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Back To Vidyya National Cholesterol Education Program

Second Revised Report

Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults

Executive Summary

Contents



Introduction
The Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II, or ATP II) presents the National Cholesterol Education Program's updated recommendations for cholesterol management. It is similar to the first in general outline, and the fundamental approach to treatment of high blood cholesterol is comparable. This report continues to identify low density lipoproteins (LDL) as the primary target of cholesterol-lowering therapy. As before, it emphasizes the role of the clinical approach in primary prevention of coronary heart disease (CHD). Dietary therapy remains the first line of treatment of high blood cholesterol, and drug therapy is reserved for patients considered to be at high risk for CHD. As in the first report, the ATP II guidelines are intended to be applied with clinical judgment to individualize treatment for each patient. However, the report contains new features that distinguish it from the first. These include:

  • Increased emphasis on CHD risk status as a guide to type and intensity of cholesterol-lowering therapy

    • Identification of the patient with existing CHD or other atherosclerotic diseases as being at the highest risk, and establishment of lower targets for LDL-cholesterol in these patients

    • Addition of age to the list of major CHD risk factors, defined as =>45 years in men and =>55 years in women

    • Recommendation of delaying the use of drug therapy in most young adult men and premenopausal women with high LDL-cholesterol who are otherwise at low risk for CHD in the near future

    • Enhanced recognition that high-risk postmenopausal women, and high-risk elderly patients who are otherwise in good health, are candidates for cholesterol-lowering therapy

  • More attention to high density lipoprotein (HDL) as a CHD risk factor

    • Addition of HDL-cholesterol to initial cholesterol testing

    • Designation of a high HDL-cholesterol as a "negative" CHD risk factor

    • Consideration of HDL-cholesterol levels in the choice of drug therapy

  • Increased emphasis on physical activity and weight loss as components of the dietary therapy of high blood cholesterol.

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A. Background

This report reaffirms that an increased blood cholesterol level, specifically high LDL-cholesterol, increases risk for coronary heart disease (CHD). Conversely, lowering total cholesterol and LDL-cholesterol levels reduces CHD risk. Two approaches can be taken to lower blood cholesterol levels in the American population. One is a clinical approach that defines individuals at high risk who need intensive intervention efforts. The second is a public health (population) approach that aims to shift the distribution of cholesterol levels in the entire population to a lower range through dietary change. The two approaches are complementary, and together represent a coordinated strategy for reducing coronary risk.

The first Adult Treatment Panel report published in 1988 outlined a systematic clinical approach to treatment of high blood cholesterol in adults. It was followed in 1990 by the report of the Laboratory Standardization Panel, which made recommendations for improving the accuracy of cholesterol measurement, and by the report of the Population Panel, which set forth a public health approach, and in 1991 by the Children's Panel report. Together these four reports provide the basis for the National Cholesterol Education Program's strategy for control of high blood cholesterol in Americans.

Since the first ATP report was published in 1988, several issues have emerged that receive special attention in the second report. The primary new issues will be summarized briefly in this section, and consideration will be given to the others under section E, Other Issues.

  • CHD Risk Status as a Guide to Intensity of Therapy

The intensity of treatment of the individual patient depends on the patient's risk status. Those at higher risk for CHD should receive more aggressive intervention than patients at lower risk. There is a spectrum of risk from very high to low, and patients should be categorized into three general risk categories when a decision is made about the appropriate cholesterol-lowering therapy: these include (1) those at highest risk for future CHD events because of prior CHD or other atherosclerotic disease (e.g., peripheral arterial disease or symptomatic carotid artery disease), (2) patients without evident CHD who are at high risk because of high blood cholesterol together with multiple other CHD risk factors, and (3) patients with high blood cholesterol but who are at low risk otherwise. The latter group especially includes young adult men (<35 years) or premenopausal women.

  • Cholesterol Management in Patients With CHD and Other Atherosclerotic Diseases

Clinical trials demonstrate conclusively that serum cholesterol lowering will reduce morbidity and mortality from CHD in patients with established CHD. In addition, pooling of data from available clinical trials reveals a definite trend toward decreased total mortality in these patients. Treatment of elevated LDL-cholesterol in patients with prior CHD and/or other atherosclerotic disease is called "secondary prevention," whereas clinical management of patients without CHD is called "primary prevention." This distinction is somewhat arbitrary, since atherosclerosis is a long-term process and the risk status of high-risk individuals is not fundamentally different on the day before their myocardial infarction than on the day after it. Secondary prevention nonetheless receives increased emphasis in this report, since a substantial proportion of new CHD events occurs in patients with established CHD, and it appears that many CHD patients are not getting the aggressive cholesterol-lowering therapy that is warranted.

