American Association of Clinical Endocrinologists and American College of Endocrinology Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease

      ABSTRACT

      Objective

      The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs).

      Methods

      Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols.

      Results

      The Executive Summary of this document contains 87 recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. These detailed, evidence- based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real- world medical care. The evidence base presented in the subsequent Appendix provides relevant supporting information for Executive Summary Recommendations. This update contains 695 citations of which 203 (29.2 %) are EL 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 236 (34.0%) are EL 4 (no clinical evidence).

      Conclusion

      This CPG is a practical tool that endocrinologists, other health care professionals, health-related organizations, and regulatory bodies can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of individuals with various lipid disorders. The recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously endorsed and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to individuals with diabetes, familial hypercholesterolemia, women, and youth with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions. (Endocr Pract. 2017:Suppl2;23:1-87)

      Abbreviations:

      4S
      Scandinavian Simvastatin Survival Study
      A1C
      glycated hemoglobin
      AACE
      American Association of Clinical Endocrinologists
      AAP
      American Academy of Pediatrics
      ACC
      American College of Cardiology
      ACE
      American College of Endocrinology
      ACS
      acute coronary syndrome
      ADMIT
      Arterial Disease Multiple Intervention Trial
      ADVENT
      Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial
      AFCAPS/TexCAPS
      Air Force/Texas Coronary Atherosclerosis Prevention Study
      AHA
      American Heart Association
      AHRQ
      Agency for Healthcare Research and Quality
      AIM-HIGH
      Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides trial
      ASCVD
      atherosclerotic cardiovascular disease
      ATP
      Adult Treatment Panel
      apo
      apolipoprotein
      BEL
      best evidence level
      BIP
      Bezafibrate Infarction Prevention trial
      BMI
      body mass index
      CABG
      coronary artery bypass graft
      CAC
      coronary artery calcification
      CARDS
      Collaborative Atorvastatin Diabetes Study
      CDP
      Coronary Drug Project trial
      CI
      confidence interval
      CIMT
      carotid intimal media thickness
      CKD
      chronic kidney disease
      CPG(s)
      clinical practice guideline(s)
      CRP
      C-reactive protein
      CTT
      Cholesterol Treatment Trialists
      CV
      cerebrovascular
      CVA
      cerebrovascular accident
      EL
      evidence level
      FH
      familial hypercholesterolemia
      FIELD
      Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes trial
      FOURIER
      Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial
      HATS
      HDL-Atherosclerosis Treatment Study
      HDL-C
      high- density lipoprotein cholesterol
      HeFH
      heterozygous familial hypercholesterolemia
      HHS
      Helsinki Heart Study
      HIV
      human immunodeficiency virus
      HoFH
      homozygous familial hypercholesterolemia
      HPS
      Heart Protection Study
      HPS2-THRIVE
      Treatment of HDL to Reduce the Incidence of Vascular Events trial
      HR
      hazard ratio
      HRT
      hormone replacement therapy
      hsCRP
      high-sensitivity CRP
      IMPROVE- IT
      Improved Reduction of Outcomes: Vytorin Efficacy International Trial
      IRAS
      Insulin Resistance Atherosclerosis Study
      JUPITER
      Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin
      LDL-C
      low-density lipoprotein cholesterol
      Lp-PLA2
      lipoprotein-associated phospholipase A2
      MACE
      major cardiovascular events
      MESA
      Multi-Ethnic Study of Atherosclerosis
      MetS
      metabolic syndrome
      MI
      myocardial infarction
      MRFIT
      Multiple Risk Factor Intervention Trial
      NCEP
      National Cholesterol Education Program
      NHLBI
      National Heart, Lung, and Blood Institute
      PCOS
      polycystic ovary syndrome
      PCSK9
      proprotein convertase subtilisin/kexin type 9
      Post CABG
      Post Coronary Artery Bypass Graft trial
      PROSPER
      Prospective Study of Pravastatin in the Elderly at Risk trial
      QALY
      quality-adjusted life-year
      ROC
      receiver-operator characteristic
      SOC
      standard of care
      SHARP
      Study of Heart and Renal Protection
      T1DM
      type 1 diabetes mellitus
      T2DM
      type 2 diabetes mellitus
      TG
      triglycerides
      TNT
      Treating to New Targets trial
      VA-HIT
      Veterans Affairs High- Density Lipoprotein Cholesterol Intervention Trial
      VLDL-C
      very low-density lipoprotein cholesterol
      WHI
      Women’s Health Initiative

      I. INTRODUCTION

      In 2016, approximately 660,000 U.S. residents will have a new coronary event (defined as a first hospitalized myocardial infarction [MI] or atherosclerotic cardiovascular disease [ASCVD] death), and approximately 305,000 will have a recurrent event. The estimated annual incidence of MI is 550,000 new and 200,000 recurrent attacks. The average age at first MI is 65.1 years for men and 72.0 years for women (
      • Mozaffarian D.
      • Benjamin E.J.
      • Go A.S.
      • et al.
      Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association.
      [EL 4; NE]). Dyslipidemia is a primary, major risk factor for ASCVD and may even be a prerequisite for ASCVD, occurring before other major risk factors come into play. Epidemiologic data also suggest that hypercholesterolemia and perhaps coronary atherosclerosis itself are risk factors for ischemic cerebrovascular accident (CVA) (
      • Nicholls S.
      • Lundman P.
      The emerging role of lipoproteins in atherogenesis: beyond LDL cholesterol.
      [EL 4; NE]). According to data from 2009 to 2012, >100 million U.S. adults ≥20 years of age have total cholesterol levels ≥200 mg/dL; almost 31 million have levels ≥240 mg/ dL (
      • Mozaffarian D.
      • Benjamin E.J.
      • Go A.S.
      • et al.
      Heart Disease and Stroke Statistics-2016 Update: A Report From the American Heart Association.
      [EL 4; NE]). Increasing evidence also points to insulin resistance—which results in increased levels of plasma triglycerides (TG) and low-density lipoprotein cholesterol (LDL-C) and a decreased concentration of high-density lipoprotein cholesterol (HDL-C)—as an important risk factor for peripheral vascular disease (
      • Wild S.H.
      • Byrne C.D.
      • Tzoulaki I.
      • et al.
      Metabolic syndrome, haemostatic and inflammatory markers, cerebrovascular and peripheral arterial disease: The Edinburgh Artery Study.
      [EL 2; PCS]), CVA, and ASCVD (
      • Rodriguez-Colon S.M.
      • Mo J.
      • Duan Y.
      • et al.
      Metabolic syndrome clusters and the risk of incident stroke: the atherosclerosis risk in communities (ARIC) study.
      [EL 2; PCS]).
      Analysis of 30-year national trends in serum lipid levels shows improvements in total cholesterol and LDL-C levels. This may in part be explained by the steady increase in the use of lipid-lowering drug therapy (self-reported rate of lipid-medication use, 38%). However, 69% of U.S. adults have LDL-C concentrations above 100 mg/dL. Furthermore, the doubling in prevalence of individuals who have obesity, the high percentage with elevated TG levels (33%), and the correlation between obesity and elevated TG point to the need for continued vigilance on the part of physicians to reduce ASCVD risk (
      • Cohen J.D.
      • Cziraky M.J.
      • Cai Q.
      • et al.
      30-year trends in serum lipids among United States adults: results from the National Health and Nutrition Examination Surveys II, III, and 1999-2006. (Erratum in: Am J Cardiol. 2010;106:1826).
      [EL 3; SS]).
      This clinical practice guideline (CPG) is for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease. The mandate for this CPG is to provide a practical guide for endocrinologists to reduce the risks and consequences of dyslipidemia. This CPG extends and updates existing CPGs available in the literature, such as the American Association of Clinical Endocrinologists (AACE) Medical Guidelines for Clinical Practice for the Diagnosis and Treatment of Dyslipidemia and Prevention of Atherosclerosis (
      • Jellinger P.S.
      • Smith D.A.
      • Mehta A.E.
      • et al.
      American Association of Clinical Endocrinologists’ guidelines for management of dyslipidemia and prevention of atherosclerosis.
      [EL 4; NE]), and complements the AACE Diabetes Mellitus Comprehensive Care Plan CPG (
      • Handelsman Y.
      • Mechanick J.I.
      • Blonde L.
      • et al.
      American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for developing a diabetes mellitus comprehensive care plan.
      [EL 4; NE]). The landmark National Cholesterol Education Program (NCEP) guidelines (
      [EL 4; NE]) serve as the backbone of these lipid recommendations.
      This CPG is unique in that it supports the use of apoli- poprotein (apo) B level and/or LDL particle concentration to refine efforts to achieve effective LDL-C lowering, provides screening recommendations for individuals of different ages, and identifies special issues for children and adolescents. This CPG also discusses the challenges associated with atherosclerosis and heart disease that are specific to women. It continues to emphasize the importance of LDL-C lowering and supports the measurement of inflammatory markers to stratify risk in certain situations. Finally, this CPG presents an evaluation of the cost-effectiveness of lipid-lowering management.
      This document is organized based on discrete clinical questions, with an Executive Summary of key recommendations followed by the supporting evidence base. The objectives of this CPG are to provide:
      • An overview of the screening recommendations, assessment of risk, and treatment recommendations for various lipid disorders;
      • Special consideration for individuals with diabetes, women, and children/adolescents with dyslip- idemia; and
      • Cost-effectiveness data to support therapeutic decision-making.

