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National Lipid Association Recommendations - Part 1| Volume 9, ISSUE 2, P129-169, March 2015

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National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 1—Full Report

Published:March 26, 2015DOI:https://doi.org/10.1016/j.jacl.2015.02.003

      Abstract

      The leadership of the National Lipid Association convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. An Executive Summary of those recommendations was previously published. This document provides support for the recommendations outlined in the Executive Summary. The major conclusions include (1) an elevated level of cholesterol carried by circulating apolipoprotein B-containing lipoproteins (non–high-density lipoprotein cholesterol and low-density lipoprotein cholesterol [LDL-C], termed atherogenic cholesterol) is a root cause of atherosclerosis, the key underlying process contributing to most clinical atherosclerotic cardiovascular disease (ASCVD) events; (2) reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering through multiple modalities, including lifestyle and drug therapies; (3) the intensity of risk-reduction therapy should generally be adjusted to the patient's absolute risk for an ASCVD event; (4) atherosclerosis is a process that often begins early in life and progresses for decades before resulting a clinical ASCVD event. Therefore, both intermediate-term and long-term or lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies; (5) for patients in whom lipid-lowering drug therapy is indicated, statin treatment is the primary modality for reducing ASCVD risk; (6) nonlipid ASCVD risk factors should also be managed appropriately, particularly high blood pressure, cigarette smoking, and diabetes mellitus; and (7) the measurement and monitoring of atherogenic cholesterol levels remain an important part of a comprehensive ASCVD prevention strategy.

      Keywords

      Tabled 1Evidence grading: strength of recommendation
      The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines3 and adapted from the original GRADE system of evidence rating.13
      GradeStrength of recommendation
      AStrong recommendation

      There is high certainty based on the evidence that the net benefit
      Net benefit is defined as benefits minus risks/harms of the service/intervention.
      is substantial
      BModerate recommendation

      There is moderate certainty based on the evidence that the net benefit is moderate to substantial, or there is high certainty that the net benefit is moderate
      CWeak recommendation

      There is at least moderate certainty based on the evidence that there is a small net benefit
      DRecommend against

      There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits
      EExpert opinion

      There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends
      NNo recommendation for or against

      There is insufficient evidence or evidence is unclear or conflicting
      Taken from Jacobson et al.
      • Jacobson T.A.
      NLA Task Force on Statin Safety—2014 update.
      Originally published in James et al.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      and Stone et al.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating system (NHLBI cardiovascular-based methodology) used in the new American Heart Association/American College of Cardiology cholesterol guidelines
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      and adapted from the original GRADE system of evidence rating.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE Working Group
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      Net benefit is defined as benefits minus risks/harms of the service/intervention.
      Tabled 1Evidence grading: quality of evidence
      Type of evidenceQuality rating
      The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute's (NHLBI's) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement.
      Well-designed, well-executed RCTs that adequately represent populations to which the results are applied and directly assess effects on health outcomesHigh
      Well-conducted meta-analyses of such studies
      Highly certain about the estimate of effect; further research is unlikely to change our confidence in the estimate of effect
      RCTs with minor limitations affecting confidence in, or applicability of, the resultsModerate
      Well-designed, well-executed nonrandomized controlled studies and well-designed, well-executed observational studies
      Well-conducted meta-analyses of such studies
      Moderately certain about the estimate of effect; further research may have an impact on our confidence in the estimate of effect and may change the estimate
      RCTs with major limitationsLow
      Nonrandomized controlled studies and observational studies with major limitations affecting confidence in, or applicability of, the results
      Uncontrolled clinical observations without an appropriate comparison group (eg, case series, case reports)

      Physiological studies in humans

      Meta-analyses of such studies
      Low certainty about the estimate of effect; further research is likely to have an impact on our confidence in the estimate of effect and is likely to change the estimate.
      RCT, randomized controlled trial.
      This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      that were published in the 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults Report from the Panel members appointed to the Eighth Joint National Committee.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      Taken from Jacobson et al.
      • Jacobson T.A.
      NLA Task Force on Statin Safety—2014 update.
      Originally published in James et al.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      and Stone et al.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      The evidence quality rating system used in this guideline was developed by the National Heart, Lung, and Blood Institute's (NHLBI's) Evidence-Based Methodology Lead (with input from NHLBI staff, external methodology team, and guideline panels and work groups) for use by all the NHLBI cardiovascular disease guideline panels and work groups during this project. As a result, it includes the evidence quality rating for many types of studies, including studies that were not used in this guideline. Additional details regarding the evidence quality rating system are available in the online Supplement.
      Various organizations and agencies have issued recommendations for the management of dyslipidemia.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      • Catapano A.L.
      • Reinzer Z.
      • De Backer G.
      • et al.
      European Society of Cardiology (ESC); European Atherosclerosis Society (EAS)
      ESC/EAS guidelines for the management of dyslipidaemias. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      • Jellinger P.S.
      • Smith D.A.
      • Mehta A.E.
      • et al.
      AACE Task Force for Management of Dyslipidemia and Prevention of Atherosclerosis
      American Association of Clinical Endocrinologists' guidelines for management of dyslipidemia and prevention of atherosclerosis.
      • Anderson T.J.
      • Gregoire J.
      • Hegele R.A.
      • et al.
      2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • et al.
      2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.

      National Institute for Health Care and Excellence. Lipid modification: cardiovascular risk assessment and the modification of blood lipids for the primary and secondary prevention of cardiovascular disease. NICE clinical guideline 181. Issued July 2014.

      American Diabetes Association
      Standards of medical care in diabetes—2015. Section 8. Cardiovascular disease and risk management.
      Although many commonalities exist among them, material differences are present as well. The leadership of the National Lipid Association (NLA) convened an Expert Panel to develop a consensus set of recommendations for patient-centered management of dyslipidemia in clinical medicine. A presentation containing the main elements of these recommendations was made available to the public and other organizations involved with the prevention of atherosclerotic cardiovascular disease (ASCVD) to solicit input during an open comment period. Comments and suggestions were received from many members of the NLA, as well as other individuals and organizations, and were collated for consideration and adjudication by the panel in formulating the final set of recommendations contained herein.
      • Jacobson T.A.
      • Ito M.K.
      • Maki K.C.
      • et al.
      National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—executive summary.
      The NLA Expert Panel graded the type and strength of the evidence supporting their recommendations using a hybrid of the rating system developed by the National Heart, Lung, and Blood Institute's Evidence-Based Methodology Lead and adapted from the original GRADE system of evidence rating.
      • Jacobson T.A.
      NLA Task Force on Statin Safety—2014 update.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE Working Group
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      Part 1 of the NLA Expert Panel recommendations for patient-centered management of dyslipidemia covers the following:
      • Background and conceptual framework for formulation of the NLA Expert Panel recommendations;
      • Screening and classification of lipoprotein lipid levels in adults (>20 years);
      • Targets for intervention in dyslipidemia management;
      • ASCVD risk assessment and treatment goals based on risk category;
      • Atherogenic cholesterol—non–high-density lipoprotein (non-HDL) cholesterol (non-HDL-C) and low-density lipoprotein (LDL) cholesterol (LDL-C)—as the primary targets of therapy; and
      • Lifestyle and drug therapies intended to reduce morbidity and mortality associated with dyslipidemia.
      Part 2 is in development and will cover the following topics:
      • Lifestyle therapies (to provide a greater depth of information than is included in part 1);
      • Groups with special considerations:
        • Children and adolescents;
        • Gender, including pregnancy;
        • Ethnic groups;
        • Older patients;
        • Patients with human immunodeficiency virus;
        • Patients with selected chronic inflammatory states;
        • Patients with residual risk despite statin therapy;
      • Strategies to assist with patient adherence; and
      • Team-based collaborative care.