  • The Total Mortality Issue in Primary Prevention of CHD

Clinical trials demonstrate that serum cholesterol lowering will reduce new CHD events and CHD mortality in primary prevention, i.e., in patients without established CHD. An important question is whether cholesterol lowering will also reduce total mortality in primary prevention. Individual clinical trials have not had the size or power to evaluate the issue of total mortality and have not provided a conclusive answer to this question. Neither individual clinical trials nor meta-analyses of pooled data reveal a reduction in total mortality. Some analyses of drug trials raise the possibility of increases in non-CHD mortality resulting from drug therapy that offset the benefit of reduction in CHD mortality. However, the causes of non-CHD mortality are different in different trials, and it is not known whether these reported increases in non-CHD mortality are due to drug therapy or to chance. Dietary therapy has not been found to be associated with increased non-CHD mortality. Therefore, evidence that cholesterol lowering will reduce CHD morbidity and mortality supports efforts to use dietary therapy in primary prevention for patients with high cholesterol levels and to reserve drug treatment for high-risk patients in whom the benefits outweigh the potential side effects. The possibility of adverse effects from drug treatment as well as considerations of cost warrant the recommendation to be cautious about drug therapy in primary prevention for patients not at high risk from multiple risk factors or very high LDL-cholesterol levels. Cholesterol lowering through dietary means and physical activity is safer, and these should be the major form of therapy for primary prevention. These considerations led the panel to recommend that drug treatment be used sparingly in young adult men and premenopausal women.

  • Low HDL-Cholesterol

There is growing evidence that a low HDL-cholesterol level imparts increased risk for CHD. Therefore, a low HDL-cholesterol (<35 mg/dL) is classified as a major risk factor for CHD, and HDL-cholesterol should be measured in initial risk assessment when accurate testing is available. A high HDL-cholesterol also appears to be protective against CHD, and levels =>60 mg/dL can be called a "negative" risk factor. LDL-cholesterol is the primary target of cholesterol-lowering therapy because direct clinical trial evidence for the benefit of lowering LDL is strong, and similar evidence for raising HDL is less conclusive. However, therapeutic decisions should take into account HDL-cholesterol levels. For low HDL levels, hygienic therapies are the first line of treatment: physical activity, smoking cessation, and weight loss in the overweight. If drug therapy is needed to lower LDL levels in a patient with a high LDL who also has a low HDL, agents that raise HDL levels should be considered.

  • Young Adults

In young men (<35 years) and premenopausal women, elevated total and LDL-cholesterol levels increase the long-term risk of CHD. Nevertheless, young men and premenopausal women with moderately high LDL-cholesterol levels (160 to 220 mg/dL) are at relatively low risk for CHD in the near future unless they have multiple other risk factors, particularly diabetes mellitus or a family history of premature CHD. For these patients who are otherwise at low risk, cholesterol lowering through dietary means and increased physical activity is warranted, but drug therapy should be delayed. For most young adult men and premenopausal women, drug therapy should be considered when LDL-cholesterol levels are very high (=>220 mg/dL) or multiple other risk factors are also present.

  • High Blood Cholesterol in Women

Elevated blood cholesterol levels increase the risk of CHD in women, although after age 65 the relationship is somewhat less consistent than before that age. In general, women are at lower risk for CHD than are men of the same age. As indicated above, premenopausal women in particular are at low risk. Although CHD risk in women lags behind that of men by about 10 years, risk increases progressively after the menopause. Therefore, dietary therapy, combined with weight reduction in the obese, and increased physical activity are indicated in women with high cholesterol levels, but a more cautious approach in use of drugs is warranted for women compared to men of the same age. In premenopausal women, drug therapy for high cholesterol levels should generally be delayed. If postmenopausal women have unusually high LDL-cholesterol levels or multiple other risk factors, they can be considered for drug therapy; however, in many women with high LDL-cholesterol levels, use of estrogen replacement therapy may obviate the need for drug treatment.

