TOC Sections
Cholesterol 2.0 - Cholesterol Management System™


The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III, or ATP III) constitutes the National Cholesterol Education Program’s (NCEP’s) updated clinical guidelines for cholesterol testing and management. The full ATP III document is an evidence-based and extensively referenced report that provides the scientific rationale for the recommendations contained in the executive summary. ATP III builds on previous ATP reports and expands the indications for intensive cholesterol-lowering therapy in clinical practice. It should be noted that these guidelines are intended to inform, not replace, the physician’s clinical judgment, which must ultimately determine the appropriate treatment for each individual.
The third ATP report updates the existing recommendations for clinical management of high blood cholesterol. The NCEP periodically produces ATP clinical updates as warranted by advances in the science of cholesterol management. Each of the guideline reports—ATP I, II, and III—has a major thrust. ATP I outlined a strategy for primary prevention of coronary heart disease (CHD) in persons with high levels of low density lipoprotein (LDL) cholesterol (160 mg/dL) or those with borderline-high LDL cholesterol (130-159 mg/dL) and multiple (2+) risk factors. ATP II affirmed the importance of this approach and added a new feature: the intensive management of LDL cholesterol in persons with established CHD. For CHD patients, ATP II set a new, lower LDL cholesterol goal of 100 mg/dL. ATP III adds a call for more intensive LDL-lowering therapy in certain groups of people, in accord with recent clinical trial evidence, but its core is based on ATP I and ATP II. Some of the important features shared with previous reports are shown in Table A in the Appendix.

While ATP III maintains attention to intensive treatment of patients with CHD, its major new feature is a focus on primary prevention in persons with multiple risk factors. Many of these persons have a relatively high risk for CHD and will benefit from more intensive LDL-lowering treatment than recommended in ATP II. Table 1 shows the new features of ATP III.

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Research from experimental animals, laboratory investigations, epidemiology, and genetic forms of hypercholesterolemia indicate that elevated LDL cholesterol is a major cause of CHD. In addition, recent clinical trials robustly show that LDL-lowering therapy reduces risk for CHD. For these reasons, ATP III continues to identify elevated LDL cholesterol as the primary target of cholesterol-lowering therapy. As a result, the primary goals of therapy and the cutpoints for initiating treatment are stated in terms of LDL.
A basic principle of prevention is that the intensity of risk-reduction therapy should be adjusted to a person’s absolute risk. Hence, the first step in selection of LDL-lowering therapy is to assess a person’s risk status. Risk assessment requires measurement of LDL cholesterol as part of lipoprotein analysis and identification of accompanying risk determinants.

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In all adults aged 20 years or older, a fasting lipoprotein profile (total cholesterol, LDL cholesterol, high density lipoprotein (HDL) cholesterol, and triglyceride) should be obtained once every 5 years. If the testing opportunity is nonfasting, only the values for total cholesterol and HDL cholesterol will be usable. In such a case, if total cholesterol is 200 mg/dL or HDL is <40 mg/dL, a followup lipoprotein profile is needed for appropriate management based on LDL. The relationship between LDL cholesterol levels and CHD risk is continuous over a broad range of LDL levels from low to high. Therefore, ATP III adopts the classification of LDL cholesterol levels shown in Table 2, which also shows the classification of total and HDL cholesterol levels.

Risk determinants in addition to LDL-cholesterol include the presence or absence of CHD, other clinical forms of atherosclerotic disease, and the major risk factors other than LDL (see Table 3). (LDL is not counted among the risk factors in Table 3 because the purpose of counting those risk factors is to modify the treatment of LDL.) Based on these other risk determinants, ATP III identifies three categories of risk that modify the goals and modalities of LDL-lowering therapy. Table 4 defines these categories and shows corresponding LDL-cholesterol goals.

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The category of highest risk consists of CHD and CHD risk equivalents. The latter carry a risk for major coronary events equal to that of established CHD, i.e., >20% per 10 years (i.e., more than 20 of 100 such individuals will develop CHD or have a recurrent CHD event within 10 years). CHD risk equivalents comprise:

  • Other clinical forms of atherosclerotic disease (peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease);
  • Diabetes;
  • Multiple risk factors that confer a 10-year risk for CHD >20%.

  • Diabetes counts as a CHD risk equivalent because it confers a high risk of new CHD within 10 years, in part because of its frequent association with multiple risk factors. Furthermore, because persons with diabetes who experience a myocardial infarction have an unusually high death rate either immediately or in the long term, a more intensive prevention strategy is warranted. Persons with CHD or CHD risk equivalents have the lowest LDL cholesterol goal (<100 mg/dL). The second category consists of persons with multiple (2+) risk factors in whom 10-year risk for CHD is 20%. Risk is estimated from Framingham risk scores (see Appendix). The major risk factors, exclusive of elevated LDL cholesterol, are used to define the presence of multiple risk factors that modify the goals and cutpoints for LDL-lowering treatment, and these are listed in Table 3. The LDL cholesterol goal for persons with multiple (2+) risk factors is <130 mg/dL. The third category consists of persons having 0-1 risk factor; with few exceptions, persons in this category have a 10-year risk <10%. Their LDL cholesterol goal is <160 mg/dL.
    Risk status in persons without clinically manifest CHD or other clinical forms of atherosclerotic disease is determined by a 2-step procedure.

