Abstract
An Expert Panel convened by the National Lipid Association previously developed a consensus set of recommendations for the patient-centered management of dyslipidemia in clinical medicine (part 1). These were guided by the principle that reducing elevated levels of atherogenic cholesterol (non–high-density lipoprotein cholesterol and low-density lipoprotein cholesterol) reduces the risk for atherosclerotic cardiovascular disease. This document represents a continuation of the National Lipid Association recommendations developed by a diverse panel of experts who examined the evidence base and provided recommendations regarding the following topics: (1) lifestyle therapies; (2) groups with special considerations, including children and adolescents, women, older patients, certain ethnic and racial groups, patients infected with human immunodeficiency virus, patients with rheumatoid arthritis, and patients with residual risk despite statin and lifestyle therapies; and (3) strategies to improve patient outcomes by increasing adherence and using team-based collaborative care.
Keywords
Introduction
In 2014, the National Lipid Association (NLA) convened an Expert Panel to develop a consensus set of recommendations for the patient-centered management of dyslipidemia (Part 1).
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The evidence base used was derived from randomized controlled trials (RCTs), meta-analyses of results from RCTs, and review of results from observational, genetic, metabolic, and mechanistic studies. Based on the totality of evidence, the Part 1 NLA Recommendations for Patient-Centered Management of Dyslipidemia laid out several conclusions and core principles.- 1.An elevated level of cholesterol carried by circulating apolipoprotein (apo) B-containing lipoproteins (non-high-density lipoprotein cholesterol [non-HDL-C] 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;
- 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 in a clinical ASCVD event. Therefore, both intermediate-term and long-term/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.Treatment goals and periodic monitoring of atherogenic cholesterol levels (non-HDL-C and LDL-C) are important tools in the implementation of a successful treatment strategy. These aid the clinician in assessing the adequacy of treatment and facilitate active participation by the patient through feedback and reinforcement of the beneficial effects of lifestyle and pharmaceutical therapies; and
- 7.Non-lipid ASCVD risk factors should also be managed appropriately, particularly high blood pressure, cigarette smoking, and diabetes mellitus.
The NLA Part 1 Recommendations emphasize the importance of taking a patient-centered approach in counseling patients about the benefits and hazards of lifestyle and drug therapies. Using the principle of shared decision making, the patient should be an active participant in the process, engaging with the clinician in a dialogue about the objectives and potential benefits of therapy, as well as risks, side effects, and costs. The initial step is a determination of the patient's risk for an ASCVD event (Table 1).
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Lifestyle counseling is a key element of preventive efforts at all levels of risk, and dietary adjuncts may be used to enhance atherogenic cholesterol reduction. If lifestyle therapies, including dietary adjuncts, are insufficient to achieve desired levels of atherogenic cholesterol, evidence-based drug therapy, particularly moderate- to high-intensity statin therapy should be considered. If goal levels of atherogenic cholesterol are not achieved with maximally tolerated statin therapy, combining a statin with a second (and sometimes a third) agent may be considered for selected patients. Alternative strategies may be needed for patients who are statin intolerant, or who prefer not to use statin therapy. Lastly, regular patient and lipid follow-up is warranted to assess adherence and adequacy of the atherogenic cholesterol responses to therapy.Table 1NLA Part 1 Recommendations for Patient-Centered Management of Dyslipidemia–Criteria for ASCVD risk assessment, treatment goals for atherogenic cholesterol, and levels at which to consider drug therapy
| Risk category | Criteria | Treatment goal | Consider drug therapy |
|---|---|---|---|
| Non–HDL-C, mg/dL LDL-C, mg/dL | Non–HDL-C, mg/dL LDL-C, mg/dL | ||
| Low | • 0–1 major ASCVD risk factors | <130 | ≥190 |
| • Consider other risk indicators, if known | <100 | ≥160 | |
| Moderate | • 2 major ASCVD risk factors | <130 | ≥160 |
| • Consider quantitative risk scoring | <100 | ≥130 | |
| • Consider other risk indicators | |||
| High | • ≥3 major ASCVD risk factors | <130 | ≥130 |
| • Diabetes mellitus (type 1 or 2) | <100 | ≥100 | |
| ○ 0–1 other major ASCVD risk factors and | |||
| ○ No evidence of end-organ damage | |||
| • Chronic kidney disease stage 3B or 4 ‡ For patients with chronic kidney disease (CKD) stage 3B (estimated glomerular filtration rate [eGFR], 30–44 mL/min/1.73 m2) or stage 4 (eGFR, 15–29 mL/min/1.73 m2) risk calculators should not be used because they may underestimate risk. Stage 5 CKD (or on hemodialysis) is a very high-risk condition, but results from randomized, controlled trials of lipid-altering therapies have not provided convincing evidence of reduced ASCVD events in such patients. Therefore, no treatment goals for lipid therapy have been defined for stage 5 CKD. | |||
| • LDL-C of ≥190 mg/dL (severe hypercholesterolemia) § If LDL-C is ≥190 mg/dL, consider severe hypercholesterolemia phenotype, which includes familial hypercholesterolemia. Lifestyle intervention and pharmacotherapy are recommended for adults with the severe hypercholesterolemia phenotype. If it is not possible to attain desirable levels of atherogenic cholesterol, a reduction of at least 50% is recommended. For familial hypercholesterolemia patients with multiple or poorly controlled other major ASCVD risk factors, clinicians may consider attaining even lower levels of atherogenic cholesterol. Risk calculators should not be used in such patients. | |||
| • Quantitative risk score reaching the high-risk threshold High-risk threshold is defined as ≥10% using Adult Treatment Panel III Framingham Risk Score for hard coronary heart disease (CHD; myocardial infarction or CHD death), ≥15% using the 2013 Pooled Cohort Equations for hard ASCVD (myocardial infarction, stroke, or death from CHD or stroke), or ≥45% using the Framingham long-term cardiovascular disease (myocardial infarction, CHD death or stroke) risk calculation. Clinicians may prefer to use other risk calculators, but should be aware that quantitative risk calculators vary in the clinical outcomes predicted (eg, CHD events, ASCVD events, cardiovascular mortality); the risk factors included in their calculation; and the timeframe for their prediction (eg, 5 years, 10 years, or long-term or lifetime). Such calculators may omit certain risk indicators that can be very important in individual patients, provide only an approximate risk estimate, and require clinical judgment for interpretation. | |||
| Very high | • ASCVD | <100 | ≥100 |
| • Diabetes mellitus (type 1 or 2) | <70 | ≥70 | |
| ○ ≥2 other major ASCVD risk factors or | |||
| ○ Evidence of end-organ damage | |||
| For patients with ASCVD or diabetes mellitus, consideration should be given to use of moderate or high-intensity statin therapy, irrespective of baseline atherogenic cholesterol levels. | |||
ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.
Taken from Jacobson TA, et al. J Clin Lipidol. 2015;9:129–169.
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∗ For those at moderate risk, additional testing may be considered for some patients to assist with decisions about risk stratification.
† For patients with diabetes plus 1 major ASCVD risk factor, treating to a non–HDL-C goal of <100 mg/dL (LDL-C of <70 mg/dL) is considered a therapeutic option.
‡ For patients with chronic kidney disease (CKD) stage 3B (estimated glomerular filtration rate [eGFR], 30–44 mL/min/1.73 m2) or stage 4 (eGFR, 15–29 mL/min/1.73 m2) risk calculators should not be used because they may underestimate risk. Stage 5 CKD (or on hemodialysis) is a very high-risk condition, but results from randomized, controlled trials of lipid-altering therapies have not provided convincing evidence of reduced ASCVD events in such patients. Therefore, no treatment goals for lipid therapy have been defined for stage 5 CKD.
§ If LDL-C is ≥190 mg/dL, consider severe hypercholesterolemia phenotype, which includes familial hypercholesterolemia. Lifestyle intervention and pharmacotherapy are recommended for adults with the severe hypercholesterolemia phenotype. If it is not possible to attain desirable levels of atherogenic cholesterol, a reduction of at least 50% is recommended. For familial hypercholesterolemia patients with multiple or poorly controlled other major ASCVD risk factors, clinicians may consider attaining even lower levels of atherogenic cholesterol. Risk calculators should not be used in such patients.
|| High-risk threshold is defined as ≥10% using Adult Treatment Panel III Framingham Risk Score for hard coronary heart disease (CHD; myocardial infarction or CHD death), ≥15% using the 2013 Pooled Cohort Equations for hard ASCVD (myocardial infarction, stroke, or death from CHD or stroke), or ≥45% using the Framingham long-term cardiovascular disease (myocardial infarction, CHD death or stroke) risk calculation. Clinicians may prefer to use other risk calculators, but should be aware that quantitative risk calculators vary in the clinical outcomes predicted (eg, CHD events, ASCVD events, cardiovascular mortality); the risk factors included in their calculation; and the timeframe for their prediction (eg, 5 years, 10 years, or long-term or lifetime). Such calculators may omit certain risk indicators that can be very important in individual patients, provide only an approximate risk estimate, and require clinical judgment for interpretation.
¶ End-organ damage indicated by increased albumin-to-creatinine ratio (≥30 mg/g), CKD (eGFR, <60 mL/min/1.73 m2), or retinopathy.
NLA Part 2 recommendations
The creation of the NLA Part 2 Recommendations for Patient-Centered Management of Dyslipidemia was intended to expand upon the NLA Part 1 Recommendations in areas where clinicians may desire additional guidance, particularly where the evidence base is less robust or is lacking results from RCTs on clinical ASCVD events to guide clinical decisions. Based on feedback from NLA members and other important stakeholders, several major content areas were identified for inclusion.