  • Age

CHD rates are much higher in elderly patients than in younger groups. As a result, despite the fact that the relative risk of CHD conferred by an elevated cholesterol is weaker in the elderly than in young or middle-age adults, a high cholesterol level leads to more events in the elderly. A high proportion of all CHD events occurs in the elderly. While there are limited clinical trial data available in the elderly population, extrapolation of data from trials showing reduction in CHD risk in middle-age patients seems reasonable. Angiographic studies show that even advanced coronary atherosclerosis responds to cholesterol-lowering treatment. These considerations suggest that substantial benefit in CHD risk reduction for the elderly may be achieved by cholesterol lowering. In spite of these generalizations, many elderly patients will not be suitable candidates for aggressive cholesterol lowering. These include patients of advanced physiologic or chronologic age or those with severe competing illnesses (e.g., chronic congestive heart failure, dementia, advanced cerebrovascular disease, or active malignancy). On the other hand, elderly patients who are otherwise in good health and who can expect a reasonably long life in the absence of CHD should not be excluded from cholesterol-lowering therapy. The level of aggressiveness in cholesterol lowering depends on the assessment of CHD risk. Patients with established CHD or with multiple risk factors may warrant drug therapy, in addition to dietary therapy, whereas those at lower risk should be treated prudently with diet and exercise.

Consideration of all the above issues led the panel to make two changes in the guidelines. (1) The presence of CHD now places a patient in a separate category in which the goal for LDL-cholesterol lowering is set lower than before. (2) As in the first ATP report, determination of the risk status in patients without CHD depends not only on LDL-cholesterol levels but on other CHD risk factors as well. However, ATP II identifies and defines the risk factors that modify the target goal for LDL-cholesterol somewhat differently from ATP I. These now include age (=>45 years in men and =>55 years in women), a family history of premature CHD, cigarette smoking, hypertension, low levels of HDL-cholesterol (<35 mg/dL), and diabetes mellitus. A high level of HDL-cholesterol (=>60 mg/dL) is called a "negative" risk factor. In addition to these listed risk factors, obesity and physical inactivity are important CHD risk factors which physicians should treat as targets of intervention.

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B. Clinical Management of High Blood Cholesterol

Serum total cholesterol should be measured in all adults 20 years of age and over at least once every 5 years; HDL-cholesterol should be measured at the same time if accurate results are available. These measurements may be made in the nonfasting state. In individuals free of CHD, total cholesterol levels below 200 mg/dL are classified as "desirable blood cholesterol," those 200 to 239 mg/dL as "borderline-high blood cholesterol," and those 240 mg/dL and above as "high blood cholesterol." The cutpoint that defines high blood cholesterol (240 mg/dL) is a value above which risk for CHD rises more steeply and corresponds approximately to the 80th percentile of the adult U.S. population (NHANES III). An HDL-cholesterol level below 35 mg/dL is defined as "low," and a low HDL-cholesterol level constitutes a CHD risk factor.

For primary prevention in adults without evidence of CHD, initial classification is based on total cholesterol and HDL-cholesterol. For individuals with desirable blood cholesterol (<200 mg/dL), the level of HDL-cholesterol determines the appropriate followup. Those with HDL-cholesterol =>35 mg/dL are given general educational materials about dietary modification, physical activity, and other risk-reduction activities and advised to have repeat total cholesterol and HDL-cholesterol analysis in 5 years. Those with HDL-cholesterol levels less than 35 mg/dL should proceed to lipoprotein analysis. For individuals with total cholesterol levels of 200 to 239 mg/dL, the level of HDL-cholesterol and the presence or absence of multiple other CHD risk factors determine the followup. Those with an HDL-cholesterol of 35 mg/dL or greater and fewer than two other risk factors are given instruction in dietary modification, physical activity, and other risk-reduction activities and are advised to repeat total cholesterol and HDL-cholesterol analysis in 1 to 2 years. Patients with total cholesterol levels of 200 to 239 mg/dL who have an HDL-cholesterol less than 35 mg/dL or two or more other risk factors should have a lipoprotein analysis. Lipoprotein analysis is also required for those whose total cholesterol is 240 mg/dL or greater. Lipoprotein analysis includes measurement of fasting levels of total cholesterol, total triglyceride, and HDL-cholesterol. From these values, LDL-cholesterol is calculated as follows:

LDL-cholesterol = total cholesterol - HDL-cholesterol - (triglyceride/5).

Levels of LDL-cholesterol of 160 mg/dL or greater are classified as "high-risk LDL-cholesterol," those 130-159 mg/dL as "borderline-high-risk LDL-cholesterol," and those <130 mg/dL as "desirable LDL-cholesterol."

