Cholesterol

What is cholesterol? Cholesterol is a fatty substance (a lipid) that is an important part of the outer lining (membrane) of cells in the body of animals. Cholesterol is also found in the blood circulation of humans. The cholesterol in a person's blood originates from two major sources; dietary intake and liver production. Dietary cholesterol comes mainly from meat, poultry, fish, and dairy products. Organ meats, such as liver, are especially high in cholesterol content, while foods of plant origin contain no cholesterol. After a meal, cholesterol is absorbed by the intestines into the blood circulation and is then packaged inside a protein coat. This cholesterol-protein coat complex is called a chylomicron. The liver is capable of removing cholesterol from the blood circulation as well as manufacturing cholesterol and secreting cholesterol into the blood circulation. After a meal, the liver removes chylomicrons from the blood circulation. In between meals, the liver manufactures and secretes cholesterol back into the blood circulation. What are LDL and HDL cholesterol? Cholesterol, like oil, cannot dissolve in the blood unless it is combined with special proteins called lipoproteins. (Without combining with lipoproteins, cholesterol in the blood will turn into a solid substance.) The cholesterol that is secreted by the liver into the blood is combined either with very low-density lipoproteins (VLDL) or high-density lipoproteins (HDL). VLDL cholesterol is then metabolized in the bloodstream to produce LDL cholesterol. Cholesterol that is combined with lowdensity lipoproteins is called LDL cholesterol. Cholesterol that is combined with high-density lipoproteins is called HDL cholesterol. LDL cholesterol is called "bad" cholesterol, because elevated levels of LDL cholesterol are associated with an increased risk of coronary heart disease. LDL lipoprotein deposits cholesterol on the artery walls, causing the formation of a hard, thick substance called cholesterol plaque. Over time, cholesterol plaque causes thickening of the artery walls and narrowing of the arteries, a process called atherosclerosis. HDL cholesterol is called the "good cholesterol" because HDL cholesterol particles prevent atherosclerosis by extracting cholesterol from the artery walls and disposing of them through the liver. Thus, high levels of LDL cholesterol and low levels of HDL cholesterol (high LDL/HDL ratios) are risk factors for atherosclerosis, while low levels of LDL cholesterol and high level of HDL cholesterol (low LDL/HDL ratios) are desirable. Total cholesterol is the sum of LDL (low density) cholesterol, HDL (high density) cholesterol, VLDL (very low density) cholesterol, and IDL (intermediate density) cholesterol. What determines the level of LDL cholesterol in the blood? The liver not only manufactures and secretes LDL cholesterol into the blood; it also removes LDL cholesterol from the blood. To remove LDL cholesterol from the blood, the liver relies on special proteins called LDL receptors that are normally present on the surface of liver cells. LDL receptors snatch LDL cholesterol particles from the blood and transport them inside the liver. A high number of active LDL receptors on the liver surfaces is associated with the rapid removal of LDL cholesterol from the blood and low blood LDL cholesterol levels. A deficiency of LDL receptors is associated with high LDL cholesterol blood levels. Both heredity and diet have a significant influence on a person's LDL, HDL and total cholesterol levels. For example, familial hypercholesterolemia (FH) is a common inherited disorder whose victims have a diminished number or nonexistent LDL receptors on the surface of liver cells. The

resultant decreased activity of the LDL receptors limits the liver's ability to remove LDL cholesterol from blood. Thus, affected family members have abnormally high LDL cholesterol levels in the blood. They also tend to develop atherosclerosis and heart attacks during early adulthood. Diets that are high in saturated fats and cholesterol decrease the LDL receptor activity in the liver, thereby raising the levels of LDL cholesterol in the blood. Fats are classified as saturated or unsaturated according to their chemical structure. Saturated fats are derived primarily from meat and dairy products and can raise blood cholesterol levels. Some vegetable oils made from coconut, palm, and cocoa are also high in saturated fats. Does lowering LDL cholesterol prevent heart attacks and strokes? Thirty years ago, observational studies suggested that high blood cholesterol could cause coronary atherosclerosis and heart attacks . Doctors in those days suspected (correctly) that lowering blood cholesterol could reduce heart attacks. They recommended a low fat diet and exercise to lower blood cholesterol and prescribed medications, such as statin drugs, only when diet and exercise failed. However, doctors were not satisfied with observational studies because they are not as reliable as prospective, randomized, double-blind, placebo-controlled trials (controlled trials) in proving the safety and effectiveness of any treatment. An observational study is a retrospective analysis comparing health status of one group of subjects to another group (for example, comparing the rate of heart attacks among patients with high blood cholesterol levels to those with lower blood cholesterol levels). Observational studies can only demonstrate an association between higher cholesterol in the blood and higher risks of heart attacks. Conclusive proof that lowering one's blood cholesterol levels prevents heart attacks has to come from prospective, randomized, and placebo-controlled trials. Therefore, researchers initiated numerous large-scale controlled trials to determine if lowering cholesterol actually prevents heart attacks. In a controlled trial, patients who are similar in age, sex, genetic background, and other characteristics, such as health status and diet are randomly assigned to receive either the test medication or a placebo. A placebo is a biologically inert substance (sugar powder or salt placed in capsules that are made to look like the test medication) that does not have any effect on the disease. The study is conducted in a double-blind fashion, meaning neither the patients nor the researchers know who is receiving the test medication or the placebo. At the end of the trial, treatment results from the medication treated group are compared to the placebo treated group to determine if the test medication is more effective than the placebo. The random assignment of study subjects and double blinding of subjects and researchers are important to eliminate human bias from these trials. Today, many of the large, multi-year controlled trials have been completed. These trials have consistently and conclusively shown that lowering LDL cholesterol reduces the risk of heart attacks and strokes and prolongs life. These trials have further shown that the benefits of lowering cholesterol outweigh the risks of side effects of the statin medications. Therefore, doctors are much more willing to use medications, such as statins, to lower cholesterol, and the "desirable cholesterol level" has been rapidly reduced. Lowering LDL cholesterol is currently the primary focus in preventing atherosclerosis and heart attacks. Most doctors now believe that the benefits of lowering LDL cholesterol include: Reducing or stopping the formation of new cholesterol plaques on the artery walls; Reducing existing cholesterol plaques on the artery walls; Widening narrowed arteries; Preventing the rupture of cholesterol plaques, which initiates blood clot formation; Decreasing the risk of heart attacks; and Decreasing the risk of strokes. The same measures that retard atherosclerosis in coronary arteries also benefit the carotid and cerebral arteries (arteries that deliver blood to the brain).