- 1.Lifestyle therapies–nutrition and exercise/physical activity;
- 2.Groups with special considerations that span the lifespan from children to seniors and from pregnancy to menopause;
- 3.Ethnic groups including Hispanics/Latinos, African Americans (AAs), South Asians (SAs), and American Indians (AIs)/Alaska Natives (ANs);
- 4.Groups with increased ASCVD risk, including patients with human immunodeficiency virus (HIV), rheumatologic disease, and those with high residual risk despite statin and lifestyle therapies; and
- 5.Strategies to improve patient outcomes centered on improving adherence and maximizing team-based collaborative care.
NLA Part 2 represents a continuation of previous NLA recommendations developed by a diverse and interdisciplinary panel of experts. The process began with appointment of an executive Steering Committee. Section Chairs and Expert Panel members with expertise in core topic areas were identified and approved by the Steering Committee (Table 2). After an initial draft of the consensus recommendations was compiled, this was made available to the public for an open comment period. Input was solicited from stakeholders, including the general public, NLA members, other professional societies, and governmental agencies. Comments and suggestions were then collated for adjudication by the NLA Expert Panel members, and final recommendations were presented to the NLA Board for approval.
Table 2NLA Part 2 Recommendations for Patient-Centered Management of Dyslipidemia–Expert Panel
| NLA expert panel steering committee members Terry A. Jacobson, MD, FNLA, Chair; Kevin C. Maki, PhD, CLS, FNLA; Carl Orringer, MD, FNLA; Peter Jones, MD, FNLA I. Lifestyle therapies section Nutrition Penny Kris-Etherton, PhD, RDN, CLS, FNLA, Co-Chair; Geeta Sikand, MA, RDN, CLS, FNLA, Co-Chair; Kevin C. Maki, PhD, CLS, FNLA, Co-Chair; Julie Bolick, MS, RDN, CLS, FNLA; Mary R. Dicklin, PhD; Carol Kirkpatrick, PhD, RDN, CLS, FNLA; Katherine Rhodes, PhD, RDN; Nancy T. Smith, MS, RDN, CDE, CLS Exercise Ralph La Forge, MSc, FNLA, Chair; Kevin C. Maki, PhD, FNLA II. The lifespan—children to seniors section Children and adolescents Stephen Daniels, MD, PhD, FNLA, Co-Chair; Don Wilson, MD, FNLA, Co-Chair; Piers Blackett, MD, FNLA; Sarah DeFerranti, MD; Samuel Gidding MD, FNLA; Rae-Ellen W. Kavey, MD, MPH; Brian McCrindle, MD; Catherine McNeal, MD, PhD, FNLA; Elaine Urbina, MD Women's health Pamela Morris, MD, FNLA, Chair From pregnancy to menopause Robert Wild, MD, MPH, PhD, FNLA, NCMP, Chair; Thomas Dayspring, MD, FNLA, NCMP; James A. Underberg, MS, MD, FNLA Older patients Carl Orringer, MD, FNLA, Co-Chair; Scott Grundy, MD, PhD, FNLA, Co-Chair; Joyce Ross, MSN, CRNP, FNLA III. Ethnic and racial groups section Hispanics/Latinos Martha Daviglus, MD, PhD, Chair; J Antonio G. Lopez, MD, FNLA; Amber Pirzada, MD; Carlos Jose Rodriguez, MD, MPH, FACC African Americans Keith Ferdinand, MD, FNLA, Chair South Asians Kris Vijay, MD, FNLA, Co-Chair; Prakash Deedwania, MD, Co-Chair American Indians/Alaska Natives Kevin C. Maki, PhD, FNLA, Co-Chair; Ralph La Forge, MSc, FNLA, Co-Chair IV. High-risk conditions and residual risk section HIV-infected persons Judith Aberg, MD, Chair; Carl J. Fichtenbaum, MD; Joel E. Gallant, MD; Michael A. Horberg, MD; Christopher T. Longenecker, MD; Merle Myerson, MD, FNLA; E. Turner Overton, MD Patients with rheumatoid arthritis Katherine Liao, MD, MPH, Chair; Jonathon S. Coblyn, MD; Jeffrey Curtis, MD, MS, MPH; Jorge Plutzky, MD, FNLA; Daniel Solomon, MD, MPH Patients with residual risk despite statin and lifestyle therapy Peter Jones, MD, FNLA, Co-Chair; James McKenney, PharmD, FNLA, Co-Chair V. Improving patient outcomes section Patient adherence Joyce Ross, MSN, CRNP, FNLA, Co-Chair; Lynne Braun, PhD, CNP, FNLA, Co-Chair Team-based collaborative care Lynne Braun, PhD, CNP, FNLA, Co-Chair; Matthew Ito, PharmD, FNLA, Co-Chair; Joyce Ross, MSN, CRNP, FNLA, Co-Chair VI. Additional general panel members Harold Bays, MD, FNLA; W. Virgil Brown, MD, FNLA |
HIV, human immunodeficiency virus; NLA, National Lipid Association.
The NLA Expert Panel graded the recommendations using an adapted grading system from both the National Heart, Lung, and Blood Institute's Evidence-Based Methodology Team
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, 3
and the Grading of Recommendations Assessment, Development and Evaluation system of evidence rating (Table 3).- 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.
J Am Coll Cardiol. 2014; 63: 2889-2934
4
For each recommendation, the strength of the recommendation was assigned, with consideration given to the “net benefit” after taking into account potential benefits and risks or harms associated with the service or intervention. The quality of the evidence rating was determined using the rating system developed by the National Heart, Lung, and Blood Institute's Evidence-Based Methodology Panel, as published in the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults.3
- 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.
J Am Coll Cardiol. 2014; 63: 2889-2934
Table 3Grading of the strength of recommendations and quality of evidence
Permission to reuse table granted from the American Medical Association.
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Taken from Jacobson TA, et al. J Clin Lipidol. 2015;9:129–169.- 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.
J Am Coll Cardiol. 2014; 63: 2889-2934
1
Originally published in James PA, et al. JAMA. 2014;311:507–520 and Stone NJ, et al. J Am Coll Cardiol. 2014;63(25 Pt B):2889–2934.2
, 3
- 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.
J Am Coll Cardiol. 2014; 63: 2889-2934
| Evidence 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 thè new American Heart Association/American College of Cardiology cholesterol guidelines3 and adapted from the original GRADE system of evidence rating.4 | |
|---|---|
| Grade | Strength of recommendation |
| A | Strong recommendation |
| There is high certainty based on the evidence that the net benefit 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 | |
| Evidence grading: quality of evidence | |
| Type of evidence | Quality 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. |
| Well-designed, well-executed RCTs that adequately represent populations to which the results are applied and directly assess effects on health outcomes 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 | High |
| RCTs with minor limitations affecting confidence in, or applicability of, the results 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 | Moderate |
| RCTs with major limitations 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 | Low |
RCT, randomized controlled trial.
This was the system used in the new American Heart Association/American College of Cardiology cholesterol guidelines
3
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.- 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.
J Am Coll Cardiol. 2014; 63: 2889-2934
3
- 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.
J Am Coll Cardiol. 2014; 63: 2889-2934
∗ The system was adapted as a hybrid of the National Heart Lung and Blood Institutes (NHLBI) rating System (NHLBI cardiovascular-based methodology) used in thè new American Heart Association/American College of Cardiology cholesterol guidelines
3
and adapted from the original GRADE system of evidence rating.- 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.
J Am Coll Cardiol. 2014; 63: 2889-2934
4
† Net benefit is defined as benefits minus risks/harms of the service/intervention.
‡ 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.
Lifestyle therapies
Lifestyle therapies are central to dyslipidemia management and should be advised for all patients, whether or not drug therapy is also prescribed. As outlined in Part 1 of the NLA Recommendations for Patient-Centered Management of Dyslipidemia,
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a trial of lifestyle therapies should be attempted prior to use of drug therapy for most patients. Exceptions include patients at very high or high risk for whom clinicians may wish to simultaneously begin lifestyle and drug therapies.Targets of lifestyle therapies and rationale for their use
The targets of lifestyle therapies will principally be levels of atherogenic cholesterol, which include LDL-C and non-HDL-C. The non-HDL-C concentration is comprised mainly of LDL-C and very low-density lipoprotein cholesterol (VLDL-C) levels. VLDL-C concentration is highly correlated with the circulating level of triglycerides (TG). The TG level per se is not a recommended target of therapy, except when very high (≥500 mg/dL). In these patients, lowering the TG concentration to <500 mg/dL is the primary objective of therapy to reduce the risk of acute pancreatitis. When the TG level is < 500 mg/dL, attaining goal levels of atherogenic cholesterol is the main objective of therapy. High-density lipoprotein cholesterol (HDL-C) is not a target of therapy, although low HDL-C is a strong predictor of ASCVD event risk. Lifestyle changes that lower levels of atherogenic cholesterol often alter HDL-C, but the clinical relevance of these changes is uncertain at present. Additional targets of lifestyle interventions include excess adiposity for those who are overweight or obese, and other ASCVD risk factors, such as elevated blood pressure, hyperglycemia (and diabetes), and smoking. The focus of the evidence summarized below is on the influence of lifestyle interventions on lipoprotein lipid levels, but clinicians should be aware that changes in other risk factors contribute to ASCVD risk.
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Limited evidence is available from randomized clinical trials to assess the impacts of lifestyle therapies on ASCVD event risk. However, evidence from epidemiologic studies consistently supports a strong relationship between circulating levels of atherogenic cholesterol and ASCVD event risk.