The clinical evaluation should include a complete history, physical examination, and basic laboratory tests. The aim is to determine whether a high LDL-cholesterol level is secondary to another disease or a drug, and whether a familial lipoprotein disorder is present. The patient's total coronary risk and clinical status, including age and sex, should be considered in developing a cholesterol-lowering program.

For primary prevention, subsequent classification is based on LDL-cholesterol. Individuals with desirable LDL-cholesterol levels (<130 mg/dL) do not need further evaluation and active medical therapy; they should be given information on diet and exercise designed for the general population and be reevaluated at 5 years. Those with borderline-high-risk LDL-cholesterol levels (130-159 mg/dL) who have fewer than two other CHD risk factors should be given instruction in dietary modification and physical activity and be reevaluated in 1 year. Patients with high-risk LDL-cholesterol levels (>160 mg/dL) and those with borderline-high-risk LDL-cholesterol (130-159 mg/dL) who have two or more risk factors should be evaluated clinically and begin active cholesterol-lowering dietary therapy. Assignment of patients to these last two categories should be done on the basis of the average of two LDL-cholesterol determinations to account for biologic variation.

For secondary prevention in adults with evidence of CHD or other clinical atherosclerotic disease, lipoprotein analysis is required in all patients and classification is based on LDL-cholesterol. For these patients, the optimum LDL-cholesterol is 100 mg/dL or lower. When a patient has an optimum LDL-cholesterol level, instruction on diet and physical activity should be individualized and lipoprotein analysis repeated annually. When the LDL-cholesterol level is above optimal (>100 mg/dL), appropriate clinical evaluation should be carried out and cholesterol-lowering therapy should be initiated.

For patients without CHD or other atherosclerotic disease, the LDL-cholesterol levels for initiation of dietary therapy are: (a) =>160 mg/dL in patients with fewer than two other CHD risk factors or (b) =>130 mg/dL in patients with two (or more) CHD risk factors. The target goals of therapy are to lower LDL-cholesterol to levels below the cutpoints for initiating therapy: (a) to below 160 mg/dL if fewer than two other risk factors are present or (b) to below 130 mg/dL if two (or more) CHD risk factors are present. Patients whose LDL-cholesterol exceeds these levels are candidates for dietary therapy and increased physical activity. However, if an elevated LDL-cholesterol persists after an appropriate trial of dietary therapy, drug therapy may be considered. Candidates for drug therapy include patients with multiple CHD risk factors or severe forms of hypercholesterolemia. A limited number of patients with less severe elevations of LDL-cholesterol and fewer than two other CHD risk factors also may be candidates for drug therapy; examples are patients with diabetes mellitus or a family history of premature CHD. The LDL-cholesterol levels at which drug therapy may be considered after an adequate trial of dietary therapy are: (a) =>190 mg/dL in patients with fewer than two other CHD risk factors, or (b) =>160 mg/dL in patients with two (or more) CHD risk factors. Often drug therapy can be delayed in young adult men (<35 yrs) and premenopausal women who have LDL-cholesterol levels below 220 mg/dL and who are not otherwise at high risk.

In patients with CHD, therapy should be initiated if the LDL-cholesterol level is >100 mg/dL. The goal of therapy is to reduce LDL-cholesterol to 100 mg/dL or below. Maximal dietary therapy should be employed in patients in this category. If the LDL-cholesterol level remains =>130 mg/dL with dietary therapy, drug treatment should be considered. However, if the LDL-cholesterol level is 100 to 129 mg/dL with maximal dietary therapy, clinical judgment must be used as to whether to use cholesterol-lowering drugs. Likewise, if one drug brings the LDL-cholesterol level to this range, clinical judgment is required as to whether to add a second drug.

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C. Dietary Therapy and Physical Activity

The general aim of dietary therapy is to reduce elevated serum cholesterol while maintaining a nutritionally adequate eating pattern. Dietary therapy should occur in two steps, the Step I and Step II Diets; these are designed to progressively reduce intakes of saturated fatty acids (saturated fat) and cholesterol and to promote weight loss in patients who are overweight by eliminating excess total calories and increasing physical activity. The appropriate use of physical activity is considered an essential element in the nonpharmacologic therapy of elevated serum cholesterol.

