In early 2013, the National Lipid Association (NLA) convened an Expert Panel to develop a consensus set of lipid management recommendations. Published as an Executive Summary in 2014¹ and as a full report in 2015,² the NLA Recommendations for the Patient-Centered Management of Dyslipidemia: Part I shared many similarities with the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Blood Cholesterol Guideline.³ Both documents emphasized the importance of identifying high-risk patients, including those with atherosclerotic cardiovascular disease (ASCVD), type 2 diabetes, and familial hypercholesterolemia, and recommended that such patients engage in a provider-patient discussion focused on the value of ASCVD preventive treatment with lifestyle therapy and moderate- or high-intensity statins. They also agreed on the importance of ongoing lipid and lipoprotein monitoring, although the objective of such monitoring was identified primarily as statin adherence in the ACC/AHA guideline and effective reduction of non-high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) in the NLA recommendations.

Other differences included the breadth of the evidence base employed; the value of using lipoprotein goals; an ASCVD risk assessment and treatment algorithm that focused on the identification of statin benefit groups (ACC/AHA) versus one that employed risk factor counting for clinical decision making (NLA); the value of depending upon the new ACC/AHA ASCVD Risk Estimator to guide treatment decisions; and the indications for use of combination lipid-lowering therapy. Importantly, the results of Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin (IMPROVE-IT)⁴ showed a reduction in ASCVD events in those receiving simvastatin and ezetimibe versus those on simvastatin monotherapy. These results were not available to the ACC/AHA guideline writers but were published prior to the publication of the full report of NLA recommendations (Part I) in 2015. Both the ACC/AHA guideline and the NLA recommendations acknowledged the need for expert guidance in certain special populations that had not been as thoroughly studied, including those comprised of younger and older individuals; certain high-risk ethnic groups; and patients with HIV, rheumatologic disease and other chronic inflammatory states.

The NLA Expert Panel's recommendations were based upon the following conclusions: 1) an elevated level of apolipoprotein B containing lipoproteins (non-HDL-C and LDL-C, termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most ASCVD events; 2) reduction of elevated levels of atherogenic cholesterol lowers ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced; 3) the intensity of risk reduction therapy should generally be adjusted to the patient's absolute risk for an ASCVD event; 4) because of the progressive long-term natural history of ASCVD, both intermediate- and long-term or lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies; 5) lifestyle therapy is the underpinning of all risk reduction strategies and when lipid-lowering therapy is indicated, statin therapy is the primary modality for reducing ASCVD risk; 6) non-lipid risk factors should be managed appropriately, particularly high blood pressure, cigarette smoking and diabetes mellitus; and 7) the measurement and monitoring of atherogenic cholesterol levels is an important part of a comprehensive ASCVD prevention strategy. The NLA paradigm identifies very-high-risk patients as those with ASCVD; or diabetes mellitus with two additional ASCVD risk factors, or with retinopathy, microalbuminuria or chronic kidney disease. Further classification into high-, moderate- or low-risk categories employs a strategy based upon risk factor counting. Non-HDL-C and LDL-C are the lipoprotein parameters of primary emphasis in the treatment paradigm. However, non-HDL-C is identified as the more important measure because of its demonstrated greater accuracy than LDL-C for predicting ASCVD events both on and off statin treatment, its widespread availability, lack of need for measurement in the fasting state and low cost. Minimal goals for non-HDL-C and LDL-C are < 130 mg/dL and < 100 mg/dL for primary prevention, and < 100 mg/dL and < 70 mg/dL for secondary prevention. Optional apolipoprotein B goals of < 90 mg/dL and < 80 mg/dL are recommended for primary and secondary prevention, respectively.

The NLA Expert Panel recognized that a strategy of treating patients to pre-specified levels of LDL-C or non-HDL-C has not been specifically tested in any of the large randomized clinical trials assessing ASCVD morbidity and mortality. Nevertheless, the panel maintained the importance of employing non-HDL-C and LDL-C treatment goals to enhance patient-provider interaction and help patients focus on the established beneficial effects of atherogenic cholesterol reduction using multiple evidence-based modalities.

In addition to appropriate-intensity statin therapy, the NLA recommendations advise referral, whenever possible, for dietary counseling under the guidance of a registered dietitian-nutritionist. Additive lipid therapies, generally beginning with ezetimibe, may be employed in selected patients after careful consideration of net benefit, additional cost and patient preference. Specific strategies for maximizing statin adherence and diagnosing and managing statin-related muscle symptoms are outlined, and approaches to therapy in these patients are similar to those provided in the ACC/AHA Blood Cholesterol Guideline. In addition, the clinical significance and the management of the metabolic syndrome and hypertriglyceridemia are discussed. Lifestyle therapy is first-line treatment in such patients. Pharmacologic therapy is generally employed in those with triglycerides ≥ 500 mg/dL in order to reduce the risk of hypertriglyceridemia-induced pancreatitis. In those with triglycerides of 200-499 mg/dL, intensified lifestyle intervention with a focus on achieving non-HDL-C and LDL-C treatment goals is recommended. Pharmacologic therapy is considered in those patients whose lipids remain above goal despite lifestyle counseling.

