New Features of the National Cholesterol Education Program Adult Treatment Panel III Lipid-Lowering Guidelines

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1 Clin. Cardiol. Vol. 26 (Suppl. III), III-19 III-24 (2003) New Features of the National Cholesterol Education Program Adult Treatment Panel III Lipid-Lowering Guidelines H. BRYAN BREWER, JR, M.D. Molecular Disease Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA Summary: The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines for lipid-lowering therapy to reduce coronary heart disease (CHD) risk contain a number of features that distinguish them from the previous ATP guidelines. These new features include modifications in lipid/lipoprotein levels considered optimal, abnormal, or reflective of risk; increased focus on primary prevention through use of Framingham risk scoring to define risk in persons with multiple lipid/nonlipid risk factors; and increased focus on the association of the metabolic syndrome with CHD risk. The introduction of the category of CHD risk equivalents including persons with atherosclerotic disease, diabetes, or 10-year CHD risk > 20% based on Framingham scoring results in an increase over previous guidelines in the proportion of patients categorized as being at high risk and therefore eligible for more intensive low-density lipoprotein cholesterol (LDL-C)-lowering therapy. Use of the new secondary therapeutic target of non-high-density lipoprotein cholesterol should improve management of lipid risk factors in patients who have elevated triglyceride levels after LDL-C goals have been met. These new features of the NCEP ATP III guidelines should improve identification and treatment of patients with dyslipidemias associated with CHD risk. Key words: statins, low-density lipoprotein cholesterol, hypercholesterolemia, Adult Treatment Panel III Address for reprints: H. Bryan Brewer, Jr, M.D. Chief, Molecular Disease Branch National Heart, Lung, and Blood Institute National Institutes of Health Building 10 - Magnuson CC, Room 7N Center Drive Bethesda, MD 20814, USA bryan@mail.nih.gov. Introduction The National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) has provided updated guidelines for the clinical management of patients with dyslipidemia. 1 New features of the guidelines include alterations in categorical definitions of optimal, normal, or elevated lipid/ lipoprotein levels; increased focus on global risk assessment, including introduction of the concept of coronary heart disease (CHD) risk equivalents; increased focus on the metabolic syndrome; and introduction of the new treatment target of nonhigh-density lipoprotein cholesterol (non-hdl-c) in patients with elevated triglycerides. Under the ATP III guidelines, an estimated 36 million U.S. individuals are eligible for cholesterol-lowering therapy a 140% increase over ATP II. 2 Changes in Lipid/Lipoprotein Categories Low-density lipoprotein cholesterol (LDL-C) continues to be the primary target of cholesterol-lowering therapy to reduce CHD risk. Animal experiments, laboratory investigations, epidemiologic studies, and studies of genetic forms of hypercholesterolemia indicate that LDL-C is a major cause of CHD and demonstrate that LDL is the most abundant and best-characterized atherogenic lipoprotein. 1 Numerous clinical trials of lipid-lowering therapy have demonstrated that LDL-C-lowering therapy reduces risk for CHD. 3 8 Thus, as with previous guidelines, the primary goals of lipid-lowering therapy and the cut points for initiating therapy are expressed in terms of LDL- C levels. 1 Other changes in lipid/lipoprotein classification include updated HDL-C and triglyceride classifications. Low-Density Lipoprotein Cholesterol Under the ATP III guidelines, the optimal LDL-C level for all persons is identified as < 100 mg/dl a marked reduction from the desirable level of < 130 mg/dl under ATP II guidelines. The classification of LDL-C levels, as shown in Table I, reflects the recognition that the relation of LDL-C to CHD risk

2 III-20 Clin. Cardiol. Vol. 26 (Suppl. III) April 2003 TABLE I Adult Treatment Panel III classification of low-density lipoprotein cholesterol, total cholesterol, high-density lipoprotein cholesterol, and triglycerides Lipid value is continuous over the range of LDL-C levels. It is important to note that the recent findings from the Heart Protection Study may have a significant impact on LDL-C targets and treatment initiation levels in lipid-lowering therapy. 