How can LDL cholesterol levels be lowered? In order to lower LDL cholesterol, the activity level of the LDL receptors must be increased. LDL receptor activities can be increased by diets that are low in cholesterol and saturated fats and by medications. Therapeutic lifestyle changes to lower cholesterol Lowering LDL cholesterol involves losing excess weight, exercising regularly, and following a diet that is low in saturated fat and cholesterol. (Please visit the Therapeutic Lifestyle Changes (TLC) section (http://www.nhlbi.nih.gov/chd/lifestyles.htm) for more detailed information on diet and exercise to lower blood cholesterol.) Medications to lower cholesterol Medications are prescribed when lifestyle changes cannot reduce the LDL cholesterol to desired levels. The most effective and widely used medications to lower LDL cholesterol are called statins. Most of the large controlled trials that demonstrated the heart attack and stroke prevention benefits of lowering LDL cholesterol used one of the statins. Other medications used in lowering LDL cholesterol and in altering cholesterol profiles include nicotinic acid (niacin), fibrates such as gemfibrozil (Lopid), resins such as cholestyramine (Questran), and ezetimibe, Zetia. (An in-depth discussion of these drugs is presented in this article starting at the heading: What are the statin drugs?) What are "normal" cholesterol blood levels? There are no established "normal" blood levels for total and LDL cholesterol. In most other blood tests in medicine, normal ranges can be set by taking measurements from large number of healthy subjects. For example, normal fasting blood sugar levels can be established by performing blood tests among healthy subjects without diabetes mellitus. If a patient's fasting blood glucose falls within this normal range, he/she most likely does not have diabetes mellitus, whereas if the patient's fasting blood sugar tests higher than the normal range, he/she probably has diabetes mellitus and further tests can be performed to confirm the diagnosis. Medications, such as insulin or oral diabetes medications can be prescribed to lower abnormally high blood sugar levels. Unfortunately, the normal range of LDL cholesterol among "healthy" adults (adults with no known coronary heart disease) in the United States may be too high. The atherosclerosis process may be quietly progressing in many healthy adults with average LDL cholesterol blood levels, putting them at risk of developing coronary heart diseases in the future. What are desirable cholesterol blood levels? Since no "normal" cholesterol levels have been established, doctors rely on "desirable cholesterol levels" in making treatment recommendations. However, the "desirable" levels of total cholesterol and LDL cholesterol have been moving targets; they have been steadily declining over the years as more and more controlled trials have demonstrated that the risk of heart attacks and strokes can be reduced further with lower LDL cholesterol levels. In 1985, the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health gathered a panel of cholesterol experts to form the National Cholesterol Education Program (NCEP). This expert panel reviewed data mainly from large controlled cholesterol-lowering trials, and published their blood cholesterol treatment recommendations in two separate reports; one published in May, 2001, the other in June, 2004. The NECP report published in May 2001 is called the Adult Treatment Panel III (ATP III). This report included desirable anvcd undesirable levels for LDL cholesterol, HDL cholesterol, and triglycerides (see below), as well as LDL cholesterol lowering target goals.

Since the publication of the ATP III report in 2001, several large controlled trials have been published, showing that aggressively lowering LDL cholesterol further reduced heart attacks and strokes. Therefore in June, 2004, the expert panel lowered the LDL cholesterol targets, especially for patients who have very high risks of developing heart attacks (see below). Optimal, undesirable, and desirable lipid levels (published in 2001) LDL cholesterol (mg/dl) <100 Optimal 100-129 near or above optimal 130-159 Borderline high 160-189 High > 190 Very high Total cholesterol (mg/dl) <200 Desirable 200-239 Borderline high >240 High HDL cholesterol (mg/dl) <40 Low (undesirable) >60 High (desirable) Triglycerides (mg/dl) <150 Normal 150-199 Borderline-high 200-499 High >500 Very high What were the 2001 NCEP cholesterol treatment guidelines? The ATP III recommended goal of LDL cholesterol lowering is tailored to a person's heart attack risk. The expert panel recommended that patients with a higher risk of heart attacks should be more aggressively treated so as to achieve lower LDL cholesterol levels than patients with lower risks of heart attacks. For example, patients with prior heart attacks (these patients are at high risk of having a repeat heart attack) should have an LDL cholesterol goal of < 100 mg/dl, whereas healthy subjects with no prior heart attacks and no other risk factors should have an LDL cholesterol goal of <160mg/dl. (For a detailed explanation of very high risk, high risk, moderate high risk, moderate risk, and low risk patients, please see below). Even then (in 2001), some cardiologists and cholesterol experts believed that aggressively lowering LDL cholesterol below 80 mg/dl further decreases atherosclerosis and heart attack rates among high risk patients. But, in order to achieve these lower LDL cholesterol levels, moderate to high doses of a statin drug (or drug combinations) often will be necessary on a long-term basis in addition to lifestyle changes (please see discussion above). The safety of moderate to high doses of statins over several decades is unknown. Therefore, based on scientific information available at that time, the ATP III LDL cholesterol target level of < 100mg/dl for high risk patients represents a compromise, balancing the benefits of LDL cholesterol-lowering against the potential side effects of long term moderate to high dose statins. What were the findings of the large controlled trials published after 2001? Since the publication of ATP III in 2001, five large controlled cholesterol-lowering trials have been published. Three of these trials showed that aggressively lowering LDL cholesterol (below 70-80 mg/dl) further decreased the risk of heart attacks and strokes without significant increases in side effects during the study period (usually from 3-5 years). These trials are: 1) Heart Protection Study