The NCEP's eating pattern recommendation for the general public is similar in nutrient intake to the Step I Diet. Consequently, at time of detection of high blood cholesterol, many patients may already be adhering to the recommended diet. Therefore an assessment of the patient's current dietary habits is necessary before prescribing a therapeutic diet. If the patient has not adopted the Step I Diet, this should be the first step of dietary therapy. The Step I Diet should be prescribed and explained by the physician and other involved health professionals. This diet involves an intake of saturated fat of 8 percent to 10 percent of total calories, 30 percent or less of calories from total fat, and cholesterol less than 300 mg/day. If the patient is already adhering to the Step I Diet at the time of detection, or if this diet proves inadequate to achieve the goals of dietary therapy, the patient should proceed to the Step II Diet. This diet calls for further reduction in saturated fat intake to less than 7 percent of calories and in cholesterol to less than 200 mg/day. The Step I Diet calls for the reduction of the major and obvious sources of saturated fat and cholesterol in the diet; for many patients this can be achieved without a radical alteration in dietary habits. The Step II Diet requires careful attention to the whole diet so as to reduce intake of saturated fat and cholesterol to a minimal level while maintaining an acceptable and nutritious diet. Involvement of a registered dietitian or other qualified nutrition professional is very useful, particularly for intensive dietary therapy such as the Step II Diet.

Weight reduction in overweight patients and increased physical activity are extremely important elements of therapy for high blood cholesterol. Weight reduction enhances the LDL-cholesterol lowering that can be achieved by reducing intakes of saturated fats and cholesterol. Both weight reduction and exercise not only promote reduction of cholesterol levels but have other benefits, i.e., reducing triglycerides, raising HDL-cholesterol, reducing blood pressure, and decreasing the risk for diabetes mellitus. Thus they reduce risk for CHD in several ways beyond lowering LDL-cholesterol levels.

Patients with established CHD or other atherosclerotic disease should begin immediately on the Step II Diet. If the goals of therapy are achieved, as outlined above for secondary prevention, the patient will remain on this therapy. Assistance from a dietitian can facilitate maintenance of the Step II Diet in CHD patients. If the goals of therapy are not met, consideration can be given to using drugs. Dietary therapy is particularly important in these patients at high risk of recurrent CHD events, but the period for observing the results of the diet before initiating drug therapy can be relatively short.

In patients without CHD, after starting the therapeutic diet, the serum total cholesterol level should be measured and adherence to the diet assessed at 4-6 weeks and at 3 months. Although the goal of therapy is to lower LDL-cholesterol, most patients can be managed during dietary therapy on the basis of their total cholesterol levels. This has the advantage of avoiding the additional cost and the inconvenience of obtaining a fasting blood sample required to estimate LDL-cholesterol levels. For most patients, serum total cholesterol levels of 240 and 200 mg/dL correspond roughly to LDL-cholesterol levels of 160 and 130 mg/dL, respectively. Thus, the monitoring goals during dietary therapy are to lower serum total cholesterol to below 240 mg/dL for patients with an LDL-cholesterol goal of less than 160 mg/dL, or to below 200 mg/dL for patients with an LDL-cholesterol goal of less than 130 mg/dL. If the total cholesterol monitoring goal is met, then the LDL-cholesterol level should be measured to confirm that the LDL goal has been achieved. If this is the case, the patient enters a long-term monitoring program, and is seen quarterly for the first year and twice yearly thereafter. At these visits total cholesterol levels should be measured, and dietary and physical activity recommendations reinforced.

If the cholesterol goal has not been achieved with the Step I Diet, the patient generally should be referred to a dietitian. With the aid of the dietitian, the patient should progress to the Step II Diet, or to another trial on the Step I Diet (with progression to the Step II Diet if the response is still not satisfactory). On the Step II Diet, total cholesterol levels again should be measured and adherence to the diet assessed after 4-6 weeks and at 3 months of therapy. If the desired goal for total cholesterol (and for LDL-cholesterol) lowering has been attained, long-term monitoring can begin. If not, there is the option for the patient to further reduce saturated fat, and total fat if additional weight loss is needed. If the LDL-cholesterol level remains substantially above the target goal after dietary therapy, drug therapy should be considered. A minimum of 6 months of intensive dietary therapy and counseling generally should be carried out in primary prevention before initiating drug therapy; shorter periods can be considered in patients with severe elevations of LDL-cholesterol (=>220 mg/dL). Drug therapy should be added to dietary therapy and not substituted for it.

