Prophylaxis of coronary heart disease: drugs that help normalize cholesterol and triglyceride levels

CHAPTER 50


Prophylaxis of coronary heart disease: drugs that help normalize cholesterol and triglyceride levels


Marshal Shlafer


Our main topic for the chapter is drugs used to lower cholesterol. Drugs used to lower triglycerides are considered as well. Why focus on cholesterol? Because of its impact on coronary artery atherosclerosis (thickening of the coronary arteries), also known as coronary heart disease (CHD). Moderate CHD usually manifests first as anginal pain. Severe CHD sets the stage for acute coronary syndrome (ACS) and myocardial infarction (MI). In the United States, CHD is the leading killer of men and women, causing 406,000 deaths in 2007. According to the American Heart Association, about 16 million Americans have a history of coronary events (angina, MI, or both). More than half of these people are women. Additional sobering statistics are presented in Table 50–1.



Until recently, atherosclerosis was largely a disease of older people. Not so any more. Why? Because lifestyles have changed. A generation ago, diets included generally healthy made-from-scratch “balanced” meals, and children were shooed out of the house to play. Nowadays, fast-food restaurants and heat-and-eat meals are the new tradition, even though (or because?) they may be loaded with all sorts of heart-unhealthy fats, along with the heart’s other big enemy: salt. And while many youngsters are shuttled off to school, then to soccer, then to baseball, track, or swimming, too many others seem to be in competition for Couch-Potato-of-the-Year, earning points on their video games or otherwise devoting much time to their smart phones or the Internet. So now, rather than developing CHD in their fourth or fifth decade, people are getting the disease sooner, as can be attested to by attending clinicians and the pathologists doing the autopsies.


How does atherosclerosis develop? Very briefly, it begins as a fatty streak in the arterial wall. This is followed by deposition of fibrous plaque. As atherosclerotic plaque grows, it impedes coronary blood flow, causing anginal pain. Worse yet, coronary atherosclerosis encourages formation of thrombi, which can block flow entirely, thereby causing MI.


It is important to appreciate that atherosclerosis is not limited to arteries of the heart: Atherosclerotic plaque can develop in any artery, and can thereby compromise circulation to any tissue. Furthermore, adverse effects can occur at sites distant from the original lesion: A ruptured lesion can produce a thrombus, which can travel downstream to block a new vessel. Blockage in the lungs and brain is of particular concern.


The risk of developing CHD is directly related to increased levels of blood cholesterol, in the form of low-density lipoproteins (LDLs). By reducing levels of LDL cholesterol, we can slow progression of atherosclerosis, reduce the risk of serious CHD and its potential consequences, and prolong life. The preferred method for lowering LDL cholesterol is modification of diet combined with exercise. Drugs are employed only when diet modification and exercise are insufficient.


We approach our primary topic—cholesterol and its impact on CHD—in three stages. First, we discuss cholesterol itself, plasma lipoproteins (structures that transport cholesterol in blood), and the process of atherogenesis. Second, we discuss guidelines for cholesterol screening and management of high cholesterol. Third, we discuss the pharmacology of the cholesterol-lowering drugs, as well as drugs used to lower triglycerides.




Cholesterol


Cholesterol has several physiologic roles. Of greatest importance, cholesterol is a component of all cell membranes and membranes of intracellular organelles. In addition, cholesterol is required for synthesis of certain hormones (estrogen, progesterone, testosterone, adrenal corticosteroids) and for synthesis of bile salts, which are needed to absorb and digest dietary fats. Also, cholesterol is deposited in the stratum corneum of the skin, where it reduces evaporation of water and blocks transdermal absorption of water-soluble compounds.


Some of our cholesterol comes from dietary sources (exogenous cholesterol) and some is manufactured by cells (endogenous cholesterol), primarily in the liver. More cholesterol comes from endogenous production than from the diet. A critical step in hepatic cholesterol synthesis is catalyzed by an enzyme named 3-hydroxy-3-methylglutaryl coenzyme A reductase, or simply HMG-CoA reductase. As discussed below, drugs that inhibit this enzyme—the statins—are our most effective and widely used cholesterol-lowering agents.


An increase in dietary cholesterol produces only a small increase in cholesterol in the blood, primarily because a rise in cholesterol intake inhibits endogenous cholesterol synthesis. Interestingly, an increase in dietary saturated fats produces a substantial (15% to 25%) increase in circulating cholesterol. Why? Because the liver uses saturated fats to make cholesterol. Accordingly, when we want to reduce cholesterol levels, it is more important to reduce intake of saturated fats than to reduce intake of cholesterol itself, although cholesterol intake should definitely be lowered.



Plasma lipoproteins


Structure and function of lipoproteins





Basic structure.

The basic structure of lipoproteins is depicted in Figure 50–1. As indicated, lipoproteins are tiny, spherical structures that consist of a hydrophobic core, composed of cholesterol and triglycerides, surrounded by a hydrophilic shell, composed primarily of phospholipids. Because the hydrophilic shell completely covers the lipid core, the entire structure is soluble in the aqueous environment of the plasma.


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Figure 50–1  Basic structure of plasma lipoproteins.


Apolipoproteins.

All lipoproteins have one or more apolipoprotein molecules embedded in their shell (see Fig. 50–1). Apolipoproteins, which constitute the protein component of lipoproteins, have three functions:



The apolipoproteins of greatest clinical interest are labeled A-I, A-II, and B-100. All lipoproteins that deliver cholesterol and triglycerides to nonhepatic tissues contain apolipoprotein B-100. Conversely, all lipoproteins that transport lipids from nonhepatic tissues back to the liver (ie, that remove lipids from tissues) contain apolipoprotein A-I.



Classes of lipoproteins


There are six major classes of plasma lipoproteins. Distinctions among classes are based on size, density, apolipoprotein content, transport function, and primary core lipids (cholesterol or triglyceride). From a pharmacologic perspective, the features of greatest interest are lipid content, apolipoprotein content, and transport function.


For two reasons, the topic of lipoprotein density deserves comment. First, naming of lipoprotein types is based on their density. Second, differences in density provide the basis for the physical isolation and subsequent measurement of plasma lipoproteins, as is done in research and clinical laboratories. The various classes of lipoproteins differ in density because they differ in their percent composition of lipid and protein. Because protein is more dense than lipid, lipoproteins that have a high percentage of protein (and a low percentage of lipid) have a relatively high density. Conversely, lipoproteins with a lower percentage of protein have a lower density.


Of the six major classes of lipoproteins, three are especially important in coronary atherosclerosis. These classes are named (1) very-low-density lipoproteins (VLDLs), (2) low-density lipoproteins (LDLs), and (3) high-density lipoproteins (HDLs). Properties of these classes are summarized in Table 50–2.





Low-density lipoproteins

LDLs contain cholesterol as their primary core lipid, and they account for the majority (60% to 70%) of all cholesterol in blood. The physiologic role of LDLs is delivery of cholesterol to nonhepatic tissues. Each LDL particle contains one molecule of apolipoprotein B-100, which is needed for binding of LDL particles to LDL receptors on cells. LDLs can be viewed as by-products of VLDL metabolism, in that the lipids and apolipoproteins that compose LDLs are remnants of VLDL degradation.


Cells that require cholesterol meet their needs through endocytosis (engulfment) of LDLs from the blood. The process begins with binding of LDL particles to LDL receptors on the cell surface. When cellular demand for cholesterol increases, cells synthesize more LDL receptors and thereby increase their capacity for LDL uptake. Accordingly, cells that are unable to make more LDL receptors cannot increase cholesterol absorption. Increasing the number of LDL receptors on cells is an important mechanism by which certain drugs increase LDL uptake, and thereby reduce LDL levels in blood.


Of all lipoproteins, LDLs make the greatest contribution to coronary atherosclerosis. The probability of developing CHD is directly related to the level of LDLs in blood. Conversely, by reducing LDL levels, we decrease the risk of CHD. Accordingly, when cholesterol-lowering drugs are used, the main goal is to reduce elevated LDL levels. Multiple studies have shown that, by reducing LDL levels, we can arrest or perhaps even reverse atherosclerosis, and can thereby reduce mortality from CHD. In fact, for each 1% reduction in the LDL level, there is about a 1% reduction in the risk of a major cardiovascular (CV) event.





Role of LDL cholesterol in atherosclerosis


LDLs initiate and fuel development of atherosclerosis. The process begins with transport of LDLs from the arterial lumen into endothelial cells that line the lumens of blood vessels. From there, they move into the space that underlies the arterial epithelium. Once in the subendothelial space, components of LDLs undergo oxidation. This step is critical in that oxidized LDLs



As macrophages engulf more and more cholesterol, they become large and develop large vacuoles. When macrophages assume this form, they are referred to as foam cells. Foam cell accumulation beneath the arterial epithelium produces a fatty streak, which makes the surface of the arterial wall lumpy, causing blood flow to become turbulent. Continued accumulation of foam cells can eventually cause rupture of the endothelium, thereby exposing the underlying tissue to the blood. This results in platelet adhesion and formation of microthrombi. As the process continues, smooth muscle cells migrate to the site, synthesis of collagen increases, and there can be repeated rupturing and healing of the endothelium. The end result is a mature atherosclerotic lesion, characterized by a large lipid core and a tough fibrous cap. In less mature lesions, the fibrous cap is not strong, and hence the lesions are unstable and more likely to rupture. As a result, arterial pressure and shear forces (from turbulent blood flow) can cause the cap to rupture. Accumulation of platelets at the site of rupture can rapidly cause thrombosis, and can thereby cause infarction. Infarction is less likely at sites of mature atherosclerotic lesions. The atherosclerotic process is depicted in Figure 50–2.


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Figure 50–2  Progression of atherosclerosis.
A, Damaged endothelium. B, Diagram of fatty streak and lipid core formation. C, Diagram of fibrous plaque. Raised plaques are visible: some are yellow and some are white. D, Diagram of a complicated lesion, showing a thrombus (in red) and collagen (in blue). (From McCance KL, Huether SE: Pathophysiology: The Biologic Basis for Disease in Adults and Children, 5th ed. St. Louis: Elsevier Mosby, 2006.)

It is important to appreciate that atherogenesis involves more than just deposition of lipids. In fact, atherogenesis is now considered primarily a chronic inflammatory process. When LDLs penetrate the arterial wall, they cause mild injury. The injury, in turn, triggers an inflammatory response that includes infiltration of macrophages, T lymphocytes, and other potentially noxious chemicals (eg, C-reactive protein [CRP]). In the late stage of the disease process, inflammation can weaken atherosclerotic plaque, leading to plaque rupture and subsequent thrombosis. The roles of inflammation and CRP in atherothrombosis are discussed further in Box 50–1.



imageBOX 50–1    SPECIAL INTEREST TOPIC


INFLAMMATION, C-REACTIVE PROTEIN, AND CARDIOVASCULAR RISK


Although we know about several risk factors for CHD—advancing age, obesity, hypertension, diabetes, smoking, high LDL cholesterol, and sedentary lifestyle—it is clear that other risk factors must exist. Why? Because many young, lean, active, normotensive, nondiabetic, nonsmokers with low cholesterol still manage to die from MI. Obviously, additional risk factors must be involved. The leading suspect is inflammation.


There is good evidence that inflammation plays a central role in atherosclerosis. Although inflammation normally protects tissues, it can also do harm. For example, inflammation in the lungs leads to bronchospasm in asthma, and inflammation of joints underlies tissue injury in arthritis. In arteries, inflammation appears to set the stage for atherogenesis. In addition, inflammation may weaken the surface of atherosclerotic plaques, thereby increasing the risk of plaque rupture. Factors that might evoke an inflammatory response include smoking, diabetes, and infection.


The strongest evidence implicating inflammation in CHD comes from measuring plasma levels of C-reactive protein (CRP), a compound that is produced when inflammation occurs. Large amounts are produced during major inflammatory disorders (eg, arthritis, infection), causing blood levels of CRP to climb very high. In contrast, relatively small amounts are produced by inflammation in arteries. Nonetheless, these amounts are still big enough to cause a measurable increase in blood levels, albeit much smaller than the increase seen in conditions like arthritis or infection. Please note that CRP itself is harmless: The compound is simply a biomarker for ongoing inflammatory processes; it does not cause injury by itself.


In clinical studies, elevation of CRP has been associated with increased CV risk. For example, in the Physicians’ Health Study, high levels of CRP predicted danger 6 to 8 years in advance: Among people with no prior CV events, high levels of CRP were associated with a threefold increased risk of heart attacks and a twofold increased risk of stroke. In the Women’s Health Study, similar results were obtained: Over an 8-year period, women with the highest levels of CRP experienced 4.5 times as many heart attacks or strokes as did women with the lowest levels. Furthermore, not only did elevated CRP predict CV risk, it did so for women whose LDL cholesterol was normal—not just those whose LDL cholesterol was high. This is important. Why? Because it means that elevated CRP is an independent risk factor for CV events; it’s not simply a surrogate for LDL cholesterol. Hence, measuring CRP and LDL cholesterol might identify different risk groups.


Cardiovascular protection conferred by aspirin and statins may result in part from anti-inflammatory actions. It is well known that aspirin suppresses platelet aggregation, and thereby helps protect against MI. However, there is evidence that aspirin is most beneficial in patients with high levels of CRP, suggesting that aspirin’s anti-inflammatory actions may also contribute to CV benefits. Likewise, it is well known that statins reduce LDL cholesterol levels, and thereby protect against CHD. However, in patients with normal cholesterol levels and high levels of CRP, pravastatin still offers protection. Specifically, the drug can lower CRP levels by 17% and reduce the risk of recurrent MI—again suggesting that anti-inflammatory actions may partly explain clinical benefits.


Given that elevated CRP may predict CV events, should we screen people to see if their CRP is high? Yes, we should, according to a 2003 statement issued by an expert panel convened jointly by the American Heart Association (AHA) and the Centers for Disease Control and Prevention (CDC). However, the AHA/CDC panel does not recommend screening for everyone. Rather, screening should be limited to patients deemed at intermediate CV risk (ie, having a 10% to 20% risk of developing CHD in the next 10 years) as indicated by their age, LDL cholesterol level, and other traditional risk criteria. The panel does not recommend screening for patients considered at high or low risk. Why? Because the test results are unlikely to reveal information that would alter treatment decisions: With people at high risk, we already have sufficient information to guide treatment; with people at low risk, CRP tests are unlikely to reveal a previously unknown risk that would indicate a need for treatment.


How should CRP be tested? The AHA/CDC panel recommends using a high-sensitivity CRP (hsCRP) test, rather than a conventional CRP test, even though both tests measure the same molecule (CRP). Why use the high-sensitivity test? Because it can accurately measure low levels of CRP (1 to 10 mg/L)—levels in the range affected by arterial inflammation. The conventional test cannot accurately measure levels this low. Because levels of hsCRP can vary over time, two tests should be done, about 2 weeks apart. The degree of CV risk associated with specific hsCRP levels is as follows:



People in the high-risk group have a twofold greater risk of an adverse CV event compared with people in the low-risk group.


If the hsCRP level indicates high risk, what should be done? Recall that hsCRP testing is recommended only for patients already classified as having intermediate risk, as determined by traditional risk criteria. For these people, a high level of hsCRP would signal a need for more intensive intervention.


It is important to note that hsCRP should not be tested in the presence of trauma, infection, or systemic inflammatory disorders. Why? Because these conditions can raise hsCRP levels substantially, up to 50 mg/L or even higher. Hence, if hsCRP test results were high, we couldn’t tell if these conditions or vascular inflammation were the cause.


Does lowering CRP reduce CV risk? Yes! This was shown for the first time in two sister studies: the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE-IT) trial and the Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial. In both studies, patients with existing CHD were randomized to receive either standard doses of pravastatin [Pravachol] or high doses of atorvastatin [Lipitor]. The results? In PROVE-IT, patients on the high-dose regimen experienced greater reductions in LDL and CRP levels than did patients on the standard regimen, and they also experienced fewer CV events. Furthermore, whether LDL levels were low or high, reducing CRP levels improved outcomes. The REVERSAL trial, which monitored progression of coronary atherosclerosis, produced parallel results. That is, reductions in LDL and CRP were independently associated with slowed progression of atheroma volume. In fact, among patients with the greatest reductions in LDL and CRP, atheroma volume actually declined.


The results of PROVE-IT and REVERSAL were reinforced and extended by a major new trial—Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER)—designed to see if statins can reduce CV events in people with elevated CRP, but with healthy levels of LDL cholesterol. The study enrolled nearly 18,000 healthy men and women with LDL cholesterol levels below 130 mg/dL, and with CRP levels of 2 mg/L or higher (ie, levels associated with increased cardiovascular risk). Half the participants received rosuvastatin (20 mg/day) and the other half received a daily placebo. JUPITER was supposed to last 4 years, but was stopped after just 1.9 years. Why? Because early results showed “unequivocal evidence” that rosuvastatin reduced cardiovascular morbidity and mortality: Compared with controls, the rosuvastatin group had a 55% relative reduction in nonfatal MI, a 48% reduction in nonfatal stroke, and a 47% reduction in “hard cardiac events,” defined as the combination of MI (fatal or not), stroke (fatal or not), the need for coronary vessel revascularization (eg, by angioplasty and placement of a stent), and overall death from cardiovascular causes. What was the effect on LDL cholesterol and CRP? Rosuvastatin reduced LDL cholesterol by 50% and CRP by 37%. By comparison, LDL cholesterol and CRP were largely unchanged in the control group. Some experts reviewing these results were underawed. Why? Because, although treatment produced a notable reduction in the relative risk, the reduction in absolute risk was less impressive. As one authority calculated, we would have to treat 120 patients for nearly 2 years to prevent just one death from cardiovascular causes. Nonetheless, when we consider that millions of patients are at risk, this treatment could easily save tens of thousands of lives.


Taken together, the PROVE-IT, REVERSAL, and JUPITER studies indicate that reducing CRP levels with statins provides protection against CV events independent of the protection ascribable to reducing LDL.


Since we know that reducing CRP is beneficial, how can we do it? Interestingly, the same measures that reduce LDL cholesterol—healthy diet, exercise, weight loss, smoking cessation, and statin therapy—also reduce levels of CRP. Drugs designed specifically to reduce CRP are in development.



Detection, evaluation, and treatment of high cholesterol: recommendations from ATP III


It is well established that high levels of cholesterol (primarily LDL cholesterol) cause substantial morbidity and mortality, and that aggressive treatment can save lives. Accordingly, periodic cholesterol screening and risk assessment are recommended. If the assessment indicates CHD risk, lifestyle changes—especially diet and exercise—should be implemented. If CHD risk is high, LDL-lowering drugs should be added to the regimen.


In 1988, the National Cholesterol Education Program (NCEP) began issuing guidelines on cholesterol detection and management. The most recent update was issued in 2001 and amended in 2004. A summary of the 2001 guidelines—Executive Summary of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (also known as Adult Treatment Panel III or simply ATP III)—was published in JAMA (Vol. 285, No. 19, 2486–2497, 2001) and is available online at www.nhlbi.nih.gov/guidelines/cholesterol/atp3xsum.pdf. The 2004 changes to the 2001 guidelines were published in Circulation (Vol. 110, 227–239, 2004) and are available online at www.nhlbi.nih.gov/guidelines/cholesterol/atp3upd04.pdf. Previous NCEP guidelines were issued in 1988 (ATP I) and 1993 (ATP II). The discussion below reflects recommendations in ATP III, including the 2004 updates.


Like earlier NCEP guidelines, ATP III focuses on the role of high cholesterol in CHD and stresses the importance of treatment. However, owing to revised risk assessment criteria, ATP III recommends drug therapy for many more Americans: about 50 million, compared with only 13 million under ATP II. In addition, ATP III addresses two new concerns: elevated triglycerides and metabolic syndrome (formerly known as syndrome X or insulin resistance syndrome).


Note: An update of ATP III—ATP IV—is long overdue. Publication was originally scheduled for 2010, but has been postponed until at least 2012. When ATP IV is finally released, we will revise the chapter and publish the revision on the Evolve site. Elsevier sales reps will inform faculty when the revised chapter is available.



Cholesterol screening



Adults

Management of high LDL cholesterol begins with screening, generally done every 5 years for adults over the age of 20. The ATP III guidelines recommend a more thorough screen than before, consisting of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides (TGs). Blood for these tests should be drawn after fasting. Classification of total cholesterol and LDL cholesterol levels in ATP III (Table 50–3) is nearly identical to the older ATP II classifications. (The only change is that optimal LDL cholesterol is now defined in ATP III as less than 100 mg/dL, compared with less than 130 mg/dL under ATP II. In addition, the cutoff for low HDL cholesterol is now less than 40 mg/dL, up from less than 35 mg/dL under ATP II.



TABLE 50–3 


Health Classification of Blood Cholesterol and Triglyceride Levels*























































Cholesterol Type Level (mg/dL) Classification
LDL cholesterol <100 Optimal
100–129 Near/above optimal
130–159 Borderline high
160–189 High
≥190 Very high
Total cholesterol <200 Desirable
200–239 Borderline high
≥240 High
HDL cholesterol <40 Low
≥60 High
Triglycerides <150 Normal
150–199 Borderline high
200–499 High
≥500 Very high


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*Cholesterol values are from the Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–2497, 2001. Triglyceride values are from the National Heart, Lung, and Blood Institute of the National Institutes of Health.



Children and adolescents

Elevated cholesterol in pediatric patients is a growing concern, and is not addressed in ATP III. However, it is addressed in other guidelines, including one created in 2011 by an expert panel appointed by the National Heart, Lung, and Blood Institute, and endorsed by the American Academy of Pediatrics. This report—Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents—is available online at www.nhlbi.nih.gov/guidelines/cvd_ped/summary.xhtml#chap9.


When should testing be done? The guideline recommends lipid screening for all children between ages 9 and 11 years, followed by another screen between ages 18 and 21 years. For children with a family history of high cholesterol or heart disease, screening should start sooner: between ages 2 and 8 years. Cholesterol classification for children and adolescents is presented in Table 50–4.



If LDL cholesterol is high, what should be done? All patients and their families should receive nutritional counseling. In addition, patients should focus on weight reduction and increased activity, as indicated. Should children use cholesterol-lowering drugs? For two reasons, the answer is “Probably not.” First, these children are in no immediate danger: Their risk of developing clinically significant CHD in the next 20 years is close to zero. And second, we have no data from randomized, controlled trials showing that these drugs will improve outcomes when given to children.



CHD risk assessment


Under ATP III, CHD risk assessment is directed at determining the patient’s absolute risk of developing clinical coronary disease over the next 10 years. The LDL goal and the mode of intervention are determined by the individual’s degree of risk.



Factors in risk assessment

In order to assess the CHD risk for an individual, we need three kinds of information. Specifically, we need to (1) identify CHD risk factors, (2) calculate 10-year CHD risk, and (3) identify CHD risk equivalents.



Identifying CHD risk factors.

Major risk factors that modify LDL treatment goals are summarized in Table 50–5. The table lists five positive risk factors (advancing age, family history of premature CHD, hypertension, cigarette smoking, and low HDL cholesterol) and one negative risk factor (high HDL cholesterol). (LDL itself is not listed because the reason for counting these risk factors is to modify treatment of high LDL.) For the purpose of CHD risk assessment, each positive factor counts as 1 point; if the patient has high HDL cholesterol (a negative risk factor), 1 point is subtracted. For example, if the subject were a 62-year-old female hypertensive smoker with an HDL level of 62 mg/dL, her point total score would be 2 (3 points for the three positive risk factors minus 1 point for the one negative risk factor).



It should be noted that diabetes carries more weight in risk assessment in ATP III than in ATP II. Why? Because we now know that diabetes is a very strong predictor of developing CHD. Accordingly, we no longer consider diabetes to be a risk factor (as it was in ATP II). Instead, for the purpose of risk assessment, diabetes is now considered a CHD risk equivalent. That is, having diabetes is considered equivalent to having CHD as a predictor of a major coronary event.


Box 50–1 discusses one additional factor—C-reactive protein (CRP)—that could aid with CHD risk prediction.



Calculating 10-year CHD risk.

ATP III defines three 10-year risk categories: more than 20%, 10% to 20%, and less than 10%. Some people are automatically in the highest risk group—specifically, those with existing CHD (or other forms of atherosclerotic disease) and those with diabetes. For all other people, 10-year risk must be calculated. The instrument employed most often is the Framingham Risk Prediction Score, which takes five factors into account: age, total cholesterol, HDL cholesterol, smoking status, and systolic blood pressure. These are similar to risk factors noted above. Framingham scores can be determined using either (1) the tables for men and women shown in Figure 50–3 or (2) a web-based risk calculator, such as the one provided by the NCEP at hp2010.nhlbihin.net/atpiii/calculator.asp.


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Figure 50–3  Tables for calculating Framingham Risk Prediction Scores.
To determine an individual’s 10-year risk of developing clinical coronary disease, simply circle the appropriate points for each of the five risk factors considered (age, total cholesterol, smoking status, HDL cholesterol, and systolic blood pressure) and then add up the points. The point total indicates the 10-year risk. For example, a total of 13 points indicates a 10-year risk of 12% for men. (Framingham scores can also be determined using a web-based calculator, such as the one provided by the NCEP at hp2010.nhlbihin.net/atpiii/calculator.asp.)



Identifying an individual’s chd risk category

Under ATP III, there are four categories of CHD risk, labeled I, II, III, and IV (Table 50–6). People in category I are at highest risk: Their risk of a major coronary event within 10 years is over 20%. In comparison, the 10-year risk for people in category IV is low—less than 10%.



TABLE 50–6 


LDL Cholesterol Goals and Therapeutic Interventions for People in Specific CHD Risk Categories






























CHD Risk Category LDL Goal LDL Level at Which to Initiate TLCs* LDL Level at Which to Consider Drug Therapy
I High Risk: Has CHD or a CHD risk equivalent† (10-year risk is >20%) <100 mg/dL (with an optional goal of <70 mg/dL)‡ Any level ≥100 mg/dL (at <100 mg/dL, LDL-lowering drugs are optional)§
II Moderately High Risk: Has 2 or more risk factors, but not CHD, and 10-year risk is 10–20% <130 mg/dL (with an optional goal of <100 mg/dL) Any level ≥130 mg/dL (between 100 and 129 mg/dL, LDL-lowering drugs are optional)§
III Moderate Risk: Has 2 or more risk factors, but not CHD, and 10-year risk is <10% <130 mg/dL ≥130 mg/dL ≥160 mg/dL
IV Low to Moderate Risk: Has 0–1 risk factor, but not CHD (10-year risk is probably <10%) <160 mg/dL ≥160 mg/dL ≥190 mg/dL (between 160 and 189 mg/dL, LDL-lowering drugs are optional)


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*TLCs = therapeutic lifestyle changes.


†CHD risk equivalents include diabetes, forms of atherosclerosis other than CHD (eg, peripheral arterial disease, symptomatic coronary artery disease), and any combination of risk factors that creates a 10-year Framingham Risk Prediction Score of greater than 20%.


‡For patients at very high risk (eg, those with a recent heart attack or those with CV disease combined with diabetes), the LDL goal may be set at less than 70 mg/dL, rather than 100 mg/dL.


§When LDL-lowering drugs are used in patients at high risk or moderately high risk, treatment should be sufficient to decrease the LDL level by 30% to 40%.


Almost all people with 0 to 1 risk factor and no CHD have a 10-year risk below 10%, and hence formal evaluation of 10-year risk is not needed.


Modified from the Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 285:2486–2497, 2001; as updated in Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation 110:227–239, 2004.


Category assignment is based on (1) the presence or absence of CHD (or a CHD risk equivalent, such as diabetes), (2) the number of risk factors the individual has (other than high LDL cholesterol), and (3) the individual’s 10-year Framingham Risk Prediction Score. Although this assessment sounds complicated, it’s not. Let’s consider the hypothetical case of Ralph J.—and follow along by looking at Figure 50–3. Mr. J. is 62 years old, hypertensive, and smokes—but, remarkably, his HDL cholesterol is high (above 60 mg/dL). He has no family history of premature CHD, does not have CHD himself, and does not have diabetes. His 10-year Framingham Risk Prediction Score is 11%. What CHD risk category does he belong in? Well, his age, blood pressure, and smoking status represent three major risk factors, but his high (healthy) HDL cholesterol allows subtraction of one risk factor, leaving a net of two risk factors. The presence of two major risk factors plus the 11% Framingham score place Mr. J. in CHD risk category II (the next to highest risk group). Pretty easy, huh? And even easier if you use an online computational tool, such as the ones available at www.framinghamheartstudy.org/risk/index.html.


Risk category IV deserves comment. People assigned to this group have either no CHD risk factors or just one, and do not have CHD. As a rule, their 10-year CHD risk is not calculated. Why? Because there’s no need: With so few risk factors, their 10-year risk is almost always below 10%.




Treatment of high LDL cholesterol


Treatment of high LDL cholesterol is based on the individual’s CHD risk category: The greater the 10-year risk, the more aggressive the treatment. As CHD risk increases, the target LDL goal gets lower, as does the LDL level at which treatment should commence. For example, among individuals in risk category I, the LDL goal is quite low (below 100 mg/dL—or below 70 in people at highest risk), compared with the higher goal (below 160 mg/dL) for people in category IV. Similarly, for individuals in category I, drugs are recommended if the LDL level is 100 mg/dL or above, compared with a much higher value (190 mg/dL or above) for those in category IV. Table 50–6 summarizes the LDL goal and the LDL levels at which to initiate treatment for people in all four CHD risk categories.


To reduce LDL levels, ATP III recommends two forms of intervention: (1) therapeutic lifestyle changes (TLCs) and (2) drug therapy. For some people, cholesterol can be reduced adequately with TLCs alone. Others require TLCs plus cholesterol-lowering drugs. Please note: Drugs should be used only as an adjunct to TLCs—not as a substitute.



Therapeutic lifestyle changes

Therapeutic lifestyle changes are nondrug measures used to lower LDL cholesterol. TLCs focus on four main issues: diet, exercise, weight control, and smoking cessation. These measures are first-line treatment for LDL reduction, and should be implemented before trying drugs. Unfortunately, TLCs can be a challenge simply because some people just won’t eat healthier diets, nor will they exercise. Furthermore, arthritis and other physical conditions can limit attempts at exercise.



The TLC diet.

This diet has two objectives: (1) reducing LDL cholesterol and (2) establishing and maintaining a healthy weight. The central feature of the diet is reduced intake of cholesterol and saturated fats: Individuals should limit intake of cholesterol to 200 mg/day or less and intake of saturated fat to 7% or less of total calories. Intake of trans fats—found primarily in crackers, commercial baked goods, and French fries—should be minimized. (Many food manufacturers are adding “no trans fat” labels to their product labels, making shopping somewhat easier.) ATP III recommendations for cholesterol, fats, and other nutrients are summarized in Table 50–7. A list of specific foods to choose, eat in moderation, or avoid, appears in Table 50–8.




TABLE 50–8 


Recommended Dietary Modifications to Lower Serum Cholesterol

































































  Recommendation
Food Type Choose Decrease
Fish, chicken, turkey, and lean meats Fish; poultry without skin; lean cuts of beef, lamb, pork, or veal; shellfish Fatty cuts of beef, lamb, or pork; spareribs; organ meats; regular cold cuts; sausage; hot dogs
Milk, cheese, yogurt, and other dairy products Skim and 1% fat milk (liquid, powdered, evaporated), buttermilk 4% fat milk (regular, evaporated, condensed), 2% fat milk, cream, half-and-half, imitation milk products, most nondairy creamers, whipped toppings
Nonfat (%) or low-fat yogurt Whole-milk yogurt
Low-fat cottage cheese (1% or 2% fat) Whole-milk cottage cheese (4%)
Low-fat cheeses, farmer or pot cheeses (all of these cheeses should have no more than 2–6 gm of fat per ounce) All natural cheeses (eg, blue, Roquefort, Camembert, cheddar, Swiss)
Cream cheese (including low-fat and “light” types), sour cream (including low-fat and “light” types)
 
Sherbet, sorbet Ice cream
Eggs Egg whites (2 whites = 1 whole egg in recipes), cholesterol-free egg substitutes Egg yolks*
Fruits and vegetables Fresh, frozen, canned, and dried fruits and vegetables Vegetables prepared in butter, cream, and other sauces
Breads and cereals Homemade baked goods using unsaturated oils sparingly, angel food cake, low-fat crackers, low-fat cookies Commercial baked goods: pies, cakes, muffins, doughnuts, croissants, biscuits, high-fat crackers, high-fat cookies
Rice, pasta Egg noodles
Whole-grain breads and cereals (oatmeal, whole wheat, rye, bran, multigrain, etc.) Breads in which eggs are a major ingredient
Fats and oils Unsaturated vegetable oils: corn, olive, canola (rapeseed), safflower, sesame, soybean, sunflower oils
Margarine (regular or diet),† shortening made from one of the unsaturated oils listed above		 Butter, the so-called “tropical oils” (coconut oil, palm oil, palm kernel oil), lard, bacon fat
Mayonnaise, salad dressings made with one of the unsaturated oils listed above; low-fat or (preferred) fat-free dressings Dressings made with egg yolk
Seeds and nuts (especially walnuts) Coconut
Baking cocoa Chocolate


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*Author’s note: Consuming up to 1 egg/day is not associated with an increased risk of fatal or nonfatal MI or ischemic or hemorrhagic stroke, except possibly in people with diabetes.


†Author’s note: Since the publication of this table in 1988, new evidence indicates that stick margarine (but probably not newer low-fat spreads), which contains 17% trans fat, raises LDL cholesterol and lowers HDL cholesterol, and hence should not be recommended.


From the National Cholesterol Education Program Adult Treatment Panel report. Arch Intern Med 148:36, 1988.


If the basic TLC diet fails to lower LDL cholesterol adequately, ATP III recommends two additional measures: increased intake of soluble fiber (10 to 25 gm/day; oatmeal is a good source) and increased intake of plant stanols and sterols (2 gm/day). Plant stanols and sterols are cholesterol-lowering chemicals found (albeit in very small amounts) in certain vegetable oils (eg, canola), nuts (walnuts are a good source), certain fruits, and most beans and many other vegetables. They are also found in some of the cholesterol-lowering margarines, commonly advertised as “buttery spreads” (see below under Plant Stanol and Sterol Esters).


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