighter men should also drink less. Pregnant women, anyone who cannot drink moderately , and people with liver disease should not drink at all.

Treatment

In 2002, the National Cholesterol Education Program's Adult Treatment Panel issued its latest recommendations. The results of these guidelines would increase the number of Americans who should LDL-lowering agents from 15 million to 36 million, with significant increases occurring in people younger than 45, those older than 65, and among men in all age groups. An interim update to the NCEP guidelines is expected in 2004.

Starting Medications. According to a 2003 report, only 5.4% of patients with hypercholesterolemia are adequately treated, meaning that they have reached their target cholesterol levels with lipid-lowering therapy. 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 experts 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 pose a 10% to 20% risk for a heart attack within 10 years. 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 for heart disease. 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.)

In 2004, two major studies found that aggressive lipid lowering with high-dose statin therapy is more beneficial than standard statin therapy in patients with existing cardiovascular disease. In one study of patients who had recently been hospitalized for high-risk unstable angina or myocardial infarction, those who achieved a mean LDL-C level of 62 mg/dL on high-dose statin therapy had a significantly lower risk of death, MI, recurrent unstable angina, stroke, and the need for revascularization therapy than did patients on standard therapy. The second study found treatment with high-dose statin therapy halted the progression of atherosclerosis, whereas standard-dose statin therapy allowed atherosclerosis to progress.

Three additional studies evaluating the benefits of high-dose versus moderate- or low-dose stating therapy are expected to report their results in late 2004 or early 2005. As clear benefits of aggressive lipid lowering with high-dose statin therapy start to emerge, experts predict that future cholesterol guidelines will recommend target LDL-C well below the current target of 100 mg/dL in patients with diagnosed cardiovascular disease.

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 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 agents for most people who require LDL-lowering therapy. Bile-acid binding resins or niacin may be considered. (Another LDL-lowering agent, probucol, is usually limited to people with genetic disorders that cause severely high cholesterol levels.) 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 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.

Statins

Statins are the most effective drugs for the treatment of high cholesterol, and may even become important agents for many people at risk for heart disease who have normal cholesterol levels or below. Statins inhibit the liver enzyme hMG-CoA reductase, which is used in the manufacturing of cholesterol. These agents effectively reduce the risk of major coronary events, including first and second heart attacks, in both women and men and in adults at any age (including the elderly) with unhealthy cholesterol levels. 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.) These drugs may also help improve the outcome in patients with heart disease who have had angioplasty.

Furthermore, important 2002 studies 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 proportionately similar in these people regardless of gender, age, or the presence of specific heart risk factors, such as diabetes or peripheral artery disease. One major 2002 study, however, muddied these findings by reporting no reduction in mortality rates or heart disease in high-risk patients with moderately high LDL levels. Some experts believe that statin treatment was not aggressive enough in this study.

Brands. The statins may currently be categorized into three 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 reduce LDL more effectively at equal doses to the natural statins. Lipitor has also now been approved for children. One 2002 study further reported an association between atorvastatin and a reversal in coronary artery disease. Disease only stabilized with the use of less potent statins.
• The newer statins, called "superstatins" by their manufacturers, include rosuvastatin (Crestor) and itavastatin, which has not yet been FDA approved. Crestor is more effective in lowering LDL and increasing HDL levels than most other statins, and enables more patients to achieve target LDL-C goals. Itavastatin, a Japanese agent, 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.

Statins are generally administered once a day, typically in the evening because most cholesterol synthesis occurs between midnight and 3 A.M. (One interesting 2002 study suggested that Lipitor could be taken every other day, which reduces its cost, and still remain effective.)

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.) Furthermore, evidence now strongly suggests that statins have mechanisms beyond lowering cholesterol levels that offer health benefits -- not only to the heart but to other organs. Some studies suggest the following:

• Statins improves the function of the endothelium (the lining of blood vessels), thereby improving blood flow. (Oddly, 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 curtail blood clotting, a major factor in heart attacks.

Beneficial Effects Outside the Heart. Studies are also suggesting that the benefits of statins go beyond the heart. At this time, nearly all these studies on the following conditions have been conducted with the 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 did patients who were not on statin therapy, suggesting that statin therapy may provide additional benefits to patients who develop stroke.
• Diabetes. Studies have suggested that statins may have a number of effects that can be very helpful for patients with diabetes, and may even prevent it 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 helps prevent cardiovascular events including coronary death, MI, stroke, and the need for revascularization therapy in patients with diabetes, even in those who do not have high cholesterol levels or established coronary disease.
• High Blood Pressure. An important 2002 study, patients with high blood pressure but normal 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 had shown similar benefits with the statin simvastatin.
• Alzheimer's Disease. Of considerable interest are a number of studies now reporting a significantly lower risk for Alzheimer's disease in people who were taking specific statins. Some evidence suggests they may even improve mental function in people without unhealthy cholesterol levels. Those showing promise include lovastatin (Mevacor), pravastatin (Pravachol), and atorvastatin (Lipitor.) Such statins appear to reduce levels of beta-amyloid. Other statins have not been associated with an 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. There have been some reports and animal studies suggesting 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 agent can be helpful. Few clinical trials have been published, to date, and more work is needed to confirm any effect on bones.
• Kidney Disease. Statins may prove to safely protect against heart disease in patients with mild kidney disorders. According to a 2004 study, statins may also help slow the progression of existing kidney disease.
• Eye Disease. In one small 2002 study, statins appeared to help prevent macular degeneration, an age-related eye disease that can lead to blindness.