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    First, the number of risk factors is counted (Table 3). Second, for persons with multiple (2+) risk factors, 10-year risk assessment is carried out with Framingham scoring (see Appendix) to identify individuals whose short-term (10-year) risk warrants consideration of intensive treatment. Estimation of the 10-year CHD risk adds a step to risk assessment beyond risk factor counting, but this step is warranted because it allows better targeting of intensive treatment to people who will benefit from it. When 0-1 risk factor is present, Framingham scoring is not necessary because 10-year risk rarely reaches levels for intensive intervention; a very high LDL level in such a person may nevertheless warrant consideration of drug therapy to reduce long-term risk. Risk factors used in Framingham scoring include age, total cholesterol, HDL cholesterol, blood pressure, and cigarette smoking. Total cholesterol is used for 10-year risk assessment because of a larger and more robust Framingham database for total than for LDL cholesterol, but LDL cholesterol is the primary target of therapy. Framingham scoring divides persons with multiple risk factors into those with 10-year risk for CHD of >20%, 10-20%, and <10%. It should be noted that this 2-step sequence can be reversed with essentially the same results.* Initial risk assessment in ATP III uses the major risk factors to define the core risk status. Only after the core risk status has been determined should any other risk modifiers be taken into consideration for adjusting the therapeutic approach.

    * If Framingham scoring is carried out before risk factor counting, persons with <10 percent risk are then divided into those with 2+ risk factors and 0-1 risk factor by risk factor counting to determine the appropriate LDL goal (see Table 4).

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    ATP III recognizes that risk for CHD is influenced by other factors not included among the major, independent risk factors (Table 3). Among these are life-habit risk factors and emerging risk factors. The former include obesity, physical inactivity, and atherogenic diet; the latter consist of lipoprotein (a), homocysteine, prothrombotic and proinflammatory factors, impaired fasting glucose, and evidence of subclinical atherosclerotic disease. The life-habit risk factors are direct targets for clinical intervention, but are not used to set a lower LDL cholesterol goal of therapy. The emerging risk factors do not categorically modify LDL cholesterol goals; however, they appear to contribute to CHD risk to varying degrees and can have utility in selected persons to guide intensity of risk-reduction therapy. Their presence can modulate clinical judgment when making therapeutic decisions.
    Many persons have a constellation of major risk factors, life-habit risk factors, and emerging risk factors that constitute a condition called the metabolic syndrome. Factors characteristic of the metabolic syndrome are abdominal obesity, atherogenic dyslipidemia (elevated triglyceride, small LDL particles, low HDL cholesterol), raised blood pressure, insulin resistance (with or without glucose intolerance), and prothrombotic and proinflammatory states. ATP III recognizes the metabolic syndrome as a secondary target of risk-reduction therapy, after the primary target—LDL cholesterol. Diagnosis and treatment of the metabolic syndrome is described beginning on page 15 under “Benefit Beyond LDL Lowering: The Metabolic Syndrome as a Secondary Target of Therapy.”
    In ATP III, a primary aim is to match intensity of LDL-lowering therapy with absolute risk. Everyone with elevated LDL cholesterol is treated with lifestyle changes that are effective in lowering LDL levels. Persons at relatively high risk are also candidates for drug treatment, which is very effective but entails significant additional expense. The cutpoints for drug treatment are based primarily on risk-benefit considerations: those at higher risk are likely to get greater benefit. However, cutpoints for recommended management based on therapeutic efficacy are checked against currently accepted standards for cost effectiveness. Lifestyle changes are the most cost-effective means to reduce risk for CHD. Even so, to achieve maximal benefit, many persons will require LDL-lowering drugs. Drug therapy is the major expense of LDL-lowering therapy, and it dominates cost-effectiveness analysis. However, the costs of LDL-lowering drugs are currently in flux and appear to be declining. This report recognizes that as drug prices decline it will be possible to extend drug use to lower risk persons and still be cost effective. In addition, ATP III recognizes that some persons with high long-term risk are candidates for LDL-lowering drugs even though use of drugs may not be cost effective by current standards.
    Primary prevention of CHD offers the greatest opportunity for reducing the burden of CHD in the United States. The clinical approach to primary prevention is founded on the public health approach that calls for lifestyle changes, including: 1) reduced intakes of saturated fat and cholesterol, 2) increased physical activity, and 3) weight control, to lower population cholesterol levels and reduce CHD risk, but the clinical approach intensifies preventive strategies for higher risk persons. One aim of primary prevention is to reduce long-term risk (>10 years) as well as short-term risk (10 years). LDL goals in primary prevention depend on a person’s absolute risk for CHD (i.e., the probability of having a CHD

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    event in the short term or the long term)—the higher the risk, the lower the goal. Therapeutic lifestyle changes are the foundation of clinical primary prevention. Nonetheless, some persons at higher risk because of high or very high LDL cholesterol levels or because of multiple risk factors are candidates for LDL-lowering drugs. Recent primary prevention trials show that LDL-lowering drugs reduce risk for major coronary events and coronary death even in the short term.