      Background and conceptual framework for formulation of the NLA Expert Panel recommendations

      Clinical decisions often need to be made in the absence of ideal or complete evidence, and well-informed experts will not always evaluate or interpret the evidence base in the same way. Clinical recommendations aim to assist clinicians in making decisions about the best strategies for management of a condition, taking into account potential benefits and risks of the available options. The NLA Expert Panel recommendations are intended to inform, not replace, clinical judgment. A patient-centered approach dictates that clinical judgment take into account the circumstances, objectives, and preferences of each individual patient.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      • Walsh M.N.
      • Bove A.A.
      • Cross R.R.
      • et al.
      American College of Cardiology Foundation
      ACCF 2012 health policy statement on patient-centered care in cardiovascular medicine: a report of the American College of Cardiology Foundation Clinical Quality Committee.
      • Sniderman A.D.
      • LaChapelle K.J.
      • Rachon N.A.
      • Furberg C.D.
      The necessity for clinical reasoning in the era of evidence-based medicine.
      The patient should be an active participant in the process, having engaged with the clinician in a dialog about the objectives of therapy, including potential risks and side effects, as well as benefits and costs. Patient-provider collaboration in treatment decisions tends to improve long-term adherence.
      • Robinson J.H.
      • Callister L.C.
      • Berry J.A.
      • Dearing K.A.
      Patient-centered care and adherence: definitions and applications to improve outcomes.
      • Calvert S.B.
      • Kramer J.M.
      • Anstrom K.J.
      • Kaltenbach L.A.
      • Stafford J.A.
      • Allen LaPointe N.M.
      Patient-focused intervention to improve long-term adherence to evidence-based medications: a randomized trial.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      The NLA recognizes the major contribution that dyslipidemia management has made to the progressive reduction in ASCVD morbidity and mortality that has been observed during recent decades (Fig. 1).
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics—2014 update; a report from the American Heart Association.
      This reduction in risk occurred under the guidance provided by previous guidelines and recommendations, most notably the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) Guidelines.
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      • Grundy S.M.
      • Cleeman J.I.
      • Merz C.N.
      • et al.
      Coordination Committee of the National Cholesterol Education Program
      Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
      The NLA Expert Panel consensus view is that the evidence that has accumulated since the 2004 update of the NCEP ATP III guidelines warrants a modest refinement of previous lipid-related risk management strategies, as outlined in the present report.
      Figure thumbnail gr1
      Figure 1US age-standardized death rates attributable to CVD, 2000 to 2010.
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics—2014 update; a report from the American Heart Association.
      Taken from Go AS et al.
      • Go A.S.
      • Mozaffarian D.
      • Roger V.L.
      • et al.
      American Heart Association Statistics Committee and Stroke Statistics Subcommittee
      Heart disease and stroke statistics—2014 update; a report from the American Heart Association.
      with permission. CHD, coronary heart disease; CVD, cardiovascular disease. †Total CVD: International Classification of Diseases, 10th Revision (ICD-10) from I00 to I99 and from Q20 to Q28. §Stroke (all cerebrovascular disease): ICD-10 from I60 to I69. ¶CHD: ICD-10 from I20 to I25. ∗∗Other CVD: ICD-10 from I00 to I15, from I26 to I51, from I70 to I78, from I80 to I89, and from I95 to I99.
      The evidence base considered in the development of consensus for these recommendations emphasized results from randomized controlled trials (RCTs) to evaluate lipid-altering interventions on clinical ASCVD events (mainly myocardial infarction, coronary death, and stroke), including subgroup assessments and pooled analyses from multiple trials, where available. Although the panel acknowledges that the primary results from RCTs represent the strongest evidence from which to draw conclusions about benefits and risks of treatment strategies, it also recognizes that many important clinical questions have not been addressed in RCTs (hence the evidence base is incomplete), and RCT evidence may have uncertain relevance to particular patients because the RCTs were performed in highly selected groups with characteristics that may differ in important ways from the patient for whom treatment decisions need to be made.
      Observational evidence from epidemiologic studies is subject to possible bias and confounding and is therefore sometimes excluded from deliberations regarding treatment recommendations.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      However, where the available observational evidence is of high quality, with consistent results across investigations in multiple cohorts by different investigators, such evidence can play an important role to inform clinical investigations. Genetic epidemiologic studies, because they examine genetic variants that often produce lifelong differences in levels of lipoprotein lipid concentrations, overcome many of the difficulties with the potential for bias and confounding inherent in other observational studies. Therefore, in addition to data from RCTs, evidence from epidemiologic and genetic studies as well as metabolic and mechanistic investigations has been considered in the development of these recommendations. This approach allowed inclusion of a broad evidence base for clinical decision making and was consistent with the approach taken by the NCEP ATP III and many other international recommendations committees.
      • Catapano A.L.
      • Reinzer Z.
      • De Backer G.
      • et al.
      European Society of Cardiology (ESC); European Atherosclerosis Society (EAS)
      ESC/EAS guidelines for the management of dyslipidaemias. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
      • Anderson T.J.
      • Gregoire J.
      • Hegele R.A.
      • et al.
      2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      JBS3 Board
      Joint British Societies' consensus recommendations for the prevention of cardiovascular disease (JBS3).

