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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.
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
Grade
Strength of recommendation
A
Strong 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
B
Moderate 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
C
Weak recommendation There is at least moderate certainty based on the evidence that there is a small net benefit
D
Recommend against There is at least moderate certainty based on the evidence that it has no net benefit or that the risks/harms outweigh benefits
E
Expert opinion There is insufficient evidence or evidence is unclear or conflicting, but this is what the expert panel recommends
N
No recommendation for or against There is insufficient evidence or evidence is unclear or conflicting
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).
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
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.
Well-designed, well-executed RCTs that adequately represent populations to which the results are applied and directly assess effects on health outcomes
High
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 results
Moderate
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 limitations
Low
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
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.
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).
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).
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.
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.
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).
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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).
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.
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 1US age-standardized death rates attributable to CVD, 2000 to 2010.
American Heart Association Statistics Committee and Stroke Statistics Subcommittee Heart disease and stroke statistics—2014 update; a report from the American Heart Association.
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.
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.
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).
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.
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.
Liposome-like particles isolated from human atherosclerotic plaques are structurally and compositionally similar to surface remnants of triglyceride-rich lipoproteins.
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.
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.
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.
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).
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.
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.
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.
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).
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.
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).
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.
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.
In patients with FH, the removal of apo B–containing lipoproteins by lipoprotein apheresis has been shown to markedly reduce arterial wall inflammation.
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.
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.
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.
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,
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.
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.
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).
Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment.
on behalf of the European Atherosclerosis Society Consensus Panel The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.
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.
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.
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.
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)
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.
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.
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).
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.
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.
JAMA.2005; 294 (Erratum in JAMA 2005;294:3092): 2437-2445
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.
Circulation.2014; 130 (Presented at AHA 2014. Chicago, IL): 2105-2126
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.
Coordination Committee of the National Cholesterol Education Program Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines.
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.
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).
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.
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.
JAMA.2005; 294 (Erratum in JAMA 2005;294:3092): 2437-2445
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.
Circulation.2014; 130 (Presented at AHA 2014. Chicago, IL): 2105-2126
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.
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.
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.
Lescol Intervention Prevention Study (LIPS) Investigators Fluvastatin for prevention of cardiac events following successful first percutaneous coronary intervention: a randomized controlled trial.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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 5Relationship between on-treatment low-density lipoprotein cholesterol (LDL-C) concentration and coronary heart disease (CHD) events in studies of primary prevention.
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.
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.
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).
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.
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.
JAMA.2005; 294 (Erratum in JAMA 2005;294:3092): 2437-2445
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.
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.
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.
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.
OmniHeart Collaborative Research Group Effects of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial.
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.
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.
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.
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.
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.
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.
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.
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.
Circulation.2014; 130 (Presented at AHA 2014. Chicago, IL): 2105-2126
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.
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.
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.
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,
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
INTERHEART Study Investigators Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART Study): case-control study.
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.
When identified, these risk factors, particularly high blood pressure, cigarette smoking, and diabetes mellitus, require management to maximize ASCVD risk reduction.
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).
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.
Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomized controlled trials.
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.
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).
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.
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.
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.
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.
Mediterranean diet, traditional risk factors, and the rate of cardiovascular complications after myocardial infarction: final report of the Lyon Diet Heart Study.
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.
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,
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.
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.
Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment.
on behalf of the European Atherosclerosis Society Consensus Panel The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.
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.
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.
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).
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.
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.
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.
Predictors of statin adherence, switching, and discontinuation in the USAGE survey: understanding the use of statins in America and gaps in patient education.
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.
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
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
Recommendations
Strength
Quality
A fasting or nonfasting lipoprotein profile including at least total-C and HDL-C should be obtained at least every 5 y.
E
Moderate
Lipoprotein lipid levels should be considered in conjunction with other ASCVD risk determinants to assess treatment goals and strategies.
E
Moderate
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.
E
Moderate
For individuals with atherogenic cholesterol levels in the desirable range, public health recommendations regarding lifestyle should be emphasized.
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.
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.
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.
Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
Lipoprotein particle profiles by nuclear magnetic resonance compared with standard lipids and apolipoproteins in predicting incident cardiovascular disease in women.
Figure 9Risk of major cardiovascular events by low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (non-HDL-C) categories.
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.
Association of LDL cholesterol, non-HDL cholesterol, and apolipoprotein B levels with risk of cardiovascular events among patients treated with statins: a meta-analysis.
Possible explanations for the superiority of non–HDL-C over LDL-C for predicting ASCVD event risk in those who are untreated and those receiving lipid-altering therapy include (1) as with LDL, some triglyceride-rich lipoprotein particles (remnants) enter the arterial wall and thus contribute to the initiation and progression of atherosclerosis; (2) non–HDL-C correlates more closely than LDL-C with apo B, thus may be a better indicator of the total burden of atherogenic particles
Statin therapy alters the relationship between apolipoprotein B and low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol targets in high-risk patients: the MERCURY II (Measuring Effective Reductions in Cholesterol Using Rosuvastatin) trial.
Correlation of non-high-density lipoprotein cholesterol and low-density lipoprotein cholesterol with apolipoprotein B during simvastatin + fenofibrate therapy in patients with combined hyperlipidemia (a subanalysis of the SAFARI trial).
Comparisons of apolipoprotein B levels estimated by immunoassay, nuclear magnetic resonance, vertical auto profile, and non-high-density lipoprotein cholesterol in subjects with hypertriglyceridemia (SAFARI Trial).
; (3) elevated levels of triglycerides and triglyceride-rich lipoprotein cholesterol indicate hepatic production of particles with greater atherogenic potential, such as those having poor interactivity with hepatic receptors, resulting in longer residence time in the circulation
; and (4) elevated levels of triglyceride-rich lipoproteins, particularly in the postprandial state, may trigger an inflammatory response by monocytes, increasing their propensity to become macrophages.
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