    Recent clinical trials demonstrate that LDL-lowering therapy reduces total mortality, coronary mortality, major coronary events, coronary artery procedures, and stroke in persons with established CHD. As shown in Table 2, an LDL cholesterol level of <100 mg/dL is optimal; therefore, ATP III specifies an LDL cholesterol <100 mg/dL as the goal of therapy in secondary prevention. This goal is supported by clinical trials with both clinical and angiographic endpoints and by prospective epidemiological studies. The same goal should apply for persons with CHD risk equivalents. When persons are hospitalized for acute coronary syndromes or coronary procedures, lipid measures should be taken on admission or within 24 hours. These values can guide the physician on initiation of LDL-lowering therapy before or at discharge. Adjustment of therapy may be needed after 12 weeks.
    The two major modalities of LDL-lowering therapy are therapeutic lifestyle changes (TLC) and drug therapy. Both are described in more detail later. The TLC Diet stresses reductions in saturated fat and cholesterol intakes. When the metabolic syndrome or its associated lipid risk factors (elevated

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    triglyceride or low HDL cholesterol) are present, TLC also stresses weight reduction and increased physical activity. Table 5 defines LDL cholesterol goals and cutpoints for initiation of TLC and for drug consideration for persons with three categories of risk: CHD and CHD risk equivalents; multi-ple (2+) risk factors (10-year risk 10-20% and <10%); and 0-1 risk factor.

    For persons with CHD and CHD risk equivalents, LDL-lowering therapy greatly reduces risk for major coronary events and stroke and yields highly favorable cost-effectiveness ratios. The cut-points for initiating lifestyle and drug therapies are shown in Table 5.

    If baseline LDL cholesterol is 130 mg/dL, intensive lifestyle therapy and maximal control of other risk factors should be started. Moreover, for most patients, an LDL-lowering drug will be required to achieve an LDL cholesterol <100 mg/dL; thus an LDL cholesterol lowering drug can be started simultaneously with TLC to attain the goal of therapy.

    If LDL cholesterol levels are 100-129 mg/dL, either at baseline or on LDL-lowering therapy, several therapeutic approaches are available:

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  • Initiate or intensify lifestyle and/or drug therapies specifically to lower LDL.
  • Emphasize weight reduction and increased physical activity in persons with the metabolic syndrome.
  • Delay use or intensification of LDL-lowering therapies and institute treatment of other lipid or nonlipid risk factors; consider use of other lipid-modifying drugs (e.g., nicotinic acid or fibric acid) if the patient has elevated triglyceride or low HDL cholesterol.

  • If baseline LDL cholesterol is <100 mg/dL, further LDL-lowering therapy is not required. Patients should nonetheless be advised to follow the TLC Diet on their own to help keep the LDL level optimal. Several clinical trials are currently underway to assess benefit of lowering LDL cholesterol to well below 100 mg/dL. At present, emphasis should be placed on controlling other lipid and nonlipid risk factors and on treatment of the metabolic syndrome, if present.
    For persons with multiple (2+) risk factors and 10-year risk 20%, intensity of therapy is adjusted according to 10-year risk and LDL cholesterol level. The treatment approach for each category is summarized in Table 5.

    Multiple (2+) risk factors and a 10-year risk of 10-20%. In this category, the goal for LDL cholesterol is <130 mg/dL. The therapeutic aim is to reduce short-term risk as well as long-term risk for CHD. If baseline LDL cholesterol is 130 mg/dL, TLC is initiated and maintained for 3 months. If LDL remains 130 mg/dL after 3 months of TLC, consideration can be given to starting an LDL-lowering drug to achieve the LDL goal of <130 mg/dL. Use of LDL-lowering drugs at this risk level reduces CHD risk and is cost-effective. If the LDL falls to less than 130 mg/dL on TLC alone, TLC can be continued without adding drugs. In older persons (65 years), clinical judgment is required for how intensively to apply these guidelines; a variety of factors, including con-comitant illnesses, general health status, and social issues may influence treatment decisions and may suggest a more conservative approach.

    Multiple (2+) risk factors and a 10-year risk of <10%. In this category, the goal for LDL cholesterol also is <130 mg/dL. The therapeutic aim, however, is primarily to reduce longer-term risk. If baseline LDL cholesterol is 130 mg/dL, the TLC Diet is initiated to reduce LDL cholesterol. If LDL is <160 mg/dL on TLC alone, it should be continued. LDL-lowering drugs generally are not recommended because the patient is not at high short-term risk. On the other hand, if

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    LDL cholesterol is 160 mg/dL, drug therapy can be considered to achieve an LDL cholesterol <130 mg/dL; the primary aim is to reduce long-term risk. Cost-effectiveness is marginal, but drug therapy can be justified to slow development of coronary atherosclerosis and to reduce long-term risk for CHD.
    Most persons with 0-1 risk factor have a 10-year risk <10%. They are managed according to Table 5. The goal for LDL cholesterol in this risk category is <160 mg/dL. The primary aim of therapy is to reduce long-term risk. First-line therapy is TLC. If after 3 months of TLC the LDL choles-terol is <160 mg/dL, TLC is continued. However, if LDL cholesterol is 160-189 mg/dL after an adequate trial of TLC, drug therapy is optional depending on clinical judgment. Factors favoring use of drugs include:

    A severe single risk factor (heavy cigarette smoking, poorly controlled hypertension, strong family history of premature CHD, or very low HDL cholesterol);
    Multiple life-habit risk factors and emerging risk factors (if measured);
    10-year risk approaching 10% (if measured; see Appendix).