8 This study, in patients with vascular disease, hypertension, or diabetes, has shown significant CHD event reduction in commonly observed plasma cholesterol concentrations, including among patients initiating therapy at LDL-C levels < 100 mg/dl. High-Density Lipoprotein Cholesterol Classification LDL-C (mg/dl) <100 Optimal Near or above optimal Borderline high High 190 Very high Total cholesterol (mg/dl) < 200 Desirable Borderline high 240 High HDL-C (mg/dl) < 40 Low 60 High Triglycerides (mg/dl) <150 Normal Borderline high High 500 Very high Abbreviations: LDL-C = low-density lipoprotein cholesterol, HDL- C = high-density lipoprotein cholesterol. Low HDL-C is recognized as a strong predictor of CHD, although its strength as an independent predictor continues to be controversial. Although clinical trial evidence suggests that increasing HDL-C reduces risk of CHD, 9 insufficient evidence exists to establish a therapeutic goal for HDL-C. The ATP III guidelines change the definition of categorical low HDL-C as a risk factor from < 35 to < 40 mg/dl to reflect better the risk associated with decreased HDL-C levels. The change was based on a number of considerations, including (1) the fact that the inverse relation of HDL-C and CHD risk is a continuous variable, and risk associated with low HDL-C is clearly evident at levels > 35 mg/dl; (2) the desire to raise awareness of the status of low HDL-C as an indicator of the presence of other risk factors; and (3) the fact that such modifiable risk factors as obesity and inactivity contribute modestly to decreased HDL-C levels. Triglycerides It remains a matter of debate whether elevated triglyceride levels constitute an independent risk factor for CHD. However, increased evidence of an independent association has accumulated since the ATP II guidelines were formulated, 10 and evidence suggests that increased quantities of atherogenic remnant lipoproteins augment CHD risk beyond that predicted by LDL when triglyceride levels are 200 mg/dl. For these reasons, and since detection of elevated triglycerides can help identify patients at risk for CHD via other lipid and nonlipid factors, ATP III has substantially lowered the triglyceride levels defined as normal, borderline high, high, and very high (Table I). 1 Global Risk Assessment Using the Framingham Scoring System The ATP III increases the focus on primary CHD prevention in persons with multiple risk factors, since many exhibit relatively high risk for CHD and would benefit from more intensive LDL-C-lowering treatment than was previously recommended. 1 The guidelines have introduced the concept of CHD risk equivalents, indicating conditions or combinations of risk factors that place patients at future risk of CHD events equivalent to that in patients with established CHD. The category of CHD risk equivalents includes documented atherosclerotic disease other than CHD (including peripheral vascular disease, abdominal aortic aneurysm, and carotid artery disease), diabetes, and a 10-year risk for CHD > 20% based on the Framingham risk scoring system. The inclusion of diabetes as a CHD risk equivalent is based on a substantial body of data indicating that diabetes in persons without CHD is associated with risk of CHD events equivalent to risk for events in those with established CHD. 11, 12 The Framingham scoring system is intended to be used primarily in persons with two or more CHD risk factors. are assigned, added, and subtracted on the basis of age, total cholesterol level, smoking versus nonsmoking, HDL-C level, and systolic blood pressure (Tables IIA and IIB). 1 Point totals correlate with absolute 10-year risk for CHD, with patients being categorized according to whether their risk is > 20%, 10 to 20%, or < 10%; these categories are used to determine recommended intensity of LDL-C-lowering therapy and LDL-C levels at which to initiate therapy (Table III). Persons with a 10- year CHD risk > 20% are in the CHD risk-equivalent category and have the same treatment initiation level and LDL-C target as patients with established CHD or other CHD risk equivalents. This high-risk LDL-C target has been changed from 100 to < 100 mg/dl. Persons with a 10-year risk of 10 to 20% have a lower threshold for initiating drug treatment than those with a lower 10-year risk, with both subcategories having the same treatment target. In ATP III, the category of CHD risk equivalents and the use of a risk-factor scoring system in risk assessment result in an increase in the proportion of patients considered to be at

3 H. B. Brewer, Jr.: NCEP ATP III lipid-lowering guidelines III-21 TABLE IIA Estimate of 10-year risk for men (Framingham point scores) Point total 10-year risk (%) <0 < Age (years) HDL (mg/dl) <40 2 Total Age Age Age Age Age cholesterol (mg/dl) years years years years years < Age Age Age Age Age years years years years years Nonsmoker Smoker Systolic blood pressure (mmhg) If untreated If treated < high risk for CHD and thus having lower LDL-C goals. Using data from the Third National Health and Nutrition Examination Survey (NHANES III), a comparison of ATP II guidelines with those of ATP III reveals a 140% increase in the number of U.S. patients eligible for LDL-C-lowering therapy under ATP III. 2 Metabolic Syndrome The ATP III has increased the focus on metabolic syndrome by defining it as a secondary target of therapy after LDL-C reduction and providing a clinical schema for diagnosis. 1 The presence of metabolic syndrome augments the risk of CHD at any given LDL-C level. A recent report on NHANES III data indicates an age-adjusted prevalence of the metabolic syndrome of 23.7% in the U.S. adult population, with the prevalence increasing from 6.7% in those 20 to 29 years of age to 43.5% in those 60 to 69 years of age, and 42.0% in those 70 years or older. 