1
, 5
, 6
In particular, studies of genetic variants that influence LDL-C and VLDL-C levels show that even relatively small differences in these lipoprotein lipid levels are associated with changes in ASCVD event risk.7
, - Ference B.A.
- Majeed F.
- Brook R.D.
- Hedquist L.
- Penumetcha R.
- Flack J.M.
Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR or both: a 2x2 factorial Mendelian randomization study.
J Am Coll Cardiol. 2015; 65: 1552-1561
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, 9
Moreover, the differences in ASCVD risk for a given difference in atherogenic cholesterol level produced by genetic variants is larger than would be predicted from RCTs of lipid-altering drug therapies.7
, - Ference B.A.
- Majeed F.
- Brook R.D.
- Hedquist L.
- Penumetcha R.
- Flack J.M.
Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR or both: a 2x2 factorial Mendelian randomization study.
J Am Coll Cardiol. 2015; 65: 1552-1561
8
, 10
, - Brown B.G.
- Stukovsky K.H.
- Zhao X.Q.
Simultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials.
Curr Opin Lipidol. 2006; 17: 631-636
11
In RCTs, each reduction of 1% in LDL-C or non-HDL-C is associated with a 1% reduction in coronary heart disease (CHD) event risk over a period of ∼5 years.12
, 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.
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.
Circulation. 2002; 106: 3143-3421
13
Genetic variants that alter LDL-C have a stronger association with CHD event risk than would be predicted based on RCT results, generally showing that each 1% difference in LDL-C induced by genetic variants is associated with a 2–3% difference in CHD risk.10
, - Brown B.G.
- Stukovsky K.H.
- Zhao X.Q.
Simultaneous low-density lipoprotein-C lowering and high-density lipoprotein-C elevation for optimum cardiovascular disease prevention with various drug classes, and their combinations: a meta-analysis of 23 randomized lipid trials.
Curr Opin Lipidol. 2006; 17: 631-636
11
These findings are consistent with the hypothesis that relatively small differences in levels of atherogenic cholesterol have important impacts on ASCVD risk if maintained over an extended period. They also suggest that results from intervention studies lasting only ∼5 years likely underestimate the potential benefit of decades-long exposure to lower levels of atherogenic lipoprotein cholesterol levels.Genetic variants that alter VLDL-C, without affecting LDL-C, are also associated with differences in ASCVD event risk. The magnitude of the differences observed with genetically induced differences in VLDL-C are at least as large as those associated with differences in LDL-C for a given mg/dL difference.
9
, 14
For example, in the Copenhagen Heart Studies, each 38.7 mg/dL (1 mmol/L) difference in LDL-C was associated with a 47% difference in CHD event risk. However, each 38.7 mg/dL (1 mmol/L) difference in VLDL-C (referred to as remnant cholesterol by the investigators) was associated with a CHD risk difference of 182%.9
These findings are consistent with a causal role for VLDL-C (or some variable closely correlated with VLDL-C) in ASCVD event risk, and support the importance of both LDL-C and non-HDL-C (the sum of LDL-C and VLDL-C) as targets of therapy.In addition to strong and consistent associations in observational studies between levels of atherogenic cholesterol and ASCVD event risk, the diet and lifestyle patterns recommended based on their ability to lower levels of atherogenic cholesterol in RCTs have also been associated with lower ASCVD risk in observational studies.
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, 16
, 17
These findings are almost certainly explained in part by associations with major ASCVD risk factors, such as lipoprotein lipid and blood pressure levels. However, the recommended lifestyle patterns have also been linked with potentially favorable differences in emerging and non-traditional ASCVD risk factors, including markers of insulin resistance, inflammation, thrombogenicity, and oxidative stress.18
Therefore, clinicians should be aware that effective lifestyle therapies elicit changes in biochemical parameters with potential clinical relevance beyond those that are typically measured in clinical practice.Counseling on implementation of lifestyle changes
Patients with dyslipidemia, metabolic syndrome, overweight or obesity should be referred for lifestyle modification counseling whenever possible. A registered dietitian nutritionist plays an important role in counseling the patient to develop and implement an individualized cardioprotective eating plan (i.e., medical nutrition therapy [MNT] for dyslipidemia). Other health professionals, such as an exercise specialist, behavioral health specialist, social worker and/or psychologist, also are important in achieving physical activity/exercise goals, stress management, identification and management of triggers for unhealthy eating patterns, and tobacco cessation.
General principles for a healthy lifestyle
The 2010 Dietary Guidelines for Americans (DGA) present general principles for a healthy lifestyle.
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They emphasize a balance between energy intake and expenditure to maintain a healthy body weight. This includes controlling energy intake to avoid weight gain and assist with weight loss in overweight/obese persons, maintaining adequate physical activity, and minimizing time spent in sedentary behaviors as also recommended by the American College of Sports MedicineU.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans – 2010. Available at: http://www.cnpp.usda.gov/dietary-guidelines-2010. Accessed June 28, 2015.
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and the American Council on Exercise.21
The DGA also emphasize avoiding excessive sodium intake, limiting consumption of energy from saturated fats, trans fats, added sugars, refined grains, and for adults who choose to consume alcohol, to do so in moderation. The DGA emphasize consuming fruits and vegetables; nuts, peas and legumes; whole grains; lean sources of protein; low-fat or fat-free dairy products; seafood; and liquid vegetable oils. Recommended macronutrient ranges for adults are 45–65% of energy from carbohydrate, 10–35% from protein, and 20–35% of energy from fat. As of this writing, the 2015 DGA had not yet been released, but the 2015 Dietary Guidelines Advisory Committee's (DGAC) Scientific Report recommended removal of the upper limit for dietary fat to allow greater flexibility, particularly with regard to reducing intakes of cholesterol-raising (12–16 carbon saturated and trans unsaturated) fatty acids and refined grains and sugars.22
In place of these dietary components, greater emphasis is placed on increasing consumption of foods containing unsaturated fatty acids, such as nuts and liquid vegetable oils.22
Lifestyle therapies for dyslipidemia management
The NLA Expert Panel recommends lifestyle therapies as an integral component of treatment plans for management of dyslipidemia and ASCVD event risk reduction at all levels of risk. For lowering levels of atherogenic cholesterol, the main features include a cardioprotective dietary pattern low in cholesterol-raising fatty acids (<7% of energy from saturated fatty acids and minimal intake of trans unsaturated fatty acids) and dietary cholesterol (<200 mg/day), as well as regular physical activity (at least 150 min per week of moderate or higher intensity activity). Dietary adjuncts, including plant sterols/stanols and viscous fibers, may be used to enhance the reductions in atherogenic cholesterol. Energy restriction and further increases in physical activity are recommended for overweight or obese patients for whom weight loss and additional reductions in atherogenic cholesterol levels are desired. These lifestyle interventions should be implemented within the general principles outlined above from the 2010 DGA. Reviews of the evidence in support of specific recommendations and additional details about their implementation are outlined below.
Nutrition
Dietary patterns to reduce risk of ASCVD
The focus of much contemporary nutrition research is on dietary patterns because they represent the totality of the diet, including the myriad of combinations and quantities of foods and nutrients that are consumed.
23
There is evidence that particular dietary patterns, as well as specific nutrients (and also physical activity), play significant roles in the prevention and treatment of ASCVD by beneficially modifying major ASCVD risk factors, particularly lipoprotein lipids and blood pressure.Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Available at: http://www.health.gov/dietaryguidelines/2015-scientific-report/. Accessed March 12, 2015.
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- Eckel R.H.
- Jakicic J.M.
- Ard J.D.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014; 63: 2960-2984
Recommended dietary patterns share many characteristics. For example, the 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk
24
made the following recommendation, which is similar to other recommended diets (described below):- Eckel R.H.
- Jakicic J.M.
- Ard J.D.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014; 63: 2960-2984
Advise adults who would benefit from LDL-C lowering to consume a dietary pattern that emphasizes intake of vegetables, fruits and whole grains; includes low-fat dairy products, poultry, fish, legumes, non-tropical vegetable oils and nuts; and limits intakes of sweets, sugar-sweetened beverages and red meats. The dietary patterns that are recommended and representative of these foods/food groups are the DASH dietary pattern, the USDA Food Pattern, or the AHA diet. These recommended dietary patterns provide 5–6% of calories from saturated fat and are low in trans fats.
Dietary Approaches to Stop Hypertension (DASH) dietary patterns
The DASH dietary pattern emphasizes consumption of vegetables, fruits, and low-fat milk and dairy products; includes whole grains, poultry, seafood, and nuts; and is lower in sodium, red and processed meats, sweets, and sugar-containing beverages (e.g., soda, juice drinks). The DASH dietary pattern assessed in the initial DASH RCTs provides approximately 27% of calories from total fat (6% saturated fatty acids, 13% monounsaturated fatty acids [MUFA], 8% polyunsaturated fatty acids [PUFA]), 58% of calories from carbohydrate, and 15% of calories from protein.
25
, 26
Two DASH dietary pattern variations include replacing 10% of total energy from carbohydrate with either protein or unsaturated fat.27
United States Department of Agriculture (USDA) food patterns
The USDA food patterns recommend daily amounts of foods from the 5 major food groups (vegetables, fruits, grains, dairy products, and protein foods).
19
The patterns include an allowance for liquid vegetable oils (and spreads made from liquid vegetable oils) and limitations on the quantity of calories consumed from solid fats and added sugars.U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans – 2010. Available at: http://www.cnpp.usda.gov/dietary-guidelines-2010. Accessed June 28, 2015.