(HPS); 2)Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA); and 3) Pravastatin or Atorvastatin Evaluation and Infection (PROVE IT). The HPS trial randomly assigned more than 20,000 adults (aged 40 to 80 years) with high heart attack risks to receive either a placebo or simvastatin (Zocor) 40 mg daily. The study found that there was an approximate 25% reduction in heart attacks and strokes in men and women treated with simvastatin. This reduction occurred even among patients whose LDL cholesterol was lower than 100 mg/dl at base line (before treatment), suggesting that there was a further benefit in lowering LDL cholesterol levels below the target levels recommended by ATP III. The ASCOT-LLA trial randomly assigned more than 10, 000 patients with high blood pressure to receive either a placebo or atorvastatin (Lipitor) 10 mg/day. These patients had not suffered prior heart attacks. The study was stopped after 3.3 years (sooner than planned) because there was a convincing reduction in heart attacks and strokes (by approximately 25%-30%) among the atorvastatin treated patients. The average LDL cholesterol level dropped 29%, from 132 mg/dl to 90 mg/dl in the atorvastatin treated group. The PROVE IT trial was designed to determine whether aggressively loweringe LDL cholesterol with a high dose, potent, statin drugs would reduce heart attacks more than standard doses of statins. The patients involved in this study were very high risk, having acute coronary syndromes (ACS), and thus were often in imminent danger of experiencing heart attacks. Four thousand of these patients were randomly assignedized to receive either a high dose (80 mg/day) of atorvastatin (Lipitor) or a standard dose (40 mg/day) of pravastatin (Pravachol). As expected, the average LDL cholesterol attained with high dose atorvastatin was 62 mg/dl, much lower than achieved with standard dose pravastatin, which was 95 mg/dl. At the end of two years, the incidence of heart attacks, strokes, and the need for coronary artery bypass surgery were lowered by 16% in the atorvastatin group as compared with the paravastin group. The PROVE IT study suggests that aggressive lowering of LDL cholesterol below 70 mg/dl further reduces heart attacks and other major coronary events (such as the need for coronary artery bypass surgery) in patients at very high risk of heart attacks. What are the 2004 NCEP cholesterol treatment guidelines? After reviewing these large randomized cholesterol-lowering trials, The National Cholesterol Education Program (NCEP) expert panel published their new recommendations. The new NCEP recommendations, presented in the June, 2004 issue of Circulation, are: 1. The report advised physicians to consider more intensive LDL cholesterol-lowering for people at very high, high, and moderately high risk for a heart attack. These options include setting lower treatment goals for LDL cholesterol and initiating cholesterol-lowering drug therapy at lower LDL thresholds, as compared to ATP III guidelines published in 2001. For example, for patients with a very high risk of heart attacks, the LDL cholesterol treatment goal remains at <100mg/dl, but the report advised doctors to consider the option of lowering the LDL cholesterol (usually using a statin plus lifestyle changes) to < 70 mg/dl. 2. The report emphasized the importance of initiating therapeutic lifestyle changes (TLC) to modify lifestyle-related risk factors (obesity, physical inactivity, metabolic syndrome, high blood triglyceride levels and low HDL cholesterol levels). TLC Lifestyle changes have the potential to reduce heart attack and stroke risks through several mechanisms beyond the lowering of LDL cholesterol. 3. When LDL-lowering medication is used for very high, high or moderately high risk patients, the report advises that the intensity of LDL-lowering drug therapy be sufficient to achieve at least a 30 to 40 percent reduction in LDL cholesterol levels. 4. When a very high or high risk patient also has high blood triglyceride or low HDL cholesterol levels, doctors may consider combining nicotinic acid or a fibrate with a statin. Nicotinic acid and fibrates are more effective than statins in lowering triglycerides and increasing HDL.

5. Age should not be a consideration since older persons also benefit from lowering LDL cholesterol. Thust, it is never too late or the patient too old to begin lifestyle changes and medications to lower LDL cholesterol. A word of caution is in order. Elderly patients are more likely to have liver and kidney dysfunction, and are also more likely to be on multiple medications some of which may interfere with the breakdown of cholesterol-lowering drugs such as statins. Thus lower dosing may be necessary to avoid adverse side effects. The 2004 NCEP treatment goals according to risk categories Risk category LDL goal < 100 mg/dl < 100 mg/dl < 70 mg/dl More Initiate TLC Consider drugs + intense LDL if LDL is: TLC if LDL is: goal option > 100 mg/dl >100 mg/dl

High risk

Very high risk

> 100 mg/dl <100 mg/dl >130mg/dl, consider drug > 130 mg/dl option if LDL is 100-129 mg/dl > 130 mg/dl >160 mg/dl >190 mg/dl, consider drug > 160 mg/dl optional if LDL is 160-189 mg/dl

Moderately high risk (10 yr. risk 10-20%)

<130 mg/dl

<100 mg/dl

Moderate risk (10 <130 yr. risk <10%) mg/dl

Lower risk

<160 mg/dl

High risk patients are those who already have coronary heart disease (such as a prior heart attack), diabetes mellitus, abdominal aortic aneurysm, or those who already have atherosclerosis of the arteries to the brain and extremities (such as patients with strokes, TIA's (mini-strokes), and peripheral vascular diseases). High risk patients also include those with 2 or more risk factors (e.g., smoking, hypertension, or a family history of early heart attacks) that places them at a greater than 20 percent chance of having a heart attack within 10 years. (A person's chance of having a heart attack can be calculated by using the Framingham Heart Study Score Sheets, at http://nhlbi.nih.gov/about/framingham/riskabs.htm). Very high -risk patients are those who have coronary heart disease in addition to having either multiple risk factors (especially diabetes), or severe and poorly controlled risk factors (such as continued smoking), or metabolic syndrome (a constellation of risk factors associated with obesity, including high triglycerides and low HDL). Patients hospitalized for acute coronary syndromes are also at very high risk. Moderately high risk patients are those who have neither coronary heart disease nor diabetes mellitus, but have multiple (2 or more) risk factors for coronary heart disease that put them at a 10 to 20 percent risk of heart attack within 10 years. (Use the Framingham Heart Study Score Sheets, at http://nhlbi.nih.gov/about/framingham/riskabs,htm to calculate the 10 year risk.) Moderate risk patients are those who have neither CHD nor diabetes mellitus, but have 2 or