      Major conclusions of the NLA Expert Panel

      The NLA Expert Panel found the evidence to be compelling to support the following conclusions, which guided the development of the recommendations.
      • 1.
        An elevated level of cholesterol carried by circulating apolipoprotein (apo) 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 clinical ASCVD events.
      HDL, LDL, intermediate-density lipoprotein (IDL), very low–density lipoprotein (VLDL), and chylomicrons are the 5 major classes of lipoproteins. Of these, LDL is the predominant cholesterol-carrying lipoprotein comprising ∼75% of cholesterol carried by non-HDL particles, with the remaining ∼25% of non–HDL-C in triglyceride-rich particles, which include VLDL, IDL, chylomicrons, and their remnants.
      • Chung B.H.
      • Tallis G.
      • Yalamoori V.
      • Anantharamaiah G.M.
      • Segrest J.P.
      Liposome-like particles isolated from human atherosclerotic plaques are structurally and compositionally similar to surface remnants of triglyceride-rich lipoproteins.
      • Rapp J.H.
      • Lespine A.
      • Hamilton R.L.
      • et al.
      Triglyceride-rich lipoproteins isolated by selected affinity anti-apolipoprotein B immunoadsorption from human atherosclerotic plaque.
      • Havel R.J.
      Remnant lipoproteins as therapeutic targets.
      • Veniant M.M.
      • Sullivan M.A.
      • Kim S.K.
      • et al.
      Defining the atherogenicity of large and small lipoproteins containing apolipoprotein B100.
      • Twickler T.
      • Dallinga-Thie G.M.
      • Chapman M.J.
      • Cohn J.S.
      Remnant lipoproteins and atherosclerosis.
      • Varbo A.
      • Benn M.
      • Tybaerg-Hansen A.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • Nordestgaard B.G.
      Remnant cholesterol as a causal risk factor for ischemic heart disease.
      • Varbo A.
      • Benn M.
      • Nordestgaard B.G.
      Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment.
      Each LDL particle contains a single apo B100 particle, whereas the major apos of VLDL are apo B100, apo A4, apo C (1, 2, and 3), and apo E. Chylomicron particles contain the same apos as VLDL, except that they also contain apo A (1, 2, and 4), and apo B48 is present instead of apo B100. It should be noted that clinical laboratories typically report the LDL-C concentration as a calculated value using the Friedewald equation (LDL-C = total cholesterol [total-C] – HDL-C – triglycerides/5 with all values in mg/dL) as long as the triglyceride level is below ∼400 mg/dL.
      • Friedewald W.T.
      • Levy R.I.
      • Fredrickson D.S.
      Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
      This calculated value includes cholesterol carried by true LDL particles, as well as IDL particles. Also, some particles, mostly in the LDL density range, are covalently bound to apolipoprotein (a). LDL-C estimated by the Friedwald equation also includes cholesterol carried by these lipoprotein (a) [Lp (a)] particles.
      Non–HDL-C (calculated as total-C – HDL-C) represents the sum of cholesterol carried by all potentially atherogenic, apo B-containing lipoprotein particles, including LDL, IDL, Lp (a), VLDL (including VLDL remnants), and chylomicron particles and remnants. The NCEP ATP III acknowledged the importance of non–HDL-C in atherogenesis in 2002, but, at that time, instructions to target non–HDL-C concentration pertained only to individuals with hypertriglyceridemia because it was understood that elevated levels of VLDL cholesterol (VLDL-C) and its remnants are more prevalent in those with hypertriglyceridemia.
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      • Jeppesen J.
      • Hein H.O.
      • Suadicani P.
      • Gyntelberg F.
      Triglyceride concentration and ischemic heart disease: an eight-year follow-up in the Copenhagen Male Study.
      However, a substantial body of evidence has since accumulated to support the view that non–HDL-C is more strongly related to risk for ASCVD than LDL-C and that this relationship is evident in those with and without hypertriglyceridemia.
      • Cui Y.
      • Blumenthal R.S.
      • Flaws J.A.
      • et al.
      Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality.
      • Farwell W.R.
      • Sesso H.D.
      • Buring J.E.
      • Gaziano J.M.
      Non-high-density lipoprotein cholesterol versus low-density lipoprotein cholesterol as a risk factor for a first nonfatal myocardial infarction.
      • Ridker P.M.
      • Rifai N.
      • Cook N.R.
      • Bradwin G.
      • Buring J.E.
      Non-HDL cholesterol, apolipoproteins A-I and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women.
      • Liu J.
      • Sempos C.T.
      • Donahue R.P.
      • Dorn J.
      • Trevisan M.
      • Grundy S.M.
      Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease.
      • Holme I.
      • Aastveit A.H.
      • Jungner I.
      • Walldius G.
      Relationships between lipoprotein components and risk of myocardial infarction: age, gender and short versus longer follow-up periods in the Apolipoprotein MOrtality RISk study (AMORIS).
      • Di Angelantonio E.
      • Sarwar N.
      • Perry P.
      • et al.
      Emerging Risk Factors Collaboration
      Major lipids, apolipoproteins, and risk of vascular disease.
      • Robinson J.G.
      • Wang S.
      • Smith B.J.
      • Jacobson T.A.
      Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk.
      Atherosclerosis has been described as a lipid-driven inflammatory disorder of the arterial wall.
      • Ross R.
      Atherosclerosis—an inflammatory disease.
      • Tabas I.
      • Williams K.J.
      • Boren J.
      Subendothelial lipoprotein retention as the initiating process in atherosclerosis: update and therapeutic implications.
      • Frostegard J.
      Immunity, atherosclerosis and cardiovascular disease.
      • Van Wijk D.F.
      • Sjouke B.
      • Figueroa A.
      • et al.
      Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia.
      Atherogenic lipoproteins (LDL and some smaller species of the triglyceride-rich lipoproteins) have the ability to infiltrate the arterial wall thereby initiating atherosclerosis. After entering the arterial wall, the particles bind to proretentive extracellular molecules, become trapped, and are modified through oxidation and other processes, which increase their inflammatory properties and their unregulated uptake by macrophages.
      • Frostegard J.
      Immunity, atherosclerosis and cardiovascular disease.
      • Steinberg D.
      The LDL modification of atherogenesis: an update.
      As the macrophages become engorged with lipid, they form foam cells, and this process triggers a potentiation of the inflammatory response through release of compounds that increase recruitment of additional monocytes and macrophages. The accumulation of foam cells leads to the development of a fatty streak that initiates smooth muscle proliferation. The proliferation of smooth muscle cells creates a fibrous cap or plaque.
      • Wang J.
      • Razuvaev A.
      • Folkersen L.
      • et al.
      The expression of IGFs and IGF binding proteins in human carotid atherosclerosis, and the possible role of IGF binding protein-1 in the regulation of smooth muscle cell proliferation.
      As the plaque matures and atherogenic particles continue to infiltrate, lipid-rich areas form within the fibrous plaque.
      • Van Wijk D.F.
      • Sjouke B.
      • Figueroa A.
      • et al.
      Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia.
      Inflammation triggers processes that weaken the fibrous cap and make the plaque susceptible to rupture.
      • Falk E.
      • Nakano M.
      • Bentzon J.F.
      • Finn A.V.
      • Virmani R.
      Update on acute coronary syndromes: the pathologists' view.
      Thus, atherogenic lipoproteins play important roles in the initiation of atherosclerosis, progression to a mature plaque and, eventually, plaque instability and rupture. When plaque rupture occurs, subendothelial components are exposed to the blood, and luminal thrombosis occurs, which, if sufficiently large, can occlude arterial flow. Atherosclerotic plaque rupture is generally the proximal cause of acute coronary syndromes (eg, myocardial infarction, unstable angina).
      • Libby P.
      Molecular bases of the acute coronary syndromes.
      • Libby P.
      • Schoenbeck U.
      • Mach F.
      • Selwyn A.P.
      • Ganz P.
      Current concepts in cardiovascular pathology: the role of LDL cholesterol in plaque rupture and stabilization.
      • Théroux P.
      • Fuster V.
      Acute coronary syndromes: unstable angina and non-Q-wave myocardial infarction.
      • Fuster V.
      • Fayad Z.A.
      • Badimon J.J.
      Acute coronary syndromes: biology.
      Epidemiologic studies have demonstrated a strong relationship between serum cholesterol levels and increased ASCVD risk, and, conversely, low rates of ASCVD are associated with low levels of cholesterol (Fig. 2).
      Pooling Project Research Group
      Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the pooling project.
      • Stamler J.
      • Wentworth D.
      • Neaton J.D.
      Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).
      • Anderson K.M.
      • Castelli W.P.
      • Levy D.
      Cholesterol and mortality: 30 years of follow-up from the Framingham Study.
      • Anderson K.M.
      • Wilson P.W.
      • Garrison R.J.
      • Castelli W.P.
      Longitudinal and secular trends in lipoprotein cholesterol measurements in a general population sample. The Framingham Offspring Study.
      • Law M.R.
      • Wald N.J.
      • Thompson S.G.
      By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?.
      The importance of LDL-C in ASCVD is corroborated by the existence of familial hypercholesterolemia (FH), an autosomal codominant genetic disorder characterized by very high levels of LDL-C (and LDL particles) and early ASCVD.
      • Hopkins P.N.
      • Toth P.P.
      • Ballantyne C.M.
      • Rader D.J.
      National Lipid Association Expert Panel on Familial Hypercholesterolemia
      Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
      • Izar M.C.
      • Machado V.A.
      • Fonseca F.A.
      Genetic screening for homozygous and heterozygous familial hypercholesterolemia.
      In patients with FH, the removal of apo B–containing lipoproteins by lipoprotein apheresis has been shown to markedly reduce arterial wall inflammation.
      • Van Wijk D.F.
      • Sjouke B.
      • Figueroa A.
      • et al.
      Nonpharmacological lipoprotein apheresis reduces arterial inflammation in familial hypercholesterolemia.
      Individuals with proprotein convertase subtilisin kexin type 9 (PCSK9) mutations and with polymorphisms in Niemann-Pick C1-like 1 (NPC1L1) protein that result in reduced levels of LDL-C throughout life are associated with markedly reduced risk for ASCVD events.
      • Cohen J.C.
      • Boerwinkle E.
      • Mosley Jr., T.H.
      • Hoobs H.H.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      • Ference B.A.
      • Majeed F.
      • Brook R.D.
      • Hedquist L.
      • Penumetcha R.
      • Flack J.M.