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D. Drug Treatment

For primary prevention, drug treatment can be considered for an adult patient who despite dietary therapy has an LDL-cholesterol level of (a) 190 mg/dL or higher without two other risk factors, or (b) 160 mg/dL with two other risk factors. The goals of drug therapy are the same as those of dietary therapy: to lower LDL-cholesterol to below 160 mg/dL, or to below 130 mg/dL if two other risk factors are present. These are minimal goals; if possible, lowering levels of LDL-cholesterol even more is desirable. Drug therapy should be delayed in young adult men (<35 yrs) and premenopausal women without other risk factors whose LDL-cholesterol levels are in the range of 190 to 220 mg/dL.

Particularly in primary prevention, individualized clinical judgment is needed for patients who do not meet the criteria for drug therapy, but have not attained their minimal goals on dietary therapy and physical activity. These patients include those without two other risk factors whose LDL-cholesterol remains in the range of 160-190 mg/dL (or young adults in the range of 190-220 mg/dL) and patients with two other risk factors in the range of 130-160 mg/dL, on adequate dietary therapy. In general, maximal efforts should be made in this group to achieve lower cholesterol levels and lower CHD risk by means of nonpharmacologic approaches (diet, physical activity, and reduction of other CHD risk factors). Consideration may also be given to use of low doses of bile acid sequestrants in patients in these categories, especially in men.

For secondary prevention, the goal of therapy is an LDL-cholesterol of 100 mg/dL or lower. Drug therapy generally is indicated in patients with established CHD or other atherosclerotic disease if LDL-cholesterol levels are 130 mg/dL or greater after maximal dietary therapy. If the level is in the range of 100 to 129 mg/dL, clinical judgment that weighs potential benefit, possible side effects, and costs must be used in the decision for drug therapy.

In this report, drugs are classified into major drugs (bile acid sequestrants, nicotinic acid, and HMG CoA reductase inhibitors [statins]) and other drugs (fibric acids and probucol). Estrogen replacement in postmenopausal women is listed as a possible alternative or adjunct to drug therapy in those with elevated LDL-cholesterol levels.

Bile acid sequestrants (cholestyramine and colestipol) have a strong efficacy and safety record. They are especially valuable in patients with moderately elevated LDL-cholesterol, in primary prevention, and when drug therapy is necessary in young adult men and premenopausal women. They also have utility in severe forms of hypercholesterolemia in combination with other drugs (e.g., statins). Low doses of bile acid sequestrants can be effective in many patients whose LDL-cholesterol is not markedly elevated above the goal of therapy.

Nicotinic acid is effective in lowering total cholesterol and triglycerides and raising HDL-cholesterol levels. There is evidence that it reduces total mortality in secondary prevention trials. However, nicotinic acid has several side effects that limit its use in some patients; these include flushing and itching of the skin, gastrointestinal distress, liver toxicity, hyperglycemia, and hyperuricemia. Nicotinic acid is valuable in treating high blood cholesterol in patients with low HDL-cholesterol levels or when combined hyperlipidemia (elevated cholesterol and triglyceride) is present.

Statins (lovastatin, pravastatin, and simvastatin) are highly effective in lowering LDL-cholesterol. They appear to be relatively safe but long-term safety remains to be demonstrated. Therefore, they should be used with particular caution in young adult men and premenopausal women. The statins have not been proven to reduce risk for CHD when used alone, but in view of their efficacy for lowering LDL-cholesterol, they are attractive agents for treatment of severe forms of hypercholesterolemia and for maximal lowering of LDL levels in secondary prevention.

Fibric acids (e.g., gemfibrozil) are effective triglyceride-lowering drugs. In some patients they modestly lower LDL-cholesterol and raise HDL-cholesterol levels. They are not listed as major drugs because they do not usually produce substantial reductions in LDL-cholesterol levels. Thus they are not appropriate for maximal lowering of LDL levels in secondary prevention. However, these agents are valuable for treatment of very high triglyceride levels and for patients with familial dysbetalipoproteinemia (type 3 hyperlipoproteinemia). They also may have therapeutic utility for combined hyperlipidemia, as suggested by a controlled clinical trial, and for diabetic patients with elevated triglycerides.

Probucol is approved for treatment of high cholesterol levels. However, it has only a modest LDL-lowering effect and it has not been proven to reduce CHD rates in a clinical trial. It is therefore not listed as a major cholesterol-lowering drug.