    If LDL cholesterol is 190 mg/dL despite TLC, drug therapy should be considered to achieve the LDL goal of <160 mg/dL.

    The purpose of using LDL-lowering drugs in persons with 0-1 risk factor and elevated LDL cholesterol (160 mg/dL) is to slow the development of coronary atherosclerosis, which will reduce long-term risk. This aim may conflict with cost-effectiveness considerations; thus, clinical judgment is required in selection of persons for drug therapy, although a strong case can be made for using drugs when LDL cholesterol is 190 mg/dL after TLC.

    For persons whose LDL cholesterol levels are already below goal levels upon first encounter, instructions for appropriate changes in life habits, periodic followup, and control of other risk factors are needed.

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    ATP III recommends a multifaceted lifestyle approach to reduce risk for CHD. This approach is designated therapeutic lifestyle changes (TLC). Its essential features are:

    Reduced intakes of saturated fats (<7% of total calories) and cholesterol (<200 mg per day) (see Table 6 for overall composition of the TLC Diet)
    Therapeutic options for enhancing LDL lowering such as plant stanols/sterols (2 g/day) and increased viscous (soluble) fiber (10-25 g/day)
    Weight reduction
    Increased physical activity

    A model of steps in TLC is shown in Figure 1. To initiate TLC, intakes of saturated fats and cholesterol are reduced first to lower LDL cholesterol. To improve overall health, ATP III’s TLC Diet generally contains the recommendations embodied in the Dietary Guidelines for Americans 2000. One exception is that total fat is allowed to range from 25-35% of total calories provided saturated fats and trans fatty acids are kept low. A higher intake of total fat, mostly in the form of unsaturated fat, can help to reduce triglycerides and raise HDL cholesterol in persons with the metabolic syndrome. In accordance with the Dietary Guidelines, moderate physical activity is encouraged. After 6 weeks, the LDL response is determined; if the LDL cholesterol goal has not been achieved, other therapeutic options for LDL lowering such as plant stanol/sterols and viscous fiber can be added.

    After maximum reduction of LDL cholesterol with dietary therapy, emphasis shifts to management of the metabolic syndrome and associated lipid risk factors. The majority of persons with these latter abnormalities are overweight or obese and sedentary. Weight reduction therapy for over-weight or obese patients will enhance LDL lowering and will provide other health benefits including modifying other lipid and nonlipid risk factors.

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    Assistance in the management of overweight and obese persons is provided by the Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults from the NHLBI Obesity Education Initiative (1998). Additional risk reduction can be achieved by simultane-ously increasing physical activity.

    At all stages of dietary therapy, physicians are encouraged to refer patients to registered dietitians or other qualified nutritionists for medical nutrition therapy, which is the term for the nutritional intervention and guidance provided by a nutrition professional.

    A portion of the population whose short-term or long-term risk for CHD is high will require LDL-lowering drugs in addition to TLC to reach the desig-nated goal for LDL cholesterol (see Table 5). When drugs are prescribed, attention to TLC should always be maintained and reinforced. Currently available drugs that affect lipoprotein metabolism and their major charac-teristics are listed in Table 7.

    Some cholesterol-lowering agents are currently available over-the-counter (OTC) (e.g., nicotinic acid), and manufacturers of several classes of LDL-lowering drugs (e.g., statins, bile acid sequestrants) have applied to the

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    Food and Drug Administration (FDA) to allow these agents to become OTC medications. At the time of publication of ATP III, the FDA has not granted permission for OTC status for statins or bile acid sequestrants. If an OTC cholesterol-lowering drug is or becomes available, patients should continue to consult with their physicians about whether to initiate drug treatment, about setting the goals of therapy, and about monitoring for therapeutic responses and side effects.

    * Lovastatin (20-80 mg), pravastatin (20-40 mg), simvastatin (20-80 mg), fluvastatin (20-80 mg), atorvastatin (10-80 mg), cerivastatin (0.4-0.8 mg).
    † Cyclosporine, macrolide antibiotics, various antifungal agents and cytochrome P-450 inhibitors (fibrates and niacin should be used with appropriate caution).
    ‡ Cholestyramine (4-16 g), colestipol (5-20 g), colesevelam (2.6-3.8 g).
    ¥ Immediate release (crystalline) nicotinic acid (1.5-3 g), extended release nicotinic acid (Niaspan ®) (1-2 g), sustained release nicotinic acid (1-2 g).
    § Gemfibrozil (600 mg BID), fenofibrate (200 mg), clofibrate (1000 mg BID).