      Effect of naturally random allocation to lower LDL-C mediated polymorphisms in NPC1L1, HMGCR or both on the risk of coronary heart disease: a 2x2 factorial Mendelian randomization study.
      The Myocardial Infarction Genetics Consortium Investigators
      Inactivating mutations in NPC1L1 and protection from coronary heart disease.
      Figure thumbnail gr2
      Figure 2Log-linear relationship between serum cholesterol and coronary heart disease (CHD) mortality from the Multiple Risk Factor Intervention Trial (N = 356,222).
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      • Stamler J.
      • Wentworth D.
      • Neaton J.D.
      Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).
      A causal relationship between triglyceride-rich lipoprotein cholesterol levels (sometimes referred to as “remnant cholesterol” [calculated as total-C – HDL-C – LDL-C]) is supported by an association between elevated triglycerides and increased ASCVD risk,
      • Austin M.A.
      Plasma triglyceride and coronary heart disease.
      • Hokanson J.E.
      • Austin M.A.
      Plasma triglyceride level is a risk factor for cardiovascular disease independent of high-density lipoprotein cholesterol level: a meta-analysis of population-based prospective studies.
      • Nordestgaard B.G.
      • Benn M.
      • Schnohr P.
      • Tybjærg-Hansen A.
      Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women.
      • Nordestgaard B.G.
      • Varbo A.
      Triglycerides and cardiovascular disease.
      • Freiberg J.J.
      • Tybjærg-Hansen A.
      • Jensen J.S.
      • Nordestgaard B.G.
      Nonfasting triglycerides and risk of ischemic stroke in the general population.
      • Chapman M.J.
      • Ginsberg H.N.
      • Amarenco P.
      • et al.
      for the European Atherosclerosis Society Consensus Panel
      Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.
      as well as by the high risk for ASCVD among individuals with atherogenic dyslipidemia (combination of elevated triglycerides and low HDL-C).
      • Chapman M.J.
      • Ginsberg H.N.
      • Amarenco P.
      • et al.
      for the European Atherosclerosis Society Consensus Panel
      Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.
      Genetic mutations that result in increased circulating levels of triglycerides and triglyceride-rich lipoprotein cholesterol (eg, variants associated with lipoprotein lipase, apo C3, and apo A5) are associated with elevated ASCVD risk (Fig. 3).
      • Varbo A.
      • Benn M.
      • Tybaerg-Hansen A.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • Nordestgaard B.G.
      Remnant cholesterol as a causal risk factor for ischemic heart disease.
      • Varbo A.
      • Benn M.
      • Nordestgaard B.G.
      Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment.
      • Nordestgaard B.G.
      • Varbo A.
      Triglycerides and cardiovascular disease.
      • Sarwar N.
      • Sanghu M.S.
      • Ricketts S.L.
      • et al.
      Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration
      Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.
      • Johansen C.T.
      • Kathiresan S.
      • Hegele R.A.
      Genetic determinants of plasma triglycerides.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • West A.S.
      • Grande P.
      • Nordestgaard B.G.
      • Tybjaerg-Hansen A.
      Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • Nordestgaard B.C.
      • Tybjaerg-Hansen A.
      Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.
      • Hegele R.A.
      • Ginsberg H.N.
      • Chapman M.J.
      • et al.
      on behalf of the European Atherosclerosis Society Consensus Panel
      The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.
      Figure thumbnail gr3
      Figure 3Association between elevated triglycerides and remnant cholesterol and risk of myocardial infarction.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • West A.S.
      • Grande P.
      • Nordestgaard B.G.
      • Tybjaerg-Hansen A.
      Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction.
      The observational risk estimates for a doubling in nonfasting triglycerides or calculated remnant cholesterol are from the Copenhagen City Heart Study as hazard ratios. The causal risk estimates for a doubling in nonfasting triglycerides or calculated remnant cholesterol levels are for the combined genotypes (c.-3A>G, S19W, and c.*31C>T genotypes) in the Copenhagen General Population Study, the Copenhagen City Heart Study and the Copenhagen Ischemic Heart Disease studies combined (n = 60,113). Adjustment was for age, sex, smoking, hypertension, and diabetes mellitus. P values are for significance of risk estimates, and P values for comparison are for differences between observational and causal genetic risk estimates. Taken from Jorgensen AB et al.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • West A.S.
      • Grande P.
      • Nordestgaard B.G.
      • Tybjaerg-Hansen A.
      Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction.
      with permission of Oxford University Press. CI, confidence interval.
      As discussed in more detail in the following, RCTs of lipid-altering interventions that lower levels of LDL-C and/or triglyceride-rich lipoprotein cholesterol levels have demonstrated reduced ASCVD event risk, further supporting a causal role of apo B–containing lipoproteins in the atherothrombotic process. The relative importance of lowering atherogenic particle concentrations vs the levels of cholesterol carried by atherogenic particles is incompletely understood. Non–HDL-C has been regularly shown to be a better predictor of ASCVD event risk than LDL-C, which may, at least in part, reflect the stronger relationship between the non–HDL-C concentration and circulating levels of atherogenic particles.
      • Mora S.
      • Buring J.E.
      • Ridker P.M.
      Discordance of low-density lipoprotein (LDL) cholesterol with alternative LDL-related measures and future coronary events.
      Thus, the panel included both LDL-C and triglyceride-rich lipoprotein cholesterol (non–HDL-C is the sum of LDL-C and triglyceride-rich lipoprotein cholesterol) as atherogenic cholesterol components.
      • 2.
        Reducing elevated levels of atherogenic cholesterol will lower ASCVD risk in proportion to the extent that atherogenic cholesterol is reduced. This benefit is presumed to result from atherogenic cholesterol lowering through multiple modalities, including lifestyle and drug therapies.
      Numerous clinical trials of atherogenic cholesterol–lowering therapies have demonstrated their ability to reduce the incidence of ASCVD in proportion to the amount of LDL-C and non–HDL-C reduction (Fig. 4).
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      • Robinson J.G.
      • Wang S.
      • Smith B.J.
      • Jacobson T.A.
      Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk.
      • Rossouw J.E.
      • Lewis B.
      • Rifkind B.M.
      The value of lowering cholesterol after myocardial infarction.
      • Gordon D.J.
      Cholesterol lowering and total mortality.
      Examinations of on-treatment LDL-C concentration compared with coronary heart disease (CHD) events in studies of primary prevention (ie, in subjects initially free from CHD; Fig. 5)
      • Shepherd J.
      • Cobbe S.M.
      • Ford I.
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
      • Downs J.R.
      • Clearfield M.
      • Weis S.
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
      • Sever P.S.
      • Dahlof B.
      • Poulter N.R.
      • et al.
      ASCOT Investigators
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentrations in the ANGLO-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicenter randomised controlled trial.
      • Ridker P.M.
      • Danielson E.
      • Fonseca F.A.
      • et al.
      JUPITER Study Group
      Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
      and in studies of secondary prevention (ie, in patients with established ASCVD; Fig. 6)
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      • Lewis S.J.
      • Moye L.A.
      • Sacks F.M.
      • et al.
      Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.
      The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group
      Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      • Pedersen T.R.
      • Faergeman O.
      • Kastelein J.J.
      • et al.
      Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group
      High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • et al.
      Treating to New Targets (TNT) Investigators
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      Cannon CP on behalf of the IMPROVE IT Investigators
      IMPROVE-IT Trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Late-breaking clinical trial abstracts and clinical science special reports abstracts from the American Heart Association's Scientific Sessions 2014.
      also show a strong positive correlation. These effects are evident not only with atherogenic cholesterol–lowering drug therapies but also diet/lifestyle and surgical therapies.
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      • Grundy S.M.
      • Cleeman J.I.
      • Merz C.N.
      • et al.
      Coordination Committee of the National Cholesterol Education Program
      Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
      • Rossouw J.E.
      • Lewis B.
      • Rifkind B.M.
      The value of lowering cholesterol after myocardial infarction.
      • Gordon D.J.
      Cholesterol lowering and total mortality.
      • Shepherd J.
      • Cobbe S.M.
      • Ford I.
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
      • Downs J.R.
      • Clearfield M.
      • Weis S.
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
      • Sever P.S.
      • Dahlof B.
      • Poulter N.R.
      • et al.
      ASCOT Investigators
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentrations in the ANGLO-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicenter randomised controlled trial.
      Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      • Lewis S.J.
      • Moye L.A.
      • Sacks F.M.
      • et al.
      Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.
      The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group
      Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      • Pedersen T.R.
      • Faergeman O.
      • Kastelein J.J.
      • et al.
      Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group
      High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • et al.
      Treating to New Targets (TNT) Investigators
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      Cannon CP on behalf of the IMPROVE IT Investigators
      IMPROVE-IT Trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. Late-breaking clinical trial abstracts and clinical science special reports abstracts from the American Heart Association's Scientific Sessions 2014.
      Lipid Research Clinics Program
      The Lipid Research Clinics Coronary Primary Prevention Trial results. I: Reduction in the incidence of coronary heart disease.
      Lipid Research Clinics Program
      The Lipid Research Clinics Coronary Primary Prevention Trial results. II: The relationship of reduction in incidence of coronary heart disease to cholesterol lowering.