      II. METHODS

      This CPG was developed in accordance with the AACE Protocol for Standardized Production of Clinical Practice Guidelines (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]). Reference citations in the text of this document include the reference number, numerical descriptor (EL 1-4), and semantic descriptor (explained in Table 1) (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]).
      Table 12014 American Association of Clinical Endocrinologists Protocol for Production of Clincal Practice Guidelines - Step I: Evidence Rating
      Adapted from: Endocr Pract. 2014;20:692-702 (9 [EL 4; NE]).
      Numerical descriptor (evidence level)
      1 = strong evidence; 2 = intermediate evidence; 3 = weak evidence; 4 = no evidence.
      Semantic descriptor
      1Meta-analysis of randomized controlled trials (MRCT)
      1Randomized controlled trial (RCT)
      2Meta-analysis of nonrandomized prospective or case-controlled trials
      2Nonrandomized controlled trial (NRCT)
      2Prospective cohort study (PCS)
      2Retrospective case-control study (RCCS)
      3Cross-sectional study (CSS)
      3Surveillance study (registries, surveys, epidemiologic study, retrospective chart review, mathematical modeling or database) (SS)
      3Consecutive case series (CCS)
      3Single case report (SCR)
      4No evidence (theory, opinion, consensus, review, or preclinical study) (NE)
      a Adapted from: Endocr Pract. 2014;20:692-702 (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]).
      b 1 = strong evidence; 2 = intermediate evidence; 3 = weak evidence; 4 = no evidence.
      All primary writers have made disclosures regarding multiplicities of interests and have attested that they are not employed by industry. In addition, all primary writers are AACE members and credentialed experts. Primary writers submitted contributions to specific clinical questions, which were subsequently reviewed, discussed, and integrated into the final document. This valuable input provides the basis for the recommendations herein. The format of this CPG is based on specific and relevant clinical questions (labeled “Q”).
      Recommendations (labeled “R”) are assigned Grades that map to the best evidence level (BEL) ratings based on the highest quality supporting evidence level (EL) (Table 1, Table 2; Figure 1) (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]), all of which have also been rated based on scientific substantiation (Table 3) (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]). Recommendation Grades are designated “A,” “B,” or “C” when there is scientific evidence available, or “D” when there is only expert opinion or a lack of conclusive scientific evidence. Technically, the BEL follows the recommendation Grade in the Executive Summary. Briefly, there are 4 intuitive levels of evidence: 1 = strong, 2 = intermediate, 3 = weak, and 4 = no evidence (Table 3). Comments may be appended to the recommendation Grade and BEL regarding any relevant subjective factors that may have influenced the grading process (Table 4) (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]). Details regarding each recommendation may be found in the upcoming corresponding section of the CPG Evidence Base Appendix and will include a complete list of supporting References. Thus, the process leading to a final recommendation and grade is not rigid, but rather incorporates complex expert integration of objective and subjective factors meant to reflect optimal real-life clinical decision-making, options, and individualization of care. This document is a guideline, and since individual circumstances and presentations differ, ultimate clinical management is based on what is in the best interest of the individual and involves his or her input (“patient- centered care”) and reasonable clinical judgment by treating clinicians.
      Table 22014 American Association of Clinical Endocrinologists Protocol for Production of Clinical Practice Guidelines—Step II: Evidence Analysis and Subjective Factors
      Reprinted from: Endocr Pract. 2014;20:692-702 (9 [EL 4; NE]).
      Study designData analysisInterpretation of results
      Premise correctnessIntent-to-treatGeneralizability
      Allocation concealment (randomization)Appropriate statisticsLogical
      Selection biasIncompleteness
      Appropriate blindingValidity
      Using surrogate endpoints (especially in “first-in-its-class” intervention)
      Sample size (beta error)
      Null hypothesis vs. Bayesian statistics
      a Reprinted from: Endocr Pract. 2014;20:692-702 (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]).
      Fig. 1
      Fig. 12014 American Association of Clinical Endocrinologists Clinical Practice Guideline Methodology. Current American Association of Clinical Endocrinologists Clinical Practice Guidelines have a problem-oriented focus that results in a shortened production timeline, middle-range literature searching, emphasis on patient-oriented evidence that matters, greater transparency of intuitive evidence rating and qualifications, incorporation of subjective factors into evidence level to recommendation grade mapping, cascades of alternative approaches, and an expedited multilevel review mechanism (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]).
      Table 32014 American Association of Clinical Endocrinologists Protocol for Production of Clinical Practice Guidelines —Step III: Grading of Recommendations; How Different Evidence Levels Can Be Mapped to the Same Recommendation Grade
      Starting with the left column, best evidence levels (BELs), subjective factors, and consensus map to recommendation grades in the right column. When subjective factors have little or no impact (“none”), then the BEL is directly mapped to recommendation grades. When subjective factors have a strong impact, then recommendation grades may be adjusted up (“positive” impact) or down (“negative” impact). If a two-thirds consensus cannot be reached, then the recommendation grade is D. NA, not applicable (regardless of the presence or absence of strong subjective factors, the absence of a two-thirds consensus mandates a recommendation grade D).
      Reprinted from Endocr Pract. 2014;20:692-702 (9 [EL 4; NE]).
      Best evidence levelSubjective factor impactTwo-thirds consensusMappingRecommendation grade
      1NoneYesDirectA
      2PositiveYesAdjust upA
      2NoneYesDirectB
      1NegativeYesAdjust downB
      3PositiveYesAdjust upB
      3NoneYesDirectC
      2NegativeYesAdjust downC
      4PositiveYesAdjust upC
      4NoneYesDirectD
      3NegativeYesAdjust downD
      1, 2, 3,4NANoAdjust downD
      a Starting with the left column, best evidence levels (BELs), subjective factors, and consensus map to recommendation grades in the right column. When subjective factors have little or no impact (“none”), then the BEL is directly mapped to recommendation grades. When subjective factors have a strong impact, then recommendation grades may be adjusted up (“positive” impact) or down (“negative” impact). If a two-thirds consensus cannot be reached, then the recommendation grade is D. NA, not applicable (regardless of the presence or absence of strong subjective factors, the absence of a two-thirds consensus mandates a recommendation grade D).
      b Reprinted from Endocr Pract. 2014;20:692-702 (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]).
      Table 42014 American Association of Clinical Endocrinologists Protocol for Production of Clinical Practice Guidelines— Step IV: Examples of Qualifiers That May Be Appended to Recommendations
      Reprinted from Endocr Pract. 2014;20:692-702 (9 [EL 4; NE]).
      Cost-effectiveness Risk-benefit analysis
      Evidence gaps
      Alternative physician preferences (dissenting opinions)
      Alternative recommendations (“cascades”)
       Resource availability
       Cultural factors
      Relevance (patient-oriented evidence that matters)
      a Reprinted from Endocr Pract. 2014;20:692-702 (
      • Mechanick J.I.
      • Camacho P.M.
      • Garber A.J.
      • et al.
      American Association of Clinical Endocrinologists and American College of Endocrinology Protocol for Standardized Production of Clinical Practice Guidelines, Algorithms, and Checklists - 2014 Update and the AACe G4G Program.
      [EL 4; NE]).
      This CPG was reviewed and approved by the primary writers, other invited experts, the AACE Publications Committee, the AACE Board of Directors, and the ACE Board of Trustees before submission for peer review by Endocrine Practice. The efforts of all those involved are greatly appreciated.

      III. EXECUTIVE SUMMARY

      In this update, there are 87 Recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. There is a greater percentage of Recommendations that are Grade A or B (72%) compared with those that are Grade C and Grade D (28%). The evidence base presented here provides relevant information for the recommendations in the Executive Summary.

       3Q1. HOW SHOULD INDIVIDUALS BE SCREENED FOR THE DETECTION OF DYSLIPIDEMIA?