more risk factors for coronary heart disease that put them at a <10% risk of heart attack within 10 years. Lower risk patients are those with 0 to 1 risk factor for coronary heart disease. Why is HDL the good cholesterol? HDL is the good cholesterol because it protects the arteries from the atherosclerosis process. HDL cholesterol extracts cholesterol particles from the artery walls and transports them to the liver to be disposed through the bile. It also interferes with the accumulation of LDL cholesterol particles in the artery walls. The risk of atherosclerosis and heart attacks in both men and is strongly related to HDL cholesterol levels. Low levels of HDL cholesterol are linked to a higher risk, whereas high HDL cholesterol levels are associated with a lower risk. Very low and very high HDL cholesterol levels can run in families. Families with low HDL cholesterol levels have a higher incidence of heart attacks than the general population, while families with high HDL cholesterol levels tend to live longer with a lower frequency of heart attacks. Like LDL cholesterol, life style factors and other conditions influence HDL cholesterol levels. HDL cholesterol levels are lower in persons who smoke cigarettes, eat a lot of sweets, are overweight and inactive, and in patients with type II diabetes mellitus. HDL cholesterol is higher in people who are lean, exercise regularly, and do not smoke cigarettes. Estrogen increases a person's HDL cholesterol, which explains why women generally have higher HDL levels than men do. For individuals with low HDL cholesterol levels, a high total or LDL cholesterol blood level further increases the incidence of atherosclerosis and heart attacks. Therefore, the combination of high levels of total and LDL cholesterol with low levels of HDL cholesterol is undesirable whereas the combination of low levels of total and LDL cholesterol and high levels of HDL cholesterol is favorable. What are LDL/HDL and total/HDL ratios? The total cholesterol to HDL cholesterol ratio (total chol/HDL) is a number that is helpful in estimating the risk of developing atherosclerosis. The number is obtained by dividing total cholesterol by HDL cholesterol. (High ratios indicate a higher risk of heart attacks, whereas low ratios indicate a lower risk). High total cholesterol and low HDL cholesterol increases the ratio and is undesirable. Conversely, high HDL cholesterol and low total cholesterol lowers the ratio and is desirable. An average ratio would be about 4.5. Ideally, one should strive for ratios of 2 or 3 (less than 4). What are the treatment guidelines for low HDL cholesterol? In clinical trials involving lowering LDL cholesterol, scientists also studied the effect of HDL cholesterol on atherosclerosis and heart attack rates. They found that even small increases in HDL cholesterol could reduce the frequency of heart attacks. For each 1 mg/dl increase in HDL cholesterol, there is a 2 to 4% reduction in the risk of coronary heart disease. Although there are no formal NCEP (please see discussion above) target treatment levels of HDL cholesterol, an HDL level of <40 mg/dl is considered undesirable and measures should be taken to increase it. How can levels of HDL cholesterol be raised? The first step in increasing HDL cholesterol levels (and decreasing LDL/HDL ratios) is therapeutic life style changes. When these modifications are insufficient, medications are used. In prescribing medications or medication combinations, doctors have to take into account medication side effects as

well as the presence or absence of other abnormalities in cholesterol profiles. Regular aerobic exercise, loss of excess weight (fat), and cessation of smoking cigarettes will increase HDL cholesterol levels. Regular alcohol consumption (such as one drink a day) will also raise HDL cholesterol. Because of other adverse health consequences of excessive alcohol consumption, alcohol is not recommended as a standard treatment for low HDL cholesterol. Medications that are effective in increasing HDL cholesterol include nicotinic acid (niacin), gemfibrozil (Lopid), estrogen, and to a much lesser extent, the statin drugs (discussed below). A newer medicine, fenofibrate (Tricor) has shown much promise in selectively increasing HDL levels and reducing serum triglycerides. What are triglycerides, chylomicrons, and VLDL? Triglyceride is a fatty substance that is composed of three fatty acids. Each of these acids is attached to a glycerol molecule. Like cholesterol, triglyceride in the blood either comes from the diet or the liver. Also, like cholesterol, triglyceride cannot dissolve and circulate in the blood without combining with a lipoprotein. Thus, after a meal, the triglyceride and cholesterol that are absorbed into the intestines are packaged into round particles called chylomicrons before they are released into the blood circulation. A chylomicron is a collection of cholesterol and triglyceride that is surrounded by a lipoprotein outer coat. (Chylomicrons contain 90% triglyceride and 10% cholesterol.) There are special enzymes on the blood vessels that break up the triglyceride inside the chylomicrons, releasing fatty acids in the process. The fatty acids can either be used by the muscles as energy, or absorbed by fat cells where they are incorporated again into triglyceride that can be stored in the fat cells for future energy needs. The chylomicrons are then removed from the circulation by the liver. The liver not only removes triglyceride and chylomicrons from the blood, it also synthesizes and packages triglyceride into VLDL (very low-density lipoprotein) particles and releases them back into the blood circulation. Therefore, before breakfast after an overnight fast, most of the triglyceride in the blood comes from the liver in the form of VLDL particles. Like chylomicrons, VLDL particles contain mostly triglyceride. Some of the VLDL particles lose triglyceride in the blood and become cholesterol-rich LDL particles. Do high triglyceride levels cause atherosclerosis? Whether elevated triglyceride levels in the blood lead to atherosclerosis and heart attacks is controversial. While most doctors now believe that an abnormally high triglyceride level is a risk factor for atherosclerosis, it is difficult to conclusively prove that elevated triglyceride by itself can cause atherosclerosis. However, it is increasingly recognized that elevated triglyceride is often associated with other conditions that increase the risk of atherosclerosis, including obesity, low levels of HDL- cholesterol, insulin resistance and poorly controlled diabetes mellitus, and small, dense LDL cholesterol particles. What are the causes of elevated triglyceride levels? In some people, abnormally high triglyceride levels (hypertriglyceridemia) are inherited. Examples of inherited hypertriglyceridemia disorders include mixed hypertriglyceridemia, familial hypertriglyceridemia, and familial dysbetalipoproteinemia. Hypertrigleridemia can often be caused by non-genetic factors such as obesity, excessive alcohol intake, diabetes mellitus, kidney disease, and estrogen- containing medications such as birth control pills. How can elevated blood triglyceride levels be treated? The first step in treating hypertriglyceridemia is a low fat diet with a limited amount of sweets,