For postmenopausal women with high serum cholesterol, consideration can be given to estrogen replacement therapy. Estrogens lower LDL-cholesterol levels and raise HDL-cholesterol levels. Epidemiologic studies suggest that their use reduces the risk for CHD, but there have been no large-scale controlled clinical trials to confirm this effect. In addition to CHD risk reduction, there is evidence for a retardation of osteoporosis. However, unopposed estrogen use is associated with side effects including increased risk for uterine cancer. Estrogen replacement therapy can be employed in postmenopausal women with elevated LDL-cholesterol, although confirmation of benefit in CHD risk reduction from clinical trials is still needed for certainty. Epidemiologic evidence for benefit of estrogen therapy is especially strong for secondary prevention in women with prior CHD.

After starting drug therapy, the LDL-cholesterol level should be measured at 4-6 weeks, and then again at 3 months. If the response to drug therapy is adequate (i.e., the LDL-cholesterol goal has been achieved), the patient should be seen every 4 months, or more frequently when drugs requiring closer followup are used, to monitor the cholesterol response and possible side effects of therapy. For long-term monitoring, serum total cholesterol alone can be measured at most followup visits, with lipoprotein analysis (and LDL-cholesterol estimation) carried out once a year.

If the response to initial drug therapy is not adequate, the patient should be switched to another drug, or to a combination of two drugs. The combination of a bile acid sequestrant with either nicotinic acid or a statin has the potential of lowering LDL-cholesterol levels by 40-50 percent or more. For most patients, the judicious use of one or two drugs should provide an adequate LDL-cholesterol-lowering effect. Combined drug therapy is particularly indicated in those with severe forms of hypercholesterolemia and combined hyperlipidemia. Most cholesterol-lowering drugs can be used in combination, but a statin plus fibric acid (and possibly a statin plus nicotinic acid) carries an increased risk of myopathy.

Drug therapy is likely to continue for many years or a lifetime. Hence, the decision to add drug therapy to the regimen should be made only after vigorous efforts at dietary therapy have not proven sufficient. The patient must be well informed about the goals and side effects of medication and the need for long-term commitment. Consultation with a lipid specialist generally is needed only for patients with unusually severe, complex, or refractory lipid disorders, and the primary care provider can oversee the management of high blood cholesterol in most patients.

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E. Other Issues

1. Hypertriglyceridemia

Elevated serum triglycerides are positively correlated with risk for CHD in univariate analysis, but they lose some or most of their ability to predict CHD in multivariate analysis, i.e., when other lipid risk factors are added to the model. The link between triglycerides and CHD appears to be complex, and it may be explained by the association between high triglycerides, low HDL levels, and unusually atherogenic forms of LDL. In addition, elevated triglycerides often reflect an increase in triglyceride-rich, remnant lipoproteins that have atherogenic potential. In this document, triglyceride levels are classified as normal (<200 mg/dL), borderline-high (200-400 mg/dL), high (400-1,000 mg/dL), and very high (>1,000 mg/dL). Patients with borderline-high and high triglycerides may have accompanying dyslipidemias that increase risk for CHD (e.g., familial combined hyperlipidemia and diabetic dyslipidemia). Those with triglyceride levels in excess of 1,000 mg/dL are at increased risk for acute pancreatitis. Nonpharmacologic therapy (weight reduction in overweight patients, alcohol restriction, and increased physical activity) is recommended for all patients with elevated triglycerides. When triglycerides are elevated in association with "atherogenic" dyslipidemias (e.g., familial combined hyperlipidemia), drug therapy may be indicated; the choice of drug preferably is one that effectively lowers triglycerides (e.g., nicotinic acid). Drug therapy (fibric acids or nicotinic acid) generally is indicated in patients with very high triglycerides to prevent acute pancreatitis.

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2. Secondary Dyslipidemias

Common causes of secondary dyslipidemia include diabetes mellitus, the nephrotic syndrome, chronic renal failure, and hypothyroidism. Noninsulin-dependent diabetes mellitus (NIDDM) is frequently accompanied by elevated triglycerides and low HDL-cholesterol; in addition, LDL-cholesterol levels commonly are in the borderline-high-risk range. Because of the high risk for CHD resulting from NIDDM, aggressive lowering of LDL-cholesterol levels, similar to that recommended for established CHD, can be applied to diabetic patients. This is true for women diabetic patients as well as men because the protection against CHD normally afforded to women appears to be abolished in the presence of diabetes. Although nicotinic acid produces a favorable modification of the lipoprotein profile in NIDDM patients, it tends to worsen glucose tolerance, which limits the drug's utility. When high cholesterol levels predominate in diabetic patients, bile acid sequestrants or statin drugs appear to be preferable, whereas fibric acids may be preferred when elevated triglycerides predominate.

