Commentary

Appraisal of the National Lipid Association recommendations on cholesterol management

by Matthew J. Czarny, MD; Seth S. Martin, MD; and Roger S. Blumenthal, MD

In the past year, we have observed a major shift in thinking about the management of dyslipidemia, which was exemplified by the release of the 2013 American College of Cardiology/American Heart Association cholesterol treatment guideline.

The guideline defines four “statin-benefit groups” and focuses on statin doses rather than cholesterol level targets. Its implementation has the potential to make many more patients eligible for statin use for primary prevention after a detailed clinician–patient discussion.

Matthew J. Czarny, MD

Matthew J. Czarny

Critiques have been many and have focused on the use of only randomized clinical trial evidence in guideline development; shortcomings in the accompanying and heavily relied-upon Pooled Cohort Risk Equations; a focus on statins as the only acceptable pharmacotherapy; and the elimination of target LDL cholesterol and non-HDL cholesterol levels.

Subsequently, the National Lipid Association convened an expert panel to review all of the available evidence and provide an alternative set of recommendations for the management of dyslipidemia, with the notable consideration of both randomized clinical trials and observational data. The National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia (hereinafter referred to as “the NLA recommendations”) are the subject of this editorial.

Risk assessment, classification

The NLA recommends that all patients with atherosclerotic CVD (ASCVD) have a lipoprotein profile at or shortly after diagnosis and, like the 2013 ACC/AHA guideline, all adults aged 20 years and older in the primary prevention setting have a lipoprotein profile at least every 5 years. The lipoprotein profile should include, at a minimum, total cholesterol and HDL to enable calculation of non-HDL (total cholesterol minus HDL), and neither of these measurements depends on the fasting state. If the patient is fasting, triglycerides can be measured; if triglycerides are <400 mg/dL, the estimated LDL can be calculated by the Friedewald equation. The results of the lipid profile are then interpreted depending on the patient’s risk classification.

Seth S. Martin, MD

Seth S. Martin

Central to the assessment of ASCVD risk by the NLA guidelines are the classical “major ASCVD risk factors,” which are defined as:

  • older age (≥45 years for men, ≥55 years for women);
  • early CHD in a first-degree relative (<55 years for men, <65 years for women);
  • current cigarette smoking;
  • hypertension (BP ≥140 mm Hg/90 mm Hg or antihypertensive therapy); and
  • low HDL (<40 mg/dL for men, <50 mg/dL for women). 

The risk–assessment algorithm then begins with identification of those at “very high risk,” including patients with clinical ASCVD (defined as a history of ACS, arterial revascularization, transient ischemic attack or stroke, atherosclerotic peripheral arterial disease) and those with diabetes plus two or more ASCVD risk factors or end-organ complications of diabetes (urine albumin/creatinine ratio ≥30 mg/g, chronic kidney disease or retinopathy). 

“High-risk” patients are defined as those with three or more major ASCVD risk factors, diabetes plus one major ASCVD risk factor and no end-organ damage, stage 3B or 4 CKD or LDL ≥190 mg/dL.

“Moderate-risk” patients are defined as those with two major ASCVD risk factors (approximate 10-year ASCVD risk 5% to <15%).

“Low-risk” patients are defined as those with one or no major ASCVD risk factors.

However, the risk of all patients in the moderate-risk category should be further refined through the use of quantitative risk scoring or other “risk indicators,” which will allow some patients to be reclassified to high risk. In addition, low-risk patients should be assessed for any risk indicators that may elevate their risk to moderate or high. Of note, there is no mention of use of quantitative risk scoring or risk indicators to lower an individual’s risk estimate.

The NLA guidelines do not recommend any one particular quantitative risk-scoring system, but suggest that a high-risk classification should be given to those with a 2001 Adult Treatment Panel III Framingham risk score of at least 10%, a 2013 Pooled Cohort Equation 10-year risk of at least 15% (unlike the >7.5% threshold for the 2013 ACC/AHA guidelines) or a Framingham long-term CVD risk of at least 45%. Other risk indicators that may be considered to further refine the risk classification of patients at low or moderate risk by risk factor counting may include a major ASCVD risk factor present to a severe degree (eg, a strong family history), coronary artery calcium (CAC) score of at least 300 Agatston units, LDL ≥160 mg/dL or non-HDL ≥190 mg/dL or high-sensitivity C-reactive protein ≥2 mg/dL. Patients at moderate risk by the major risk factors who have one or more of these indicators could be classified as high risk. The same strategy can be applied to lower-risk patients if the clinical circumstances warrant.

Targets of therapy

The NLA recommends that patients in the very high-risk group have the most aggressive treatment goals, which are non-HDL <100 mg/dL and LDL <70 mg/dL, with an optional goal of apolipoprotein B <80 mg/dL. The treatment goals for low-, moderate-, and high-risk patients are non-HDL <130 mg/dL and LDL <100 mg/dL, with an optional goal of ApoB <90 mg/dL.

The NLA panel concluded that non-HDL is a better primary goal than LDL because it represents all atherogenic particles and more strongly predicts adverse outcomes. Therefore, they recommend using non-HDL as the primary target; if this target has been reached and LDL is above goal, further therapy should aim to get LDL to the target. ApoB can be considered a secondary goal once the non-HDL target has been reached because it generally is a marker of residual on-treatment risk.

Roger S. Blumenthal, MD

Roger S. Blumenthal

Lipid-lowering therapies

The NLA recommends lifestyle interventions without pharmacotherapy as the initial treatment for low-to-moderate ASCVD risk patients with a lipid profile not at goal. These include a diet low in saturated fat, at least moderate physical activity, weight loss for those with BMI ≥25 kg/m2 and smoking cessation if needed. Referral to nutrition and exercise specialists also is encouraged to increase the likelihood of achieving meaningful change. Patients should be re-evaluated with a clinic visit and a lipid profile at least 3 months after the initiation of lifestyle interventions to determine progress toward goals. Patients who have not reached goals should be considered for “dietary adjuncts,” including plant sterols and fiber supplementation, and the lifestyle interventions should be reinforced.

Patients who have reached their lipid profile goals by the third office visit should be followed at 6- to 12-month intervals. For those who have not reached their goals, drug therapy should be considered. Furthermore, patients at high to very high risk for ASCVD could initiate drug therapy at even the first visit, simultaneous with the initiation of lifestyle interventions. The NLA recommends that initiation of any drug therapy should be a decision that is highly individualized to each particular patient. For example, it may be appropriate to start a lower-risk patient on statin therapy if they have a strong family history and a preference for pharmacotherapy, whereas an elderly person on several other medications with a multitude of competing risks may decide to forgo any medical therapy for dyslipidemia. 

Statins should be the primary pharmacotherapy initiated, and it is left to the patient and physician to determine whether to start with a high dose and maintain it, or down-titrate to the desired effect or start with a moderate dose and up-titrate. The exception to this “statin-first” rule is patients with triglycerides ≥500 mg/dL, for whom the primary goal is triglyceride lowering to prevent pancreatitis (consistent with the 2013 ACC/AHA guideline). For these patients, initial therapy should include a triglyceride-lowering drug such as a fibrate, long-chain omega-3 fatty acids or nicotinic acid. After initiation of pharmacotherapy, the lipid profile should be periodically monitored (every 4 to 12 months), and the statin regimen adjusted to reach the desired goal.

Several strategies can be considered for patients with intolerance to a statin, including a change to another statin, daily dose reduction or once- to three-times weekly dosing. Patients intolerant of statins despite these strategies, as well as patients not meeting lipid profile goals despite maximal statin therapy, should be considered for non-statin drug therapy. Although not specifically mentioned in the NLA guidelines, this would appear to be a reasonable place to include ezetimibe (Zetia, Merck) preferentially, based on the long-awaited positive results of the IMPROVE-IT trial.

Editor's note: This is part one of a two-part commentary. Click here for the conclusion, which will compare the NLA recommendations to the 2013 ACC/AHA cholesterol treatment guidelines. Share your thoughts on these guidelines in the comments section below.

References:

Goff DC Jr. Circulation. 2014;129(25 Suppl 2):S49-73.

Jacobson TA. J Clin Lipidol. 2014;8:473-488.

Martin SS. Circulation. 2014;129:77-86.

 Muntner P. JAMA. 2014;311:1406-1415.

Pencina MJ. N Engl J Med. 2014;370:1422-1431.

Silverman MG. Eur Heart J. 2014;35:2232-2241.

Stone NJ. Circulation. 2014;129(25 Suppl 2):S1-45.

Wenger NK. J Am Coll Cardiol. 2014;64:2193-2195.

Matthew J. Czarny, MD, and Seth S. Martin, MD, are clinical fellows at The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. Martin also is a member of the Cardiology Today Fellows Advisory Board. Roger S. Blumenthal, MD, is director of the Ciccarone Center for the Prevention of Heart Disease and is the CHD and Prevention Section Editor of Cardiology Today.

Disclosures: The authors report no relevant financial disclosures.

by Matthew J. Czarny, MD; Seth S. Martin, MD; and Roger S. Blumenthal, MD

In the past year, we have observed a major shift in thinking about the management of dyslipidemia, which was exemplified by the release of the 2013 American College of Cardiology/American Heart Association cholesterol treatment guideline.

The guideline defines four “statin-benefit groups” and focuses on statin doses rather than cholesterol level targets. Its implementation has the potential to make many more patients eligible for statin use for primary prevention after a detailed clinician–patient discussion.

Matthew J. Czarny, MD

Matthew J. Czarny

Critiques have been many and have focused on the use of only randomized clinical trial evidence in guideline development; shortcomings in the accompanying and heavily relied-upon Pooled Cohort Risk Equations; a focus on statins as the only acceptable pharmacotherapy; and the elimination of target LDL cholesterol and non-HDL cholesterol levels.

Subsequently, the National Lipid Association convened an expert panel to review all of the available evidence and provide an alternative set of recommendations for the management of dyslipidemia, with the notable consideration of both randomized clinical trials and observational data. The National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia (hereinafter referred to as “the NLA recommendations”) are the subject of this editorial.

Risk assessment, classification

The NLA recommends that all patients with atherosclerotic CVD (ASCVD) have a lipoprotein profile at or shortly after diagnosis and, like the 2013 ACC/AHA guideline, all adults aged 20 years and older in the primary prevention setting have a lipoprotein profile at least every 5 years. The lipoprotein profile should include, at a minimum, total cholesterol and HDL to enable calculation of non-HDL (total cholesterol minus HDL), and neither of these measurements depends on the fasting state. If the patient is fasting, triglycerides can be measured; if triglycerides are <400 mg/dL, the estimated LDL can be calculated by the Friedewald equation. The results of the lipid profile are then interpreted depending on the patient’s risk classification.

Seth S. Martin, MD

Seth S. Martin

Central to the assessment of ASCVD risk by the NLA guidelines are the classical “major ASCVD risk factors,” which are defined as:

  • older age (≥45 years for men, ≥55 years for women);
  • early CHD in a first-degree relative (<55 years for men, <65 years for women);
  • current cigarette smoking;
  • hypertension (BP ≥140 mm Hg/90 mm Hg or antihypertensive therapy); and
  • low HDL (<40 mg/dL for men, <50 mg/dL for women). 

The risk–assessment algorithm then begins with identification of those at “very high risk,” including patients with clinical ASCVD (defined as a history of ACS, arterial revascularization, transient ischemic attack or stroke, atherosclerotic peripheral arterial disease) and those with diabetes plus two or more ASCVD risk factors or end-organ complications of diabetes (urine albumin/creatinine ratio ≥30 mg/g, chronic kidney disease or retinopathy). 

“High-risk” patients are defined as those with three or more major ASCVD risk factors, diabetes plus one major ASCVD risk factor and no end-organ damage, stage 3B or 4 CKD or LDL ≥190 mg/dL.

“Moderate-risk” patients are defined as those with two major ASCVD risk factors (approximate 10-year ASCVD risk 5% to <15%).

“Low-risk” patients are defined as those with one or no major ASCVD risk factors.

However, the risk of all patients in the moderate-risk category should be further refined through the use of quantitative risk scoring or other “risk indicators,” which will allow some patients to be reclassified to high risk. In addition, low-risk patients should be assessed for any risk indicators that may elevate their risk to moderate or high. Of note, there is no mention of use of quantitative risk scoring or risk indicators to lower an individual’s risk estimate.

The NLA guidelines do not recommend any one particular quantitative risk-scoring system, but suggest that a high-risk classification should be given to those with a 2001 Adult Treatment Panel III Framingham risk score of at least 10%, a 2013 Pooled Cohort Equation 10-year risk of at least 15% (unlike the >7.5% threshold for the 2013 ACC/AHA guidelines) or a Framingham long-term CVD risk of at least 45%. Other risk indicators that may be considered to further refine the risk classification of patients at low or moderate risk by risk factor counting may include a major ASCVD risk factor present to a severe degree (eg, a strong family history), coronary artery calcium (CAC) score of at least 300 Agatston units, LDL ≥160 mg/dL or non-HDL ≥190 mg/dL or high-sensitivity C-reactive protein ≥2 mg/dL. Patients at moderate risk by the major risk factors who have one or more of these indicators could be classified as high risk. The same strategy can be applied to lower-risk patients if the clinical circumstances warrant.

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Targets of therapy

The NLA recommends that patients in the very high-risk group have the most aggressive treatment goals, which are non-HDL <100 mg/dL and LDL <70 mg/dL, with an optional goal of apolipoprotein B <80 mg/dL. The treatment goals for low-, moderate-, and high-risk patients are non-HDL <130 mg/dL and LDL <100 mg/dL, with an optional goal of ApoB <90 mg/dL.

The NLA panel concluded that non-HDL is a better primary goal than LDL because it represents all atherogenic particles and more strongly predicts adverse outcomes. Therefore, they recommend using non-HDL as the primary target; if this target has been reached and LDL is above goal, further therapy should aim to get LDL to the target. ApoB can be considered a secondary goal once the non-HDL target has been reached because it generally is a marker of residual on-treatment risk.

Roger S. Blumenthal, MD

Roger S. Blumenthal

Lipid-lowering therapies

The NLA recommends lifestyle interventions without pharmacotherapy as the initial treatment for low-to-moderate ASCVD risk patients with a lipid profile not at goal. These include a diet low in saturated fat, at least moderate physical activity, weight loss for those with BMI ≥25 kg/m2 and smoking cessation if needed. Referral to nutrition and exercise specialists also is encouraged to increase the likelihood of achieving meaningful change. Patients should be re-evaluated with a clinic visit and a lipid profile at least 3 months after the initiation of lifestyle interventions to determine progress toward goals. Patients who have not reached goals should be considered for “dietary adjuncts,” including plant sterols and fiber supplementation, and the lifestyle interventions should be reinforced.

Patients who have reached their lipid profile goals by the third office visit should be followed at 6- to 12-month intervals. For those who have not reached their goals, drug therapy should be considered. Furthermore, patients at high to very high risk for ASCVD could initiate drug therapy at even the first visit, simultaneous with the initiation of lifestyle interventions. The NLA recommends that initiation of any drug therapy should be a decision that is highly individualized to each particular patient. For example, it may be appropriate to start a lower-risk patient on statin therapy if they have a strong family history and a preference for pharmacotherapy, whereas an elderly person on several other medications with a multitude of competing risks may decide to forgo any medical therapy for dyslipidemia. 

Statins should be the primary pharmacotherapy initiated, and it is left to the patient and physician to determine whether to start with a high dose and maintain it, or down-titrate to the desired effect or start with a moderate dose and up-titrate. The exception to this “statin-first” rule is patients with triglycerides ≥500 mg/dL, for whom the primary goal is triglyceride lowering to prevent pancreatitis (consistent with the 2013 ACC/AHA guideline). For these patients, initial therapy should include a triglyceride-lowering drug such as a fibrate, long-chain omega-3 fatty acids or nicotinic acid. After initiation of pharmacotherapy, the lipid profile should be periodically monitored (every 4 to 12 months), and the statin regimen adjusted to reach the desired goal.

Several strategies can be considered for patients with intolerance to a statin, including a change to another statin, daily dose reduction or once- to three-times weekly dosing. Patients intolerant of statins despite these strategies, as well as patients not meeting lipid profile goals despite maximal statin therapy, should be considered for non-statin drug therapy. Although not specifically mentioned in the NLA guidelines, this would appear to be a reasonable place to include ezetimibe (Zetia, Merck) preferentially, based on the long-awaited positive results of the IMPROVE-IT trial.

Editor's note: This is part one of a two-part commentary. Click here for the conclusion, which will compare the NLA recommendations to the 2013 ACC/AHA cholesterol treatment guidelines. Share your thoughts on these guidelines in the comments section below.

References:

Goff DC Jr. Circulation. 2014;129(25 Suppl 2):S49-73.

Jacobson TA. J Clin Lipidol. 2014;8:473-488.

Martin SS. Circulation. 2014;129:77-86.

 Muntner P. JAMA. 2014;311:1406-1415.

Pencina MJ. N Engl J Med. 2014;370:1422-1431.

Silverman MG. Eur Heart J. 2014;35:2232-2241.

Stone NJ. Circulation. 2014;129(25 Suppl 2):S1-45.

Wenger NK. J Am Coll Cardiol. 2014;64:2193-2195.

Matthew J. Czarny, MD, and Seth S. Martin, MD, are clinical fellows at The Johns Hopkins Ciccarone Center for the Prevention of Heart Disease. Martin also is a member of the Cardiology Today Fellows Advisory Board. Roger S. Blumenthal, MD, is director of the Ciccarone Center for the Prevention of Heart Disease and is the CHD and Prevention Section Editor of Cardiology Today.

Disclosures: The authors report no relevant financial disclosures.