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    For persons with CHD and CHD risk equivalents, the goal is to attain an LDL cholesterol level <100 mg/dL. The cutpoints for initiating lifestyle and drug therapies are shown in Table 5, and the approach to treatment is discussed immediately after Table 5. Most CHD patients will need LDL-lowering drug therapy. Other lipid risk factors may also warrant considera-tion of drug treatment. Whether or not lipid-modifying drugs are used, nonlipid risk factors require attention and favorable modification.

    In persons admitted to the hospital for a major coronary event, LDL cholesterol should be measured on admission or within 24 hours. This value can be used for treatment decisions. In general, persons hospitalized for a coronary event or procedure should be discharged on drug therapy if the LDL cholesterol is 130 mg/dL. If the LDL is 100–129 mg/dL, clinical judgment should be used in deciding whether to initiate drug treatment at discharge, recognizing that LDL cholesterol levels begin to decline in the first few hours after an event and are significantly decreased by 24-48 hours and may remain low for many weeks. Thus, the initial LDL cholesterol level obtained in the hospital may be substantially lower than is usual for the patient. Some authorities hold drug therapy should be initiated whenever a patient hospitalized for a CHD-related illness is found to have an LDL cholesterol >100 mg/dL. Initiation of drug therapy at the time of hospital discharge has two advantages. First, at that time patients are particularly motivated to undertake and adhere to risk-lowering interventions; and second, failure to initiate indicated therapy early is one of the causes of a large “treatment gap,” because outpatient followup is often less consistent and more fragmented.
    Table 5 shows the cutpoints for considering drug treatment in primary pre-vention. The general approach to management of drug therapy for primary prevention is outlined in Figure 2.

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    When drug therapy for primary prevention is a consideration, the third visit of dietary therapy (see Figure 1) will typically be the visit to initiate drug treatment. Even if drug treatment is started, TLC should be continued. As with TLC, the first priority of drug therapy is to achieve the goal for LDL cholesterol. For this reason, an LDL-lowering drug should be started. The usual drug will be a statin, but alternatives are a bile acid sequestrant or nicotinic acid. In most cases, the statin should be started at a moderate dose. In many patients, the LDL cholesterol goal will be achieved, and high-er doses will not be necessary. The patient’s response should be checked about 6 weeks after starting drug therapy. If the goal of therapy has been achieved, the current dose can be maintained. However, if the goal has not been achieved, LDL-lowering therapy can be intensified, either by increasing the dose of statin or by combining a statin with a bile acid sequestrant or nicotinic acid.

    After 12 weeks of drug therapy, the response to therapy should again be assessed. If the LDL cholesterol goal is still not achieved, consideration can be given to further intensification of drug therapy. If the LDL goal cannot be attained by standard lipid-lowering therapy, consideration should be given to seeking consultation from a lipid specialist. Once the goal for LDL cholesterol has been attained, attention can turn to other lipid risk factors and nonlipid factors. Thereafter, patients can be monitored for response to therapy every 4 to 6 months, or more often if considered necessary.
    Evidence is accumulating that risk for CHD can be reduced beyond LDL-lowering therapy by modification of other risk factors. One potential

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    secondary target of therapy is the metabolic syndrome, which represents a constellation of lipid and nonlipid risk factors of metabolic origin. This syndrome is closely linked to a generalized metabolic disorder called insulin resistance in which the normal actions of insulin are impaired. Excess body fat (particularly abdominal obesity) and physical inactivity promote the development of insulin resistance, but some individuals also are genetically predisposed to insulin resistance.

    The risk factors of the metabolic syndrome are highly concordant; in aggregate they enhance risk for CHD at any given LDL cholesterol level. For purposes of ATP III, the diagnosis of the metabolic syndrome is made when three or more of the risk determinants shown in Table 8 are present. These determinants include a combination of categorical and borderline risk factors that can be readily measured in clinical practice.

    * Overweight and obesity are associated with insulin resistance and the metabolic syndrome. However, the presence of abdominal obesity is more highly correlated with the metabolic risk factors than is an elevated body mass index (BMI). Therefore, the simple measure of waist circumference is recommended to identify the body weight component of the metabolic syndrome.
    † Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased, e.g., 94-102 cm (37-39 in). Such patients may have a strong genetic contribution to insulin resistance. They should benefit from changes in life habits, similarly to men with categorical increases in waist circumference.

    Management of the metabolic syndrome has a two-fold objective: (1) to reduce underlying causes (i.e., obesity and physical inactivity), and (2) to treat associated nonlipid and lipid risk factors.
    First-line therapies for all lipid and nonlipid risk factors associated with the metabolic syndrome are weight reduction and increased physical activity, which will effectively reduce all of these risk factors. Therefore, after

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    appropriate control of LDL cholesterol, TLC should stress weight reduction and physical activity if the metabolic syndrome is present.