      • Buchwald H.
      • Varco R.L.
      • Boen J.R.
      • et al.
      Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias.
      • Schwartz G.G.
      • Olsson A.G.
      • Ezekowitz M.D.
      • et al.
      Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) Study Investigators
      Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial.
      • Serruys P.W.
      • de Feyter P.
      • Macaya C.
      • et al.
      Lescol Intervention Prevention Study (LIPS) Investigators
      Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      The PROSPER study group. PROspective Study of Pravastatin in the Elderly at Risk
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      • Holdaas H.
      • Fellstrom B.
      • Jardine A.G.
      • et al.
      Assessment of Lescol in Renal Transplantation (ALERT) Study Investigators
      Effect of fluvastatin on cardiac outcomes in renal transplant recipients: a multicentre, randomised, placebo controlled trial.
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • et al.
      CARDS Investigators
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      • Baigent C.
      • Keech A.
      • Kearney P.M.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      • de Lemos J.A.
      • Blazing M.A.
      • Wiviott S.D.
      • et al.
      for the A to Z Investigators
      Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial.
      • Ray K.K.
      • Cannon C.P.
      • McCabe C.H.
      • et al.
      PROVE IT-TIMI 22 Investigators
      Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial.
      • Amarenco P.
      • Bogousslavsky J.
      • Callahan 3rd, A.
      • et al.
      High-dose atorvastatin after stroke or transient ischemic attack.
      • Mozaffarian D.
      • Appel L.J.
      • Van Horn L.
      Components of a cardioprotective diet: new insights.
      Furthermore, the relationship is present across the full spectrum of LDL-C and non–HDL-C levels (Fig. 7).
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      • Robinson J.G.
      • Wang S.
      • Smith B.J.
      • Jacobson T.A.
      Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk.
      • Baigent C.
      • Keech A.
      • Kearney P.M.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      • Boekholdt S.M.
      • Hovingh G.K.
      • Mora S.
      • et al.
      Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
      The Cholesterol Treatment Trialists' meta-analysis of more- vs less-intensive statin regimens demonstrated that a 1.0 mmol/L (38.7 mg/dL) change in LDL-C resulted in a 22% relative risk reduction (hazard ratio of 0.78) for major ASCVD events.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      In addition, there was no evidence of an LDL-C threshold within the range studied. Larger LDL-C reductions, for example 2 to 3 mmol/L (77.4–116.1 mg/dL), could yield up to 40% to 50% relative risk reduction for ASCVD.
      • 3.
        The intensity of risk-reduction therapy should generally be adjusted to the patient's absolute risk for an ASCVD event.
      Figure thumbnail gr4
      Figure 4Relationship between percent reduction in total cholesterol and percent reduction in coronary heart disease (CHD) incidence.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      Figure thumbnail gr5
      Figure 5Relationship between on-treatment low-density lipoprotein cholesterol (LDL-C) concentration and coronary heart disease (CHD) events in studies of primary prevention.
      • Shepherd J.
      • Cobbe S.M.
      • Ford I.
      • et al.
      Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group.
      • Downs J.R.
      • Clearfield M.
      • Weis S.
      • et al.
      Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
      • Sever P.S.
      • Dahlof B.
      • Poulter N.R.
      • et al.
      ASCOT Investigators
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower than average cholesterol concentrations in the ANGLO-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicenter randomised controlled trial.
      • Ridker P.M.
      • Danielson E.
      • Fonseca F.A.
      • et al.
      JUPITER Study Group
      Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein.
      Pl, placebo; Rx, treatment.
      Figure thumbnail gr6
      Figure 6Relationship between on-treatment low-density lipoprotein cholesterol (LDL-C) concentration and coronary heart disease (CHD) events in studies of secondary prevention.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      Scandinavian Simvastatin Survival Study Group
      Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      • Lewis S.J.
      • Moye L.A.
      • Sacks F.M.
      • et al.
      Effect of pravastatin on cardiovascular events in older patients with myocardial infarction and cholesterol levels in the average range. Results of the Cholesterol and Recurrent Events (CARE) trial.
      The Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID) Study Group
      Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      • Pedersen T.R.
      • Faergeman O.
      • Kastelein J.J.
      • et al.
      Incremental Decrease in End Points Through Aggressive Lipid Lowering (IDEAL) Study Group
      High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial.
      • LaRosa J.C.
      • Grundy S.M.
      • Waters D.D.
      • et al.
      Treating to New Targets (TNT) Investigators
      Intensive lipid lowering with atorvastatin in patients with stable coronary disease.
      Figure thumbnail gr7
      Figure 7Major CV event risk according to LDL-C and non–HDL-C levels achieved with statin therapy in a meta-analysis of statin trials.
      • Boekholdt S.M.
      • Hovingh G.K.
      • Mora S.
      • et al.
      Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
      CI, confidence interval; CV, cardiovascular; HR, hazard ratio; LDL-C, low-density lipoprotein cholesterol; non–HDL-C, non–high-density lipoprotein cholesterol; Ref, referent.
      Available therapeutic options for lowering atherogenic cholesterol and reducing risk for an ASCVD event include lifestyle and drug therapies. Lifestyle therapy is considered to be first-line intervention and is nearly universally acknowledged to be appropriate and necessary for the management of dyslipidemia among individuals ranging from lowest to highest risk for ASCVD.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      • Mozaffarian D.
      • Appel L.J.
      • Van Horn L.
      Components of a cardioprotective diet: new insights.
      • Lloyd-Jones D.M.
      • Hong Y.
      • Labarthe D.
      • et al.
      on behalf of the American Heart Association Strategic Planning Task Force and Statistics Committee
      Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic impact goal through 2020 and beyond.
      LDL-C (and non–HDL-C) reductions with lifestyle changes are most often in the range of 5% to 15%,
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      • Appel L.J.
      • Sacks F.M.
      • Carey V.J.
      • et al.
      OmniHeart Collaborative Research Group
      Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial.
      an amount that, if maintained over a long period, may result in meaningful ASCVD risk reduction.
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      • Brown M.S.
      • Goldstein J.L.
      Biomedicine. Lowering LDL—not only how low, but how long?.
      The relationship between the degree of change in atherogenic cholesterol concentration due to lifestyle changes and the difference in CHD risk aligns with the relationship for atherogenic cholesterol–lowering drug therapies.
      • Mozaffarian D.
      • Appel L.J.
      • Van Horn L.
      Components of a cardioprotective diet: new insights.
      However, in individuals at moderate to higher risk for ASCVD, a larger magnitude of atherogenic cholesterol lowering than can be achieved with lifestyle changes alone is generally warranted to substantially lower ASCVD risk. Decisions regarding the addition of atherogenic cholesterol–lowering drug therapy to lifestyle therapies for dyslipidemia management, as well as the intensity of the drug to be used, should include an investigation of the patient's absolute risk for ASCVD, including long-term risk (as described more fully within this document), tempered by clinical judgment and consideration of the interactions of cost, benefit, and safety of the drug therapies.
      • 4.
        Atherosclerosis is a process that often begins early in life and progresses for decades before resulting in a clinical ASCVD event. Therefore, both intermediate-term and long-term or lifetime risk should be considered when assessing the potential benefits and hazards of risk-reduction therapies.
      An early stage of atherosclerosis has been identified as fatty streaks in the coronary arteries of adolescents and young adults.
      • McGill Jr., H.C.
      • McMahan C.A.
      • Malcom G.T.
      • Oalmann M.C.
      • Strong J.P.
      for the PDAY Research Group
      Effects of serum lipoproteins and smoking on atherosclerosis in young men and women.
      • McGill Jr., H.C.
      • McMahan C.A.
      Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Determinants of atherosclerosis in the young.
      • McGill Jr., H.C.
      • McMahan C.A.
      • Zieske A.W.
      • et al.
      The Pathobiological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Associations of coronary heart disease risk factors with the intermediate lesion of atherosclerosis in youth.
      Long-term follow-up in prospective studies has demonstrated that elevated serum cholesterol in early adulthood predicted an increased incidence of CHD in middle age.
      • Anderson K.M.
      • Castelli W.P.
      • Levy D.
      Cholesterol and mortality: 30 years of follow-up from the Framingham Study.
      • Klag M.J.
      • Ford D.E.
      • Mead L.A.
      • et al.
      Serum cholesterol in young men and subsequent cardiovascular disease.
      • Stamler J.
      • Daviglus M.L.
      • Garside D.B.
      • Dyer A.R.
      • Greenland P.
      • Neaton J.D.
      Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.
      Thus, lowering serum cholesterol levels earlier in life is likely beneficial for altering long-term or lifetime risk for developing ASCVD. Clinical trials of statins generally indicate that each 1% decrease in LDL-C concentration is associated with about a 1% decrease in risk for CHD.
      • Law M.R.
      • Wald N.J.
      • Thompson S.G.
      By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease?.
      • Law M.R.
      • Wald N.J.
      • Rudnicka A.R.
      Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.
      However, results from epidemiologic and Mendelian randomization studies suggest a larger effect of lower LDL-C levels on CHD in groups with lower cholesterol levels throughout life.
      • Cohen J.C.
      • Boerwinkle E.
      • Mosley Jr., T.H.
      • Hoobs H.H.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      • Brown M.S.
      • Goldstein J.L.
      Biomedicine. Lowering LDL—not only how low, but how long?.
      • Keys A.
      • Menotti A.
      • Aravanis C.
      • et al.
      The seven countries study: 2,289 deaths in 15 years.