Part II of the NLA recommendations employs the knowledge of 51 authors whose expertise covers a wide spectrum of lipid-related topics confronted in daily practice.⁵ The authors begin by providing a detailed overview of the most current information on lifestyle therapies. In addition to reviewing the data supporting various evidence-based dietary approaches including: Dietary Approaches to Stop Hypertension; the United States Department of Agriculture (Healthy US–Style), AHA, Mediterranean-style, and vegetarian/vegan diets; evidence on the additive value of plant sterols and stanols, whole grains and dietary fiber, long-chain omega 3 fatty acids, nuts, seeds, legumes and soy protein is examined. In addition, moderate-intensity aerobic exercise for at least 150 minutes per week is advised for health and weight maintenance, and 200-300 minutes per week for those who require weight loss. The document places a major focus on ASCVD risk assessment and management of dyslipidemia in selected special populations, including: children and adolescents; women throughout the lifespan (including pregnancy); older patients; Hispanic/Latinos; African Americans; South Asians; American Indians and Alaskan natives; and those with HIV or rheumatoid arthritis (Table 1).

Table 1: NLA Recommendations in Special Populations: Key Points

• Children
  • Universal lipid screening at age 9-11 years. For family history of premature ASCVD, screen beginning at age 2 years. Treat to non-HDL-C < 145 mg/dL and LDL-C < 130 mg/dL.
  • For familial hypercholesterolemia (FH): Lower LDL-C by at least 50% from baseline.
• Women
  • Higher lifetime ASCVD risk than men because of greater longevity.
  • Response to statin therapy similar to men, but drug therapy during pregnancy and nursing should generally be avoided.
• Elderly
  • Response to statins is similar to younger patients.
  • Consider using moderate-intensity statins in those age 80 years and above, only after careful patient provider discussion.
• Hispanics/Latinos
  • Risk estimation may be difficult due to their ethnic diversity; increased risk for type 2 diabetes (T2DM) and metabolic syndrome, especially in women; lower incidence of ASCVD than non-Hispanic whites (NHW).
• African Americans
  • Increased risk for ASCVD and T2DM. Risk is less driven by dyslipidemia than in NHW, so particular attention should be paid to managing non-lipid risk factors.
• South Asians
  • Increased risk for ASCVD, atherogenic dyslipidemia with low HDL-C and high triglycerides, and T2DM. Risk assessment methods may underestimate true risk.
• American Indians and Alaskan Natives
  • Increased risk for ASCVD and are more likely to be obese, have the metabolic syndrome, T2DM and be smokers. Treatment strategies must also address non-lipid risk factors.
• HIV
  • Increased risk for ASCVD and insulin resistance. HIV positivity should be considered equivalent to one additional risk factor. Consider drug-drug interactions in lipid treatment regimens.
• Rheumatoid Arthritis (RA)
  • Increased risk for ASCVD. RA should be considered equivalent to one additional risk factor. LDL-C may be lower during a flare, so check lipids when disease activity is low. Statins are first-line therapy.

The section on management of lipids in patients with residual risk despite evidence-based lifestyle and statin therapy addresses the controversial issue of indications for combination therapy and includes perspectives on the use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, recognizing that ASCVD outcome studies on these agents are not yet available. The Expert Panel recommended that these drugs be considered primarily in the following patients on maximally-tolerated statin (± ezetimibe) therapy: 1) ASCVD patients who have LDL-C ≥ 100 mg/dL (non-HDL-C ≥ 130 mg/dL); and 2) heterozygous FH patients without ASCVD who have LDL-C ≥ 130 mg/dL (non-HDL-C ≥ 160 mg/dL). PCSK9 inhibitor therapy may also be considered for use in other selected high-risk patients, including those with recurrent ASCVD events and persistent LDL-C ≥ 70 mg/dL (non-HDL-C ≥ 100 mg/dL), and those ASCVD patients with statin intolerance who require substantial additional atherogenic cholesterol reduction. Such use would be based upon clinical judgment, weighing the potential benefits relative to anticipated ASCVD event reduction and the risks and costs of such therapy.

The final part of the NLA Recommendations focuses on strategies to improve patient outcomes by addressing adherence. The document recognizes the central importance of establishing a high-quality and supportive provider-patient relationship. This approach enables the clinician to give non-judgmental counseling on strategies to enhance adherence, clearly explains the consequences of non-adherence and promotes the important role of team-based care to facilitate optimal ASCVD risk reduction.

References

1. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 - Executive Summary. J Clin Lipidol 2014;8:473-88.
2. Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part 1 - Full Report. J Clin Lipidol 2015;9:129-69.
3. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63(25 Pt B):2889-934.
4. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015;372:2387-97.
5. Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: Part II. J Clin Lipidol 2015:9(6)S.

Keywords: Acute Coronary Syndrome, African Americans, Algorithms, Apolipoproteins, Arthritis, Rheumatoid, Atherosclerosis, Cholesterol, Cholesterol, LDL, Decision Making, Consensus, Counseling, Diabetes Mellitus, Type 2, Dietary Fiber, Drug Interactions, Ethnic Groups, Exercise, Fabaceae, Fasting, Fatty Acids, Omega-3, Goals, HIV Infections, Hispanic Americans, Hyperlipoproteinemia Type II, Hypertension, Hypertriglyceridemia, Incidence, Indians, North American, Insulin Resistance, Life Style, Lipids, Lipoproteins, HDL, Lipoproteins, LDL, Longevity, Metabolic Syndrome, Nutritionists, Nuts, Outcome Assessment, Health Care, Pancreatitis, Patient Preference, Phytosterols, Population Groups, Primary Prevention, Proprotein Convertases, Referral and Consultation, Renal Insufficiency, Chronic, Risk Assessment, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Simvastatin, Smoking, Soybean Proteins, Subtilisins, Triglycerides, Diet, Vegetarian, Weight Loss

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