    Weight control. In ATP III overweight and obesity are recognized as major, underlying risk factors for CHD and identified as direct targets of interven-tion. Weight reduction will enhance LDL lowering and reduce all of the risk factors of the metabolic syndrome. The recommended approaches for reducing overweight and obesity are contained in the clinical guidelines of the NHLBI Obesity Education Initiative.

    Physical activity. Physical inactivity is likewise a major, underlying risk factor for CHD. It augments the lipid and nonlipid risk factors of the meta-bolic syndrome. It further may enhance risk by impairing cardiovascular fit-ness and coronary blood flow. Regular physical activity reduces very low density lipoprotein (VLDL) levels, raises HDL cholesterol, and in some persons, lowers LDL levels. It also can lower blood pressure, reduce insulin resistance, and favorably influence cardiovascular function. Thus, ATP III recommends that regular physical activity become a routine component in management of high serum cholesterol. The evidence base for this recommendation is contained in the U.S. Surgeon General’s Report on Physical Activity.
    Beyond the underlying risk factors, therapies directed against the lipid and nonlipid risk factors of the metabolic syndrome will reduce CHD risk. These include treatment of hypertension, use of aspirin in patients with CHD to reduce the prothrombotic state (guidelines for aspirin use in primary prevention have not been firmly established), and treatment of elevated triglycerides and low HDL cholesterol as discussed below under Management of Specific Dyslipidemias.
    Very high LDL cholesterol (190 mg/dL). Persons with very high LDL cholesterol usually have genetic forms of hypercholesterolemia: monogenic familial hypercholesterolemia, familial defective apolipoprotein B, and polygenic hypercholesterolemia. Early detection of these disorders through cholesterol testing in young adults is needed to prevent premature CHD. Family testing is important to identify similarly affected relatives. These

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    disorders often require combined drug therapy (statin + bile acid seques-trant) to achieve the goals of LDL-lowering therapy.

    Elevated serum triglycerides. Recent meta-analyses of prospective studies indicate that elevated triglycerides are also an independent risk factor for CHD. Factors contributing to elevated (higher than normal) triglycerides in the general population include: obesity and overweight, physical inactivity, cigarette smoking, excess alcohol intake, high carbohydrate diets (>60% of energy intake), several diseases (e.g., type 2 diabetes, chronic renal failure, nephrotic syndrome), certain drugs (e.g., corticosteroids, estrogens, retinoids, higher doses of beta-adrenergic blocking agents), and genetic disorders (familial combined hyperlipidemia, familial hypertriglyceridemia, and familial dysbetalipoproteinemia).

    In clinical practice, elevated serum triglycerides are most often observed in persons with the metabolic syndrome, although secondary or genetic factors can heighten triglyceride levels. ATP III adopts the following classification of serum triglycerides:

    Normal triglycerides: <150 mg/dL
    Borderline-high triglycerides: 150-199 mg/dL
    High triglycerides: 200-499 mg/dL
    Very high triglycerides: 500 mg/dL

    The finding that elevated triglycerides are an independent CHD risk factor suggests that some triglyceride-rich lipoproteins are atherogenic. The latter are partially degraded VLDL, commonly called remnant lipoproteins. In clinical practice, VLDL cholesterol is the most readily available measure of atherogenic remnant lipoproteins. Thus, VLDL cholesterol can be a target of cholesterol-lowering therapy. ATP III identifies the sum of LDL+VLDL cholesterol [termed non-HDL cholesterol (total cholesterol minus HDL cholesterol)] as a secondary target of therapy in persons with high triglycerides (200 mg/dL). The goal for non-HDL cholesterol in persons with high serum triglycerides can be set at 30 mg/dL higher than that for LDL cholesterol (Table 9) on the premise that a VLDL cholesterol level 30 mg/dL is normal.

    The treatment strategy for elevated triglycerides depends on the causes of the elevation and its severity. For all persons with elevated triglycerides, the primary aim of therapy is to achieve the target goal for LDL cholesterol. When triglycerides are borderline high (150-199 mg/dL), emphasis should also be placed on weight reduction and increased physical activity. For high triglycerides (200-499 mg/dL), non-HDL cholesterol becomes a secondary

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    target of therapy. Aside from weight reduction and increased physical activity, drug therapy can be considered in high-risk persons to achieve the non-HDL cholesterol goal. There are two approaches to drug therapy. First, the non-HDL cholesterol goal can be achieved by intensifying therapy with an LDL-lowering drug; or second, nicotinic acid or fibrate can be added, if used with appropriate caution, to achieve the non-HDL cholesterol goal by further lowering of VLDL cholesterol. In rare cases in which triglycerides are very high (500 mg/dL), the initial aim of therapy is to prevent acute pancreatitis through triglyceride lowering. This approach requires very low fat diets (15% of calorie intake), weight reduction, increased physical activity, and usually a triglyceride-lowering drug (fibrate or nicotinic acid). Only after triglyceride levels have been lowered to <500 mg/dL should attention turn to LDL lowering to reduce risk for CHD.