regular aerobic exercise, loss of excess weight, reduction of alcohol consumption, and stopping cigarette smoking. In patients with diabetes mellitus, meticulous control of elevated blood glucose is also important. When medications are necessary, fibrates (such as Lopid), nicotinic acid, and statin medications can be used. Lopid not only decreases triglyceride levels but also increases HDL cholesterol levels and LDL cholesterol particle size. Nicotinic acid lowers triglyceride levels, increases HDL cholesterol levels and the size of LDL cholesterol particles, as well as lowers the levels of Lp (a) cholesterol. The statin drugs have been found effective in decreasing triglyceride as well as LDL cholesterol levels and, to a lesser extent, in elevating HDL cholesterol levels. A relatively new medicine, fenofibrate (Tricor), shows promise as an effective agent in lowering serum triglyceride levels as well as raising HDL levels, particularly in patients who have had suboptimal responses to Lopid. In some patients, a combination of Lopid or Tricor with adjunctive statin therapy (see below) may be prescribed. While this combination is often effective in patients with complex lipid disorders, the potential for side effects may be increased and such patients should be under strict medical supervision. What are lipid-altering medications? Lipid altering medications are used in lowering blood levels of undesirable lipids such as LDL cholesterol and triglycerides and increasing blood levels of desirable lipids such as HDL cholesterol. Several classes of medications are available in the United States, including HMG CoA reductase inhibitors (statins), nicotinic acid, fibric acid derivatives, and medications that decrease intestinal cholesterol absorption (bile acid sequestrants and cholesterol absorption inhibitors). Some of these medications are primarily useful in lowering LDL cholesterol, others in lowering triglycerides, and some in elevating HDL cholesterol. Medications also can be combined to more aggressively lower LDL, as well as in lowering LDL and increasing HDL at the same time. Lipid altering medications commonly used in the United States Medication class Medication examples Pravachol, Mevacor, Lipitor, Lescol, Crestor, Zocor Effects on blood lipids Most effective in lowering LDL, mildly effective in increasing HDL, mildly effective in lowering triglycerides Most effective in increasing HDL, effective in lowering triglycerides, mildly to modestly effective in lowering LDL Most effective in lowering triglycerides, effective in increasing HDL, minimally effective in lowering LDL

statins

Nicotinic acid (Niacin)

Niacin, Niaspan, Slo-Niacin

Fibric acid

Lopid, Tricor

Bile acid sequestrants Cholesterol

Mildly to modestly effective in Questran, Welchol, lowering LDL, no effect on Colestid HDL and triglycerides Zetia Mildly to modestly effective in

absorption inhibitors

lowering LDL, no effect on HDL and triglycerides

Combining Advicor Effective in lowering LDL and nicotinic acid with (lovastatin+niaspan triglycerides and increasing statin ) HDL Combining a statin Vytorin (Zocor + with an absorption Zetia) inhibitor What are the statin drugs? The statins are the most widely used, and also the most powerful medications for lowering LDL cholesterol. Numerous large, randomized, double-blind, placebo-controlled, , clinical trials (controlled trials) have shown that statins reduce heart attacks (and strokes) and improve survival. Statins are well tolerated with low side effect rates when used long term. Statins not only lower blood LDL cholesterol levels, they also modestly increase HDL cholesterol levels and modestly decrease triglyceride levels. The statins that are now on pharmacy shelves in the U.S. (putting the generic name first followed by the brand name in parentheses) are: rosuvastatin ( Crestor) fluvastatin sodium (Lescol) made by Novartis atorvastatin calcium (Lipitor) made by Parke-Davis and Pfizer lovastatin (Mevacor) made by Merck pravastatin sodium (Pravachol) made by Bristol-Myers Squibb simvastatin (Zocor) made by Merck The statins act by repressing or inhibiting an enzyme called HMG-CoA reductase. The role of this enzyme is the promotion of a chemical reaction early in the production (synthesis) of cholesterol. By inhibiting HMG-CoA reductase, the statins hinder the production of cholesterol by the liver. The diminished synthesis of cholesterol in the liver in turn stimulates (increases) the activity of LDL receptors on the surface of liver cells. Increasing LDL receptor activity decreases LDL cholesterol levels in blood. Studies have consistently shown that lowering LDL cholesterol with diet and statins reduces the risk of a second heart attack. The prevention of recurrent heart attacks in patients who have already suffered a heart attack is called secondary prevention. Studies have also demonstrated that reducing LDL cholesterol with lifestyle changes and statins reduces the risk of having the first heart attack. Prevention of heart attacks in those who have never had a heart attack is called primary prevention. Studies have also confirmed that reducing LDL cholesterol benefits both men and women, and the elderly. What are side effects of statins? Statins are generally well tolerated and side effects are rare. The most common side effects are headache, nausea, vomiting, constipation, diarrhea, headache, rash, weakness, and muscle pain. Statins can cause muscle injury, ranging from myalgias (muscle pain), myositis (muscle inflammation), to rhabdomyolysis (death of muscle cells that can lead to kidney failure). Myalgias can occur at a frequency of 2%-10%, and will resolve upon discontinuing the statins. The more Synergistic in lowering LDL and effective in lowering LDL with low doses of each ingredient

serious rhabdomyolysis fortunately is rare, occurring at a frequency of less than 0.1%. It occurs more often when statins are used in combination with other drugs that themselves cause rhabdomyolysis (example; gemfibrozil), or with drugs that prevent the elimination of statins and raise the levels of statins in the blood (for example; cyclosporine, verapamil, erythromycin, ketoconazole, amiodarone, or one quart daily of grapefruit juice). Rhabdomyolysis often begins as muscle pain and then progresses to cause kidney damage. Therefore, unexplained joint or muscle pain that occurs while taking statins should be brought to the attention of a doctor. Clinical studies have found elevations in blood levels of liver enzymes (aminotransferases; ALT and AST) at a frequency of 0.5% to 3%. But in several large controlled trials, scientists found no difference in the incidence of abnormal liver enzymes between statin users and subjects taking a placebo. Thus, scientists cannot attribute abnormal liver enzymes to statin use. Nevertheless, as a precaution, the United States FDA labeling information advises that liver enzyme blood tests be performed before and at 12 weeks following the initiation of statin treatment or elevation of dose, and periodically thereafter (for example, every 6 months). In patients with existing liver diseases or with abnormal liver blood tests at baseline (before initiating statin treatment), measures can be taken to minimize potential aggravation of liver disease. For instance, using statins that theoretically have little effect on the liver, such as pravastatin (Pravachol) or rosuvastatin (Crestor), in low doses, can be used. Liver enzyme blood tests can also be regularly monitored during statin treatment. For more information regarding the side effects, precautions, and drug interactions of the various statins, please read the article on Statins. When do doctors prescribe a statin drug? Decisions regarding when to initiate a statin drug, the choice of statin medication, and whether to use a statin in combination with another lipid altering drug, have to be individualized after consulting the doctor. Therapeutic lifestyle changes (discussed above) should be advised for all patients in need of lowering LDL cholesterol and; medications are prescribed when lifestyle changes are insufficient. Increasingly, doctors are using a statin or a statin in combination with another lipid-altering drug for secondary prevention (prevention of a second or third heart attack), for patients who have diabetes, or patients who are at high risk for heart attacks. Lifestyle changes alone are often insufficient to achieve the NCEP recommended LDL cholesterol targets for these high risk patients. Increasingly, doctors are also prescribing a statin for primary prevention (prevention of a first heart attack). The decision whether to use a statin for primary prevention must be individualized, weighing the risks and the benefits. Doctors are more likely to recommend a statin for primary prevention if a person has risk factors for coronary heart disease and lifestyle changes implemented by the patient has not lowered LDL cholesterol sufficiently to desired levels (see the NCEP recommendations above). How do doctors select statin drugs? Which statin to use is an individualized decision. There are several considerations in choosing a statin: In patients who need intense LDL cholesterol-lowering, it is more appropriate to use one of the more potent statins, such as atorvastatin (Lipitor) or rosuvastatin (Crestor). Sometimes a statin may need to be combined with another medication such as cholestyramine (Questran), ezetimide (Zetia) or nicotinic acid, in order to achieve the LDL cholesterol goals. In patients with chronic liver disease who need statin treatment, it is important to completely abstain from alcohol and use either pravastatin (Pravachol) or rosuvastatin (Crestor) in low doses. (Pravastatin and rsuvastatin are safer to use in patients with liver disease.) If LDL cholesterol goals cannot be attained with low doses of either of these two statins,

cholestyramine (Quesetran) or ezetimide (Zetia) can be added. In patients who develop muscle aches or muscle damage with a statin, it may be appropriate to try another statin, such as pravastatin (Pravachol), that probably has less of a muscle toxic effect than the other statins. In patients who are at risk of developing muscle injury (for example a patient who is already taking gemfibrozil), pravastatin (Pravachol) would also be a suitable statin to use. Atorvastatin (Lipitor) and fluvastatin (Lescol) do not require dose adjustments in patients with kidney diseases. What is nicotinic acid (niacin)? Nicotinic acid (niacin) is a B vitamin. An average American diet contains 15-30 mg of niacin per day. However, in treating blood cholesterol and triglyceride disorders, high doses (1-3 grams a day) of nicotinic acid are necessary. Nicotinic acid is available in several preparations that include immediate release niacin, sustained release prescription brand Niaspan, and over- the- counter (OTC) sustained release niacin. OTC preparations are not federally regulated, and some OTC preparations may have no active ingredient. Thus, they would be ineffective in either lowering LDL or raising HDL cholesterol. Some formulations of OTC sustained release niacin have been associated with liver toxicity and rare cases of fulminant (usually fatal without liver transplantation) hepatitis have been reported. The prescription brand sustained release Niaspan has been found in clinical trials to cause only minor elevations in blood liver enzymes without causing significant liver disease. Nicotinic acid is most effective in increasing HDL cholesterol and it is also modestly effective in lowering LDL cholesterol, Lp(a) cholesterol, and triglyceride levels (see below). Nicotinic acid is most suited for individuals whose only problem is low HDL cholesterol. Nicotinic acid used alone can raise HDL cholesterol levels by 30% or more. Nicotinic acid is not as effective as a statin in lowering LDL cholesterol levels. Therefore, when low HDL cholesterol is accompanied by high LDL cholesterol, most doctors use a statin to decrease the LDL cholesterol first. If necessary, nicotinic acid can be added to a statin to further raise HDL cholesterol levels. Advicor is a combination product approved for use in the United States. It is a combination of sustained release niacin with lovastatin. Advicor is useful in patients who need to both significantly lower their LDL cholesterol and increase HDL cholesterol. What are the side effects of niacin? The most common side effect of nicotinic acid is a flushing (which can occur in 80% of patients taking the immediate release crystalline preparations), itching, and upset stomach. Other side effects include liver toxicity, aggravating blood sugar levels in patients with diabetes mellitus, and precipitating painful arthritis attacks in patients with gout. The itching, flushing, and stomach upset can be partially alleviated by the following measures: Taking nicotinic acid with meals. The sustained release Niaspan capsules release nicotinic acid from the stomach into the blood circulation more gradually than the immediate release preparations. Therefore, Niaspan produces a lower incidence of upset stomach and skin flushing than the niacin immediate release tablets. Pretreatment with aspirin 30 minutes prior to nicotinic acid can reduce flushing. Initiating nicotinic acid treatment at low doses and gradually increasing to the targeted dosage. Liver toxicity with the immediate release nicotinic acid is usually mild and in the form of abnormal elevation of liver enzymes in the blood, which normalizes when nicotinic acid is stopped. Severe liver diseases, including fulminant hepatitis (see above), have been reported, especially with the use of over-the-counter sustained release formulations. The onset of liver damage with nicotinic acid is unpredictable. Therefore, patients taking any nicotinic acid preparations should have regular liver