       3Q1.1. Global Risk Assessment

      • R1. Identify risk factors that enable personalized and optimal therapy for dyslipidemia (Table 5) (Grade A; BEL 1).
        Table 5Major Atherosclerotic Cardiovascular Disease Risk Factors
        Major risk factorsAdditional risk factorsNontraditional risk factors
        Advancing age
        Risk factors identified in the Framingham Heart study.
        Risk factors identified in the MRFIT study (Multiple Risk Factor Intervention Trial).
        Risk factors identified in the INTERHEART study.
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        Obesity, abdominal obesity
        Risk factors identified in the INTERHEART study.
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
         Lipoprotein (a)
         Total serum cholesterol level
        Risk factors identified in the Framingham Heart study.
        Risk factors identified in the MRFIT study (Multiple Risk Factor Intervention Trial).
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        Family history of hyperlipidemia
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
         Clotting factors ft Inflammation markers
         Non-HDL-C
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
         Small, dense LDL-C
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        (hsCRP; Lp-PLA2)
         LDL-C
        Risk factors identified in the Framingham Heart study.
        d
         Apo B
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
         Homocysteine levels
        Low HDL-C
        Risk factors identified in the Framingham Heart study.
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        Elevated HDL-C is a negative risk factor.
         LDL particle concentrationApo E4 isoform
        Diabetes mellitus
        Risk factors identified in the Framingham Heart study.
        Risk factors identified in the MRFIT study (Multiple Risk Factor Intervention Trial).
        Risk factors identified in the INTERHEART study.
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        Fasting/post-prandial Uric acid
        Hypertension
        Risk factors identified in the Framingham Heart study.
        Risk factors identified in the MRFIT study (Multiple Risk Factor Intervention Trial).
        Risk factors identified in the INTERHEART study.
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        hypertriglyceridemia
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
         TG-rich remnants
        Chronic kidney disease 3,4
        Based on a pooled analysis of community-based studies (N = 22,634).
        PCOS
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        Cigarette smoking
        Risk factors identified in the Framingham Heart study.
        Risk factors identified in the MRFIT study (Multiple Risk Factor Intervention Trial).
        Risk factors identified in the INTERHEART study.
        Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        Dyslipidemic triad
        Hypertriglyceridemia; low HDL-C; and an excess of small, dense LDL-C.
        Definite myocardial infarction or sudden death before age 55 years in father or other male first-degree relative or before age 65 years in mother or other female first-degree relative.
        Family history of ASCVD
        Risk factors identified in the Framingham Heart study.
        d,g
        Abbreviations: apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; hsCRP = high-sensitivity C-reactive protein; LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; Lp-PLA2 = lipoprotein-associated phospholipase; PCOS = polycystic ovary syndrome.
        a Risk factors identified in the Framingham Heart study.
        b Risk factors identified in the MRFIT study (Multiple Risk Factor Intervention Trial).
        c Risk factors identified in the INTERHEART study.
        d Risk factors identified in guidelines and position statements (National Cholesterol Education Program Adult Treatment Panel III, American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Position Statement, American Association of Clinical Endocrinologists Insulin Resistance Syndrome Position Statement, American Diabetes Association Standards of Care 2009, American Diabetes Association/American College of Cardiology Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk, National Lipid Association, Clinical Utility of Inflammatory Markers and Advanced Lipoprotein Testing).
        e Elevated HDL-C is a negative risk factor.
        f Hypertriglyceridemia; low HDL-C; and an excess of small, dense LDL-C.
        g Definite myocardial infarction or sudden death before age 55 years in father or other male first-degree relative or before age 65 years in mother or other female first-degree relative.
        h Based on a pooled analysis of community-based studies (N = 22,634).
      • R2. Based on epidemiologic studies, individuals with type 2 diabetes (T2DM) should be considered as high, very high, or extreme risk for ASCVD (Table 6) (Grade B; BEL 3; upgraded due to high relevance).
        Table 6Atherosclerotic Cardiovascular Disease Risk Categories and LDL-C Treatment Goals
        Treatment goals
        Risk categoryRisk factors
        Major independent risk factors are high LDL-C, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure ≥140/90 mm Hg or on hypertensive medication), low HDL-C (<40 mg/dL), family history of coronary artery disease (in male, first-degree relative younger than 55 years; in female, first-degree relative younger than 65 years), chronic renal disease (CKD) stage 3/4, evidence of coronary artery calcification and age (men >45; women >55 years). Subtract 1 risk factor if the person has high HDL-C.
        /10-year risk
        Framingham risk scoring is applied to determine 10-year risk.
        LDL-C (mg/dL)Non-HDL-C (mg/dL)Apo B (mg/dL)
        Extreme risk- Progressive ASCVD including unstable angina in patients after achieving an LDL-C <70 mg/dL<55<80<70
        - Established clinical cardiovascular disease in patients with DM. CKD 3/4, or HeFH
        - History of prematare ASCVD (<55 male, <65 female)
        Very high risk- Established or recent hospitalization for ACS, coronary, carotid or peripheral vascular disease, 10-year risk >20%<70<100<80
        - Diabetes or CKD 3/4 with 1 or more risk factors)
        -HeFH
        High risk->2 risk factors and 10-year risk 10-20% Diabetes or CKD 3/4 with no other risk factors<100<130<90
        Moderate risk<2 risk factors and 10-year risk <10%<100<130<90
        Low risk0 risk factors<130<160NR
        Abbreviations: ACS = acute coronary syndrome; ASCVD = atherosclerotic cardiovascular disease; CKD = chronic kidney disease; DM = diabetes mellitus; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; LDL-C = low-density lipoprotein cholesterol; MESA = Multi-Ethnic Study of Atherosclerosis; NR = not recommended; UKPDS = United Kingdom Prospective Diabetes Study.
        a Major independent risk factors are high LDL-C, polycystic ovary syndrome, cigarette smoking, hypertension (blood pressure ≥140/90 mm Hg or on hypertensive medication), low HDL-C (<40 mg/dL), family history of coronary artery disease (in male, first-degree relative younger than 55 years; in female, first-degree relative younger than 65 years), chronic renal disease (CKD) stage 3/4, evidence of coronary artery calcification and age (men >45; women >55 years). Subtract 1 risk factor if the person has high HDL-C.
        b Framingham risk scoring is applied to determine 10-year risk.
      • R3. Based on epidemiologic and prospective cohort studies, individuals with type 1 diabetes (T1DM) and duration more than 15 years or with 2 or more major cardiovascular (CV) risk factors (e.g., albu minuria, chronic kidney disease [CKD] stage 3/4, initiation of intensive control >5 years after diagnosis), poorly controlled hemoglobin A1C (A1C) or insulin resistance with metabolic syndrome should be considered to have risk-equivalence to individuals with T2DM (Table 7, see online Appendix/Evidence Base) (Grade B; BEL 2).
      • R4. The 10-year risk of a coronary event (high, intermediate, or low) should be determined by detailed assessment using one or more of the following tools (Table 8) (Grade C; BEL 4, upgraded due to cost- effectiveness):
        Table 8Key Cardiovascular Risk Scoring Tools: Framingham, MESA, Reynolds, and UKPDS
      • R5. Special attention should be given to assessing women for ASCVD risk by determining the 10-year risk (high, intermediate, or low) of a coronary event using the Reynolds Risk Score (http://www.reynoldsriskscore.org)or the Framingham Risk Assessment Tool (http://www.framinghamheartstudy.org/risk-functions/coronary-heart-disease/hard-10- year-risk.php) (Table 8) (Grade C; BEL 4, upgraded due to cost-effectiveness).
      • R6. Dyslipidemia in childhood and adolescence should be diagnosed and managed as early as possible to reduce the levels of LDL-C that may eventually increase risk of CV events in adulthood (Table 9) (Grade A; BEL 1).
        Table 9Classification of LDL-C Levels in Children and Adolescents
        CategoryLDL-C, mg/dL
        Acceptable<100
        Borderline100-129
        High130
        Abbreviation: LDL-C = low-density lipoprotein cholesterol
      • R7. When the HDL-C concentration is >60 mg/dL, 1 risk factor should be subtracted from an individual’s overall risk profile (Grade B; BEL 2).
      • R8. A classification of elevated TG should be incorporated into risk assessments to aid in treatment decisions (Table 10) (Grade B; BEL 2).
        Table 10Classification of Elevated TG Levels
        TG categoryTG concentration, mg/dLGoal
        Normal<150<150 mg/dL
        Borderline-high150-199
        High200-499
        Very high500
        Abbreviation: TG = triglycerides
      Reproduced with permission from Garber et al. Endocr Pract. 2017;23:207-238.

       3Q1.2. Screening

       Familial Hypercholesterolemia

      • R9. Individuals should be screened for familial hypercholesterolemia (FH) when there is a family history of:
      • Premature ASCVD (definite MI or sudden death before age 55 years in father or other male first- degree relative, or before age 65 years in mother or other female first-degree relative) or
      • Elevated cholesterol levels (total, non-HDL and/ or LDL) consistent with FH (Grade C; BEL 4, upgraded due to cost-effectiveness).

       Adults With Diabetes

      • R10. Annually screen all adult individuals with T1DM or T2DM for dwyslipidemia (Grade B; BEL 2).

       Young Adults (Men Aged 20-45 Years, Women Aged 20-55 Years)

      • R11. Evaluate all adults 20 years of age or older for dyslipidemia every 5 years as part of a global risk assessment (Grade C; BEL 4, upgraded due to cost-effectiveness).