AHA diet patterns
The AHA diet patterns
24
, - Eckel R.H.
- Jakicic J.M.
- Ard J.D.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014; 63: 2960-2984
28
recommend balancing energy intake and physical activity to achieve and maintain a healthy body weight; consuming a diet rich in vegetables and fruits; choosing whole-grain, high-fiber foods; consuming fish, especially oily fish, at least twice a week; and limiting intake of saturated fat, trans (partially hydrogenated) fat, and cholesterol by choosing lean meats and non-meat alternatives and fat-free (skim) or low-fat (1% fat) dairy products. The AHA diet patterns further recommend minimizing intake of beverages and foods with added sugars and salt, and suggest that, if alcohol is consumed, this should be done in moderation (and only by adults of legal drinking age).The 2015 DGAC Scientific Report
The 2015 DGAC
23
evaluated 3 dietary patterns, all of which have been associated with health benefits. These are the healthy US.-style pattern, the healthy Mediterranean-style pattern, and the healthy vegetarian pattern. These have similar food-based characteristics to those defined by the 2013 AHA/ACC Guideline on Lifestyle Management and, compared to the average American diet, are higher in vegetables, fruits, and whole grains; low- or non-fat dairy; seafood, legumes, and nuts; moderate in alcohol (for adults); lower in red and processed meats; and low in sugar-sweetened foods/drinks and refined grains. The Committee specified that: “A healthy diet can be achieved in multiple ways and preferably with a wide variety of foods and beverages. Optimal nutrition can be attained with many dietary patterns and a single dietary pattern or approach or prescription is unnecessary.”Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Available at: http://www.health.gov/dietaryguidelines/2015-scientific-report/. Accessed March 12, 2015.
In addition, food-based recommendations for a traditional Mediterranean diet (from both Greece and Spain) were presented, which underscores the fact that this dietary pattern encompasses a wide range in cultures and food production practices in countries that border the Mediterranean Sea. Thus, the “Mediterranean diet” is not one “standard” eating pattern. Nonetheless, as is the case for the dietary patterns summarized previously, it emphasizes consumption of vegetables, fruits and nuts, and whole grains. A unique attribute is a focus on olive oil. Small amounts of meats and cheese are included routinely.
It should also be noted that there are several Asian dietary patterns, such as the traditional Japanese and Okinawan diets that have been associated with a low risk of CHD. However, there is limited information available about the composition of Asian diets, and evidence of their health benefits compared with other recommended dietary patterns also is limited. Despite this, the recommended food-based dietary patterns can be applied to a healthy Asian eating pattern.
Vegetarian and semi-vegetarian dietary patterns
There are various vegetarian dietary patterns including: an ovo-vegetarian diet that includes eggs; a lacto-vegetarian diet, which includes dairy products; a vegan diet, which is free of all meats, eggs and dairy products; a raw vegan diet, which includes only fresh and uncooked foods; a macrobiotic diet (pesco-vegetarian) that includes fish, but no other meats; and a semi-vegetarian diet, which occasionally includes meats; as well as combinations of the above. The therapeutic vegetarian dietary patterns most studied are the portfolio diet
29
; a very-low-fat vegetarian diet, such as the Ornish Plan with <10% of energy from fat30
, 31
; and low-fat vegan diet plans.32
, 33
Associations of dietary patterns with ASCVD risk
DASH dietary pattern and USDA food pattern
The recommended dietary patterns were based on the precept of reducing chronic disease risk (including ASCVD risk) and promoting health. Two papers reported the health benefits associated with different dietary patterns in several large cohorts (Multiethnic Cohort, National Institutes of Health-American Association of Retired Persons Diet and Health Study, and the Women's Health Initiative Observational Study).
34
, 35
, 36
In both reports, the dietary patterns evaluated were the Healthy Eating Index 2010 (representative of the USDA dietary pattern), the Alternative Healthy Eating Index 2010 (representative of the AHA dietary pattern), the Mediterranean-style dietary pattern, and the DASH dietary pattern. The healthy eating indexes used in these studies were based on the 2010 DGA, with adaptations made based on dietary patterns consistently associated with lower risk of chronic diseases. The Mediterranean-style dietary pattern is an adaptation of the traditional Mediterranean diet defined by Trichopoulou et al.37
Harmon et al.
35
found that higher diet quality scores on each of the indexes were associated with 11 to 26% lower risks of mortality from all causes, as well as cardiovascular and cancer mortality for both men and women. In the report by Liese et al.,36
in women, high diet quality was associated with an 18 to 26% lower risk of all-cause mortality, a 19 to 28% lower risk of cardiovascular mortality, and an 11 to 23% lower risk of cancer mortality. In men, the risk reductions associated with high diet quality were 17 to 25% for all-cause mortality, 14 to 26% for cardiovascular mortality, and 19 to 24% for cancer mortality. Similar findings have been reported recently in the Southern Community Cohort Study of low socioeconomic status AAs.38
Participants with the healthiest diets (in the top one-fifth of the Healthy Eating Index 2010 score) had approximately 20% lower risk of total mortality, and death from cancer and CVD were lower compared with individuals consuming the unhealthiest (bottom-fifth) diets. These studies provide evidence that a variety of healthy dietary patterns (albeit patterns that share many common foods and nutrient profiles) confer health benefits in diverse cohorts.In other analyses of the health effects of the DASH-style dietary pattern, results have consistently shown associations with lower risks for CVD. For example, in the Nurses' Health Study, Fung et al.
39
reported that, in the highest quintile of the DASH dietary score, there was a significant decrease in relative risk (RR) of CHD by 24% and stroke by 18%. In the Third National Health and Nutrition Examination Survey (NHANES), Parikh et al.40
reported that consumption of a DASH-like diet was associated with a significantly lower mortality from all causes (31%) and decreased risk of stroke (89%) in adults with hypertension.In an analysis of NHANES 2007–2010 data of 11,296 men and women using the 2005 Healthy Eating Index scores, consumption of AHA Heart-Check Food Certification Program-certifiable foods was positively associated with diet quality, and inversely associated with cardiometabolic risk factors.
41
Compared to the lowest quartile of diet quality score, the highest quartile score was associated with lower frequencies of obesity (26%), elevated waist circumference (24%), and metabolic syndrome (24%).Mediterranean-style dietary pattern
Several meta-analyses of epidemiologic studies have reported that consumption of a Mediterranean-style diet is associated with reduced risk for total and cardiovascular mortality.
42
, 43
, 44
, 45
In a very large meta-analysis of 18 cohorts with greater than 4 million subjects, a 2-point increase in the Mediterranean diet adherence score (score range was from 0 [minimal adherence] to 18 [maximal adherence]) was associated with an 8% reduction in overall mortality, a 10% reduction in CVD events, and a 4% reduction in neoplastic disease.44
In an analysis of 81,722 women in the Nurses' Health Study, Chiuve et al.46
reported that women in the highest quintile for the Mediterranean diet score had a 40% reduction in sudden cardiac death compared to women in the lowest quintile.In a meta-analysis of 15 prospective and cross-sectional studies and 35 clinical trials with 534,906 participants, the Mediterranean diet was highly inversely associated with the metabolic syndrome (log-hazard ratio −0.69, 95% confidence interval [CI]: −1.24 to −1.16).
47
Also, there were favorable associations of the Mediterranean diet on criteria for the metabolic syndrome, including a smaller waist circumference (−0.42 cm), higher HDL-C (1.17 mg/dL), lower TG (−6.14 mg/dL), lower systolic (−2.35 mm Hg) and diastolic (−1.58 mm Hg) blood pressures, and lower fasting glucose (−3.89 mg/dL).PREvención con DIeta MEDiterránea (PREDIMED) was a multicenter RCT conducted in Spain that evaluated the efficacy of advice to follow a Mediterranean diet on the primary prevention of CVD.
48
A total 7447 participants, 55 to 80 years of age, with type 2 diabetes or with 3 or more CVD risk factors (hypertension, hypercholesterolemia, family history of heart disease, tobacco use, or overweight/obesity) were randomized to: (1) advice to follow a low(er)-fat diet; (2) a Mediterranean diet supplemented with extra-virgin olive oil (1 L/week/family; 50 g/day per participant); or (3) a Mediterranean diet supplemented with tree nuts (30 g/day: 15 g walnuts, 7.5 g almonds, 7.5 g hazelnuts). After 4.8 years, there was a 30% reduction in the primary endpoint, which was rate of major cardiovascular events (myocardial infarction [MI] stroke, or death from cardiovascular causes) in each of the Mediterranean diet groups.The Lyon Diet Heart Study,
49
an RCT conducted in France, evaluated the effects of a Mediterranean-style diet vs a “prudent Western-style diet” on secondary prevention of MI over 104 weeks. The Mediterranean-style diet was lower in saturated fat and higher in α-linolenic acid (ALA) from a canola oil–based margarine. Subjects in the Mediterranean-style diet group were advised to consume more bread, root vegetables, green vegetables, and fish; less meat; to eat fruit every day; and to replace butter and cream in the diet, which was facilitated by provision of a canola oil-based margarine. The Mediterranean-style diet treatment group had 50% to 70% lower risk of recurrent cardiac events, major secondary events, and hospitalizations, despite no changes in blood lipids/lipoproteins and similar body mass index (BMI) and blood pressure compared to the control group.Vegetarian diet
In a systematic review and meta-analysis of 8 observational studies (183,321 participants) that evaluated clinical outcomes associated with a vegetarian diet compared to a non-vegetarian diet, Kwok et al.