      This is consistent with the hypothesis that maintaining a lower serum cholesterol concentration for periods longer than the duration of typical clinical trials (averaging roughly 5 years) has the potential to yield a greater reduction in ASCVD risk than the approximate 1% to 1% relationship and supports the benefits of approaching risk-reduction therapy from a long-term or lifetime perspective.
      • Packard C.J.
      • Ford I.
      • Murray H.
      • McCowan C.
      Lifetime clinical and economic benefits of statin-based LDL lowering in the 20-year follow-up of the West of Scotland Coronary Prevention Study. Late-breaking clinical trial abstracts and clinical science special reports abstracts from the American Heart Association's Scientific Sessions 2014.
      • Toth P.P.
      • Thanassoulis G.
      • Williams J.
      • Furberg C.D.
      • Sniderman A.
      The risk-benefit paradigm vs the causal exposure paradigm: LDL as a primary cause of vascular disease.
      Many of the multivariate risk calculators that have been designed for clinical use in ASCVD risk assessment and to guide decisions for initiating drug therapy were created to predict intermediate-term (eg, 10 year) risk for an ASCVD event.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      • Goff Jr., D.C.
      • Lloyd-Jones D.M.
      • Bennett G.
      • et al.
      2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
      Short- and intermediate-term risk reduction has an important place in the management of dyslipidemia, particularly by reducing atherogenic cholesterol in patients with preexisting ASCVD to stabilize plaques and reduce the likelihood of acute coronary syndromes.
      • Brown B.G.
      • Zhao X.Q.
      Lipid therapy to stabilize the vulnerable atherosclerotic plaque: new insights into the prevention of cardiovascular events.
      However, some individuals with a relatively low intermediate-term risk for an ASCVD event may have substantially elevated lifetime risk because of the presence of multiple or severe ASCVD risk factor disturbances. This is particularly the case for men <40 years and women <50 years of age with multiple or severe ASCVD risk factors,
      • Lloyd-Jones D.M.
      • Leip E.P.
      • Larson M.G.
      • et al.
      Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age.
      • Pencina M.J.
      • D'Agostino Sr., R.B.
      • Larson M.G.
      • Massaro J.M.
      • Vasan R.S.
      Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study.
      • Choi J.
      • Daskalopoulou S.S.
      • Thanassoulis G.
      • et al.
      GENESIS-PRAXY Investigators
      Sex- and gender-related risk factor burden in patients with premature acute coronary syndrome.
      and the NLA Expert Panel concluded that consideration of long-term or lifetime risk in such patients is useful for guiding treatment decisions.
      • 5.
        For patients in whom lipid-lowering drug therapy is indicated, statin treatment is the primary modality for reducing ASCVD risk.
      Statins block hepatic cholesterol synthesis by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase and have been shown to reduce serum LDL-C levels by 18% to 55%, non–HDL-C by 15% to 51%, and triglycerides by 7% to 30% (in hypertriglyceridemia, the reduction is typically by 20% to 50%, particularly with high-potency statins) and increase HDL-C by 5% to 15% (compiled from prescribing information). A large body of RCT evidence demonstrates that statins are safe and generally well tolerated by most patients and that they decrease risk for ASCVD events in both primary and secondary prevention in amounts proportional to their atherogenic cholesterol lowering (Fig. 8).
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      • Grundy S.M.
      • Cleeman J.I.
      • Merz C.N.
      • et al.
      Coordination Committee of the National Cholesterol Education Program
      Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • et al.
      CARDS Investigators
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      • Baigent C.
      • Keech A.
      • Kearney P.M.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaborators
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists' Collaboration
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      For these reasons, they are considered to be first-line drug treatment in both primary and secondary prevention of ASCVD. Although the predominant action of statins for reducing ASCVD risk is by lowering atherogenic lipoprotein concentrations, they may also have pleiotropic effects.
      • Robinson J.G.
      • Smith B.
      • Maheshwari N.
      • Schrott H.
      Pleiotropic effects of statins: benefit beyond cholesterol reduction?.
      • Ma S.
      • Ma C.C.
      Recent development in pleiotropic effects of statins on cardiovascular disease through regulation of transforming growth factor-beta superfamily.
      • Porter K.E.
      • Turner N.A.
      Statins and myocardial remodelling: cell and molecular pathways.
      • Davignon J.
      Pleiotropic effects of pitavastatin.
      • Mihos C.G.
      • Pineda A.M.
      • Santana O.
      Cardiovascular effects of statins, beyond lipid-lowering properties.
      Figure thumbnail gr8
      Figure 8Effects of statin therapy on major vascular events.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      In the left panel, unweighted rate ratios (RRs) for each trial of the comparison of the first event rates between randomly allocated treatment groups are plotted along with 99% confidence intervals (CIs). Trials are ordered according to the absolute reduction in low-density lipoprotein cholesterol (LDL-C) at 1 year within each type of trial comparison (more vs less statin and statin vs control). In the right panel, RRs are weighted per 1.0 mmol/L LDL-C difference at 1 year. Subtotals and totals with 95% CIs are shown by open diamonds. Taken from Cholesterol Treatment Trialists' (CTT) Collaboration.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      Because of their favorable benefit to safety profile,
      • Jacobson T.A.
      NLA Task Force on Statin Safety—2014 update.
      moderate- and high-intensity statins are reasonable for most patients. However, in hypercholesterolemic patients who are statin intolerant,
      • Guyton J.R.
      • Bays H.E.
      • Grundy S.M.
      • Jacobson T.A.
      An assessment by the Statin Intolerance Panel: 2014 update.
      alternate atherogenic cholesterol–lowering drugs (eg, bile acid sequestrants, nicotinic acid, fibric acids, or cholesterol absorption inhibitor) or alternative statin dosing regimens may need to be considered.
      • 6.
        Nonlipid ASCVD risk factors should also be managed appropriately, particularly high blood pressure, cigarette smoking, and diabetes mellitus.
      Atherogenic cholesterol lowering is the focus of dyslipidemia management, and therapies to lower cholesterol will reduce ASCVD risk even in the presence of other risk factors.
      • Ahmed S.
      • Cannon C.P.
      • Murphy S.A.
      • Braunwald E.
      Acute coronary syndromes and diabetes: is intensive lipid lowering beneficial? Results of the PROVE IT-TIMI 22 trial.
      • Beckman J.A.
      • Paneni F.
      • Cosentino F.
      • Creager M.A.
      Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part II.
      • Bangalore S.
      • Fayyad R.
      • Laskey R.
      • et al.
      Treating to New Targets Steering Committee and Investigators
      Lipid lowering in patients with treatment-resistant hypertension: an analysis from the Treating to New Targets (TNT) trial.
      • Green J.B.
      Understanding the type 2 diabetes mellitus and cardiovascular disease risk paradox.
      However, nonlipid ASCVD risk factors contribute to the acceleration of atherosclerosis and development of acute coronary syndromes.
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      INTERHEART Study Investigators
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART Study): case-control study.
      • Skoumas I.
      • Masoura C.
      • Pitsavos C.
      • et al.
      Evidence that non-lipid cardiovascular risk factors are associated with high prevalence of coronary artery disease in patients with heterozygous familial hypercholesterolemia or familial combined hyperlipidemia.
      • Skoumas I.
      • Masoura C.
      • Aznaouridis K.
      • et al.
      Impact of cardiometabolic risk factors on major cardiovascular events in patients with familial combined hyperlipidemia.
      • González-Pacheco H.
      • Vargas-Barrón J.
      • Vallejo M.
      • et al.
      Prevalence of conventional risk factors and lipid profiles in patients with acute coronary syndrome and significant coronary disease.
      • Russo G.T.
      • Giandalia A.
      • Romeo E.L.
      • et al.
      Lipid and non-lipid cardiovascular risk factors in postmenopausal type 2 diabetic women with and without coronary heart disease.
      When identified, these risk factors, particularly high blood pressure, cigarette smoking, and diabetes mellitus, require management to maximize ASCVD risk reduction.
      • James P.A.
      • Oparil S.
      • Carter B.L.
      • et al.
      2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      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) final report.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      American Diabetes Association
      Standards of medical care in diabetes—2015. Section 8. Cardiovascular disease and risk management.
      • Ray K.K.
      • Seshasi S.R.K.
      • Wijesuriya S.
      • et al.
      Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomized controlled trials.
      • Mannucci E.
      • Dicembrini I.
      • Lauria A.
      • Pozzilli P.
      Is glucose control important for prevention of cardiovascular disease in diabetes?.
      American Diabetes Association
      Standards of medical care in diabetes—2014.
      • 7.
        The measurement and monitoring of atherogenic cholesterol levels remain an important part of a comprehensive ASCVD prevention strategy.
      Results from RCTs of a variety of atherogenic cholesterol–lowering therapies as well as results from observational studies have generally found that lower on-treatment atherogenic cholesterol levels are associated with lower ASCVD risk.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      Pooling Project Research Group
      Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the pooling project.
      • Stamler J.
      • Wentworth D.
      • Neaton J.D.
      Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      • Stamler J.
      • Daviglus M.L.
      • Garside D.B.
      • Dyer A.R.
      • Greenland P.
      • Neaton J.D.
      Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.
      This suggests that treatment goals and periodic monitoring of atherogenic cholesterol are useful for allowing a clinician to match the aggressiveness of lipid-lowering therapy to a patient's absolute risk for an ASCVD event and for assessing the adequacy of a patient's response and adherence to therapy. Treatment goals and monitoring of atherogenic cholesterol are particularly valuable tools in patient–clinician communication.