       Middle-Aged Adults (Men Aged 45-65 Years, Women Aged 55-65 Years)

      • R12. In the absence of ASCVD risk factors, screen middle-aged individuals for dyslipidemia at least once every 1 to 2 years. More frequent lipid testing is recommended when multiple global ASCVD risk factors are present (Grade A; BEL 1).
      • R13. The frequency of lipid testing should be based on individual clinical circumstances and the clinician’s best judgment (Grade C; BEL 4, upgraded due to cost-effectiveness).

       Older Adults (Older Than 65 Years)

      • R14. Annually screen older adults with 0 to 1 ASCVD risk factor for dyslipidemia (Grade A; BEL 1)
      • R15. Older adults should undergo lipid assessment if they have multiple ASCVD global risk factors (i.e., other than age) (Grade C; BEL 4, upgraded due to cost-effectiveness).
      • R16. Screening for this group is based on age and risk, but not sex; therefore, older women should be screened in the same way as older men (Grade A; BEL 1).

       Children and Adolescents

      • R17. In children at risk for FH (e.g., family history of premature cardiovascular disease or elevated cholesterol), screening should be at 3 years of age, again between ages 9 and 11, and again at age 18 (Grade B; BEL 3, upgraded due to cost-effectiveness).
      • R18. Screen adolescents older than 16 years every 5 years or more frequently if they have ASCVD risk factors, have overweight or obesity, have other ele-ments of the insulin resistance syndrome, or have a family history of premature ASCVD (Grade B; BEL 3, upgraded due to cost-effectiveness).
      Table 8 Key Cardiovascular Risk Scoring Tools: Framingham, MESA, Reynolds, and UKPDS
      Abbreviations: A1C = hemoglobin A1C; ATP III = Adult Treatment Panel III; ASCVD = atherosclerotic cardiovascular disease; A1C = glycated hemoglobin; CVA = cerebrovascular accident; HDL = high-density lipoprotein; hsCRP = high-sensitivity C-reactive protein; ln = natural logarithm; MetS = metabolic syndrome; MI = myocardial infarction; T2DM = type 2 diabetes mellitus; UKPDS = United Kingdom Prospective Diabetes Study.

       3Q2. WHICH SCREENING TESTS ARE RECOMMENDED FOR THE DETECTION OF CARDIOVASCULAR RISK?

       3Q2.1. Fasting Lipid Profile

      • R19. Use a fasting lipid profile to ensure the most precise lipid assessment; this should include total cholesterol, LDL-C, TG, and non-HDL-C (Grade C; BEL 4, upgraded due to cost-effectiveness).
      • R20. Lipids, including TG, can be measured in the non-fasting state if fasting determinations are impractical (Grade D).

       3Q2.2. LDL-C

      • R21. LDL-C may be estimated using the Friedewald equation: LDL-C = (total cholesterol - HDL-C) - TG/5; however, this method is valid only for values obtained during the fasting state and becomes increasingly inaccurate and invalid when TG levels are greater than 200 mg/dL and 400 mg/dL, respectively (Grade C; BEL 3).
      • R22. LDL-C should be directly measured in certain high-risk individuals such as those with fasting TG levels greater than 250 mg/dL or those with diabetes or known vascular disease (Grade C; BEL 3).

       3Q2.3. HDL-C

      • R23. Measurement of HDL-C should be included in screening tests for dyslipidemia (Grade B; BEL 2).

       3Q2.4. Non-HDL-C

      • R24. The non-HDL-C (total cholesterol - HDL- C) should be calculated to assist risk stratification in individuals with moderately elevated TG (200 to 500 mg/dL), diabetes, and/or established ASCVD (Grade B; BEL 2).
      • R25. If insulin resistance is suspected, the non-HDL-C should be evaluated to gain useful information regarding the individual’s total atherogenic lipoprotein burden (Grade D).

       3Q2.5. TG

      • R26. TG levels should be part of routine lipid screening: moderate elevations (≥150 mg/dL) may identify individuals at risk for the insulin resistance syndrome and levels ≥200 mg/dL may identify individuals at substantially increased ASCVD risk (Grade B; BEL 2).

       3Q2.6. Apolipoproteins

      • R27. Apo B and/or an apo B/apo A1 ratio calculation and evaluation may be useful in at-risk individuals (TG ≥150, HDL-C <40, prior ASCVD event, T2DM, and/or the insulin resistance syndrome [even at target LDL-C levels]) to assess residual risk and guide decision-making (Grade A; BEL 1).
      • R28. Apo B measurements (reflecting the particle concentration of LDL and all other atherogenic lipoproteins) may be useful to assess the success of LDL-C- lowering therapy (Grade A; BEL 1).

       3Q2.7. Secondary Causes of Dyslipidemia

      • R29. Rule out secondary causes of dyslipidemia (Table 11) (Grade B; BEL 2).
        Table 11Common Secondary Causes of Dyslipidemia
        Aff00ted lipidsConditions
        ↑ Total cholesterol and LDL-C• Hypothyroidism
        • Nephrosis
        • Dysgammaglobulinemia (systemic lupus erythematosus, multiple myeloma)
        • Progestin
        Progestational agents, especially those with androgenic activity, can increase LDL-C and decrease HDL-C.
        or anabolic steroid treatment
        • Cholostatic diseases of the liver due to abnormal lipoproteins, as in primary biliary cirrhosis
        • Protease inhibitors for treatment of HIV infection
        Protease inhibitors can induce peripheral lipodystrophy, increased visceral fat, insulin resistance, and diabetes. Protease inhibitor- induced dyslipidemia may include elevated LDL-C and/or the atherogenic dyslipidemia pattern of high TG; small, dense, LDL-C; and low HDL-C. However, newer generation protease inhibitors may have improved lipid profiles.
        ↑ TG andVLDL-C• Chronic renal failure
        • T2DM
        Diabetic dyslipidemia is often similar to atherogenic dyslipidemia: high TG, small, dense LDL-C, and low HDL-C.
        • Obesity
        • Excessive alcohol intake
        • Hypothyroidism
        • Antihypertensive medications (thiazide diuretics and β-adrenergic blocking agents)
        • Corticosteroid therapy (or severe stress that increases endogenous corticosteroids)
        • Orally administered estrogens
        Transdermally administered estrogens are not associated with increased TG levels.
        , oral contraceptives, pregnancy
        • Protease inhibitors for treatment of HIV infection
        Protease inhibitors can induce peripheral lipodystrophy, increased visceral fat, insulin resistance, and diabetes. Protease inhibitor- induced dyslipidemia may include elevated LDL-C and/or the atherogenic dyslipidemia pattern of high TG; small, dense, LDL-C; and low HDL-C. However, newer generation protease inhibitors may have improved lipid profiles.
        Abbreviations: HIV= human immunodeficiency virus; LDL-C = low-density lipoprotein cholesterol; T2DM = type 2 diabetes mellitus; TG = triglycerides
        a Progestational agents, especially those with androgenic activity, can increase LDL-C and decrease HDL-C.
        b Protease inhibitors can induce peripheral lipodystrophy, increased visceral fat, insulin resistance, and diabetes. Protease inhibitor- induced dyslipidemia may include elevated LDL-C and/or the atherogenic dyslipidemia pattern of high TG; small, dense, LDL-C; and low HDL-C. However, newer generation protease inhibitors may have improved lipid profiles.
        c Diabetic dyslipidemia is often similar to atherogenic dyslipidemia: high TG, small, dense LDL-C, and low HDL-C.
        d Transdermally administered estrogens are not associated with increased TG levels.

       3Q2.8. Additional Tests

      • R30. Use hsCRP to stratify ASCVD risk in individuals with a standard risk assessment that is borderline, or in those with an intermediate or higher risk with an LDL-C concentration <130 mg/dL (Grade B; BEL 2).
      • R31. Measure lipoprotein-associated phospholipase A2 (Lp-PLA2), which in some studies has demonstrated more specificity than hsCRP, when it is necessary to further stratify an individual’s ASCVD risk, especially in the presence of hsCRP elevations (Grade A; BEL 1).
      • R32. The routine measurement of homocysteine, uric acid, plasminogen activator inhibitor-1, or other inflammatory markers is not recommended because the benefit of doing so is not sufficiently proven (Grade D).
      • R33. Coronary artery calcification (CAC) measurement has been shown to be of high predictive value and is useful in refining risk stratification to determine the need for more aggressive treatment strategies (Grade B; BEL 2).
      • R34. Carotid intima media thickness (CIMT) may be considered to refine risk stratification to determine the need for more aggressive ASCVD preventive strategies (Grade B; BEL 2).

       3Q3. WHAT ARE THE TREATMENT RECOMMENDATIONS IN INDIVIDUALS WITH DYSLIPIDEMIA AND ASCVD RISK?

       3Q3.1. Treatment Goals

      • R35. Treatment goals for dyslipidemia should be personalized according to levels of risk (Table 6, Table 11) (Grade A; BEL 1).

       3Q3.1.1. Risk Categories and LDL-C Goals (Table 6)

      • R36. For individuals at low risk (i.e., with no risk factors), an LDL-C goal <130 mg/dL is recommended (Grade A; BEL 1).
      • R37. For individuals at moderate risk (i.e., with 2 or fewer risk factors and a calculated 10-year risk of less than 10%), an LDL-C goal <100 mg/dL is recommended (Grade A; BEL 1).
      • R38. For individuals at high risk (i.e., with an ASCVD equivalent including diabetes or stage 3 or 4 CKD with no other risk factors, or individuals with 2 or more risk factors and a 10-year risk of 10%- 20%), an LDL-C goal <100 mg/dL is recommended (Grade A; BEL 1).
      • R39. For individuals at very high risk (i.e., with established or recent hospitalization for acute coronary syndrome (ACS); coronary, carotid or peripheral vascular disease; diabetes or stage 3 or 4 CKD with 1 or more risk factors; a calculated 10-year risk greater than 20%; or heterozygous familial hypercholesterolemia [HeFH]), an LDL-C goal <70 mg/dL is recommended (Grade A; BEL 1).
      • R40. For individuals at extreme risk (i.e., with progressive ASCVD, including unstable angina that persists after achieving an LDL-C <70 mg/dL, or established clinical ASCVD in individuals with diabetes, stage 3 or 4 CKD, and/or HeFH, or in individuals with a history of premature ASCVD (<55 years of age for males or <65 years of age for females), an LDL-C goal <55 mg/dL is recommended (Grade A; BEL 1).
      • R41. An LDL-C goal <100 mg/dL is considered “acceptable” for children and adolescents, with 100 to 129 mg/dL considered “borderline” and 130 mg/dL or greater considered “high” (based on recommendations from the American Academy of Pediatrics) (Table 9) (Grade D).

       3Q312. HDL-C

      • R42. HDL-C should be >40 mg/dL, but also as high as possible, primarily through the use of lifestyle interventions (e.g., weight loss, physical activity, and tobacco cessation), and if risk factors are present (e.g., borderline elevated LDL-C levels, a family history of premature ASCVD, or a personal history of ASCVD), also through the use of pharmacotherapy primarily focused on reducing LDL-C (Grade A; BEL 1).

       3Q3.1.3. Non-HDL-C

      • R43. For most individuals, a non-HDL-C goal (total cholesterol - HDL-C) 30 mg/dL higher than the individual’s specific LDL-C goal is recommended (Table 12) (Grade D).
        Table 12Lipid Goals for Patients at Risk for Atherosclerotic Cardiovascular Disease
        See text for references and evidence levels.
        Lipid parameterGoal (mg/dL)
        TC<200
        LDL-C<130 (low risk) <100 (moderate risk) <100 (high risk) <70 (very high risk) <55 (extreme risk)
        Non-HDL-C30 above LDL-C goal; 25 above LDL-C goal (extreme risk patients)
        TG<150
        Apo B<90 (patients at high risk of ASCVD, including those with diabetes) <80 (patients at very high risk with established ASCVD or diabetes plus >1 additional risk factor) <70 (patients at extreme risk)
        Abbreviations: apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; HDL-C = high- density lipoprotein cholesterol: LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides
        a See text for references and evidence levels.
      • R44. For individuals at extreme risk, a non-HDL- C goal 25 mg/dL higher than the individual-specific LDL-C goal is recommended (Table 12) (Grade A; BEL 1).

       3Q3.1.4. Apolipoproteins

      • R45. For individuals at increased risk of ASCVD, including those with diabetes, an optimal apo B goal is <90 mg/dL, while for individuals with established ASCVD or diabetes plus 1 or more additional risk factor(s), an optimal apo B goal is <80 mg/dL, and for individuals at extreme risk, an optimal apo B goal is <70 mg/dL (Table 12) (Grade A; BEL 1).

       3Q3.1.5 TG

      • R46. TG goals <150 mg/dL are recommended (Table 12) (Grade A; BEL 1).

       3Q3.2. Treatment Recommendations

      • R47. A comprehensive strategy to control lipid levels and address associated metabolic abnormalities and modifiable risk factors is recommended primarily using lifestyle changes (Grade A, BEL 1) and patient education with pharmacotherapy as needed to achieve evidence-based targets (Grade A, BEL 1).

       3Q3.2.1. Physical Activity

      • R48. A reasonable and feasible approach to fitness therapy (i.e., exercise programs that include at least 30 minutes of moderate-intensity physical activity [consuming 4-7 kcal/min] 4 to 6 times weekly, with an expenditure of at least 200 kcal/day) is recommended; suggested activities include brisk walking, riding a stationary bike, water aerobics, cleaning/ scrubbing, mowing the lawn, and sporting activities (Grade A; BEL 1).
      • R49. Daily physical activity goals can be met in a single session or in multiple sessions throughout the course of a day (10 minutes minimum per session); for some individuals, breaking activity up throughout the day may help improve adherence with physical activity programs (Grade A; BEL 1).
      • R50. In addition to aerobic activity, muscle-strengthening activity is recommended at least 2 days a week (Grade A; BEL 1).

       3Q3.2.2. Medical Nutrition Therapy

      • R51. For adults, a reduced-calorie diet consisting of fruits and vegetables (combined >5 servings/day), grains (primarily whole grains), fish, and lean meats is recommended (Grade A; BEL 1).
      • R52. For adults, the intake of saturated fats, transfats, and cholesterol should be limited, while LDL- C-lowering macronutrient intake should include plant stanols/sterols (~2 g/day) and soluble fiber (10-25 g/ day) (Grade A; BEL 1).
      • R53. Primary preventive nutrition consisting of healthy lifestyle habits is recommended in all healthy children (Grade A; BEL 1).

       3Q3.2.3. Smoking Cessation

      • R54. Tobacco cessation should be strongly encouraged and facilitated (Grade A; BEL 2; upgraded due to potential benefit).

       3Q3.2.4. Pharmacologic Therapy

      • R55. In individuals at risk for ASCVD, aggressive lipid- modifying therapy is recommended to achieve appropriate LDL-C goals (Table 13) (Grade A, BEL 1).
        Table 13Primary Lipid-Lowering Drug Classes
        Drug classMetabolic effect
        Percentage of change varies depending on baseline lipid variables and dosages. Statin potency and dosages vary.
        Main considerations
        Most frequent or serious; See prescribing information for complete contraindications, warnings, precautions, and side effects.
        HMG-CoA reductase inhibitors (statins: lovastatin, pravastatin, fluvastatin, simvastatin, atorvastatin, rosuvastatin, pitavastatin) statins and CYP450 3A4 inhibitors, cyclosporine, warfarin, and protease inhibitors. Myopathy/rhabdomyolysis in rare cases; increased risk with co-administration of some drugs (see product labeling).Primarily ↓LDL-C 21-55% by competitively inhibiting rate- limiting step of cholesterol synthesis in the liver, leading to upregulation of hepatic LDL receptors Effects on TG and HDL-C are less pronounced (↓ TG 6-30% and ↓HDL-C 2-10%)Liver function test prior to therapy and as clinically indicated thereafter.
        Myalgias and muscle weakness in some patients Potential for drug-drug interaction between some
        Simvastatin dosages of 80 mg are no longer recommended.
        Do not exceed 20 mg simvastatin daily with amlodipine or ranolazine.
        Plasma elevations of rosuvastatin may be higher among Asian persons than other ethnic groups.
        New-onset diabetes is increased in patients treated with statins; however, it is dose-related, occurs primarily in patients with MetS, appears to be less common with pravastatin and possibly pitavastatin, and occurs overall to a lesser extent than the associated decrease in ASCVD.
        Cholesterol absorption inhibitors (ezetimibe)Primarily ↓ LDL-C 1018% by inhibiting intestinal absorption of cholesterol and decreasing delivery to the liver, leading to upregulation of hepatic LDL receptors ↓Apo B 11-16%Myopathy/rhabdomyolysis (rare) Myopathy/ rhabdomyolysis (rare)
        When co-administered with statins or fenofibrate, risks associated with those drugs remain (e.g., myopathy/ rhabdomyolysis, cholelithiasis)
        In combination with statins, additional J LDL-C 25%, total ↓LDL-C 34-61%
        In combination with fenofibrate, ↓LDL-C 20-22% and ↓apo B 25-26% without reducing f HDL-C
        PCSK9 (Proprotein convertase subtilisin/kexin type 9) inhibitors (alirocumab, evolocumab)LDL-C 48-71%, J non-HDL-C 4958%, ↓Total-C 36-42%, ↓Apo B 4255% by inhibiting PCSK9 binding with LDLRs, increasing the number of LDLRs available to clear LDL, and lowering LDL-C levelsRequires subQ self-injection, and refrigeration is generally needed.

        Adverse reactions resulted in discontinuation in 2.2% overall, 1.2% more than placebo for evolocumab, and 5.3% overall, 0.2% more than placebo for alirocumab. Overall levels of adverse reactions and discontinuation very low.