    Low HDL cholesterol. Low HDL cholesterol is a strong independent predictor of CHD. In ATP III, low HDL cholesterol is defined categorically as a level <40 mg/dL, a change from the level of <35 mg/dL in ATP II. In the present guidelines, low HDL cholesterol both modifies the goal for LDL-lowering therapy and is used as a risk factor to estimate 10-year risk for CHD.

    Low HDL cholesterol levels have several causes, many of which are associated with insulin resistance, i.e., elevated triglycerides, overweight and obesity, physical inactivity, and type 2 diabetes. Other causes are cigarette smoking, very high carbohydrate intakes (>60% of calories), and certain drugs (e.g., beta-blockers, anabolic steroids, progestational agents)

    ATP III does not specify a goal for HDL raising. Although clinical trial results suggest that raising HDL will reduce risk, the evidence is insufficient to specify a goal of therapy. Furthermore, currently available drugs do not robustly raise HDL cholesterol. Nonetheless, a low HDL should receive clinical attention and management according to the following sequence. In all persons with low HDL cholesterol, the primary target of therapy is LDL

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    cholesterol; ATP III guidelines should be followed to achieve the LDL cholesterol goal. Second, after the LDL goal has been reached, emphasis shifts to weight reduction and increased physical activity (when the metabolic syndrome is present). When a low HDL cholesterol is associated with high triglycerides (200-499 mg/dL), secondary priority goes to achieving the non-HDL cholesterol goal, as outlined before. Also, if triglycerides are <200 mg/dL (isolated low HDL cholesterol), drugs for HDL raising (fibrates or nicotinic acid) can be considered; however, treatment for isolated low HDL is mostly reserved for persons with CHD and CHD risk equivalents.

    Diabetic dyslipidemia. This disorder is essentially atherogenic dyslipidemia (high triglycerides, low HDL, and small dense LDL) in persons with type 2 diabetes. Although elevated triglycerides and/or low HDL cholesterol are common in persons with diabetes, clinical trial results support the identification of LDL cholesterol as the primary target of therapy, as it is in those without diabetes. Since diabetes is designated a CHD risk equivalent in ATP III, the LDL cholesterol goal of therapy for most persons with diabetes will be <100 mg/dL. Furthermore, when LDL cholesterol is 130 mg/dL, most persons with diabetes will require initiation of LDL-lowering drugs simultaneously with TLC to achieve the LDL goal. When LDL cholesterol levels are in the range of 100-129 mg/dL at baseline or on treatment, several therapeutic options are available: increasing intensity of LDL-lowering therapy, adding a drug to modify atherogenic dyslipidemia (fibrate or nicotinic acid), or intensifying control of other risk factors including hyperglycemia. When triglyceride levels are 200 mg/dL, non-HDL cholesterol becomes a secondary target of cholesterol-lowering therapy. Several ongoing clinical trials (e.g., Antihypertensive and Lipid Lowering Heart Attack Trial [ALLHAT]) will better quantify the magnitude of the benefit of LDL-lowering treatment in older individuals with diabetes. In older persons (65 years of age) with diabetes but no additional CHD risk factors other than age, clinical judgment is required for how intensively to apply these guidelines; a variety of factors, including concomitant illnesses, general health status, and social issues may influence treatment decisions and may suggest a more conservative approach.
    Middle-aged men (35-65 years). In general, men have a higher risk for CHD than do women. Middle-aged men in particular have a high prevalence of the major risk factors and are predisposed to abdominal obesity and the metabolic syndrome. A sizable fraction of all CHD in men occurs in middle age. Thus, many middle-aged men carry a relatively high risk for CHD, and for those who do, intensive LDL-lowering therapy is needed.

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    Women (ages 45-75 years). In women, onset of CHD generally is delayed by some 10-15 years compared with that in men; thus most CHD in women occurs after age 65. All risk factors contribute to CHD in women, and most premature CHD in women (<65 years) occurs in those with multiple risk factors and the metabolic syndrome. Despite the previous belief that the gender difference in risk for CHD reflects a protective effect of estrogen in women, recent secondary and primary prevention trials cast doubt on the use of hormone replacement therapy to reduce CHD risk in postmenopausal women. In contrast, the favorable effects of statin therapy in women in clinical trials make a cholesterol-lowering drug preferable to hormone replacement therapy for CHD risk reduction. Women should be treated similarly to men for secondary prevention. For primary prevention, ATP III’s general approach is similarly applicable for women and men. However, the later onset of CHD for women in general should be factored into clinical decisions about use of cholesterol-lowering drugs.

    Older adults (men 65 years and women 75 years). Overall, most new CHD events and most coronary deaths occur in older persons ( 65 years). A high level of LDL cholesterol and low HDL cholesterol still carry predictive power for the development of CHD in older persons. Nevertheless, the finding of advanced subclinical atherosclerosis by noninvasive testing can be helpful for confirming the presence of high risk in older persons. Secondary prevention trials with statins have included a sizable number of older persons, mostly in the age range of 65 to 75 years. In these trials, older persons showed significant risk reduction with statin therapy. Thus, no hard-and-fast age restrictions appear necessary when selecting persons with established CHD for LDL-lowering therapy. For primary prevention, TLC is the first line of therapy for older persons. However, LDL-lowering drugs can also be considered when older persons are at higher risk because of multiple risk factors or advanced subclinical atherosclerosis.

    Younger adults (men 20-35 years; women 20-45 years). CHD is rare except in those with severe risk factors, e.g., familial hypercholesterolemia, heavy cigarette smoking, or diabetes. Even though clinical CHD is relatively rare in young adults, coronary atherosclerosis in its early stages may progress rapidly. The rate of development of coronary atherosclerosis earlier in life correlates with the major risk factors. In particular, long-term prospective studies reveal that elevated serum cholesterol detected in young adulthood predicts a higher rate of premature CHD in middle age. Thus, risk factor identification in young adults is an important aim for long-term prevention. The combination of early detection and early intervention on elevated LDL cholesterol with life-habit changes offers the opportunity for delaying or preventing onset of CHD later in life. For young adults with LDL cholesterol levels 130 mg/dL, TLC should be instituted and emphasized.

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    Particular attention should be given to young men who smoke and have a high LDL cholesterol (160-189 mg/dL); they may be candidates for LDL-lowering drugs. When young adults have very high LDL cholesterol levels (190 mg/dL), drug therapy should be considered, as in other adults. Those with severe genetic forms of hypercholesterolemia may require LDL-lowering drugs in combination (e.g., statin + bile acid sequestrant).

    Racial and ethnic groups. African Americans have the highest overall CHD mortality rate and the highest out-of-hospital coronary death rates of any ethnic group in the United States, particularly at younger ages. Although the reasons for the excess CHD mortality among African Americans have not been fully elucidated, it can be accounted for, at least in part, by the high prevalence of coronary risk factors. Hypertension, left ventricular hypertro-phy, diabetes mellitus, cigarette smoking, obesity, physical inactivity, and multiple CHD risk factors all occur more frequently in African Americans than in whites. Other ethnic groups and minority populations in the United States include Hispanics, Native Americans, Asian and Pacific Islanders, and South Asians. Although limited data suggest that racial and ethnic groups vary somewhat in baseline risk for CHD, this evidence did not appear sufficient to lead the ATP III panel to modify general recommendations for cholesterol management in these populations.
    Adherence to the ATP III guidelines by both patients and providers is a key to approximating the magnitude of the benefits demonstrated in clinical trials of cholesterol lowering. Adherence issues have to be addressed in order to attain the highest possible levels of CHD risk reduction. Thus, ATP III recommends the use of state-of-the-art multidisciplinary methods targeting the patient, providers, and health delivery systems to achieve the full population effectiveness of the guidelines for primary and secondary prevention (Table 10).

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    ATP III shares a set of core features with ATP III. These are shown in Table A.

    * A CHD risk equivalent is a condition that carries an absolute risk for developing new CHD equal to the risk for having recurrent CHD events in persons with established CHD.
    † Risk factors that continue to modify the LDL goal include cigarette smoking, hypertension, low HDL cholesterol, family history of premature CHD, age (male >45 years and female >55 years), and diabetes (in ATP III diabetes is regarded as a CHD risk equivalent).

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    Risk assessment for determining the 10-year risk for developing CHD is carried out using Framingham risk scoring (Table B1 for men and Table B2 for women). The risk factors included in the Framingham calculation of 10-year risk are: age, total cholesterol, HDL cholesterol, systolic blood pressure, treatment for hypertension, and cigarette smoking. The first step is to calculate the number of points for each risk factor. For initial assessment, values for total cholesterol and HDL cholesterol are required. Because of a larger database, Framingham estimates are more robust for total cholesterol than for LDL cholesterol. Note, however, that the LDL cholesterol level remains the primary target of therapy. Total cholesterol and HDL cholesterol values should be the average of at least two measurements obtained from lipoprotein analysis. The blood pressure value used is that obtained at the time of assessment, regardless of whether the person is on anti-hypertensive therapy. However, if the person is on antihypertensive treatment, an extra point is added beyond points for the blood pressure reading because treated hypertension carries residual risk (see Tables B1 and B2). The average of several blood pressure measurements, as recommended by the Joint National Committee (JNC), is needed for an accurate measure of baseline blood pressure. The designation “smoker” means any cigarette smoking in the past month. The total risk score sums the points for each risk factor. The 10-year risk for myocardial infarction and coronary death (hard CHD) is estimated from total points, and the person is categorized according to absolute 10-year risk as indicated above (see Table 5).

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    The acknowledgments section has been edited in a separate page ( Acknowledgements).

    Public Health Service
    National Institutes of Health
    National Heart, Lung, and Blood Institute

    NIH Publication No. 01-3670
    May 2001

    Important Notice: This page presents the exact version (text, tables, figures) of the NIH Publication No. 01-3670. Third Report of the NCEP ATP III (PDF format -adobe acrobat 113KB-). Page numbers as in the original document are included. Some formatting has been adapted to HTML (including anchors and hyperlinks for easier navigation).

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