      Importance of lifestyle therapies

      A key tenet of the NLA Expert Panel recommendations is the centrality of lifestyle therapies to ASCVD prevention. Lifestyle therapies for ASCVD risk reduction generally include interventions aimed at (1) altering the composition of the diet; (2) reducing total energy intake to lower body weight and adiposity for those who are overweight or obese; (3) increasing physical activity; (4) improving risk factors associated with the metabolic syndrome (adiposity, dyslipidemia, high blood pressure, and elevated plasma glucose); and (5) ceasing tobacco use. The NLA Expert Panel's specific recommendations regarding lifestyle therapy, and the rationale for those recommendations, will be explained fully in part 2.
      The application of pharmacotherapy to dyslipidemia management has been enormously successful. Many large-scale RCTs, involving, in aggregate, hundreds of thousands of participants, have shown that drug therapies (particularly statins) that lower atherogenic cholesterol levels are effective for reducing ASCVD morbidity and mortality.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      • Mihaylova B.
      • Emberson J.
      • Blackwell L.
      • et al.
      Cholesterol Treatment Trialists' Collaboration
      The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials.
      RCT evidence from studies examining lifestyle changes, and dietary interventions in particular, for reducing ASCVD risk is relatively less robust.
      • Mozaffarian D.
      • Appel L.J.
      • Van Horn L.
      Components of a cardioprotective diet: new insights.
      • Robinson J.G.
      • Smith B.
      • Maheshwari N.
      • Schrott H.
      Pleiotropic effects of statins: benefit beyond cholesterol reduction?.
      Furthermore, many of these trials were conducted several decades ago when dietary habits were much different from the typical American diet of today,
      • Mozaffarian D.
      • Appel L.J.
      • Van Horn L.
      Components of a cardioprotective diet: new insights.
      • Law M.R.
      • Wald N.J.
      • Rudnicka A.R.
      Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.
      although results from some later RCTs also suggest benefits on ASCVD outcomes with dietary interventions.
      • de Lorgeril M.
      • Salen P.
      • Martin J.L.
      • Monjaud I.
      • Delaye J.
      • Mamelle N.
      Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.
      • de Lorgeril M.
      Mediterranean diet and cardiovascular disease: historical perspective and latest evidence.
      • Estruch R.
      • Ros E.
      • Salas-Salvado J.
      • et al.
      the PREDIMED Study Investigators
      Primary prevention of cardiovascular disease with a Mediterranean diet.
      Results from observational studies strongly suggest an influence of lifestyle habits on ASCVD outcomes that is likely to be mediated, at least in part, through effects on atherogenic cholesterol levels as well as other metabolic and hemodynamic disturbances such as obesity, hypertension, and insulin resistance.
      • Stampfer M.J.
      • Hu F.B.
      • Manson J.E.
      • Rimm E.B.
      • Willett W.C.
      Primary prevention of coronary heart disease in women through diet and lifestyle.
      • Hu F.B.
      • Willett W.C.
      Diet and coronary heart disease: findings from the Nurses' Health Study and Health Professionals' Follow-up Study.
      • Mozaffarian D.
      • Hao T.
      • Rimm E.B.
      • Willet W.C.
      • Hu F.B.
      Changes in diet and lifestyle and long-term weight gain in women and men.
      Thus, although drug therapy may be needed in those with sufficient risk, the NLA Expert Panel's consensus view is that lifestyle therapies are an important element of risk-reduction efforts, whether or not drug therapy is also used. The beneficial impact of lower atherogenic cholesterol levels for reducing ASCVD risk is also supported by genetic studies of individuals with PCSK9 mutations and with polymorphisms in the NPC1L1 protein, both of which result in reduced levels of LDL-C throughout life,
      • Cohen J.C.
      • Boerwinkle E.
      • Mosley Jr., T.H.
      • Hoobs H.H.
      Sequence variations in PCSK9, low LDL, and protection against coronary heart disease.
      • Ference B.A.
      • Majeed F.
      • Brook R.D.
      • Hedquist L.
      • Penumetcha R.
      • Flack J.M.
      Effect of naturally random allocation to lower LDL-C mediated polymorphisms in NPC1L1, HMGCR or both on the risk of coronary heart disease: a 2x2 factorial Mendelian randomization study.
      The Myocardial Infarction Genetics Consortium Investigators
      Inactivating mutations in NPC1L1 and protection from coronary heart disease.
      and by findings that genetic mutations resulting in modification of circulating levels of triglycerides and triglyceride-rich lipoprotein cholesterol (eg, variants associated with lipoprotein lipase, apo C3, and apo A5) are associated with altered ASCVD risk.
      • Varbo A.
      • Benn M.
      • Tybaerg-Hansen A.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • Nordestgaard B.G.
      Remnant cholesterol as a causal risk factor for ischemic heart disease.
      • Varbo A.
      • Benn M.
      • Nordestgaard B.G.
      Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment.
      • Nordestgaard B.G.
      • Varbo A.
      Triglycerides and cardiovascular disease.
      • Sarwar N.
      • Sanghu M.S.
      • Ricketts S.L.
      • et al.
      Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration
      Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies.
      • Johansen C.T.
      • Kathiresan S.
      • Hegele R.A.
      Genetic determinants of plasma triglycerides.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • West A.S.
      • Grande P.
      • Nordestgaard B.G.
      • Tybjaerg-Hansen A.
      Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction.
      • Jorgensen A.B.
      • Frikke-Schmidt R.
      • Nordestgaard B.C.
      • Tybjaerg-Hansen A.
      Loss-of-function mutations in APOC3 and risk of ischemic vascular disease.
      • Hegele R.A.
      • Ginsberg H.N.
      • Chapman M.J.
      • et al.
      on behalf of the European Atherosclerosis Society Consensus Panel
      The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.

      Usefulness of treatment goals

      Most RCTs of lipid-lowering drug therapies have tested drug treatment against a placebo control, or a more intensive with a less-intensive treatment regimen. The strategy of treating patients to a specific level of LDL-C or non–HDL-C has not been tested in any of the large trials assessing ASCVD morbidity and mortality. However, the lack of RCTs explicitly designed to test goals does not invalidate the considerable evidence supporting use of goals. Taken together, results from RCTs that have used various methods for lowering atherogenic cholesterol (pharmacotherapy, diet, and ileal bypass surgery) have indicated that lower on-treatment levels have been consistently associated with lower absolute risk for an ASCVD event.
      Expert Dyslipidemia Panel of the International Atherosclerosis Society Panel members
      An International Atherosclerosis Society Position Paper: global recommendations for the management of dyslipidemia—full report.
      • Robinson J.G.
      • Wang S.
      • Smith B.J.
      • Jacobson T.A.
      Meta-analysis of the relationship between non-high-density lipoprotein cholesterol reduction and coronary heart disease risk.
      • Baigent C.
      • Blackwell L.
      • Emberson J.
      • et al.
      Cholesterol Treatment Trialists' (CTT) Collaboration
      Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials.
      These findings align with results from observational studies that suggest a log-linear relationship between the levels of atherogenic cholesterol and absolute ASCVD event risk.
      Pooling Project Research Group
      Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the pooling project.
      • Stamler J.
      • Wentworth D.
      • Neaton J.D.
      Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).
      • Stamler J.
      • Daviglus M.L.
      • Garside D.B.
      • Dyer A.R.
      • Greenland P.
      • Neaton J.D.
      Relationship of baseline serum cholesterol levels in 3 large cohorts of younger men to long-term coronary, cardiovascular, and all-cause mortality and to longevity.
      The Expert Panel's consensus view is that treatment goals, which have been used historically by health care providers for the past ∼25 years, continue to be useful as a systematic means to ensure that the aggressiveness of therapy to lower atherogenic cholesterol is matched to absolute risk for an event.
      • Stine N.W.
      • Chokshi D.A.
      Elimination of lipid levels from quality measures. Implications and alternatives.
      Furthermore, the view is that using treatment goals, compared with prescribing moderate- to high-intensity statins without treatment targets, will not result in undertreatment as was suggested in the American College of Cardiology (ACC)/American Heart Association (AHA) 2013 dyslipidemia recommendations.
      • Stone N.J.
      • Robinson J.G.
      • Lichtenstein A.H.
      • 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.
      Moreover, treatment goals facilitate effective communication between patients and clinicians, providing an easily interpretable means through which the clinician can communicate progress toward meeting treatment objectives, thus supporting efforts to maximize long-term adherence to the treatment plan. Many patients have periods of nonadherence and nonpersistence with use of atherogenic cholesterol–lowering medications, including statins.
      • Cohen J.D.
      • Brinton E.A.
      • Ito M.K.
      • Jacobson T.A.
      Understanding Statin Use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users.
      • Wei M.Y.
      • Ito M.K.
      • Cohen J.D.
      • Brinton E.A.
      • Jacobson T.A.
      Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education.
      Follow-up cholesterol testing to monitor goal achievement may promote increased long-term adherence,
      • Brookhart M.A.
      • Patrick A.R.
      • Schneeweiss S.
      • et al.
      Physician follow-up and provider continuity are associated with long-term medication adherence. A study of the dynamics of statin use.
      which has been shown to increase the clinical benefits of statin use in primary and secondary ASCVD prevention patients.
      • Simpson R.J.
      • Mendys P.
      The effect of adherence and persistence on clinical outcomes in patients treated with statins: a systematic review.
      A very important point regarding the treatment goals recommended by the NLA Expert Panel is that the goal is less than the stated value. Simply achieving a non–HDL-C or LDL-C level equal to the threshold value of the treatment goal is not adequate or desirable, and, in some cases, the clinician may opt to treat to values well below the thresholds.