        Adverse reactions with significantly different rates between drug and placebo were local injection site reactions (1.9% greater for alirocumab vs. placebo, 0.7% greater for evolocumab vs. placebo) and influenza (1.2% greater for alirocumab vs. placebo, 0.2% for evolocumab vs. placebo). The most common adverse reactions with similar rates for drug vs. placebo were for the following: Alirocumab (4-12%; most common to least common): nasopharyngitis, influenza, urinary tract infections, diarrhea, bronchitis, and myalgia; Evolocumab (2-4%; most common to least common): Nasopharyngitis, back pain, and upper respiratory tract infection.
        Fibric acid derivatives (gemfibrozil, fenofibrate, fenofibric acid)Primarily ↓TG 20-35%, f HDL-C 6-18% by stimulating lipoprotein lipase activityGemfibrozil may ↓LDL-C 10-15%. GI symptoms, possible cholelithiasis. May potentiate effects of orally administered anticoagulants.
        Fenofibrate may ↓TC and LDL-C 20-25% Lower VLDL-C and LDL-C; reciprocal rise in LDL-C transforms the profile into a less atherogenic form by shifting fewer LDL particles to larger size Fenofibrate ↓fibrinogen levelGemfibrozil may ↓fibrinogen level
        Results vary. Gemfibrozil has been shown to decrease, have no effect on, or increase fibrinogen depending on the study.
        . Gemfibrozil and fenofibrate can f homocdysteine independent of vitamin concentrations
        Results vary. Gemfibrozil has been shown to have no effect on or increase homocysteine.
        .
        Myopathy/rhabdomyolysis when used with statin (uncommon with gemfibrozil, but increased risk with all statins except fluvastatin); interaction less likely with fenofibrate or fenofibric acid (no apparent difference by statin).
        Fibrates are associated with increased serum creatinine levels, which may not reflect renal dysfunction.
        Fenofibrate dose should be cut by two-thirds and gemofibrozil by one-half when eGFR is 15-60, and fibrates should be avoided when eGFR is <15.
        May cause muscle disorders. Can improve diabetic retinopathy.
        Niacin (nicotinic acid)LDL-C 10-25%, ↓TG 20-30%, ↓HDL-C 1035% by decreasing hepatic synthesis of LDL-C and VLDL-CPotential for frequent skin flushing, pruritus, abdominal discomfort, hepatotoxicity (rare but may be severe), nausea, peptic ulcer, atrial fibrillation.
        Deleterious effect on serum glucose at higher dosages. Increases uric acid levels; may lead to gout.
        Lipoprotein (a) Transforms LDL-C to less atherogenic form by increasing average particle size and also decreases LDL particle concentration
        Bile acid sequestrants (cholestyramine, colestipol, colesevelamPrimarily J LDL-C 15-25% by binding bile acids and preventing their reabsorption in the ileumMay f serum TG Frequent constipation and/or bloating, which can reduce adherence
        hydrochloride)(causing hepatic cholesterol depletion and LDLR upregulation)Many potential drug interactions (decreased drug absorption), less so with colesevelam (see product labeling)
        Colesevelam J glucose and hemoglobin A1C (~0.5%); is FDA approved to treat T2DMMay reduce absorption of folic acid and fat-soluble vitamins such as vitamins A, D, and K
        MTP inhibitor (lomitapide)Up to LDL-C 40%, TC 36%, apo B 39%, TG 45%, and non- HDL-C 40% (depending on dose) in patients with HoFH by binding and inhibiting MTP, which inhibits synthesis of chylomicrons and VLDLCan cause increases in transaminases (ALT, AST). Monitoring of ALT, AST, alkaline phosphatase, and total bilirubin prior to initiation, and of ALT and AST during treatment, is required per FDA REMS.
        Causes increases in hepatic fat (steatosis) with or without concomitant elevated transaminases, which may be a risk for progressive liver diseases.
        Also causes steatosis of the small intestine with resulting abdominal pain and steatorrhea unless a very-low-fat diet is followed. May also cause fat-soluble vitamin deficiency unless vitamin supplements are taken.
        Caution should be exercised when used with other drugs with potential hepatotoxicity. Because of hepatotoxicity risk, only available through REMS program.
        Antisense apolipoprotein B oligonucleotide (mipomersen via subQ injection)LDL-C 21%, TC 19%, apo B 24%, and non-HDL-C 22% in patients with HoFH by degrading mRNA for apo B-100, the principal apolipoprotein needed for hepatic synthesis of VLDL (and subsequent intraplasma production of IDL and LDL)Can cause increases in transaminases (ALT, AST). Monitoring of ALT, AST, alkaline phosphatase, and total bilirubin prior to initiation, and of ALT and AST during treatment is recommended.
        Causes increases in hepatic fat (steatosis) with or without concomitant elevated transaminases, which may be a risk for progressive liver diseases.
        Caution should be exercised when used with other drugs with potential hepatotoxicity. Because of hepatotoxicity risk, only available through REMS program.
        Omega-3 fatty acids (icosapent ethyl, omega-3- acid ethyl esters)TG 27-45%, TC 7-10%, VLDL-C 20-42%, apo B 4%, and non- HDL-C 8-14% in individuals with severe hypertriglyceridemia, most likely by reducing hepatic VLDL-TG synthesis and/or secretion and enhancing TG clearance from circulating VLDL particles. Other potential mechanisms of action include: increased 3-oxidation; inhibition of acyl-CoA; 1,2-diacylglyceral acyltransferase; decreased hepatic lipogenesis; and increased plasma lipoprotein activity Icosapent ethyl ↓ LDL-C 5%, whereas omega-3-acid ethyl esters ↓LDL-C 45%TG levels should be carefully assessed prior to initiating therapy and periodically during therapy. Omega-3-acid ethyl esters can increase LDL-C levels.
        May prolong bleeding time. Periodic monitoring of coagulation status should be undertaken in patients receiving treatment with omega-3 fatty acids and other drugs affecting coagulation.
        Periodic monitoring of ALT and AST levels during treatment is recommended for patients with hepatic impairment. Some patients may experience increases in ALT levels only.
        Caution should be exercised when treating patients with a known hypersensitivity to fish and/or shellfish.
        The effect of omega-3 fatty acids on cardiovascular morbidity and mortality and the risk of pancreatitis has not been determined in patients with severe hypertriglyceridemia.
        In patients with paroxysmal or persistent AF, therapy with omega-3-acid ethyl esters may be associated with increased frequency of symptomatic AF or flutter, especially within the first 2 to 3 months after initiation.
        The most common adverse events in patients receiving omega-3 fatty acids included arthralgia (2.3%), eructation (4%), dyspepsia (3%), and taste perversion (4%). Patients may also experience constipation, gastrointestinal disorders, vomiting, rash, or pruritus.
        Omega-3 fatty acids should be used with caution in nursing mothers and should only be used in pregnant women if the benefits of treatment outweigh the potential risk of fetal harm.
        Abbreviations: AF = atrial fibrillation; ALT = alanine aminotransferase; AR = adverse reaction; AST = aspartate aminotransferase; apo = apolipoprotein; eGFR = estimated glomerular filtration rate; FDA = U.S. Food and Drug Administration; GI = gastrointestinal; HDL-C = high-density lipoprotein cholesterol; HMG-CoA = hydroxymethylglutaryl-coenzyme A; LDL-C = low-density lipoprotein cholesterol; LDLR = low-density lipoprotein receptor; MTP = microsomal triglyceride transfer protein; REMS = Risk Evaluation and Mitigation Strategies; subQ = subcutaneous; TC = total cholesterol; TG = triglycerides; VLDL-C, very low-density lipoprotein cholesterol
        a Percentage of change varies depending on baseline lipid variables and dosages. Statin potency and dosages vary.
        b Most frequent or serious; See prescribing information for complete contraindications, warnings, precautions, and side effects.
        c Results vary. Gemfibrozil has been shown to decrease, have no effect on, or increase fibrinogen depending on the study.
        d Results vary. Gemfibrozil has been shown to have no effect on or increase homocysteine.

       Statins

      • R56. Statin therapy is recommended as the primary pharmacologic agent to achieve target LDL-C goals on the basis of morbidity and mortality outcome trials (Grade A; BEL 1).
      • R57. For clinical decision-making, mild elevations in blood glucose levels and/or an increased risk of new- onset T2DM associated with intensive statin therapy do not outweigh the benefits of statin therapy for ASCVD risk reduction (Grade A, BEL 1).
      • R59. Very high-risk individuals with established coronary, carotid, and peripheral vascular disease, or diabetes who also have at least 1 additional risk factor should be treated with statins to target a reduced LDL-C treatment goal of <70 mg/dL (Grade A, BEL 1).
      • R60. Extreme-risk individuals should be treated with statins to target an even lower LDL-C treatment goal of <55 mg/dL (Table 6) (Grade A, BEL 1).

       Fibrates

      • R61. Fibrates should be used to treat severe hypertriglyceridemia (TG >500 mg/dL) (Table 13) (Grade A; BEL 1).
      • R62. Fibrates may improve ASCVD outcomes in primary and secondary prevention when TG concentrations are >200 mg/dL and HDL-C concentrations are <40 mg/dL (Grade A; BEL 1).

       Omega-3 Fish Oil

      • R63. Prescription omega-3 oil, 2 to 4 g daily, should be used to treat severe hypertriglyceridemia (TG >500 mg/dL). Dietary supplements are not FDA-approved for treatment of hypertriglyceridemia and generally are not recommended for this purpose. (Grade A, BEL 1).

       Niacin

      • R64. Niacin therapy is recommended principally as an adjunct for reducing TG (Grade A, BEL 1).
      • R65. Niacin therapy should not be used in individuals aggressively treated with statin due to absence of additional benefits with well-controlled LDL-C (Grade A; BEL 1).
      • Bile Acid Sequestrants
      • R66. Bile acid sequestrants may be considered for reducing LDL-C and apo B and modestly increasing HDL-C, but they may increase TG (Grade A; BEL 1).
      • Cholesterol Absorption Inhibitors
      • R67. Ezetimibe may be considered as monotherapy in reducing LDL-C and apo B, especially in statin-intolerant individuals (Grade B, BEL 2).
      • R68. Ezetimibe can be used in combination with statins to further reduce both LDL-C and ASCVD risk (Grade A; BEL 1).

       Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inhibitors

      • R69. PCSK9 inhibitors should be considered for use in combination with statin therapy for LDL-C lowering in individuals with FH (Grade A; BEL 1).
      • R70. PCSK9 inhibitors should be considered in individuals with clinical cardiovascular disease who are unable to reach LDL-C/non-HDL-C goals with maximally tolerated statin therapy. They should not be used as monotherapy except in statin-intolerant individuals (Grade A; BEL 1).

       Combination Therapy

      • R71. Combination therapy of lipid-lowering agents should be considered when the LDL-C/non-HDL-C level is markedly increased and monotherapy (usually with a statin) does not achieve the therapeutic goal (Grade A; BEL 1).

       Special Considerations: Women

      • R72. Women should be evaluated for their ASCVD risk and be treated with pharmacotherapy if lifestyle intervention is insufficient (Grade C; BEL 4; upgraded due to potential benefit).
      • R73. Hormone replacement therapy for the treatment of dyslipidemia in postmenopausal women is not recommended (Grade A; BEL 1).

       Special Considerations: Children and Adolescents

      • R74. Pharmacotherapy is recommended for children and adolescents older than 10 years who do not respond sufficiently to lifestyle modification, particularly for those satisfying the following criteria (Grade D; BEL 4):
      • LDL-C >190 mg/dL
      • LDL-C >160 mg/dL and the presence of 2 or more cardiovascular risk factors, even after vigorous intervention
      • Family history of premature ASCVD (before 55 years of age), or
      • Having overweight, obesity, or other elements of the insulin resistance syndrome

       3Q3.3. Follow-up and Monitoring

      • R75. Re-assess individuals’ lipid status 6 weeks after therapy initiation and again at 6-week intervals until the treatment goal is achieved (Grade D; BEL 4).
      • R76. While on stable lipid therapy, individuals should be tested at 6- to 12-month intervals (Grade D; BEL 4).
      • R77. While on stable lipid therapy, the specific interval of testing should depend on individual adherence to therapy and lipid profile consistency; if adherence is a concern or the lipid profile is unstable, the individual will probably benefit from more frequent assessment (Grade C; BEL 4; upgraded due to potential benefit).
      • R78. More frequent lipid status evaluation is recommended in situations such as deterioration of diabetes control, use of a new drug known to affect lipid levels, progression of atherothrombotic disease, considerable weight gain, unexpected adverse change in any lipid parameter, development of a new ASCVD risk factor, or convincing new clinical trial evidence or guidelines that suggest stricter lipid goals (Grade C; BEL 4; upgraded due to potential benefit).
      • R79. Liver transaminase levels should be measured before and 3 months after niacin or fibric acid treatment initiation because most liver abnormalities occur within 3 months of treatment initiation. Liver transaminase levels should be measured periodically thereafter (e.g., semiannually or annually) (Grade C; BEL 4; upgraded due to potential benefit).
      • R80. Creatine kinase levels should be assessed and the statin discontinued, at least temporarily, when an individual reports clinically significant myalgias or muscle weakness on statin therapy (Grade C; BEL 4; upgraded due to potential benefit).

       3Q4. IS TREATMENT OF DYSLIPIDEMIA AND PREVENTION OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE COST-EFFECTIVE?

      • R81. Nonpharmacologic interventions such as dietary management (Grade A; BEL 1) and smoking cessation are the most cost-effective options available for ASCVD prevention (Grade A; BEL 2, upgraded due to potential health benefit).
      • R82. When nonpharmacologic interventions fail, pharmacologic intervention is a recommended cost-effective option for primary and secondary intervention among individuals at moderate to high risk (Grade B; BEL 2).
      • R83. Among otherwise healthy individuals at lower risk, the cost-effectiveness of primary pharmacologic intervention varies on the basis of age and sex (with this approach being least cost-effective among women at low risk) (Grade C; BEL 3).
      • R84. Statins have proven cost-effective in both secondary and primary prevention of ASCVD events in individuals at moderate to high risk or in individuals at low risk whose LDL-C levels are very high (>190 mg/ dL) (Grade B; BEL 2).
      • R85. Treatment with fibrates has been found to be cost-effective as both monotherapy and combination therapy for lowering TG and raising HDL-C (Grade D; BEL 4), but not in reducing cardiovascular events, except in individuals with TG concentrations greater than 200 mg/dL and HDL-C concentrations less than 40 mg/dL (Grade D; BEL 4).
      • R86. Ezetimibe, co-administered with statin therapy in individuals unable to meet target LDL-C levels, has not been evaluated for cost-effectiveness in the U.S. Based on studies from Canada and the United Kingdom, ezetimibe may be a cost-effective strategy to achieve LDL-C goals, especially with price decreases for generic ezetimibe (Grade A; BEL 1).
      • R87. Bile acid sequestrants are generally not cost- effective alternatives to statin therapy despite generic availability; this is due to their low LDL-C lowering efficacy compared to statins (Grade B; BEL 2).

      IV. APPENDIX: EVIDENCE BASE

      In this update, there are 695 citations of which 203 (29.2 %) are EL 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 236 (34.0%) are EL 4 (no clinical evidence). There is a greater percentage of references that are EL 1 or 2 in the 2017 update: 340/695 (49%), which is 8% higher compared with 246/606 (41%) in the 2012 AACE CPG (
      • Jellinger P.S.
      • Smith D.A.
      • Mehta A.E.
      • et al.
      American Association of Clinical Endocrinologists’ guidelines for management of dyslipidemia and prevention of atherosclerosis.
      [EL 4; NE]). The evidence base presented here provides relevant information for the recommendations in the Executive Summary.

       4Q1. HOW SHOULD INDIVIDUALS BE SCREENED FOR THE DETECTION OF DYSLIPIDEMIA?