13 The clinical diagnosis of metabolic syndrome is determined by the presence of at least three risk factors from among abdominal obesity, elevated triglycerides, low HDL-C, elevated blood pressure, and elevated fasting glucose (Table IV). The guidelines recommend that management of patients with metabolic syndrome should focus on reducing underlying causes (e.g., obesity and physical inactivity) and treating associated lipid and nonlipid risk factors. Measures for addressing specific lipid risk factors associated with the metabolic syndrome (i.e., elevated triglycerides and low HDL-C) consist primarily of instituting therapeutic lifestyle changes (TLC) therapy and using non-hdl-c as a target of therapy, as discussed below, after LDL-C goals have been achieved. In patients with metabolic syndrome and very high triglycerides ( 500 mg/dl), triglyceride reduction is the primary focus of initial treatment. In patients with low HDL-C

4 III-22 Clin. Cardiol. Vol. 26 (Suppl. III) April 2003 TABLE IIB Estimate of 10-year risk for women (Framingham point scores) Point total 10-year risk (%) <9 < Age (years) HDL (mg/dl) <40 2 Total Age Age Age Age Age cholesterol (mg/dl) years years years years years < Age Age Age Age Age years years years years years Nonsmoker Smoker Systolic blood pressure (mmhg) If untreated If treated < without elevated triglycerides, specific therapy to increase HDL-C may be considered after LDL-C goals have been achieved and TLC therapy has been applied. Elevated Triglycerides and Non-High-Density Lipoprotein Cholesterol Treatment Targets A challenge routinely faced by clinicians is how to manage patients with hypertriglyceridemia. Currently available data indicate that not all triglycerides are the same in their effects and can thus be considered good or bad triglycerides. This observation is based in part on the finding that hypertriglyceridemia is not always associated with increased CHD risk. 14 Persons who do not appear to be at increased risk for CHD include those with elevated triglycerides in association with familial chylomicronemia syndrome, those who consume large amounts of alcohol, those with estrogen-induced hypertriglyceridemia, and a subset of persons with familial hypertriglyceridemia. However, persons with elevated triglycerides in association with combined hyperlipidemia, diabetes, and metabolic syndrome are at increased risk for CHD. The difference in risk appears to be related to differences in types of lipoprotein particles present in persons with elevated triglycerides. Triglyceride-rich remnant particles appear not to be related to increased CHD risk, whereas cholesterol-rich very-low-density lipoprotein (VLDL) or intermediate-density lipoprotein (IDL) particles are associated with increased risk. In brief, a primary factor in determining the atherogenicity of the cholesterol-rich remnant is the presence of increased concentrations of apolipoprotein (apo)-c-iii on these apo-b-containing lipoproteins. 14 Increased levels of apo-c-iii on apo-bcontaining lipoproteins result in inhibition of lipoprotein lipase, decreasing triglyceride hydrolysis and preventing effective remodeling of triglyceride-rich lipoproteins, and reduce binding of the lipoproteins to LDL and LDL receptor-related receptor proteins; thus, increased apo-c-iii is associated with decreased clearance of triglyceride-rich lipoprotein remnants and accumulation of atherogenic remnants. The formation of small, dense LDL, which is more atherogenic than larger LDL

5 H. B. Brewer, Jr.: NCEP ATP III lipid-lowering guidelines III-23 TABLE III Low-density lipoprotein cholesterol goals and cut points for therapeutic lifestyle changes and drug therapy according to risk category LDL-C level at which LDL-C level at which to Risk category LDL-C goal (mg/dl) to initiate TLC (mg/dl) consider drug therapy (mg/dl) CHD or CHD risk equivalents a < (10-year risk > 20%) ( : drug optional) More than two risk factors < year risk 10 20%: 130 (10-year risk 20%) 10-year risk <10%: 160 Zero or one risk factor b < ( : LDL-C-lowering drug optional) a CHD risk equivalents include other clinical forms of atherosclerosis (e.g., peripheral arterial disease, abdominal aortic aneurysm, symptomatic carotid artery disease), diabetes, and multiple risk factors that confer a 10-year risk of CHD > 20%. b Almost all persons with zero or one risk factor have a 10-year risk < 10%; thus, a 10-year risk assessment in those with zero or one risk factor is unnecessary. Abbreviations: CHD = coronary heart disease, LDL-C = low-density lipoprotein cholesterol, TLC = therapuetic lifestyle changes. particles, is favored by the synthesis of large VLDL particles that exhibit decreased clearance and increased shunting through the plasma delipidation cascade. The resulting triglyceride-rich remnants are good substrates for hepatic lipase, and it is hypothesized that this enzyme plays a key role in formation of the small, dense LDL. The lower levels of HDL-C in patients with elevated triglycerides may also be attributable to increased catabolism of HDL. Thus, elevated triglycerides are associated with increased