      Screening and classification of initial lipoprotein lipid levels

      In all adults (≥20 years of age), a fasting or nonfasting lipoprotein profile should be obtained at least every 5 years. At a minimum, this should include total cholesterol and HDL-C, which allows calculation of non-HDL-C (total-C – HDL-C). If fasting (generally 9–12 hours), the LDL-C level may be calculated, provided that the triglyceride concentration is <400 mg/dL.
      • Friedewald W.T.
      • Levy R.I.
      • Fredrickson D.S.
      Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge.
      • Martin S.S.
      • Blaha M.J.
      • Elshazly M.B.
      • et al.
      Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile.
      Classifications for lipoprotein lipid levels are shown in Table 1. Lipoprotein lipid levels should be considered in conjunction with other ASCVD risk determinants to assess treatment goals and strategies, as covered later in this report.
      Table 1Classifications of cholesterol and triglyceride levels in mg/dL
      Non–HDL-C
      Non–HDL-C = total cholesterol minus HDL-C.
       <130Desirable
       130–159Above desirable
       160–189Borderline high
       190–219High
       ≥220Very high
      LDL-C
       <100Desirable
       100–129Above desirable
       130–159Borderline high
       160–189High
       ≥190Very high
      HDL-C
       <40 (men)Low
       <50 (women)Low
      Triglycerides
       <150Normal
       150–199Borderline high
       200–499High
       ≥500Very high
      Severe hypertriglyceridemia is another term used for very high triglycerides in pharmaceutical product labeling.
      HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
      Non–HDL-C = total cholesterol minus HDL-C.
      Severe hypertriglyceridemia is another term used for very high triglycerides in pharmaceutical product labeling.
      If atherogenic cholesterol levels (non–HDL-C and LDL-C) are in the desirable range, lipoprotein lipid measurement and ASCVD risk assessment should be repeated in 5 years, or sooner based on clinical judgment. Examples of changes that might prompt earlier rescreening include changes in ASCVD risk factors (including weight gain), a premature ASCVD event in a first-degree relative, evidence of ASCVD in the patient, or a new potential secondary cause of dyslipidemia. For those with atherogenic cholesterol in the desirable range, public health recommendations regarding lifestyle should be emphasized. Chart 1 summarizes the recommendations for screening of initial lipoprotein lipid levels.
      Chart 1Recommendations for screening of initial lipoprotein lipid levels
      RecommendationsStrengthQuality
      A fasting or nonfasting lipoprotein profile including at least total-C and HDL-C should be obtained at least every 5 y.EModerate
      Lipoprotein lipid levels should be considered in conjunction with other ASCVD risk determinants to assess treatment goals and strategies.EModerate
      If non–HDL-C and LDL-C are in the desirable range, lipoprotein lipid measurement and ASCVD risk assessment should be repeated every 5 y, or sooner based on clinical judgment.EModerate
      For individuals with atherogenic cholesterol levels in the desirable range, public health recommendations regarding lifestyle should be emphasized.EModerate

      Targets of intervention in dyslipidemia management

      Non–HDL-C and LDL-C

      When intervention beyond public health recommendations for long-term ASCVD risk reduction is used, levels of atherogenic cholesterol (non–HDL-C and LDL-C) should be the primary targets for therapies. LDL is the major atherogenic lipoprotein carrying cholesterol in a majority of patients, and LDL-C comprises ∼75% of the cholesterol in circulation carried by lipoprotein particles other than HDL, although this percentage may be lower in those with hypertriglyceridemia. Although LDL-C has traditionally been the primary target of therapy in previous lipid guidelines and in the practice of clinical lipidology, the NLA Expert Panel's consensus view is that non–HDL-C is a better primary target for modification than LDL-C. Non–HDL-C comprises the cholesterol carried by all potentially atherogenic particles, including LDL, IDL, VLDL and VLDL remnants, chylomicron particles and chylomicron remnants, and Lp (a). Epidemiologic studies have shown that non–HDL-C is a stronger predictor of ASCVD morbidity and mortality than LDL-C.
      • Cui Y.
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      • et al.
      Non-high-density lipoprotein cholesterol level as a predictor of cardiovascular disease mortality.
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      • Grundy S.M.
      Non-high-density lipoprotein and very-low-density lipoprotein cholesterol and their risk predictive values in coronary heart disease.
      • Lu W.
      • Resnick H.E.
      • Jablonski K.A.
      • et al.
      Non-HDL cholesterol as a predictor of cardiovascular disease in type 2 diabetes: The Strong Heart Study.
      • Pischon T.
      • Girman C.J.
      • Sacks F.M.
      • Rifai N.
      • Stampfer M.J.
      • Rimm E.B.
      Non-high-density lipoprotein cholesterol and apolipoprotein B in the prediction of coronary heart disease in men.
      • Rallidis L.S.
      • Pitsavos C.
      • Panagiotakos D.B.
      • Sinos L.
      • Stefanadis C.
      • Kremastinos D.T.
      Non-high density lipoprotein cholesterol is the best discriminator of myocardial infarction in young individuals.
      • Blaha M.J.
      • Blumenthal R.S.
      • Brinton E.A.
      • Jacobson T.A.
      National Lipid Association Taskforce on Non-HDL Cholesterol. The importance of non-HDL cholesterol in reporting in lipid management.
      • Arsenault B.J.
      • Rana J.S.
      • Stroes E.S.
      • et al.
      Beyond low-density lipoprotein cholesterol: respective contributions of non-high-density lipoprotein cholesterol levels, triglycerides, and the total cholesterol/high-density lipoprotein cholesterol ratio to coronary heart disease risk in apparently healthy men and women.
      • Mahajan N.
      • Ference B.A.
      • Arora N.
      • et al.
      Role of non-high-density lipoprotein cholesterol in predicting cerebrovascular events in patients following myocardial infarction.
      • Kastelein J.J.
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      • Holme I.
      • et al.
      TNT Study Group; IDEAL Study Group
      Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment.
      Pooled analyses of data from intervention studies have shown that non–HDL-C changes and levels during treatment are at least as strongly associated with risk for CHD as changes in LDL-C or on-treatment levels of LDL-C.
      • Kastelein J.J.
      • van der Steeg W.A.
      • Holme I.
      • et al.
      TNT Study Group; IDEAL Study Group
      Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment.
      • Boekholdt S.M.
      • Arsenault B.J.
      • Mora S.
      • et al.
      Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
      Moreover, when on-treatment values are discordant (ie, only 1 of the 2 is elevated), risk is more closely aligned with non–HDL-C than LDL-C (Fig. 9).
      • Boekholdt S.M.
      • Arsenault B.J.
      • Mora S.
      • et al.
      Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
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      • Buring J.E.
      • Ridker P.M.
      Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women.
      Figure thumbnail gr9
      Figure 9Risk of major cardiovascular events by low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non-HDL-C) categories.
      • Boekholdt S.M.
      • Arsenault B.J.
      • Mora S.
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      Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
      Data markers indicate hazard ratios (HRs) and 95% confidence intervals (CIs) for risk of major cardiovascular events. Results are shown for 4 categories of statin-treated patients based on whether or not they reached the LDL-C target of 100 mg/dL and the non–HDL-C target of 130 mg/dL. HRs were adjusted for sex, age, smoking, diabetes, systolic blood pressure, and trial. Taken from Boekholdt SM et al.
      • Boekholdt S.M.
      • Arsenault B.J.
      • Mora S.
      • et al.
      Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
      with permission. Copyright © (2012) American Medical Association. All rights reserved.
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