50
reported that, for ischemic heart disease, the associations of a vegetarian diet with lower risk for ischemic heart disease compared to non-vegetarian controls, or the general population, in the Seventh Day Adventist studies was RR 0.60, 95% CI 0.43–0.80 and in the non-Seventh Day Adventist studies was RR 0.84, 95% CI 0.74–0.96. Key et al.51
reported that, compared with regular meat eaters, mortality from ischemic heart disease was 20% lower in occasional meat eaters, 34% lower in individuals who ate fish but did not eat meat, 34% lower in lacto-ovo-vegetarians, and 26% lower in vegans.Limitations of observational evidence
Several dietary patterns have been associated with reduced risk for ASCVD. These dietary patterns share many attributes because of an emphasis on plant foods and lean proteins, as well as low intakes of saturated and trans fatty acids compared with the average American diet. However, it should be noted that the average American diet has changed over time (data below for 1971–1974 from: Centers for Disease Control and Prevention [CDC] 2004
52
and data from 2011–2012 from: USDA 201453
). Results from the NHANES surveys show that mean dietary protein intake has remained relatively stable at ∼15–16% of energy. Mean energy from dietary fat has declined from 36–37% of energy in 1971–1974 to 33.8% of energy in 2011–2012, with saturated fatty acid intake declining from 13–14% of energy to 10.9% over that time. Trans fatty acid consumption has also declined, particularly after 2006 when trans fatty acid content was required to be on the Nutrition Facts label. A report from the US. Food and Drug Administration (FDA) estimated that average US consumption of industrially produced trans fatty acids decreased from about 2.0% of energy in the late 1990s to about 0.6% of energy in 2010.U.S. Department of Agriculture, Agricultural Research Service. 2014. Nutrient Intakes from Food and Beverages: Mean amounts consumed per individual, by gender and age, What We Eat in America, NHANES 2011-2012. Available at: http://www.ars.usda.gov/SP2UserFiles/Place/80400530/pdf/1112/Table_1_NIN_GEN_11.pdf. Accessed July 26, 2015.
54
The decline in the energy contribution of dietary fats has been accompanied by an increase in the percentage of energy from carbohydrate from 42–45% (1971–1974) to 48.6% (2011–2012). However, because mean energy intake has increased, the total average daily consumption of dietary fat per person has been relatively stable (69.0 g/day for women and 96.2 g/day for men), while carbohydrate intake has increased from 175 g/day in 1971–1974 to 228 g/day in 2011–2012 for women. Corresponding values for men are 260 and 305 g/day, respectively.With some exceptions, such as the results from the PREDIMED and Lyon-Diet Heart studies, little clinical trial evidence from cardiovascular outcomes trials is available from, which to fully evaluate the possible risks and benefits of these dietary patterns. It is also difficult to determine the potential for bias and confounding because dietary patterns are often associated with other lifestyle factors.
55
Nevertheless, the results from observational studies are reasonably consistent across studies, and biologically plausible, given what is known about the effects of such dietary patterns on major ASCVD risk factors from RCTs that have compared them with dietary patterns more similar to the average American diet, particularly for serum lipids and blood pressure.15
, 16
, 17
NLA Expert Panel recommendations–dietary patterns
Several dietary patterns have been associated with reduced risk for ASCVD. These dietary patterns share many attributes, with an emphasis on plant foods and lean sources of protein. Compared with an average American/Western diet, these dietary patterns are lower in saturated fats, trans fats, and cholesterol. The NLA Expert Panel recommends any of these healthy dietary patterns for lowering elevated levels of atherogenic cholesterol (LDL-C and non-HDL-C). However, the dietary pattern recommended should be individualized based on the patient's specific dyslipidemia. Also, patient preferences and cultural considerations are important for guiding decisions about recommendations to maximize dietary adherence. Nutritional counseling and follow-up/monitoring by a registered dietitian nutritionist are recommended whenever possible to individualize patients' cardioprotective dietary patterns and to promote long-term dietary adherence.
Replacements for saturated and trans fatty acids in the diet
The dietary patterns reviewed previously are lower in saturated and trans fatty acids compared to the average American diet. This is important for dyslipidemia management because these are the dietary components that have the greatest adverse effect on atherogenic cholesterol levels.
Table 4 shows the predicted effects of replacing 5% of energy from saturated fatty acids with a matched quantity of energy from PUFA, MUFA, and carbohydrates, based on results from controlled feeding trials.
24
Values are shown for LDL-C, TG, and HDL-C. Effects on VLDL-C are estimated by dividing the predicted change in TG by 5. Accordingly, based on the data shown in Table 4, the predicted changes in non-HDL-C, approximated as the sum of changes in LDL-C and estimated VLDL-C (TG/5), associated with substitution of 5% of energy from saturated fatty acids with PUFA, MUFA and carbohydrate are −9.4, −6.0, and −4.1 mg/dL, respectively.- Eckel R.H.
- Jakicic J.M.
- Ard J.D.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014; 63: 2960-2984
Table 4Predicted effects of macronutrient replacement of dietary saturated fatty acids with PUFA, MUFA, and carbohydrate on lipoprotein lipids based on results from controlled feeding trials
Source: Adapted from Eckel RH, et al. J Am Coll Cardiol. 2014;63(25 Pt B):2960–2984.
24
- Eckel R.H.
- Jakicic J.M.
- Ard J.D.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014; 63: 2960-2984
| Dietary component | Predicted effects on lipoprotein lipids of replacing 5% of energy from saturated fatty acids with 5% of energy from the specified dietary component, mg/dL | ||
|---|---|---|---|
| LDL-C | TG | HDL-C | |
| PUFA | –9.0 | –2.0 | –1.0 |
| MUFA | –6.5 | +1.0 | –6.0 |
| Carbohydrate | –6.0 | +9.5 | –2.0 |
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid; TG, triglyceride.
∗ Results are summarized from controlled feeding trials of subjects with average-to-mildly dyslipidemic baseline levels of lipoprotein lipids. Effects may be more pronounced in those with higher baseline values.
Like saturated fats, trans fatty acid consumption increases levels of atherogenic cholesterol, with each 1% of energy from trans fatty acids raising LDL-C by ∼1.5 mg/dL compared with carbohydrate and, to a somewhat greater extent, compared with MUFA and PUFA.
24
As previously discussed, intake of trans fatty acids in the average American diet has declined in recent years from ∼2.0% of energy to 0.6% of energy.- Eckel R.H.
- Jakicic J.M.
- Ard J.D.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014; 63: 2960-2984
54
Further reductions are expected due to recent actions by the FDA to remove industrially produced trans fatty acids from the list of foods Generally Recognized as Safe. For patients who consume greater than average quantities of foods that may contain trans fatty acids, such as some cookies, pastries, biscuits, crackers, deep-fried foods, microwaved popcorn, and frozen dinners, dietary advice that emphasizes the recommended food categories and food patterns discussed previously will minimize trans fatty acid consumption.Selected results from randomized controlled feeding trials
OmniHeart was a randomized, controlled feeding trial that evaluated the effects of 3 variants of the DASH dietary pattern on lipoprotein lipids and blood pressure in subjects with pre-hypertension and stage I hypertension.
27
After baseline measurements were collected with subjects consuming their habitual diets (similar to the average American diet), 3 experimental diets were compared in a randomized order: 1) a high-carbohydrate, low-saturated fat DASH diet with 58% of energy from carbohydrate, 27% from fat (6% from saturated fatty acids) and 15% from protein; 2) a higher protein diet where 10% of the energy from carbohydrate was replaced with mixed-source protein; and 3) an unsaturated fat diet where 10% of energy from carbohydrate was replaced with unsaturated fats (8% from MUFA and 2% from PUFA). Baseline values and changes in lipoprotein lipids are shown in Table 5.27
Atherogenic cholesterol levels were reduced on all 3 DASH diet variants compared with habitual intake. Changes in LDL-C and non-HDL-C levels were significantly greater during the higher protein (−14.2 and −17.3 mg/dL, respectively) and higher unsaturated fat (−13.1 and −15.1 mg/dL, respectively) diets than during the higher carbohydrate diet (−11.6 and −11.0 mg/dL, respectively). These results suggest that a diet low in saturated fatty acids that emphasizes carbohydrates, proteins, or unsaturated fats will improve the lipid profile, but that emphasis on proteins and unsaturated fats may elicit the most favorable effects on levels of LDL-C and non-HDL-C.Table 5Changes from baseline lipoprotein lipid levels by diet in OmniHeart
Source: Adapted from Appel LJ, et al. JAMA. 2005;294:2455–2464.
27
| Lipid | Diet (% energy from carbohydrate/protein/fat) | |||
|---|---|---|---|---|
| Habitual baseline diet (various) | Carbohydrate diet (58/15/27) | Protein diet (48/25/27) | Unsaturated fat diet (48/15/37) | |
| Mean, mg/dL | Mean or median change from baseline, mg/dL | |||
| LDL-C | 129 | −11.6a | −14.2b | −13.1a,b |
| Non-HDL-C | 154 | −11.0a | −17.3b | −15.1b |
| HDL-C | 50 | −1.4a | −2.6b | −0.3c |
| TG | 102 | 0.1a | −16.4b | −9.3c |
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides.
Different letters in a row denote statistically significant differences in response, P < .05.
Liquid vegetable oils are a major dietary source of unsaturated fatty acids. However, some vegetable oils are higher in MUFA, such as canola, high-oleic safflower, and olive oils, while others are higher in PUFA, such as corn and safflower oils. Consequently, consumers and clinicians should understand the effects of different vegetable oils on lipoprotein lipid levels. A controlled feeding study conducted by Maki et al.