The dyslipidemia of the nephrotic syndrome should first be addressed with treatment of the underlying renal disease. Hypercholesterolemia is the major lipid abnormality in the chronic nephrotic syndrome, and it is responsive to the statins. Nicotinic acid (or fibric acids) can be used when the predominant abnormality is hypertriglyceridemia. The major lipid abnormality with chronic renal failure is hypertriglyceridemia, and because of potential side effects of lipid-lowering drugs the preferred therapy is nonpharmacologic, i.e., weight control and minimizing use of drugs that raise triglyceride levels.

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3. Severe Forms of Hypercholesterolemia

Most severe forms of hypercholesterolemia in the absence of obvious disorders that might produce a secondary elevation of cholesterol levels are the result of genetic disorders of lipoprotein metabolism. Three such disorders are the most readily identified in clinical practice. Familial hypercholesterolemia occurs in 1 in 500 people and is characterized by severe elevations of LDL-cholesterol (often over 260 mg/dL), tendon xanthomas, and frequently premature CHD. Severe polygenic hypercholesterolemia manifests as LDL-cholesterol levels exceeding 220 mg/dL, and it occurs in about 1 percent of the adult population; premature CHD is common. Familial combined hyperlipidemia is characterized by elevations of total cholesterol, triglycerides, or both, in different members of the same family; it also occurs in about 1 percent of the population, and affected patients are prone to premature CHD. Patients presenting with severe forms of hypercholesterolemia should undergo family screening to detect other candidates for therapy.

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4. High Blood Cholesterol and Concomitant Hypertension

Both high blood cholesterol and high blood pressure are common and frequently coexist in U.S. adults. Both should be identified and treated appropriately. Diet, exercise, and other nonpharmacologic therapies are the essential first step for elevations of both blood pressure and cholesterol. Emphasis should be on weight reduction in overweight patients, but decreases in intakes of saturated fat, total fat, cholesterol, and alcohol consumption also are indicated. If drug therapy is required for blood pressure lowering, preference should be given to drugs that do not adversely affect plasma lipids; however, even though thiazides and beta-blockers may adversely affect lipids in some patients, they still may have utility in many patients because of efficacy, safety, and cost considerations. In some instances, drugs affecting lipid metabolism may interact adversely with antihypertensive agents, and awareness of possible interaction is needed in drug selection.

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5. Cost-Effectiveness Issues

The aggregate cost of CHD in the United States is enormous, costing the Nation between $50 and $100 billion per year for medical treatment and lost wages. Prevention of CHD therefore could greatly reduce this economic toll. The least expensive way to reduce CHD is through the public health approach. This approach targets the whole population in an effort to reduce the major risk factors for CHD--especially smoking, hypertension, and high blood cholesterol--by public education, governmental policy, and private sector and industry commitment. The clinical strategy, which aims to identify and treat individuals at greatest risk for CHD, complements the public health approach. The clinical strategy, although necessary for risk reduction in high-risk patients, nonetheless carries costs for detection, therapy, and long-term monitoring in patients at risk from high blood cholesterol.

Cost-effectiveness analyses have been carried out for drug treatment of high blood cholesterol. According to these analyses, the cost to produce health benefits (increased longevity and improved quality of life) will be lowest in groups with the highest near-term risk for CHD. Three categories of patients have been identified for whom the cost effectiveness of cholesterol-lowering drug treatment differs. Those at highest near-term risk for future CHD events and mortality are patients with established CHD, and the cost to produce health benefits is lowest for these patients. Next are patients with multiple risk factors or severely high cholesterol levels who also have a high risk for developing CHD in the near future. Costs are highest in those who have only moderate elevations of blood cholesterol and absence of other risk factors. These concepts parallel those for benefit/risk ratios: the greatest benefit relative to risk from cholesterol-lowering drug therapy is seen in patients at high risk for CHD. These parallel findings support the concept that drug therapy should be reserved primarily for high-risk patients, whereas those with high blood cholesterol who are otherwise at lower risk should be treated with dietary therapy and physical activity, which are safer and less expensive. Nonetheless these general principles may not always pertain to individual patients, and clinical judgment is required for shaping the best therapy for individuals.

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NIH Publication No. 93-3096


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Editor: Susan K. Boyer, RN
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