atherogenic risk when increased levels of cholesterol-rich remnants, a predominance of dense LDL, and reduced HDL-C concentrations are present. To account for the additional risk associated with the increased levels of atherogenic remnant particles, the ATP III guidelines introduce the measurement of non-hdl-c as a TABLE IV Clinical identification of the metabolic syndrome (ATP III): Three or more risk factors Risk factor Abdominal obesity (waist circumference) a Men Women Triglycerides HDL-C Men Women Blood pressure Fasting glucose Defining level > 102 cm (> 40 in) > 88 cm (> 35 in) 150 mg/dl < 40 mg/dl < 50 mg/dl 130/ 85 mmhg 110 mg/dl a Some male patients can develop multiple metabolic risk factors when waist circumference is only marginally increased (e.g., cm, or in). Such patients may have a strong genetic contribution to insulin resistance and should benefit from changes in life habits similar to men with categorical increases in waist circumference. Abbreviations: HDL-C = high-density lipoprotein cholesterol. secondary target of therapy in persons with elevated triglyceride levels. 1 Non-HDL-C is the sum of LDL, VLDL, and IDL cholesterol, and non-hdl-c is the most readily available measure of atherogenic remnant lipoproteins. Measurement of apo-b might also provide a good indicator of atherogenic risk. Apolipoprotein-B is the major apolipoprotein in all atherogenic lipoproteins, and the non-hdl-c measurement includes all apo-b-containing lipoproteins; further, apo-b levels correlate well with LDL-C levels in the setting of normal triglyceride levels and are greatly increased in hypertriglyceridemia. Thus, there is ongoing debate over whether apo-b levels should be used for lipid risk assessment in patients with elevated triglyceride levels, with some data indicating that it may be a better predictor of risk than non- HDL-C in this setting. However, the current recommendations favor use of non-hdl-c, since it has not been clearly demonstrated that use of apo-b levels in risk prediction is superior, and since measurement of non-hdl-c is straightforward and widely available. 15 As shown in Table V, the ATP III non-hdl-c goals are set at 30 mg/dl higher than the LDL-C goals corresponding to each risk category. 1 For patients with elevated triglycerides with or without low HDL-C, these levels serve as targets of treatment after LDL-C goals have been achieved. Apart from using TLC approaches, non-hdl-c goals may be met by intensifying therapy with the LDL-C-lowering drug being used, typically a statin; if further reduction is required, nicotinic acid or a fibrate may be added to statin therapy if appropriate caution is exercised. Conclusion The ATP III guidelines contain a number of new features that reflect continued evolution of our understanding of the relations among lipid risk factors, nonlipid risk factors, and CHD. These include the lowering of the LDL-C level consid-

6 III-24 Clin. Cardiol. Vol. 26 (Suppl. III) April 2003 TABLE V Non-high-density lipoprotein cholesterol goals according to risk category LDL-C goal Non-HDL-C goal Risk category (mg/dl) (mg/dl) CHD and CHD risk equivalents <100 <130 More than two risk factors and 10-year risk 20% <130 <160 Zero or one risk factor <160 <190 Abbreviations: CHD = coronary heart disease, LDL-C = low-density lipoprotein cholesterol, non-hdl-c = non-high-density lipoprotein cholesterol. ered optimal in all individuals to < 100 mg/dl, an increase in the categorical low HDL-C level to < 40 mg/dl to reflect better the risk associated with low HDL-C, and reductions in the levels of triglycerides considered normal or high to focus attention on triglycerides as a risk factor. The introduction of the category of CHD risk equivalents and the use of lipid and nonlipid risk factors to assess CHD risk have resulted in an increased focus on risk in individuals without CHD and will necessitate initiation of more intensive LDL-C-lowering therapy to reach therapeutic targets in many patients. Similarly, the guidelines increase the focus on the association of the metabolic syndrome with CHD risk and on the need to control related lipid and nonlipid risk factors. The introduction of the secondary therapeutic target of non-hdl-c is meant to improve lipid risk reduction in persons with metabolic syndrome and others with elevated triglycerides. It is hoped that the new features of the NCEP ATP III guidelines will provide opportunities to identify and treat more effectively all patients with dyslipidemias associated with increased risk of CHD. References 1. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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J Am Med Assoc 2002;287: Brewer HB Jr: Hypertriglyceridemia: Changes in the plasma lipoproteins associated with an increased risk of cardiovascular disease. Am J Cardiol 1999;83:3F 12F 15. Ballantyne CM, Andrews TC, Hsia JA, Kramer JH, Shear C, for the ACCESS Study Group: Correlation of non-high-density lipoprotein cholesterol with apolipoprotein B: Effect of 5-hydroxymethylglutaryl coenzyme A reductase inhibitors on non-high-density lipoprotein cholesterol levels. Am J Cardiol 2001;88: