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New Guidelines for Managing Hypercholesterolemia

James M. McKenney
[J Am Pharm Assoc 41(4):596-607, 2001. © 2001 American Pharmaceutical Association, Inc.]


Abstract and Introduction

Abstract

Objective. To summarize for pharmacists the Adult Treatment Panel III (ATP III), recently issued guidelines for managing hypercholesterolemia, from the National Cholesterol Education Program (NCEP).
Data Sources. Executive summary of ATP III, and other pertinent literature as determined by the author.
Study Selection. Not applicable.
Data Extraction. By the author.
Data Synthesis. Like previous guidelines issued by NCEP, ATP III focuses on lowering of low-density lipoprotein cholesterol (LDL-C) as a primary focus and using exercise, diet, and pharmacotherapy as a primary means of lowering patients' coronary heart disease (CHD) risks. The new guidelines recognize LDL-C levels of less than 100 mg/dL as optimal for all patients, and increase attention on high triglyceride levels (above 200 mg/dL). ATP III places more emphasis on identifying patients at risk for CHD and CHD events (e.g., myocardial infarctions, revascularization procedures). To apply the recommendations of ATP III in pharmaceutical care practice, pharmacists should follow a six-step process: (1) Assess the patient's lipid profile (full panel, not just total cholesterol); (2) assess and categorize the patient's CHD risk (using a point system reflecting the levels of risk inherent in certain factors); (3) establish treatment goals and approaches (the greater the risk, the more aggressive the management); (4) initiate therapeutic lifestyle changes (including new recommendations for low intake of saturated fats and dietary cholesterol); (5) initiate LDL-C lowering drug therapy (often with combination therapy); and (6) consider other lipid factors (particularly hypertriglyceridemia and the metabolic syndrome).
Conclusion. Most patients who begin lipid-lowering therapy stop it within 1 year, and only about one-third of patients reach treatment goals. The release of the ATP III guidelines provides pharmacists a great opportunity to enhance pharmaceutical care services directed specifically at patients with hyperlipidemia.

Introduction

Without interventions or improvements in care, coronary heart disease (CHD) will cause the death of about one-half of all Americans living today. One of the key steps in reducing CHD risk, many think, is lowering blood cholesterol levels. Since 1988 the National Cholesterol Education Program (NCEP)[1-3] has provided guidelines to health professionals on how people can best lower their cholesterol levels and, thereby, their risk of cardiovascular complications and death. The third iteration of the NCEP's guidelines, the Adult Treatment Panel III (ATP III), was released in May of this year.

The new guidelines seek to prevent or delay CHD events such as myocardial infarctions (MIs), revascularization procedures (i.e., angioplasty and bypass surgery), and acute coronary syndromes by modifying abnormal blood lipid levels (see Table 1). In the new guidelines, emphasis has been placed on more accurately identifying patients who have a high risk of a CHD event and matching the intensity of treatment to each patient's level of risk: the higher the CHD risk, the lower the low-density lipoprotein cholesterol (LDL-C) treatment goal and the more aggressive the treatment.

In this article, ATP III recommendations are described and suggestions are offered on how pharmacists can best use them in their daily practices. Pharmacists should think of a six-step process when applying the new guidelines in their pharmaceutical care services:

  1. Assess the patient's lipid profile.

  2. Assess and categorize the patient's CHD risk.

  3. Establish treatment goals and approaches.

  4. Initiate therapeutic lifestyle changes.

  5. Initiate LDL-C lowering drug therapy.

  6. Consider other lipid factors.

Step 1: Assess the Patient's Lipid Profile

All adults over the age of 20 should have a 12-hour fasting lipid profile performed every 5 years. The full panel profile, which includes both total cholesterol and the major subcomponents, is needed to properly evaluate and treat patients.

The key measure in this profile is LDL-C. An elevated LDL-C level is a major cause of CHD. Treatments that reduce LDL-C have been shown to reduce CHD risk by 25% to 45% over 5 years (and possibly by twice as much in 10 years). The CHD risk associated with LDL-C is graded: the higher the LDL-C level, the greater the CHD risk. A new classification scheme for LDL-C is based on this graded relationship with risk (see Table 2).

The concentration of high-density lipoprotein cholesterol (HDL-C) is inversely related to CHD risk: the lower the HDL-C level, the higher the risk. HDL-C levels below 40 mg/dL are now classified as low. These levels are generally associated with a higher CHD risk. An HDL-C level of 60 mg/dL or above is classified as high and is associated with a lower CHD risk.

ATP III also provides a new classification system for triglycerides, one that recognizes the importance placed on this component of the lipid panel (see Table 3). Evidence is accumulating that an elevated triglyceride level is an independent predictor of CHD risk. Generally, levels in the borderline high and high range (i.e., 150 mg/dL to 500 mg/dL) are associated with increased CHD risk. These levels reflect the presence of triglyceride-rich lipoproteins (i.e., remnant very-low-density lipoproteins [VLDL] and intermediate-density lipoproteins). However, it is the cholesterol -- and not the triglycerides -- in these particles that contributes to the increased CHD risk. This is described more fully in the discussion about the metabolic syndrome under Step 6. Very high triglyceride levels (i.e., > 500 mg/dL) indicate the presence of chylomicron in addition to VLDL particles. Patients with very high triglyceride levels, especially those whose triglycerides exceed 1,000 mg/dL, are at increased risk for pancreatitis.

Step 2: Assess and Categorize the Patient's CHD Risk

Once the fasting lipoprotein profile has been obtained and assessed, a history of clinical CHD events and CHD risk factors should be obtained. With this information, the patient can be classified into one of three risk categories as presented in Table 4.

  1. CHD or a CHD risk equivalent.

  2. Two or more CHD risk factors.

  3. Zero or one risk factor.

CHD or CHD Risk Equivalent

Patients who have experienced a CHD event have the highest risk of experiencing another event, a risk that exceeds 20% over 10 years. The exact level of the risk depends on the patient's cholesterol level, presence of other CHD risk factors, genetic predisposition, lifestyle, and treatment. In practice, the CHD patient can be identified by the presence of one or more of the following:

ATP III has increased the number of patients who fit into this category by adding the CHD risk equivalent patient. As the name implies, patients with a CHD risk equivalent have the same level of CHD risk (i.e., > 20% in 10 years), but have not yet experienced a CHD event. Following is a description of the three CHD risk equivalent patient groups.

Patients with Other Forms of Atherosclerotic Vascular Disease
Patients who have clinical evidence of atherosclerosis in other vascular beds have a similar CHD risk. This includes patients with:

Men and women with peripheral artery disease (PAD) and an ankle/brachial blood pressure index (ABI) of < 0.9 have a risk of 2.4% to 2.9% per year of having a CHD event (i.e., 24% to 29% in 10 years). The risk approaches 40% in 10 years in PAD patients with an ABI of < 0.7. Similarly, patients who have stenotic lesions in their carotid artery have a CHD event risk of 1.4% to 8.3% per year (14% to 83% in 10 years). Patients with an abdominal aortic aneurysm have a CHD risk of 19% in the next 10 years.

Patients with Type 2 Diabetes
Patients with type 2 diabetes are at risk for developing microvascular complications such as retinopathy, nephropathy, and gastroenteropathy, and these conditions complicate their lives greatly. But most patients with type 2 diabetes die from macrovascular disease -- that is, a CHD event. Most type 2 diabetic patients have more than a 20% risk of experiencing a CHD event in the next 10 years. The 10-year risk in diabetic patients who have already experienced a CHD event is much higher, approaching 50%. Young patients with type 2 diabetes probably have less than a 20% 10-year risk, but their lifetime risk is disproportionately large, justifying their classification into a CHD risk equivalent category.

A word of caution is appropriate here. The classification of type 2 diabetics as CHD risk equivalents is based mostly on observational data. There are no controlled clinical trials that demonstrate the benefit of LDL-C lowering in type 2 diabetic patients. Controlled clinical trials with hypoglycemic therapy have shown fewer microvascular complications (such as retinopathy and neuropathy) but not macrovascular disease (such as MI). Post hoc analyses of controlled clinical trials of lipid-lowering therapy in hypercholesterolemic patients have revealed fewer CHD events in patients with diabetes who were treated with LDL-C lowering therapy. Observational data showing a link between the presence of diabetes and CHD events are substantial and consistent, but confirmation of a benefit will have to await the results of several ongoing controlled trials in patients with diabetes.

Patients with type 1 diabetes appear to have a similar high risk of CHD, but because less information is available on the link with cholesterol levels, clinical judgment must be exercised in the management of lipid levels in these patients.

Patients with Global Risks Exceeding 20% in 10 Years

The final patient group assigned CHD risk equivalent status are those whose estimated CHD risk is 20% or more in 10 years based on a global risk assessment. This will be discussed further below.

Patients with Two or More CHD Risk Factors

Patients who have not experienced a CHD event and do not have a CHD risk equivalent but do have two or more CHD risk factors are assigned to an intermediate risk category. The list of risk factors for making this determination is presented in Table 5 and reviewed below. Note that the list does not include diabetes, which is now recognized as a CHD risk equivalent.

Age
In many respects, age is the most potent CHD risk factor. CHD risk increases sharply with advancing age such that age may be considered a surrogate marker for atherosclerotic disease. The longer a person lives, the longer his or her cumulative exposure to cholesterol deposition and other risk factors, and the greater his or her development of atherosclerosis. This perspective supports lipid-modifying treatment in both young adults to retard the progression of atherosclerotic disease and older adults to prevent disabling events.

Sex
At any age, men have a higher CHD risk than women, although ultimately CHD is the most common cause of death and disability for both groups. CHD events in women lag behind those of men by 10 to 15 years. The risk for CHD in men becomes significant in the mid-40s and in women after menopause (i.e., about 52 years of age). Before menopause, CHD risk for women is very low.

Family History of Premature CHD
Family history is considered positive when CHD events are documented in first-degree male relatives younger than 55 years of age or first-degree female relatives younger than 65 years of age. Many clinicians believe that a strong family history of premature CHD events is one of the most important ways to identify patients with a high CHD risk. Quite often, a family history of premature CHD is also accompanied by a family history of CHD risk factors, and this may be the way risk is actually transmitted.

Cigarette Smoking
Current cigarette smoking is a powerful predictor of CHD risk. This risk is proportional to the degree of smoking. When a patient stops smoking, CHD risk drops quickly (within months) and ultimately may drop as much as 45%.

Hypertension
Blood pressure at or above 140/90 mm Hg or current antihypertensive treatment defines this risk factor. The association between hypertension and CHD is also powerful. With effective treatment, CHD risk is reduced, but not to baseline. This is why a diagnosis of hypertension per se, even if blood pressure is effectively controlled with drugs, is identified as a CHD risk factor for the purposes of determining the need for lipid treatments.

Low HDL-C
An HDL-C level of less than 40 mg/dL is now considered a CHD risk factor; previously, the value was less than 35 mg/dL. HDL-C is inversely related to CHD risk. Low HDL-C is often a marker for other risk factors, including increased remnant lipoproteins; small, dense LDL-C; obesity; insulin resistance; diabetes; physical inactivity; and genetic disorders. Low HDL-C is a particularly powerful risk factor for women. HDL-C is involved in reverse cholesterol transport and is necessary for removing cholesterol deposited in extrahepatic tissue from the body. The average HDL-C level in men is about 45 mg/dL, whereas it is about 55 mg/dL in women. This difference is used when making a diagnosis of low HDL-C in the metabolic syndrome (see Step 6 below). However, when counting risk factors for the purpose of setting the LDL-C goal, the definition of low HDL-C is < 40 mg/dL for both men and women.

Other Risk Factors

A few other factors also raise a patient's CHD risk and should be assessed when evaluating patients, but these do not alter LDL-C treatment goals. Three of these "other" risk factors are obesity, physical inactivity, and an atherogenic diet. In some patients, a poor lifestyle -- especially consuming a high saturated fat, atherogenic diet -- plays a major role in causing the lipid disorder, and following a low-fat diet and increasing physical activity can often correct the problem.

Overweight or Obesity
Patients with body mass indices (BMIs) between 25 kg/m[2] and 29.9 kg/m[2] are considered overweight, and those with BMIs of 30 kg/m[2] or more are considered obese. When assessing the dyslipidemic patient, it is where the extra weight is that matters. If it is located primarily around the waist, the risk of CHD is particularly high. In practice, a handy way to identify increased CHD risk associated with weight is to record a waist circumference. One that is more than 40 inches for a man or more than 35 inches for a woman indicates increased risk. Patients with abdominal obesity often have the metabolic syndrome (see Step 6 below) and a 10-year CHD risk in excess of 20% because of the presence of multiple risk factors. Weight reduction can mitigate much of this risk.

Physical Inactivity
Physical inactivity, or more precisely, lack of physical conditioning, increases the risk of CHD. Physically fit but overweight individuals are reported to have a CHD risk similar to that of people with no other CHD risk factors, which illustrates the importance of physical activity in modulating CHD risk. Physical inactivity is often associated with other CHD risk factors, including low HDL-C, increased remnant particles, insulin resistance, and high blood pressure. For these reasons, increasing physical activity is a fundamental approach for treating dyslipidemic patients.

Additional Assessments

Literally dozens of other potential CHD risk factors have been proposed. Many of these are being evaluated to determine how much, if any, additional predictive value they provide over LDL-C and the other traditional risk factors. Until this research is complete, it is best to use these measures sparingly in the routine assessment of patients. Occasionally, they may be useful when a traditional assessment leaves questions about a patient's true risk. For example, patients with a moderately elevated LDL-C but a strong family history of premature CHD, or patients who have experienced an MI but have near optimal or optimal LDL-C levels, may be candidates for an assessment of these emerging risk factors. In those cases, the assessments may offer additional information about CHD risk for an individual patient and suggest the need for more aggressive or less aggressive therapy. Some of these emerging risk factors are:

In addition to these risk factors, other assessments can be performed to help uncover the presence of atherosclerosis and thereby identify patients at high risk for a CHD event. These assessments may also be most helpful when the clinician suspects a higher risk than is evident from a traditional assessment. For example, a person with a strong family history of premature CHD events but few CHD risk factors and no history of CHD or a CHD equivalent may be a candidate for one or more of these tests. The attractive thing about these assessments is that they are all noninvasive. However, they are not available in all communities, and many are too expensive to recommend for widespread use. Some of these assessments are discussed briefly below.

Exercise Electrocardiogram
The exercise electrocardiogram (ECG) is used to detect ischemia in patients with flow-limiting coronary stenosis. Patients with a suspicious history of exercise-associated chest discomfort may be candidates for an exercise ECG. If the test suggests the presence of atherosclerotic disease, the patient may be considered as a CHD equivalent or treated as such.

Ankle/Brachial Blood Pressure Index
The ABI is simple, widely available, inexpensive, and noninvasive, and it can confirm the diagnosis of PAD. An ABI of less than 0.9 is an indication of PAD. A low ABI identifies a patient with a CHD equivalent risk.

B-Mode Ultrasound
B-mode ultrasound is also a relatively inexpensive, safe, commonly available, and noninvasive way to determine the thickness of the intimal-medial lining of carotid, aortic, and femoral arteries. The presence of intimal-medial thickening in a carotid artery, for example, suggests the presence of atherosclerosis, which predicts an increased risk of a transient ischemic attack, stroke, and coronary event. If atherosclerosis is detected in a carotid artery, it is also likely to be present in coronary vessels.

Electron Beam Computed Tomography
Electron beam computed tomography (EBCT) has limited utility because it is not available in many communities and because the information it provides is still being evaluated. EBCT detects the presence of calcium within the coronary arterial wall. A high calcium volume score is assumed to indicate the presence of older atherosclerotic plaque (old enough for calcium to be deposited) and suggests the presence of younger, cholesterol-enriched, vulnerable plaques (without calcium deposits) that increase CHD risk. Currently, there is no proof that treating patients with a high calcium volume score with lipid-modifying therapy will reduce CHD events.

High-Sensitivity C-reactive Protein
There has been a great deal of interest in high-sensitivity C-reactive protein (hs-CRP). It is a marker of inflammation and, by inference, of atherogenesis. Kits to perform tests for hs-CRP levels are now available in most community laboratories. A high hs-CRP level has been shown to predict future coronary events in a variety of populations and correlates with CHD risk reduction with lipid-lowering treatment. A high hs-CRP level appears to offer incremental information about a patient's future CHD risk over that predicted by traditional risk factors. What is not currently known is whether treating patients with elevated hs-CRP is associated with fewer CHD events.

Global Risk Assessment

For patients who have two or more CHD risk factors, ATP III has added a further assessment step to define CHD risk more sharply and allow better targeting of lipid-modifying treatment. The tool used for this assessment is a scoring system that estimates absolute 10-year CHD risk (CHD death or nonfatal MI) built from the Framingham database (see Appendix). Included in this assessment is the same risk factor information required for the initial classification of patients (Table 5). Family history is not included in global risk assessment, as it adds little additional precision to the assessment and because it is accounted for through the presence other risk factors. Based on the global risk assessment, patients are placed into one of three categories:

Patients with a 20% or greater 10-year risk are considered CHD equivalents.

Fewer Than Two CHD Risk Factors

The final risk assessment category is for those with fewer than two CHD risk factors (Table 4). These patients almost always have a 10-year CHD risk of less than 10%, making the use of lipid-lowering medications cost-prohibitive. A therapeutic lifestyle change program is recommended for these patients (see Step 4 below).

Step 3: Establish Treatment Goals and Approaches

A basic principle of cholesterol management is that the intensity of treatment should be matched to the level of CHD risk. This approach governs the goals and therapies recommended by ATP III to reduce CHD risk (see Table 6).

CHD or CHD Risk Equivalent

The primary treatment goal for individuals with established CHD or CHD risk equivalent is to achieve the optimal LDL-C level (i.e., < 100 mg/dL) (Table 6). In all cases, lifestyle modification should be initiated. If needed, dietary adjuncts, such as stanol/sterol esters or viscous fiber, may be added to intensify LDL-C lowering. In addition, management of other CHD risk factors is needed.

For CHD or CHD risk equivalent patients with a baseline LDL-C of 130 mg/dL or more, most authorities advise that LDL-C-lowering drug therapy be started simultaneously with lifestyle modification (Table 6).

For CHD or CHD risk equivalent patients with a baseline LDL-C of between 100 mg/dL and 129 mg/dL, several options are available. Most authorities favor the initiation of LDL-C lowering drug therapy and/or the intensification of lifestyle changes to achieve the LDL-C goal. However, because one study demonstrated CHD risk reduction with gemfibrozil in patients with LDL-C concentrations in this range, some authorities believe that treatment with niacin or a fibrate should be considered when LDL-C levels are in this range, especially if the patient has triglyceride levels above 200 mg/dL or HDL-C concentrations below 40 mg/dL.

For CHD or CHD risk equivalent patients with baseline LDL-C concentrations of less than 100 mg/dL, lifestyle modification is indicated. Some authorities reason that the presence of CHD in these patients suggests that the LDL-C level is too high no matter what it is; these specialists advocate LDL-C lowering therapy for all CHD patients. However, no clinical trial evidence currently exists showing that using drug therapy to lower LDL-C levels in patients with levels already below 100 mg/dL offers benefits. Until this information is available, clinical judgment should guide the use of lipid-lowering agents in these patients. Testing these individuals for the presence of one or more of the emerging risk factors (see Additional Assessments above) may provide additional information to guide treatment choices.

Moderate-Risk Patients

The goal of treatment for patients with two or more risk factors and 10-year risk less than 20% is to achieve LDL-C levels below 130 mg/dL (Table 6). Lifestyle modification should be attempted first. As with CHD patients, dietary adjuncts may be added to a low-fat diet if needed, and other risk factors should be managed in these patients.

For patients with two or more risk factors and a 10-year CHD risk between 10% and 20%, cholesterol-lowering drug therapy may be considered if LDL-C below 130 mg is not achieved with lifestyle changes in 3 months (Table 6).

In patients with two or more risk factors and a 10-year risk of less than 10%, emphasis should be placed on reducing long-term risk with lifestyle modification. If the LDL-C is above 160 mg/dL after an adequate trial of diet and exercise for at least 3 months, consideration may be given to initiating drug therapy (Table 6).

Low-Risk Patients

These patients have zero or one risk factor and an LDL-C goal below 160 mg/dL. They have a low short-term CHD risk, making treatment with drug therapy not generally cost-effective. However, some of these patients will have a high long-term risk, making them candidates for more aggressive lipid-modifying therapy. Examples of high long-term risk patients are those with one of the following:

Step 4: Initiate Therapeutic Lifestyle Changes

Reduction in CHD risk begins with the adoption of a healthy lifestyle. ATP III has recommended a plan to achieve a healthy lifestyle, which it calls "therapeutic lifestyle changes" or "TLC." In many patients, TLC is the only approach required to achieve LDL-C goals. In most patients, it is implemented before initiating drug therapy. In high-risk patients, drug therapy may be initiated simultaneously with TLC. Wherever possible, ATP III believes that referral should be made to a registered dietitian or other qualified nutritionist for instruction and guidance on TLC. Components of TLC include:

Other components of the TLC diet are displayed in Table 7. As noted here, monounsaturated fats can provide up to 20% of the daily caloric intake and account for most of the total fat consumed. Monounsaturated fats, derived mostly from olive oil, canola oil, and fish products, help lower LDL-C concentrations. They are also a rich source of omega-3 fatty acids, a common component of the Mediterranean diet that has been associated with a reduction in CHD events in several large, controlled studies. Carbohydrates make up the major source of daily calories, but should be mostly derived from foods rich in complex carbohydrates, such as grains, especially whole grains, fruits, and vegetables, and not via the high-sugar, high-calorie, "fast food" snacks so commonly available in the food supply in the United States.

The steps to follow in implementing TLC are displayed in Figure 1. When possible, TLC should be initiated before drug therapy. High-risk patients, especially those hospitalized for an acute CHD event, generally do better if TLC and drug therapy are initiated together before discharge. For patients with no evidence of CHD or a CHD equivalent, a minimum of 12 weeks is generally required to fully implement the TLC diet and other lifestyle changes. The patient should be given 6 weeks to adopt the diet and physical activity before returning for the first follow-up appointment. At this visit, the TLC diet may be intensified, adjunct therapies may be added, and a program of physical activity may be developed. During the next follow-up visit, typically 12 weeks after starting the TLC program, drug therapy may be started if the patient is not at the LDL-C goal.

figure
Figure 1. Steps in Implementing Therapeutic Lifestyle Changes (TLC)

Step 5: Initiate LDL-C Lowering Drug Therapy

The first goal of lipid-modifying drug therapy is to lower the LDL-C to goal. Statins are the preferred way to accomplish this because they are highly effective in lowering LDL-C and are very safe. If statins cannot be used because of patient intolerance or contraindications, other LDL-C lowering agents (i.e., bile acid resins [BARs] or nicotinic acid) should be used with the TLC diet to achieve treatment goals. If monotherapy with either of these agents is not successful in achieving treatment goals, combinations of LDL-C lowering drugs may be used. For example, a statin and a BAR, or niacin and a BAR, are effective regimens for lowering LDL-C levels.

Patients should generally return for a follow-up visit after being on drug therapy for 6 weeks (see Figure 2). This is sufficient time to see the full effects of the drug. If the treatment goal has not been achieved at this visit, statin (or other) treatment may be intensified or combination therapy with statins and a BAR or niacin may be prescribed. A second follow-up visit may occur in another 6 weeks. At each visit, patient adherence to TLC and drug therapy should be evaluated and appropriate steps taken to address any problems.

figure
Figure 2. Steps in Initiating Lipid-Modifying Drug Therapy

Statins

Six statins are currently available: atorvastatin (Lipitor -- Pfizer; Parke-Davis), cerivastatin (Baycol -- Bayer), fluvastatin (Lescol -- Novartis), lovastatin (Mevacor -- Merck), pravastatin (Pravachol -- Bristol-Myers Squibb), and simvastatin (Zocor -- Merck). These statins differ somewhat in their LDL-C lowering efficacy. Generally, the greater the LDL-C lowering efficacy of the statin, the more patients will achieve treatment goals. Lovastatin, pravastatin, and simvastatin have demonstrated CHD risk reduction of 25% to 45% with 5 years of treatment in randomized, placebo-controlled clinical trials. Fluvastatin has demonstrated CHD risk reduction in an angiographic trial, and atorvastatin has demonstrated risk reduction in patients with acute coronary syndromes. Most authorities believe that these effects represent a "class" effect and that all statins (as well as all methods of lowering LDL-C for that matter) reduce CHD risk.

Statins reduce LDL-C concentrations by 18% to 55% (see Table 8). Most of this reduction is seen with the initial dose; further LDL-C reduction of 6% to 7% is seen each time doses are doubled thereafter. Maximal statin effect is usually obtained 4 to 6 weeks after initiating therapy or changing doses. Statins may be initiated with traditional starting doses and titrated up as needed to achieve greater LDL-C lowering effects. Alternatively, the dose needed to reduce LDL-C to the treatment goal may be used initially and then adjusted up or down as needed during follow-up visits.

Statins may increase transaminase enzymes, suggesting hepatotoxicity, and may cause myopathy, characterized by muscle soreness or weakness and an elevated creatine phosphokinase level of 10 times the upper limit of normal. Fortunately, liver enzyme changes documented during consecutive visits are generally seen in less than 1% of patients, quickly return to normal when the statin is withdrawn, and have not been associated with life-threatening problems such as liver failure or need for hepatic transplant. Myopathy, as defined above, occurs in less than 2 out of every 1,000 patients treated with a statin and dissipates completely and without permanent sequelae when the statin is withdrawn. About 5% to 8% of patients are intolerant of statins, experiencing a variety of symptoms including headache, muscle pain, and gastrointestinal symptoms.

Bile Acid Sequestrants or Resins

Cholestyramine (Questran -- Bristol-Myers Squibb or generic) colestipol (Colestid -- Pharmacia or generic), and colesevelam (Welchol -- Sankyo) are the BARs currently available. Their major pharmacologic effect is to lower LDL-C levels. They have been shown to reduce CHD events in hypercholesterolemic patients when evaluated in controlled clinical trials (Table 8).

When used alone, BARs reduce LDL-C levels by 10% to 30%. When given with a statin, their effect is additive. They are generally dosed two to three times a day.

One of the advantages of BARs is their lack of systemic absorption. Thus, they may be useful in the treatment of patients in whom low systemic exposure is desired, such as young patients who face years of lipid-modifying therapy and women who are attempting to become pregnant.

The older BARs cause gastrointestinal intolerance, including bloating, gas, abdominal pain, and constipation. The older BARs also interfere with the absorption of some drugs (e.g., digoxin, thyroxine, iron, fat-soluble vitamins, and warfarin), necessitating their administration 1 hour before or 4 hours after the BAR is given.

Colesevelam, the most recently marketed BAR, appears to be well tolerated and has few drug interactions.

Nicotinic Acid

Nicotinic acid or niacin lowers LDL-C and triglyceride levels. It is the most effective drug available for raising HDL-C. Niacin has also been shown to reduce recurrent MI and total mortality in a controlled clinical trial.

Nonprescription immediate-release niacin reduces LDL-C levels by an average of 20% to 25% when dosed to 3 grams daily. Niaspan (KOS), an extended-release prescription product, will lower LDL-C concentrations by 15% to 20% at its maximum dose of 2 grams daily. At doses as low as 1 gram daily, either niacin product raises HDL-C levels by 15% to 30% and reduces triglyceride concentrations by 20% to 35%. Niacin is one of the few drugs that lowers Lp(a) concentrations, and it does so by up to 30%. But the clinical relevance of this effect is not known.

The major limitation to niacin is its side effects, including flushing with both immediate- and extended-release products. This effect can be minimized by having the patient take an aspirin tablet 30 minutes before the morning dose of immediate-release niacin or the bedtime dose of Niaspan.

Nonprescription sustained-release niacin products are not FDA-approved for the treatment of hyperlipidemia, nor have they met FDA standards for good manufacturing practices. Thus, products may vary considerably in their absorption and distribution characteristics, making dosing unreliable. Sustained-release niacin has also been associated with severe liver toxicity when given in doses above 2 grams daily.

Combination Drug Therapy

The mere fact that more patients will qualify for aggressive treatment to an LDL-C below 100 mg/dL with the new guidelines means that combination therapy will be used more often. LDL-C lowering can be enhanced by combining two or more LDL-C lowering drugs, such as a statin with either a BAR or niacin, a BAR with niacin, or a statin-BAR-niacin combination. Adding a BAR or niacin to a low-dose statin regimen generally produces a LDL-C reduction similar to that achieved by quadrupling the statin dose.

Step 6: Consider Other Lipid Factors

Metabolic Syndrome

Once the LDL-C goal has been achieved, the next step is to determine whether the patient also has other lipid risk factors that increase CHD risk. One commonly encountered problem is the metabolic syndrome. These patients have atherogenic dyslipidemia characterized by borderline high to high triglyceride levels (i.e., 150 mg/dL to 500 mg/dL, indicative of increased levels of triglyceride-rich remnant lipoproteins), low HDL-C (< 40 mg/dL), and increased small, dense LDL. They also have a constellation of risk factors including some or all of the following: excess body fat distributed mostly around the abdomen, insulin resistance with impaired fasting glucose or diabetes, elevated blood pressure, a proinflammatory state, and a prothrombotic state.

In patients with the metabolic syndrome, any elevation in the LDL-C level, even one just above the optimal level, accentuates their CHD risk. Often, these patients have a 10-year CHD risk of more than 20%, which would qualify them for a CHD risk equivalent designation. Most patients with type 2 diabetes have the metabolic syndrome. Despite growing awareness of this syndrome, office-based diagnosis has been difficult. ATP III has corrected this problem with an easy-to-follow approach to diagnosis of the metabolic syndrome (see Table 9).

Weight loss and increased physical activity are the two primary interventions used in treating the metabolic syndrome. These alone can correct the problem. Additionally, high blood pressure should be reduced, and CHD patients should be given an adult aspirin daily (some authorities recommend aspirin prophylaxis for primary prevention patients as well, but proof of its value for these patients is not available). If triglyceride levels remain high and/or HDL-C levels remain low, drug therapies may be considered. Two therapies to consider for this purpose are niacin and fibrates.

Fibrates
Three fibrates are currently available in the United States: gemfibrozil (Lopid -- Pfizer or generic), fenofibrate (Tricor -- Abbott), and clofibrate (Atromid-S -- Wyeth-Ayerst; rarely used now because of its toxicity). Fibrates are primarily used for lowering triglyceride and raising HDL-C concentrations. Controlled clinical trials have demonstrated CHD risk reduction with gemfibrozil, especially in people who have the combination of elevated triglyceride, low HDL-C, and high LDL-C levels. Unlike statins, a reduction in total mortality has not been shown with fibrate therapy.

Fibrates reduce triglyceride levels by 25% to 50% and raise HDL-C concentrations by 10% to 15%. When given to patients with high triglycerides, fibrates sometimes increase LDL-C levels rather than lowering them.

Fibrates may cause myopathy, especially when used in combination with a statin. The most worrisome side effect with gemfibrozil is cholelithiasis (1% incidence). In addition, the anticoagulant effects of warfarin can be accentuated when given with gemfibrozil.

Hypertriglyceridemia

Elevated triglycerides are an independent risk factor for CHD. Whenever triglyceride levels above 150 mg/dL are encountered, a secondary cause should first be sought. Common causes include:

If any of these are present, they should be treated or removed and triglycerides reassessed. If levels remain above 200 mg/dL after correction of secondary causes and LDL-C levels are at goal, ATP III recommends the setting of a second treatment goal defined by non-HDL-C levels (see Table 10). Non-HDL-C is calculated by subtracting HDL-C from total cholesterol. The secondary non-HDL-C goal is set at 30 mg/dL above the LDL-C goal because VLDL particles normally contain up to 30 mg/dL of cholesterol and any amount above this is excessive.

The first treatment approach to achieve non-HDL-C goals is intensification of the TLC diet with restriction of calories for weight loss in obese patients and increased physical activity. If needed, drug therapy may be initiated. Two approaches may be deployed. First, the LDL-C- lowering drug regimen may be intensified (e.g., the statin dose may be escalated). This will increase removal of LDL and VLDL remnant particles via the upregulated LDL receptor. Second, a fibrate or niacin may be added to the LDL-C lowering regimen. These therapies will either increase triglyceride removal from the lipoprotein (fibrates) or reduce the secretion of VLDL particles from the liver (niacin). Patients given the statin-fibrate combination have an increased risk of myopathy and should be initially evaluated for renal or hepatic dysfunction and potentially interacting drugs, dosed with the lowest effective dose of both drugs and monitored carefully for symptoms of muscle soreness and weakness. If muscle symptoms occur, the patient should be evaluated to rule out an adverse effect from the drug regimen. With careful selection of the patients who receive this regimen and good monitoring, these drugs can be safely used together.

In patients with very high triglyceride levels -- for whom the risk of pancreatitis is a concern -- treatment consists of a very-low-fat diet (i.e., less than 15% of calories from fat), weight control, increased physical activity, and therapy with one or more triglyceride-lowering drug(s) (i.e., fibrate, niacin, and/or fish oils).

Low HDL-C

Low HDL-C is also a strong independent predictor of CHD. Athough previous guidelines set 35 mg/dL as the cutoff point for low HDL-C, ATP III defines this as less than 40 mg/dL. As with high triglyceride levels, the first step in managing a low HDL-C level is to identify and remove (or diminish) secondary causes. These include:

In patients with low HDL-C concentrations, no clinical studies have addressed whether increases in HDL-C (with little or no change in LDL-C or triglycerides) will lower CHD risk. However, the observational literature describing an increase in CHD risk with low HDL-C levels is voluminous. Based on this, most authorities believe that patients with low HDL-C concentrations should be treated.

The first step in treating low HDL-C levels is to improve life habits, specifically increasing physical activity and losing weight if the patient is overweight or obese. If the patient also has an elevated LDL-C concentration, use of a statin to reduce LDL-C also lowers the risk associated with subnormal HDL-C levels. Most often, a low HDL-C level is found with other risk factors as in patients with the metabolic syndrome, and treatment of the syndrome as described above also addresses the low HDL-C problem.

Likewise, if the low HDL-C is present with a high triglyceride level (which it almost always is), it will improve as treatment is initiated to achieve the non-HDL-C treatment goal.

Finally, for the rare patient who has an isolated low HDL-C (with LDL-C and triglyceride levels in the normal range), medications to raise HDL-C concentration -- such as niacin or a fibrate -- can be considered, especially if the patient has experienced a CHD event or has a CHD equivalent risk.

Conclusion

The Executive Summary and full text of the ATP III report can be found at www.nhlbi.nih.gov/guidelines/cholesterol. This Web site also contains a Palm Pilot program for the global risk assessment and slides of ATP III recommendations that can be downloaded.

The new guidelines have the potential to help millions of people avoid disabling and life-shortening CHD events. This great promise, however, requires that the guidelines be implemented and fully integrated into the care of patients by all health professionals. Based on past experiences with previous guidelines, this is not likely to happen. More than one-half of all patients who are candidates for treatment have yet to be identified. Most patients who are started on lipid-lowering therapy discontinue it within 1 year. Of those who receive treatment, only about one-third reach treatment goals.

We need to do better. The new guidelines provide a great opportunity as well as a great challenge to pharmacists everywhere. The question on the table is this: How will you make the new guidelines available to the patients you serve?

The author declares no conflicts of interest or financial interests in any product or service mentioned in the article, including grants, employment, gifts, stock holdings, and honoraria.

Side Bar

Appendix. Scoring System for Calculating Patient CHD 10-Year Risk

In the Executive Summary of the ATPIII guidelines (as published in JAMA[3] and on the NIH Web site [www.nhlbi.nih.gov/guidelines/cholesterol/]), a series of point scores is presented based on extensive analysis of data from the well-known Framingham Study. When summed, these points reflect estimated risk of a CHDevent (cardiac death or nonfatal myocardial infarction, or stroke) during the next 10 years.

The scheme below is a realignment of these point scores in a format that is easy for health care professionals and patients to use in determining total scores. It should be used only for patients who have 2 or more risk factors but who do not have CHD or CHD equivalent disease, as defined in Step 2 of this article. Patients with CHD and CHD equivalent diseases already need interventions that will get LDL-C levels to goal (100 mg/dL). But the patients with 2 or more risk factors and no symptomatic disease, depending on the factors shown below, may have great risk of CHDproblems, moderate risk, or low risk, and their therapy should reflect this risk.

The risk point total is determined by adding all relevant numbers shown that correspond to the patient's age, smoking status, cholesterol levels, and blood pressure. If a measurement is not listed in a section (e.g., an untreated systolic blood pressure of 125 mm Hg), that means its value is 0, and no points are added.

Once the point total is determined, the corresponding risk is determined from the table at right. Find the point total in the left column for either a man or a woman and match it with the 10-year risk to the right. The risk percentage corresponding to the patient's score is the percentage of people similar to the patient who will die from heart disease or have a heart attack within the next 10 years.

Table 1. New Concepts in ATP III

A 10-year estimate of absolute CHD risk using Framingham data is provided for use in patients with gt_equal 2 risk factors to better focus the intensity of treatment in primary prevention.
Patients with diabetes and persons with multiple risk factors plus a 10-year risk for CHD of > 20% are identified as CHD risk equivalents and targeted for more intense treatment.
Identified an LDL-C level of < 100 mg/dL as optimal.
Recommended greater restriction of saturated fats and cholesterol and use of dietary adjuncts (i.e., plant stanols/sterols and viscous fiber) as "therapeutic lifestyle changes" (TLC).
Provided a way to identify patients with the metabolic syndrome and recommended intensified TLC for these patients.
Recommended non-HDL-C goals for patients with triglycerides
> 200 mg/dL after LDL-C goal has been achieved.
Lowered the triglyceride classification.
Raised the definition of low HDL-C to < 40 mg/dL.
Presents strategies to promote adherence with lipid-modifying therapies.
Places emphasis on long-term prevention.


ATP II = Adult Treatment Panel 2nd Report; ATP III = Adult Treatment Panel 3rd Report; CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

Table 2. Classification of LDL-C Concentrations

Classification LDL-C Level (mg/dL)
Optimal < 100
Above optimal 100-129
Borderline high 130-159
High 160-189
Very high gt_equal190


LDL-C = low-density lipoprotein cholesterol.

Table 3. Classification of Triglycerides

Classification Triglyceride level (mg/dL)
Normal < 150
Borderline high 150-199
High 200-499
Very high gt_equal 500

Table 4. Initial Classification of Hyperlipidemia Patients

Risk Category LDL-C Goal
CHD and CHD risk equivalent lt_equal 100 mg/dL
Multiple (gt_equal 2) risk factors < 130 mg/dL
0-1 risk factor < 160 mg/dL


CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol.

Table 5. Major Risk Factors for CHD Other Than LDL-C

Age (men gt_equal 45 years; women gt_equal 55 years)
Family history of premature CHD (clinical CHD or sudden death documented in first-degree male relatives before age 55 or in first-degree female relatives before age 65)
Cigarette smoking (any cigarette smoking in the past month)
Hypertension (blood pressure gt_equal 140/90 mm Hg or on antihypertensive medication)
Low HDL-C (< 40 mg/dL)[a]


CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol.

[a]HDL-C gt_equal 60 mg/dL is a "negative" risk factor (i.e., its presence removes one risk factor from the total count).

Table 6. Goals of LDL-C Therapy by Risk Category

Risk Category Initiate TLC Consider Drug Therapy LDC-C Goal
CHD and CHD risk equivalent gt_equal 100 mg/dL gt_equal 130 mg/dL[a] < 100 mg/dL
Noncoronary vascular disease
Type 2 diabetes
10-year CHD risk > 20%
Multiple (2+) risk factors
10-year CHD risk 10%-20% gt_equal 130 mg/dL gt_equal 130 mg/dL < 130 mg/dL
10-year CHD risk < 10% gt_equal 130 mg/dL gt_equal 160 mg/dL < 130 mg/dL
0-1 risk factor gt_equal 130 mg/dL gt_equal 190 mg/dL < 160 mg/dL


CHD = coronary heart disease; LDL-C = low-density lipoprotein cholesterol; TLC = therapeutic lifestyle changes.

[a] Drug therapy is considered optional with LDL-C levels 100-129 mg/dL.

Table 7. Nutritional Composition of the TLC Diet

Nutrient Recommended Intake
Saturated fat[a] < 7% of total calories
Polyunsaturated fat Up to 10% of total calories
Monounsaturated fat Up to 20% of total calories
Total fat 25%-35% of total calories
Carbohydrate fiber 50%-60% of total calories
20-30 grams per day
Protein Approximately 15% of total calories
Cholesterol < 200 mg/day
Total calories[b] Adjust to maintain normal body weight


TLC = therapeutic lifestyle changes.
[a]Trans fatty acids also raise LDL-C and should also be restricted.
[b]Daily energy expenditure should occur through at least moderate physical activity (i.e., enough to consume approximately 200 cal/day).

Table 8. Drugs That Affect Lipoprotein Metabolism

Drug Class, Agents, and Daily Doses Average Lipid/Lipoprotein Effects Adverse Effects Contraindications Clinical Trial Results
Bile acid resins[a] LDL-C 15%-30%
HDL-C 3%-5%
TG -- no change or increase
GI distress, constipation, decreased absorption of other drugs Absolute:
Dysbetalipoproteinemia
G > 400 mg/dL
Relative:
TG > 200 mg/dL
Reduced major
coronary events and CHD death
HMG-CoA reductase inhibitors (statins)[b] LDL-C 18%-55%
HDL-C 5%-15%
TG 7%-30%
Myopathy, increased liver enzymes Absolute:
Active or chronic liver disease
Relative:
Concomitant use with certain drugs[c]
Reduced major coronary events, CHD deaths, and total mortality
Nicotinic acid[d] LDL-C 5%-25%
HDL-C 15%-35%
TG 20%-50%
Flushing, hyperglycemia (or gout), upper GI distress, hepatotoxicity Absolute:
Chronic liver disease
Severe gout
Relative:
Diabetes
Hyperuricemia
Reduced major coronary events, and possibly total mortality
Fibric acids[e] LDL-C 5%-20%
(may be increased in patients with high TG)
HDL-C 10%-20%
TG 10%-50%
Dyspepsia, gallstones, myopathy Absolute:
Severe renal disease
Severe hepatic disease
Reduced major coronary events, increased non-CHD mortality (2 of 5 clinical trials)


CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TG = triglycerides.

[a]Cholestyramine (4-16 g), colestipol (5-20 g), colesevelam (2.6-3.8 g).
[b]Atorvastatin (10-80 mg), cerivastatin (0.3-0.8 mg), fluvastatin (20-80 mg), lovastatin (20-80 mg), pravastatin (20-40 mg), simvastatin (20-80 mg).
[c]Cyclosporine, gemfibrozil, macrolide antibiotics, various antifungal agents and cytochrome P450 inhibitors.
[d]Immediate-release (crystalline) nicotinic acid (1.5-3 g), extended-release nicotinic acid[] (1-2 g), sustained-release nicotinic acid (1-2 g).
[e]Gemfibrozil (600 mg twice daily), fenofibrate (200 mg), clofibrate (1,000 mg twice daily).


Source: Adapted from Reference 3.

Table 9. Diagnosis of the Metabolic Syndrome

Parameter Criteria
Waist circumference Men: gt_equal 103 cm (< 40 in)
Women: gt_equal 88 cm (gt_equal 35 in)
Triglyceride level gt_equal 150 mg/dL
HDL-C level Men: < 40 mg/dL
Women: < 50 mg/dL
Blood pressure gt_equal 130/ gt_equal 85 mm Hg
Fasting glucose level gt_equal 110 mg/dL


HDL-C = high-density lipoprotein cholesterol.

Table 10. Treatment Goals for Patients with Fasting Triglycerides > 200 mg/dL after LDL-C Goal Has Been Achieved

Risk Category LDL-C Goal (mg/dL) Non-HDL-C Goal (mg/dL)
CHD and CHD risk equivalent < 100 < 130
Multiple (gt_equal 2) risk factors < 130 < 160
0-1 risk factor < 160 < 190


CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; non-HDL-C = total cholesterol - HDL-C.

Appenix. Table 1: MEN

Risk Factors Age (years)
20-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
Age -9 -4 0 3 6 8 10 11 12 13
Smoked any in past month,
add:
8 8 5 5 3 3 1 1 1 1
Total cholesterol (mg/dL)
160-199 4 4 3 3 2 2 1 1 0 0
200-239 7 7 5 5 3 3 1 1 0 0
240-279 9 9 6 6 4 4 2 2 1 1
gt_equal280 11 11 8 8 5 5 3 3 1 1
HDL cholesterol (mg/dL)
gt_equal60 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1
40-49 1 1 1 1 1 1 1 1 1 1
<40 2 2 2 2 2 2 2 2 2 2
Untreated systolic blood pressure (use this section only if the patient is not taking drugs for blood pressure)
130-159 1 1 1 1 1 1 1 1 1 1
gt_equal160 2 2 2 2 2 2 2 2 2 2
Treated systolic blood pressure (use this section only if the patient is taking drugs for high blood pressure)
120-129 1 1 1 1 1 1 1 1 1 1
130-159 2 2 2 2 2 2 2 2 2 2
gt_equal160 3 3 3 3 3 3 3 3 3 3
Score:











Appenix. Table 2: WOMEN

Risk Factors Age (years)
20-34 35-39 40-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79
Age -7 -3 0 3 6 8 10 12 14 16
Smoked any in past month,
add:
9 9 7 7 4 4 2 2 1 1
Total cholesterol (mg/dL)
160-199 4 4 3 3 2 2 1 1 1 1
200-239 8 8 6 6 4 4 2 2 1 1
240-279 11 11 8 8 5 5 3 3 2 2
gt_equal280 13 13 10 10 7 7 4 4 2 2
HDL cholesterol (mg/dL)
gt_equal60 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1
40-49 1 1 1 1 1 1 1 1 1 1
<40 2 2 2 2 2 2 2 2 2 2
Untreated systolic blood pressure (use this section only if the patient is not taking drugs for blood pressure)
120-129 1 1 1 1 1 1 1 1 1 1
130-139 2 2 2 2 2 2 2 2 2 2
140-159 3 3 3 3 3 3 3 3 3 3
gt_equal160 4 4 4 4 4 4 4 4 4 4
Treated systolic blood pressure (use this section only if the patient is taking drugs for high blood pressure)
120-129 3 3 3 3 3 3 3 3 3 3
130-139 4 4 4 4 4 4 4 4 4 4
140-159 5 5 5 5 5 5 5 5 5 5
gt_equal160 6 6 6 6 6 6 6 6 6 6
Score:











Appenix. Table 3

Men Women
Point Total 10-Year Risk % Point Total 10-Year Risk %
< 0 < 1 < 9 < 1
0 1 9 1
1 1 10 1
2 1 11 1
3 1 12 1
4 1 13 2
5 2 14 2
6 2 15 3
7 3 16 4
8 4 17 5
9 5 18 6
10 6 19 8
11 8 20 11
12 10 21 14
13 12 22 17
14 16 23 22
15 20 24 27
16 25 gt_equal 25 gt_equal 30
gt_equal 17 gt_equal 30



References

  1. Report of the National Cholesterol Evaluation Program. Expert Panel on the Detection, Evaluation and Treatment of Blood Cholesterol in Adults. The Expert Panel. Arch Intern Med. 1988;148:36-69.
  2. Expert Panel on Detection, Evaluation, and Treatment of High Blood Pressure in Adults. Summary of the Second Report of the National Cholesterol Education (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). JAMA. 1993;269:3015-23.
  3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285:2486-97.

James M. McKenney, PharmD, is Emeritus Professor, School of Pharmacy, Medical College of Virginia, Virginia Commonwealth University, and president and CEO, National Clinical Research, Richmond, Va. He represents APhA on the Coordinating Committee of the National Cholesterol Education Program.

Correspondence: James M. McKenney, PharmD, National Clinical Research, 2809 Emerywood Parkway, Suite 140, Richmond, VA 23294; Fax: 804-672-3369. E-mail: jmckenney@ncrinc.net.


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