56
evaluated the effects of a PUFA-rich corn oil and a MUFA-rich extra-virgin olive oil (4 tablespoons/day were incorporated into foods) as part of a weight maintenance diet (34% of energy from fat, ∼8% from saturated fatty acids) on lipids and lipoproteins in men and women with elevated LDL-C. Consumption of the corn oil diet reduced LDL-C by 10.9% compared to subjects' baseline (average American) diets, which was significantly greater than the reduction of 3.5% with extra-virgin olive oil. Results were similar for non-HDL-C, with a significantly greater mean reduction of 9.3% with corn oil vs 1.6% with extra-virgin olive oil. The HDL-C responses were similar between treatments; however, there was a smaller increase in TG on the corn oil (3.5%) vs the extra-virgin olive oil (13.0%) diet. These results are generally consistent with those from other studies,- Maki K.C.
- Lawless A.L.
- Kelley K.M.
- Kaden V.N.
- Geiger C.J.
- Dicklin M.R.
Corn oil improves the plasma lipoprotein lipid profile compared with extra-virgin olive oil consumption in men and women with elevated cholesterol: results from a randomized controlled feeding trial.
J Clin Lipidol. 2015; 9: 49-57
57
, 58
and support the view that greater reductions in atherogenic cholesterol levels should be expected when saturated fatty acids are replaced with PUFA (omega-6) compared to MUFA (omega-9).59
However, it should be noted that other factors, such as the higher plant sterol content of the corn oil, may have also contributed to the lipoprotein lipid changes observed in the study by Maki et al.56
- Maki K.C.
- Lawless A.L.
- Kelley K.M.
- Kaden V.N.
- Geiger C.J.
- Dicklin M.R.
Corn oil improves the plasma lipoprotein lipid profile compared with extra-virgin olive oil consumption in men and women with elevated cholesterol: results from a randomized controlled feeding trial.
J Clin Lipidol. 2015; 9: 49-57
Summary–replacements for saturated fatty acids
The NLA Expert Panel recommends consuming a diet that is low in saturated fatty acids (<7% of energy) for those in need of atherogenic cholesterol lowering. Replacing saturated fats with unsaturated fats, proteins, or carbohydrates lowers levels of atherogenic cholesterol, although replacement with unsaturated fats and proteins elicit greater reductions than carbohydrate. Unsaturated fat intake can be increased by incorporating liquid vegetable oils and oil-rich foods, such as nuts and liquid vegetable oil spreads, into the diet. PUFA (mainly omega-6) produce greater reductions in atherogenic cholesterol levels than MUFA (omega-9).
Dietary cholesterol
The 2010 US Dietary Guidelines recommended that dietary cholesterol be <300 mg per day for healthy individuals ages 2 years and older.
19
In the 2006 Diet and Lifestyle Revision,U.S. Department of Agriculture and U.S. Department of Health and Human Services. Dietary Guidelines for Americans – 2010. Available at: http://www.cnpp.usda.gov/dietary-guidelines-2010. Accessed June 28, 2015.
28
the AHA recommended <300 mg per day and, in 2011, the AHA recommended <150 mg per day for the prevention of CVD in women.60
The National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) III recommended <200 mg/day of cholesterol as part of the Therapeutic Lifestyle Changes diet.12
More recently, the 2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk did not make a recommendation for dietary cholesterol because the panel concluded that there was “insufficient evidence to determine whether lowering dietary cholesterol reduces LDL-C”.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.
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.
Circulation. 2002; 106: 3143-3421
24
The 2015 DGAC did not recommend continuation of the recommended limit of dietary cholesterol to <300 mg per day because “available evidence shows no appreciable relationship between consumption of dietary cholesterol and serum cholesterol”.- Eckel R.H.
- Jakicic J.M.
- Ard J.D.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014; 63: 2960-2984
23
Thus, the usefulness of limiting dietary cholesterol intake for the US population, and for those with elevated levels of atherogenic cholesterol, has become controversial. The available evidence was reviewed carefully by the NLA Expert Panel.Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Available at: http://www.health.gov/dietaryguidelines/2015-scientific-report/. Accessed March 12, 2015.
Effects of dietary cholesterol on total cholesterol (total-C) and LDL-C levels
The effects of dietary cholesterol on circulating levels of LDL-C and total-C (and to a lesser extent, non-HDL-C) have been evaluated in a large number of studies. Results of the effects of dietary cholesterol on serum total-C and LDL-C have been evaluated in 6 meta-analyses.
61
, 62
, 63
, 64
, 65
, 66
In aggregate, these included data from 438 studies; 424 in subjects with normolipidemia and 14 in participants with dyslipidemia. An increase of 100 mg/day in dietary cholesterol was reported to increase total-C approximately 2 to 3 mg/dL.63
, 64
, 66
Hopkins61
evaluated results from 27 studies in which controlled diets were supplied by a metabolic kitchen, and reported that the increase in serum total-C produced by a given change in dietary cholesterol is non-linear and dependent on the baseline level of dietary cholesterol. Accordingly, the increase in serum total-C predicted for an increment of 100 mg/day in dietary cholesterol would be progressively less with higher baseline levels of cholesterol intake.Weggemans et al.
66
completed a meta-analysis of results from 17 studies involving 556 subjects in which diets differed only in the amount of dietary cholesterol or number of eggs (with yolks) fed over periods of at least 14 days and for which lipoprotein lipid values were reported. They reported that an addition of 100 mg/day of dietary cholesterol would be predicted to increase total-C by 2.17 mg/dL, LDL-C by 1.93 mg/dL, and HDL-C by 0.31 mg/dL, resulting in a small increment in the total-C:HDL-C ratio of 0.02. These values align closely with those reported by Clarke et al.63
from an analysis of data reported in 395 dietary solid food experiments. It should be noted that the clinical importance of the increase in HDL-C observed with increasing dietary cholesterol is uncertain.A more recent systematic review and meta-analysis of 40 studies (17 cohort studies with 19 publications and 19 trials with 21 publications) was published by Berger et al.
67
In the review of 17 of the 19 trials, dietary cholesterol (intervention cholesterol intake was 501 to 1415 mg/day and 0 to 415 mg/day in the control conditions) significantly increased both serum total-C (11.2 mg/dL) and LDL-C (6.7 mg/dL). When the intervention intake levels were greater than 900 mg/day, there were no longer statistically significant increases in LDL-C. In this review, dietary cholesterol also increased HDL-C (3.2 mg/dL). Similar to the Hopkins results,61
the increases in total-C and LDL-C were greatest when the baseline dietary cholesterol intake was the lowest.Ginsberg et al.
68
conducted a controlled feeding study in which 4 dietary conditions were evaluated, each for 8 weeks with washouts between treatments, in 20 young, healthy men. This trial was chosen as an illustrative example of the effects of dietary cholesterol because it was a well-designed dietary intervention with controlled feeding that allowed evaluation of dose-response, and included measurements of lipoprotein lipids by ultracentrifugation, the reference standard. In this trial, average total-C and LDL-C increased by 1.47 mg/dL and 1.38 mg/dL, respectively, for each 100 mg/day increase in dietary cholesterol. HDL-C also increased by 0.29 mg/dL per 100 mg/day of dietary cholesterol, while VLDL-C and TG levels did not change. The apo B concentration rose by 1.19 mg per 100 mg/day increase in dietary cholesterol, and the change in apo B correlated significantly with the change in LDL-C. While these results are consistent with the view that an increase in dietary cholesterol modestly raises levels of atherogenic cholesterol (and lipoprotein particles), it should be noted that the responses varied widely, with 3 subjects showing a decrease in total-C with increasing cholesterol intake and some subjects displaying more than twice the mean response.Variation in responses to dietary cholesterol
Griffin and Lichtenstein reviewed results from studies on the effects of dietary cholesterol and lipoprotein lipids published between 2003 and 2013.
69
They concluded the following:Within the context of current levels of dietary cholesterol intake, the effect on plasma lipid concentrations, with primary interest in LDL-C cholesterol concentrations, is modest and appears to be limited to population subgroups. In these cases, restrictions in dietary cholesterol intake are likely warranted. The biological determinants of inter-individual variability remain a relatively understudied area.
The interpretation of the NLA Expert Panel is that the available data are consistent with the conclusion that dietary cholesterol has modest effects to increase total-C and LDL-C levels on average, although there are hypo- and hyper-responders in the population. Unfortunately, at present, there is no widely available and inexpensive method for clinical use to predict who is likely to experience a change in atherogenic cholesterol (or not) in response to changes in dietary cholesterol intake. The effects of other dietary constituents, particularly saturated and unsaturated fatty acids, on circulating levels of atherogenic cholesterol are generally larger and more predictable than that of dietary cholesterol. For most individuals, restricting saturated fat intake to <7% of energy, while following any of the recommended dietary patterns, will result in lower dietary cholesterol consumption, because saturated fats and cholesterol are both present in many foods (e.g., fatty cuts of meats, processed meats, full-fat dairy foods). However, some popular foods are particularly high in cholesterol, but not in saturated fatty acids, including eggs, shrimp and other shellfish, and some organ meats (which are commonly consumed in some regions of the United States).
70
U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 27. 2014. Nutrient Data Laboratory Home Page. Available at: http://www.ars.usda.gov/ba/bhnrc/ndl. Accessed June 1, 2015.
Observational evidence for dietary cholesterol or egg consumption and ASCVD risk
The authors of a meta-analysis of 16 prospective cohort studies with follow-up times ranging from 5.8 to 20.0 years reported that, in comparison with those who ate egg less than once per week, individuals who ate egg once per day or more did not have significantly higher risks of overall CVD, ischemic heart disease, or stroke.
71
The pooled hazard ratios (HRs) (95% CI) were 0.96 (0.88, 1.05) for overall CVD, 0.97 (0.86, 1.09) for ischemic heart disease, and 0.93 (0.81, 1.07) for stroke. The HR for ischemic heart disease mortality was 0.98 (0.77, 1.24) and for stroke mortality was 0.92 (0.56, 1.50). Thus, egg consumption was not associated with the risk of CVD and cardiac mortality in the general population. A more recent systematic review and meta-analysis of 17 cohort studies with 361,923 subjects reported that dietary cholesterol intake was not significantly associated with incidence of coronary artery disease, ischemic stroke, or hemorrhagic stroke.67
The authors noted, however that the cohort studies reviewed were heterogeneous and lacked methodological rigor, which limited definitive conclusions being made about dietary cholesterol and ASCVD outcomes.The authors of a review of 8 large prospective cohort studies (17 reports, including 9 for CHD and 8 for stroke) and a meta-analysis (3,081,269 person years and 5847 cases of incident CHD) reported an increased risk of CHD in a subgroup analysis of individuals with diabetes comparing the highest with the lowest categories of egg consumption of 1.54 (1.14 to 2.09; P = .01).
72
The association of egg consumption with increased CHD risk in those with diabetes may be a reflection of the cholesterol content of eggs (approximately 186 mg per single large egg yolk). Among 5672 women with type 2 diabetes in the Nurses' Health Study, higher consumption of dietary cholesterol was associated with increased risk of CVD.73
Each increase of 200 mg cholesterol/1000 kcal was associated with a 37% increased risk of CVD, which was a composite of fatal CHD, nonfatal MI, and stroke (Tanasescu 2014). In a prospective cohort study of 37,851 men and 80,842 women in the Health Professionals Follow-up Study, higher egg consumption was associated with an increased risk of CHD only among those subjects with diabetes.74
Men with diabetes consuming 1 egg or more daily had double the risk of CHD compared to those consuming 1 egg or less each week; women with diabetes consuming 1 egg or more daily had 1.49 times the risk of CHD than those consuming 1 egg or less per week.74
In summary, the observational evidence suggests that egg and dietary cholesterol consumption are not consistently associated with increased ASCVD risk, with the possible exception of increased risk in those with diabetes mellitus. Mechanisms to potentially explain differences in risk among those with and without diabetes are uncertain. Observational studies are subject to various types of bias and confounding,
55
including intercorrelations between types of foods consumed (e.g., a correlation between consumption of eggs and processed breakfast meats) and displacement effects (higher egg consumption may be associated with lower consumption of other foods), thus such evidence must be interpreted with caution. Accordingly, the conclusions of the NLA Expert Panel regarding dietary cholesterol intake for dyslipidemia management are based mainly on the results from well-controlled RCTs designed to evaluate the effects of dietary cholesterol on levels of atherogenic cholesterol.Conclusions from review of evidence on dietary cholesterol and ASCVD risk
Results from well-controlled RCTs indicate that dietary cholesterol has modest effects to raise levels of total-C, LDL-C, and HDL-C. The increase in HDL-C associated with increased dietary cholesterol is of uncertain clinical importance. Hyper- and hypo-responders to dietary cholesterol exist, with some individuals showing little or no increases in atherogenic cholesterol levels in response to greater intake of dietary cholesterol and others showing responses well above the average. The biological determinants of inter-individual variability are understudied, and presently no inexpensive and widely available methods are available for identifying those who are likely to be hyper- or hypo-responders. In controlled feeding RCTs, each 100 mg/day of dietary cholesterol raises LDL-C by an average of ∼1.9 mg/dL. Observational data have consistently reported no association between dietary cholesterol or egg consumption (a large contributor to dietary cholesterol intake) and ASCVD risk in the general population, but suggest that there may be increased ASCVD risk associated with greater cholesterol and egg consumption in those with diabetes mellitus. The NLA Expert Panel recommendations are, therefore, based mainly on results from controlled-feeding RCTs showing modest effects of dietary cholesterol to raise total-C and LDL-C, while recognizing that other dietary factors (saturated fatty acids, trans fatty acids, MUFA and PUFA) more reliably and predictably influence levels of atherogenic cholesterol.
Weight loss
Effects of weight loss on lipoprotein lipids
Results from systematic reviews of RCTs indicate that clinically meaningful changes in CVD risk indicators are associated with a loss of at least 2.5 kg or 3% of body weight.
75
, 76
A weight loss of 5 to 8 kg that is sustained results in a mean LDL-C reduction of approximately 5 mg/dL and a mean increase in HDL-C of between 2 and 3 mg/dL.- Jensen M.D.
- Ryan D.H.
- Apovian C.M.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice GuidelinesObesity Society
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
J Am Coll Cardiol. 2014; 63: 2985-3023
76
In addition, a 3 kg weight loss is expected to decrease TG by at least 15 mg/dL.- Jensen M.D.
- Ryan D.H.
- Apovian C.M.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice GuidelinesObesity Society
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
J Am Coll Cardiol. 2014; 63: 2985-3023
76
However, clinicians should be aware that there is marked variation in the lipid/lipoprotein responses to weight loss. In addition, all of the major lipoprotein lipid variables (LDL-C, VLDL-C, TG, and HDL-C) typically decrease during active weight loss.- Jensen M.D.
- Ryan D.H.
- Apovian C.M.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice GuidelinesObesity Society
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
J Am Coll Cardiol. 2014; 63: 2985-3023
75
, 76
The values above reflect the effects observed after lower and stable levels of body weight and adiposity have been established.- Jensen M.D.
- Ryan D.H.
- Apovian C.M.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice GuidelinesObesity Society
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
J Am Coll Cardiol. 2014; 63: 2985-3023
76
Favorable changes in lipoprotein lipids are unlikely to be sustained unless a reduced weight is maintained. Therefore, the critically important consideration for all lipoprotein changes is weight loss maintenance. Behaviors associated with successful maintenance of a reduced body weight include high levels of physical activity (discussed in detail in the section on exercise/physical activity); eating breakfast regularly; self-monitoring of weight; and maintaining consistent, calorie controlled eating patterns across weekdays and weekends.- Jensen M.D.
- Ryan D.H.
- Apovian C.M.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice GuidelinesObesity Society
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: a Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society.
J Am Coll Cardiol. 2014; 63: 2985-3023
77
LDL-C values decline with weight loss on average, but the response tends to be larger in younger subjects, and may be blunted in older individuals.
78
, 79
However, the TG and VLDL-C reductions appear to be similar among younger and older individuals. The relationship between age and lipoprotein lipid responses to weight loss is understudied and should be pursued in future research. Among lipoprotein lipid parameters, TG levels (and VLDL-C, which is highly correlated with the TG concentration) appear to respond most readily to weight loss.75
Higher baseline values and larger weight loss are associated with greater TG lowering.75
In addition, lower carbohydrate diets during weight loss and weight maintenance have been shown to lower TG more than higher carbohydrate diets.75
Loss of at least 3% of body weight also produces favorable changes in other ASCVD risk indicators, including blood pressure, glycemia, and insulin resistance.75
Effects of macronutrient distribution on weight loss and metabolic parameters
Many studies have been conducted to identify which dietary approach is most successful in promoting long-term weight loss and weight loss maintenance. It is clear that losses of body weight and fat will occur with a variety of macronutrient distributions, as long as they reduce energy intake below energy expenditure.
80
Several dietary patterns, such as Mediterranean-style, DASH, USDA, and vegetarian diets can be tailored to personal and cultural food preferences and appropriate calorie needs for weight control.23
, Scientific Report of the 2015 Dietary Guidelines Advisory Committee. Available at: http://www.health.gov/dietaryguidelines/2015-scientific-report/. Accessed March 12, 2015.
24
- Eckel R.H.
- Jakicic J.M.
- Ard J.D.
- et al.
American College of Cardiology/American Heart Association Task Force on Practice Guidelines
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines.
J Am Coll Cardiol. 2014; 63: 2960-2984
The ideal macronutrient composition for weight reducing diets and weight loss maintenance is the source of much controversy and may differ among individuals for a variety of physiological and behavioral reasons. The consensus view of the NLA Expert Panel is that there is suggestive evidence that partially replacing carbohydrate (especially refined starches and sugars, thus, also reducing dietary glycemic load) with higher protein foods may be beneficial to enhance weight loss and weight loss maintenance. This may be due, in part, to the effects of protein, compared with carbohydrate, to enhance satiety, induce a greater thermic effect of food, and to favor maintenance of fat-free mass.
81
, 82
, 83
, 84
In a review of the influence of protein intake on weight loss and weight maintenance, Westerterp-Plantenga and colleagues
82
concluded:…evidence shows that a relatively high protein intake sustains weight maintenance by (a) favoring regain of fat free mass at the cost of fat at a similar physical activity level, (b) reducing the energy efficiency with respect to the body mass regained, and (c) increasing satiety.
Wycherley et al.
84
evaluated the effects of energy-restricted high-protein, low-fat diets (25–35% energy from protein, ≤30% of energy from fat) with standard-protein, low-fat diets (12–18% of energy from protein, ≤30% of energy from fat). Twenty-four trials that included 1063 individuals satisfied the search criteria. The higher protein diets elicited greater decreases in body weight (0.79 kg), fat mass (0.87 kg), and TG (20.4 mg/dL), and smaller reductions in resting energy expenditure (596 kJ/day [142.4 kcal/day]) and fat-free mass (0.43 kg). The authors concluded that a higher protein weight loss diet provides modest benefits for reducing body weight, as well as TG, by attenuating reductions in fat-free mass and resting energy expenditure. The degree to which these differences can be attributed to increased protein vs lower carbohydrate intake (and hence reduced glycemic load) is uncertain, and both may be important contributors.In the largest trial completed to date on the effects of diet composition on weight loss maintenance, Larsen et al.
85
randomly assigned a group of 773 adults who had lost at least 8% of body weight to 5 diet groups to assess effects of protein intake and glycemic index on weight loss maintenance. The groups included a control diet with intermediate levels of protein and glycemic index with the remaining subjects assigned to lower and higher protein and lower or higher glycemic index in a 2 x 2 factorial manner. Targeted differences were 12% of energy between the lower and higher protein groups, and 15 glycemic index units for the lower and higher glycemic index groups. In an intention-to-treat analysis, the weight regain over 26 weeks was 0.93 kg less in the groups assigned to a high-protein diet than in those assigned to a low-protein diet, and 0.95 kg less in the groups assigned to a low-glycemic-index diet than in those assigned to a high-glycemic-index diet. The group that received the combination of a higher protein and lower glycemic index diet had the least weight regain (showing a small mean additional weight loss) of the 5 treatment arms, and also had the highest rate of study completion. The authors concluded that a diet with a moderately higher protein content (average intake 22–23% of energy during the intervention) and reduced glycemic index (56–57 units) improved the maintenance of weight loss, and may thus have advantages for weight regain prevention.The NLA Expert Panel acknowledges that additional research is needed to more clearly define effective dietary strategies for enhancing adherence to hypocaloric diets, and preventing weight regain after weight loss interventions.
80
, 86
However, based on the evidence discussed herein, the NLA Expert Panel consensus view is that eating patterns that contain a moderate quantity of carbohydrate, lower glycemic index and load, and higher protein, have been associated with modest benefits regarding weight loss and maintenance.82
, 84
, 85
Furthermore, the Expert Panel also strongly believes that additional research is needed to more clearly define effective dietary strategies for enhancing adherence to hypocaloric diets and preventing weight regain after weight loss interventions.80
, 86
Importance of lifestyle counseling and ongoing support
The Preventing Overweight Using Novel Dietary Strategies trial randomly assigned 811 overweight or obese subjects to 1 of 4 dietary conditions that emphasized different macronutrient distributions.
80
Participants were offered regular individual and group counseling sessions. After 6 months and 2 years of the intervention, the groups did not differ with regard to changes from baseline body weight. However, the number of sessions attended was a strong predictor of weight loss at the 2-year timepoint in all groups, with each additional session attended associated with a 0.2 kg greater loss of body weight. This illustrates the importance of lifestyle counseling and ongoing support to maximize success with weight loss interventions.Dietary adjuncts for lowering atherogenic cholesterol
If a diet based on a cardioprotective dietary pattern that is low in cholesterol-raising fatty acids and cholesterol plus regular physical activity and weight loss, if overweight or obese is insufficient to attain atherogenic cholesterol goals, clinicians may consider the use of dietary adjuncts to enhance the effects of other lifestyle interventions. The NLA Expert Panel consensus view is that there was sufficient evidence to recommend consideration of the use of supplemental plant sterols/stanols (∼2 g/day) and viscous fibers (5–10 g/day from foods and/or supplemental sources) to enhance reductions in levels of atherogenic cholesterol. Consumption of greater quantities of viscous fiber (10 to 25 g/day) as was recommended by the NCEP ATP III
12
will generally result in greater atherogenic cholesterol lowering; however, attaining this level of consumption is challenging. As is the case for other lifestyle interventions, recommendations are based primarily on results from RCTs demonstrating reductions in atherogenic cholesterol levels. ASCVD event trials are not available for these interventions, which prevents a full evaluation of the potential benefits and risks with their use.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.
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.
Circulation. 2002; 106: 3143-3421
Effects of plant (phyto) sterols/stanols on lipoprotein lipids
Phytosterols (PS), a term used to refer to both plant sterols and plant stanols, are compounds that naturally occur in foods of plant origin, particularly vegetable oils, nuts, seeds, and grain products. The typical diet consumed in the United States provides approximately 200–400 mg/day and the amount of PS consumed daily in a vegan diet is roughly twice that amount. There is a large evidence base supporting the LDL-C-lowering effect of PS, which has been summarized in multiple meta-analyses. The meta-analyses conducted by Law et al.
87
and Katan et al.88
were the first to examine the effects of PS on cholesterol levels. Both showed that consumption of 2 g/day of stanols or sterols lowered LDL-C by 5–10%. Follow-up meta-analyses by Demonty et al.89
and AbuMweis et al.90
confirmed these findings and concluded that, with an increasing dose of PS, the LDL-C-lowering effect increases, but this plateaus at doses above ∼3 g/day.- AbuMweis S.S.
- Barake R.
- Jones P.J.
Plant sterols/stanols as cholesterol lowering agents: a meta-analysis of randomized controlled trials.
Food Nutr Res. 2008; 52https://doi.org/10.3402/fnr.v3452i3400.1811
More recently Musa-Veloso et al.
91
conducted the largest meta-analysis on PS consumption, which included 114 trials representing 182 trial arms and evaluating LDL-C lowering dose-response effects separately for plant sterols and plant stanols. The range of PS intake was 0.2–9.0 g/day; however, there were only 4 studies with a PS intake >4.0 g/day. The authors concluded that at a dosage <3 g/day, effects of plant sterols and stanols are comparable.The lipid-lowering efficacy of PS-fortified products (both free plant sterols and stanols and their esterified forms) has been demonstrated in different population subgroups, including adults with type 2 diabetes mellitus, metabolic syndrome, and familial hypercholesterolemia (FH).
92
, 93
, 94
Atherogenic cholesterol lowering with plant sterols and stanols has been demonstrated in children with FH,95
although an insufficient body of evidence is available from which to draw firm conclusions about the efficacy of PS for reducing atherogenic cholesterol levels in those with FH.The efficacy of PS for lowering atherogenic cholesterol levels in various food and beverage formulations was examined by Demonty et al.
89
who reviewed studies that compared fat vs non-fat foods, dairy vs nondairy, liquid vs solid foods, and free or esterified PS. There were no significant differences in response to plant sterols vs stanols, fat-based vs non-fat-based food formats, and dairy vs nondairy foods at intake levels ≤2 g/day. It is possible (and theoretically likely) consumption of PS multiple times per day results in greater efficacy than a single intake.89
If taken in a single dose, the efficacy of PS appears to be greatest when consumed during or shortly after a meal, preferably a large enough meal that bile flow is triggered. There also appears to be an effect of baseline LDL-C concentration on the magnitude of the absolute decrease in LDL-C concentration, with larger reductions in LDL-C among individuals with higher baseline levels.89
However, when expressed as a percentage of the baseline value, LDL-C reductions are similar across a wide range of baseline LDL-C values.88
In addition to the well-established effects of PS to produce LDL-C-lowering, there also is some evidence that PS reduce TG concentrations. In a meta-analysis of 12 RCTs, PS intake in the range of 1.6 to 2.5 g/day produced a modest TG-lowering effect of about 6%.
96
More recent data reviewed by Rideout et al.97
indicate that PS supplementation results in a variable TG-lowering response ranging from 0.8 to 28%. The evidence supports the view that individuals with elevated TG (≥150 mg/dL) have a greater TG-lowering response to PS (11–28%) than subjects with normal plasma TG concentrations (0.8–7%).97
Mechanisms of action of PS
One mechanism by which PS lowers LDL-C is reducing intestinal cholesterol absorption by competing with cholesterol for limited space in mixed micelles.
98
This makes less cholesterol available to the enterocytes for transport via Niemann-Pick C1-Like 1 transporters. A second mechanism is that an increase in the intracellular level of PS in the enterocytes triggers an up-regulation of adenosine triphosphate-binding cassette transporter (ABC) G5 and ABCG8 that move sterols (including cholesterol) out of the enterocytes and into the intestinal lumen.98
The net result of these actions is to reduce hepatic cholesterol content, which then results in an up-regulation of hepatic LDL receptors that remove apo B-containing lipoproteins from the blood, thus lowering the blood cholesterol concentration, particularly LDL-C.98
Safety of supplemental PS consumption
The safety of PS has been reviewed by several regulatory agencies. The US FDA classifies PS as having Generally Recognized as Safe status. Furthermore, the FDA has authorized a health claim stating that consuming foods that include plant sterols/stanols (at least 0.75 g/serving) may reduce the risk of CHD. Potential health concerns have been raised related to elevated PS concentrations following the intake of PS-enriched foods in those with homozygous phytosterolemia (also known as sitosterolemia), a rare autosomal recessive genetic disorder.
99
Average PS concentrations in individuals consuming PS-fortified margarine-type spreads range from 0.6 to 2.0 mg/dL.88
However, patients with phytosterolemia are unable to effectively clear absorbed PS from the blood and tissues due to defects in the ABCG5 and/or ABCG8 sterol transporters. This causes PS concentrations to increase to levels that are often 20–45 times typical values.100
, 101
- Ras R.T.
- Hiemstra H.
- Lin Y.
- Vermeer M.A.
- Duchateau G.S.
- Trautwein E.A.
Consumption of plant sterol-enriched foods and effects on plasma plant sterol concentrations – a meta-analysis of randomized controlled studies.
Atherosclerosis. 2013; 230: 336-346