Macular degeneration is a disease of the retina that affects the macula in the back of the eye. The macula is important for clear cental 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 amongst 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 (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).

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. The risk for myopathy is highest at higher doses and in older people, those who are small or frail, people who abuse alcohol, and those who are hypothyroid. There is also a higher risk if statins are used before surgery, and if people are taking multiple medications.

Severe cases of myopathy warrant discontinuation. In the past, there have been a few reports of a specific myopathy called rhabdomyolysis that can lead to kidney failure. Of note, fatal events from rhabdomyolysis occurred in less than 1 out of a million prescriptions and nearly always with the statin cerivastatin (Baycol), particularly at high doses and in combination with fibrates. Baycol has been withdrawn from the market.) There have been no reports of rhabdomyolysis with current statin and fibrate combinations. Patients should tell their physicians about any unusual muscle discomfort or weakness and if their urine becomes brown-colored.

Statins also can effect the liver, particularly at higher doses, so periodic liver function tests should be administered. Statins should not be taken by anyone with liver problems or by women during pregnancy or breast-feeding. It should be noted that no studies have reported liver failure from statins, even in people with liver disease.

There have also been a few reports of peripheral neuropathy in patients taking statins. This condition causes sensation changes in the limbs, fingers and toes that can include numbness, tingling, or pain.

Interactions with Drugs and Food. Statins may have some adverse interactions with other drugs, including other cholesterol-lowering agents. Among the agents that increase the risk for adverse effects are cyclosporine, macrolide antibiotics, and certain antifungal agents. Patients should tell they physicians about any other medications they are taking. Grapefruit juice and Seville oranges (found in some marmalade and other condiments) may also increase their potency. One study suggested that antioxidant supplements, such as vitamin E and C, may blunt the effects of a statin-niacin combination.

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 add significant benefits.

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.

About 30% of patients who take niacin experience elevated levels in blood glucose, which could 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 have reported that diabetics who use niacin had little trouble with glucose control.

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 because it elevates uric acid. The role of nicotinic acid in people with diabetes is less clear.

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% 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 commonly used in powder form, which is dissolved in liquid, or as a chewable bar (Cholybar). Colesevelam (Cholestagelm, Welchol) is 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 poses 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, 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 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.

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 lower cholesterol than the Lopid. Clofibrate (Atromid-S) was the first fibrate used but is now rarely prescribed because of perceived 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. In fact, LDL may increase in patients with very high triglycerides who take these drugs. (The newer fibrates, are much more effective in lowering LDL than Lopid).
• A study on the new agent 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 general. In one study, people who took gemfibrozil had higher rates of death from other causes, including cancer. Laboratory evidence further suggests that fibrates may affect receptors involved in cancer development. However, a number of studies have found no higher incidence of cancer, and a 1999 study found, in fact, a lower cancer rate.

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.

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. 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% and is also an antioxidant. Unfortunately, it also lowers the beneficial HDL levels by 20% to 30%. Probucol 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, 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.

HRT is also more likely to produce harm than benefit in women without diagnosed heart disease. In the 2003 Women?s Health Initiative (WHI), a trial of 16,608 healthy post-menopausal women treated with estrogen plus progestin or placebo to prevent heart disease. Compared to women taking placebo, women taking estrogen plus progestin were more likely to have heart attacks, strokes, blood clots, and breast cancer. Therefore, the HRT regimen provides no protection against heart disease among healthy postmenopausal women, and may even increase the risk of heart disease. The scientists concluded that HRT should not be used to prevent CHD in healthy postmenopausal women.

If a woman's sole goal is to improve her cholesterol profile, statins are now the recommended first choice for most.

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. 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 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 a very useful adjunct to 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. (The percentages used were with the highest dose of simvastatin.) A 2004 study demonstrated that ezetimibe might be particularly useful for patients who cannot achieve their cholesterol goals with statins alone.

Investigative Therapies

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. Raloxifene may have some benefits on cholesterol levels. A 2002 study reported possible heart protection in women with existing heart disease, although the findings could have been due to chance. SERMs still pose a risk for deep vein blood clots, which may have long-term implications on heart problems. Longer studies are needed on possible risks and benefits.

Cholestin. Cholestin is a red yeast used in traditional Chinese medicine that 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. Side effects are said to include mild digestive problems. It appears to be safe, but more studies are needed. One report suggests it may also cause myopathy (muscle disease) and possibly the severe form rhabdomyolysis, which has observed with statins and other cholesterol-lowering agent.

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. Trials using the drug alone and in combination with a statin are under way.

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 agent can prevent cardiovascular events such as MI or death.

Resources

• www.rover.nhlbi.nih.gov/chd -- National Cholesterol Education Program
• www.eatright.org -- American Dietetic Association (800-366-1655)
• www.acc.org -- American College of Cardiology (800-253-4636)
• www.americanheart.org -- American Heart Association (800-242-8721)
• www.heartriskevaluations.com -- Heart risk evaluation test
• www.heartinfo.org -- Information on the heart
• www.medped.org -- Information on familial hypercholesterolemia
• www.cdc.gov/nccdphp/dnpa/bmi/calc-bmi.htm -- Calculate your BMI
• www.ama-assn.org/aps/amahg.htm -- Find a heart specialist
• www.eatright.org -- Find a dietician