enzyme blood tests. What are fibric acid derivatives (fibrates)? Fibric acid derivatives (fibrates) are effective medications in lowering blood triglyceride levels. Fibrates lower blood triglyceride levels by inhibiting the liver production of VLDL (the triglyceriderich lip-protein fraction), and by speeding up the removal of triglycerides from the blood. Fibrates are also modestly effective in increasing blood HDL cholesterol levels. However, fibrates are not effective in lowering LDL cholesterol. Examples of fibrates available in the United Sates include Gemfibrozil (Lopid) and fenofibrate (Tricor). Very high triglyceride levels (usually > 1000 mg/dl) can cause pancreatitis (inflammation of the pancreas that can result in a serious an illness with severe abdominal pain). By lowering the blood triglycerdes, fibrates are used to prevent pancreatitis. Fibrates are not effective in lowering LDL cholesterol and cannot be used alone in lowering LDL cholesterol levels. However, when a high risk patient (see NCEP recommendations above) also has high blood triglyceride or low HDL cholesterol levels, doctors may consider combining a fibrate, such as fenofibrate (Tricor), with a statin. Such a combination will not only lower the LDL cholesterol, but will also lower blood triglycerides and increase HDL cholesterol levels. Fibrates have also been used alone to prevent heart attacks especially in patients with elevated blood triglycerides and low HDL cholesterol levels. In one large study, gemfibrozil decreased the risk of heart attacks but did not affect the overall survival of persons with high cholesterol levels. What are the side effects of fibrates? The side effects of fibrates include nausea, stomach upset, and sometimes diarrhea. Fibrates can also cause liver irritation. The liver irritation is usually mild and reversible, but it occasionally can be severe enough to require stopping the drug. Fibrates can cause gallstones when used over several years. The fibrates can increase the effectiveness of blood thinners, such as Coumadin, when both medications are used together. Thus, the dose of Coumadin should be adjusted to avoid over-thinning of the blood, which can lead to excessive bleeding. Fibrates can cause muscle damage. Doctors generally avoid combining a statin with gemfibrozil because of concern over the added risk of muscle damage with the combination. Gemfibrozl interferes with the breakdown of statin, resulting in higher statin blood levels, and hence a higher likelihood of muscle toxicity. Fenofibrate does not interfere with the breakdown of a statin, and should be the safer fibrate to use whenever a fibrate-statin combination is necessary. Furthermore, pravastatin seems to have fewer muscle toxic effects than the other statins when combined with a fibrate. What are bile acid sequestrants? Bile acid sequestrants such as Cholestyramine (Questran), colestipol (Colestid), and colesevelam (Welchol) are medications for lowering LDL cholesterol. Bile acid sequestrants bind bile acids in the intestine and cause more of the bile acids to be excreted in the stool. This reduces the amount of bile acids returning to the liver and forces the liver to produce more bile acids to replace the bile acids lost in the stool. In order to produce more bile acids, the liver converts more cholesterol into bile acids, which lowers the level of cholesterol in the blood. Bile acid sequestrants have modest LDL cholesterol-lowering effects. Low doses (for example 8 gram/day of Cholestyramine) can lower LDL cholesterol by 10%-15 %. But even high doses (24 gram/day of cholestyramine) can only lower LDL cholesterol by approximately 25%. Therefore, bile acid sequestrants used alone are not as effective as statins in lowering LDL cholesterol. However, bile acid sequestrants are most useful in combining with a statin or niacin to aggressively

lower LDL cholesterol levels. The statin-bile acid sequestrant combination can lower LDL cholesterol levels by approximately 50%, lower than a statin alone. A statin-niacin combination can substantially reduce LDL cholesterol and elevate HDL cholesterol. What are the side effects of bile acid sequestrants? Bile acid squestrants are not absorbed into the body and therefore they do not have systemic side effects (affecting other organs). Therefore, their most common side effects are gastrointestinal; constipation, abdominal pain, bloating, vomiting, diarrhea, weight loss, and excessive passage of gas (flatulence). Bile acid squestrants can bind to and decrease the absorption (and hence the effectiveness) of other drugs, such as warfarin (Coumadin), thyroid hormones (Synthroid, Levoxyl), digoxin (Lanoxin), thiazide diuretics (Hydrodiuril, Oretic, Dyazide, Maxide), and many others. Therefore, these medications should be taken 1 hour before or 4-6 hours after the administration of a bile acid sequestrant. Bile acid squestrants reduces the absorption of vitamin A, D, E, and K. Long-term use may thus cause a deficiency of vitamin A, D, E, and K. What is ezetimide (Zetia)? Ezetimibe lowers blood cholesterol by blocking the absorption of cholesterol, including dietary cholesterol, from the intestines. It does not affect, however, the absorption of triglycerides or fatsoluble vitamins. Ezetimibe was approved by the FDA in October, 2002. Ezetimibe can be used alone or together with a statin drug. Ezetimibe used alone is modestly effective in lowering LDL cholesterol. At a dose of 10 mg/day it can reduce LDL cholesterol by approximately 17%. When used with a statin, it can reduce LDL cholesterol level further than a statin alone. However, there is insufficient scientific data to determine whether a statin-ezetmibe combination actually further reduces heart attack or stroke risks. A new combiniation drug, Vytorin, is available and combines 10 mg of Zetia with 20, 40, or 80 mg of Zocor. Ezetimibe is probably most useful in avoiding having to use high doses of a statin to achieve the 2004 NCEP LDL cholesterol targets in certain patients. Using lower doses of a statin probably reduces the risk of muscle injury. A statin-ezetmibe combination may also be helpful in treating patients with very high LDL cholesterol who cannot attain LDL cholesterol targets even with maximal doses of statins. Ezetimibe can be taken with or without food and at the same time as statin drugs. Ezetimibe is well-tolerated. The overall rate of side effects with ezetimibe in clinical studies was similar to that reported with a placebo (an inactive sugar pill). Diarrhea, abdominal pain, back pain, joint pain, and sinusitis were the most commonly reported side effects, occurring in 1 in every 25 to 30 patients. Is lowering LDL cholesterol enough? Unfortunately, the prevention and treatment of atherosclerosis are more complicated than just lowering LDL cholesterol levels. LDL cholesterol reduction is only half of the battle against atherosclerosis. Individuals who have normal or only mildly elevated LDL cholesterol levels can still develop atherosclerosis and heart attacks even in the absence of other risk factors such as cigarette smoking, high blood pressure, and diabetes mellitus. Additionally, successfully lowering elevated LDL cholesterol levels cannot always prevent atherosclerosis and heart attacks. In many clinical trials to lower LDL cholesterol, there were patients who adhered to their assigned diets, faithfully took their cholesterol-lowering medications, and successfully lowered their LDL cholesterol to target levels, yet still suffered progressive atherosclerosis and heart attacks. It is clear that while lowering LDL cholesterol below NCEP target levels is an important step, there are other factors involved. What are the other risk factors for heart attacks?

What are LDL cholesterol particle size patterns A and B? LDL patterns A and B refer to the size of LDL cholesterol particles in the blood. Some doctors believe that small LDL cholesterol particles in the blood may pose a greater risk for developing atherosclerosis and heart attacks than the absolute level of LDL cholesterol in the blood. The size of LDL cholesterol particles is primarily inherited. A special blood test called polyacrylamide gradient gel electrophoresis can measure particle size and determine whether a person has blood cholesterol LDL pattern A or LDL pattern B. Persons with LDL cholesterol pattern A have large, buoyant LDL cholesterol particles. Individuals with pattern A are more likely to have normal blood levels of LDL cholesterol, HDL cholesterol, and triglycerides. Pattern A is usually not associated with an increased likelihood of atherosclerosis. Persons with LDL cholesterol pattern B have predominantly small and dense LDL cholesterol particles. Pattern B is frequently associated with low HDL cholesterol levels, elevated triglyceride levels, and the tendency to develop high blood sugar levels and type II diabetes mellitus. Individuals with pattern B are also more likely to develop high blood triglyceride levels after a fatty meal (postprandial hyperlipidemia). Pattern B is associated with accelerated atherosclerosis and a 3 to 5- fold increase in heart attack risk. Pattern B is believed to be the most important cause of atherosclerosis in people with normal or near normal total and LDL cholesterol levels. Some scientists believe that the smaller LDL particles are more dangerous than the larger ones because they can more easily squeeze through the tiny gaps between the cells in the endothelium to reach inside the artery walls. The endothelium is a thin layer of cells which covers the inner wall of the arteries. The cells making up the endothelium have tiny gaps between them. Others postulate that the smaller LDL cholesterol particles are more easily oxidized. Oxidation of cholesterol is significant in the formation of cholesterol plaques. How can LDL cholesterol size be enlarged? Even though LDL cholesterol particle size is mainly genetically inherited, individuals who have small LDL particles (pattern B) can increase their particle size through diet, exercise, and medications. Diets that are low in saturated fat and cholesterol, regular aerobic exercise, and loss of excess body fat have been determined to decrease the number of small LDL particles and increase the number of large LDL particles in the blood. In other words, lifestyle modifications can change pattern B to pattern A. When lifestyle changes alone are unsuccessful, medications can be used. Even though the statin medications (discussed above) are effective in lowering the absolute levels of LDL cholesterol, they appear to have a limited effect on LDL cholesterol size pattern. Medications such as nicotinic acid (niacin) and gemfibrozil (Lopid) have been found effective in many instances in increasing the size of LDL cholesterol particles. What is lipoprotein (a), (Lp(a)) cholesterol? Lipoprotein (a) (Lp(a)) is an LDL cholesterol particle that is attached to a special protein called apo(a). In large part, a person's level of Lp(a) in the blood is genetically inherited. Elevated levels of Lp(a) (higher than 20 mg/dl to 30 mg/dl) in the blood are linked to a greater likelihood of atherosclerosis and heart attacks in both men and women. The risk is even more significant if the Lp(a) cholesterol elevation is accompanied by high LDL/HDL ratios. Certain diseases are associated with elevated Lp(a) levels. Patients on chronic kidney dialysis and those with nephrotic syndromes (kidney diseases that cause leakage of blood proteins into the urine) tend to have high levels of Lp(a). There are many theories as to how Lp(a) causes atherosclerosis although exactly how Lp(a) accumulates cholesterol plaques on the artery walls has not been well defined. Clinical trials

conclusively proving that lowering Lp(a) reduces atherosclerosis and the risk of heart attacks have not been conducted. Currently, there is no international standard for determining Lp(a) cholesterol levels and commercial sources of Lp(a) testing may not have the same accuracy as research laboratories. Therefore, specifically measuring and treating elevated Lp(a) cholesterol levels are not widely performed in this country. How can Lp(a) cholesterol levels be reduced? Most lipid-lowering medications such as statins, Lopid, and cholestyramine have a limited effect in lowering Lp(a) cholesterol levels. Estrogen has been shown to lower Lp(a) cholesterol levels by approximately 20% in women with elevated Lp(a) cholesterol. Estrogen can also increase HDL cholesterol levels when given to postmenopausal women. Additionally, nicotinic acid (Niacin or Niaspan) in high doses has been found to be effective in lowering Lp(a) cholesterol levels by approximately 30%. Who should undergo standard lipid profile testing? It is recommended that every adult over 20 should have lipid panel tests (total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels) every 5 years if LDL cholesterol is less than 130, and every 1-3 years if LDL cholesterol is borderline (between 130 and 160). This is particularly important for those with a family history of coronary artery disease. Once these cholesterol figures are known, the chance of developing heart disease can be determined in combination with other risk factors that play a role in its development. Who should undergo testing for LDL cholesterol particle size and Lp(a) cholesterol levels? The scientific analysis for the determination of LDL size and Lp(a) is relatively new and is not standardized from laboratory to laboratory. Thus, results will vary to some degree between different laboratories. Also, because the use of any specific laboratory test is not widespread, the cost of testing remains expensive. Because of the cost and variability of testing, a determination of these cholesterol components is not necessary for everyone. Currently, persons who have been diagnosed with coronary artery disease whose risk factor profile would not otherwise predict coronary artery disease at the age at which it occurred, should be tested for these more specific cholesterol components. For example, if heart disease occurs at a young age without high LDL levels, high blood pressure, diabetes, or cigarette smoking, the physician and patient may consider testing for another risk factor such as small LDL particle size or elevated Lp(a). Among persons without coronary heart disease, those with a family history of heart disease occurring early in life should be tested for these risk factors, which are predominantly determined by genetic inheritance. As the cost and accuracy of testing improves, the evaluation of these components should become more widespread.