       4Q1.1. Global Risk Assessment

      The third report of the NCEP ATP (Adult Treatment Panel) categorizes ASCVD risk based on a system of risk factor counting and 10-year risk according to Framingham risk scoring (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      National Institutes of Health; National Heart Lung, and Blood Institute; 2002 National Cholesterol Education Program.
      [EL 4; NE]). In addition, the American Diabetes Association (ADA)/American College of Cardiology (ACC) 2008 Consensus Statement on Lipoprotein Management in Patients with Cardiometabolic Risk establishes risk categorization for individuals with diabetes (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation.
      [EL 4; NE]). An overview of accepted ASCVD risk categories and factors is outlined in Table 5 (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      National Institutes of Health; National Heart Lung, and Blood Institute; 2002 National Cholesterol Education Program.
      [EL 4; NE];
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation.
      [EL 4; NE];
      • Stamler J.
      • Wentworth D.
      • Neaton J.D.
      Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).
      [EL 2; PCS];
      • Neaton J.D.
      • Blackburn H.
      • Jacobs D.
      • et al.
      Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group.
      [EL 2; PCS];
      • Grundy S.M.
      • Balady G.J.
      • Criqui M.H.
      • et al.
      Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA Task Force on Risk Reduction.
      [EL 4; NE];
      • Einhorn D.
      • Reaven G.M.
      • Cobin R.H.
      • et al.
      American College of Endocrinology position statement on the insulin resistance syndrome.
      [EL 4; NE];
      [EL 4; NE];
      • Weiner D.E.
      • Tighiouart H.
      • Amin M.G.
      • et al.
      Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies.
      [EL 2; MNRCT];
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      [EL 2; PCS];
      American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Writing Committee American Association of Clinical Endocrinologists Position Statement on Metabolic and Cardiovascular Consequences of Polycystic Ovary Syndrome.
      [EL 4; NE];
      • Cromwell W.C.
      • Otvos J.D.
      • Keyes M.J.
      • et al.
      LDL Particle number and risk of future cardiovascular disease in the Framingham offspring study implications for LDL management.
      [EL 3; SS];
      • Kastelein J.J.
      • van der Steeg W.A.
      • Holme I.
      • et al.
      Lipids, apolipoproteins, and their ratios in relation to cardiovascular events with statin treatment.
      [EL 1; MRCT];
      [EL 4; NE]) and Table 6 (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      National Institutes of Health; National Heart Lung, and Blood Institute; 2002 National Cholesterol Education Program.
      [EL 4; NE];
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation.
      [EL 4; NE];
      • Weiner D.E.
      • Tighiouart H.
      • Amin M.G.
      • et al.
      Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies.
      [EL 2; MNRCT];
      • Stone N.J.
      Lipid management: current diet and drug treatment options.
      [EL 4; NE];
      • Stevens R.J.
      • Kothari V.
      • Adler A.I.
      • Stratton I.M.
      United Kingdom Prospective Diabetes Study (UKPDS) Group. The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56).
      [EL 3; SS];
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      [EL 1; RCT];
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      [EL 1; RCT];
      • Sever P.S.
      • Dahlöf B.
      • Poulter N.R.
      • et al.
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
      [EL 1; RCT];
      • Grundy S.M.
      • Cleeman J.I.
      • Merz C.N.
      • et al.
      Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines.
      [EL 4; NE];
      • Lloyd-Jones D.M.
      • Wilson P.W.
      • Larson M.G.
      • et al.
      Framingham and risk score prediction of lifetime risk for coronary heart disease.
      [EL 2; PCS];
      • Ridker P.M.
      • Morrow D.A.
      • Rose L.M.
      • Rifai N.
      • Cannon C.P.
      • Braunwald E.
      Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial.
      [EL 1; RCT];
      • Barter P.J.
      • Ballantyne C.M.
      • Carmena R.
      • et al.
      Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.
      [EL 4; NE];
      • Smith Jr., S.C.
      • Allen J.
      • Blair S.N.
      • et al.
      AHA/ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease: 2006 update: endorsed by the National Heart, Lung, and Blood Institute. (Erratum in: Circulation. 2006;113:e847.).
      [EL 4; NE];
      • Ridker P.M.
      • Buring J.E.
      • Rifai N.
      • Cook N.R.
      Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score.
      [EL 3; SS];
      • Boekholdt S.M.
      • Hovingh G.K.
      • Mora S.
      • et al.
      Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
      [EL 1; MRCT];
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      [EL 1; RCT];
      • McClelland R.L.
      • Jorgensen N.W.
      • Budoff M.
      • et al.
      10-year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors: derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) with validation in the HNR (Heinz Nixdorf Recall) study and the DHS (Dallas Heart Study).
      [EL 3; SS]). Several risk calculators are presented in Table 8 (
      • Cattaneo M.
      Hyperhomocysteinemia, atherosclerosis and thrombosis.
      [EL 3; SS];
      • Ridker P.M.
      • Morrow D.A.
      • Rose L.M.
      • Rifai N.
      • Cannon C.P.
      • Braunwald E.
      Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial.
      [EL 2; PCS];
      • Ridker P.M.
      • Buring J.E.
      • Rifai N.
      • Cook N.R.
      Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score.
      [EL 3; SS];
      • McClelland R.L.
      • Jorgensen N.W.
      • Budoff M.
      • et al.
      10-year coronary heart disease risk prediction using coronary artery calcium and traditional risk factors: derivation in the MESA (Multi-Ethnic Study of Atherosclerosis) with validation in the HNR (Heinz Nixdorf Recall) study and the DHS (Dallas Heart Study).
      [EL 3; SS];
      • Mosca L.
      • Appel L.J.
      • Benjamin E.J.
      • et al.
      Evidence-based guidelines for cardiovascular disease prevention in women.
      [EL 4; NE]; [EL 4; NE];
      MESA 10-Year CHD Risk with Coronary Artery Calcification.
      [EL 4; NE];
      Reynolds Risk Score: Calculating Heart and Stroke Risk for Women and Men.
      [EL 4; NE];
      UKPDS Risk Engine University of Oxford Diabetes Trial Unit, The Oxford Centre for Diabetes, Endocrinology and Metabolism.
      [EL 4; NE]). The remainder of this section will review these major ASCVD risk factors, as well as important nontradi- tional risk factors.

       Risk Factors for ASCVD

      The risk of ASCVD and ASCVD-related mortality is substantially greater in the presence of multiple risk factors. Since epidemiologic evidence indicates that ASCVD risk factors frequently cluster, it should be expected that many individuals have multiple risk factors (
      • Smith Jr., S.C.
      Multiple risk factors for cardiovascular disease and diabetes mellitus.
      [EL 4; NE];
      • Qureshi A.I.
      • Suri M.F.
      • Kirmani J.F.
      • Divani A.A.
      The relative impact of inadequate primary and secondary prevention on cardiovascular mortality in the United States.
      [EL 3; SS]). The Framingham Heart Study and the MRFIT trial (Multiple Risk Factor Intervention Trial) showed that approximately 85% of excess risk for premature ASCVD is due to 1 or more major risk factor(s) (
      • Stamler J.
      • Wentworth D.
      • Neaton J.D.
      Is relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT).
      [EL 2; PCS];
      • Grundy S.M.
      • Balady G.J.
      • Criqui M.H.
      • et al.
      Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA Task Force on Risk Reduction.
      [EL 4; NE]). The INTERHEART trial, which gathered data on 29,972 individuals in 52 countries, identified 9 ASCVD risk factors that, taken together, accounted for 90% of MI risk. However, 5 of those risk factors (smoking, lipids, hypertension, diabetes, and obesity) constituted a full 80% of observed risk (
      • Yusuf S.
      • Hawken S.
      • Ounpuu S.
      • et al.
      Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
      [EL 2; PCS]). Guidelines and position statements such as the American College of Endocrinology (ACE) Position Statements on polycystic ovary syndrome (PCOS) and the insulin resistance syndrome (available at http://www.aace.com) also identify other risk factors as having significant associations with ASCVD (
      • Einhorn D.
      • Reaven G.M.
      • Cobin R.H.
      • et al.
      American College of Endocrinology position statement on the insulin resistance syndrome.
      [EL 4; NE];
      American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Writing Committee American Association of Clinical Endocrinologists Position Statement on Metabolic and Cardiovascular Consequences of Polycystic Ovary Syndrome.
      [EL 4; NE]). Based on available evidence, Table 5 outlines the most important, current major, additional, and nontraditional ASCVD risk factors.

       Advancing Age

      Men 45 years and older and women 55 years and older have an increased risk of ASCVD; ASCVD occurs most commonly among individuals 65 years and older (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      National Institutes of Health; National Heart Lung, and Blood Institute; 2002 National Cholesterol Education Program.
      [EL 4; NE]).

       High LDL-C and Total Cholesterol

      The association between high serum cholesterol levels, especially high LDL-C, and ASCVD is causal and independent of other risk factors (
      • Betteridge D.J.
      Lipid management: past, present, and future.
      [EL 4; NE];
      • Assmann G.
      • Schulte H.
      • Cullen P.
      New and classical risk factors--the Münster heart study (PROCAM).
      [EL 2; PCS];
      • Van Horn L.
      • Kavey R.E.
      Diet and cardiovascular disease prevention: what works?.
      [EL 4; NE];
      • Assmann G.
      • Cullen P.
      • Schulte H.
      The Münster Heart Study (PROCAM). Results of follow-up at 8 years.
      [EL 2; PCS]). The CARE trial (Cholesterol and Recurrent Events) determined that LDL-C-attributable risk is not linear and increases sharply within higher ranges (
      • Pfeffer M.A.
      • Sacks F.M.
      • Moye L.A.
      • et al.
      Influence of baseline lipids on effectiveness of pravastatin in the CARE Trial. Cholesterol And Recurrent Events.
      [EL 1; RCT]). The MRFIT study found a strong and progressive relationship between elevated total cholesterol levels and death of ASCVD (
      • Neaton J.D.
      • Blackburn H.
      • Jacobs D.
      • et al.
      Serum cholesterol level and mortality findings for men screened in the Multiple Risk Factor Intervention Trial. Multiple Risk Factor Intervention Trial Research Group.
      [EL 2; PCS]).
      Since multiple studies have demonstrated that lowering LDL-C results in decreased ASCVD risk (
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      [EL 1; RCT];
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      [EL 1; RCT];
      • Sever P.S.
      • Dahlöf B.
      • Poulter N.R.
      • et al.
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
      [EL 1; RCT];
      Scandinavian Simvastatin Survival Study Group Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S).
      [EL 1; RCT];
      ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial. Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT).
      [EL 1; RCT];
      • Colhoun H.M.
      • Betteridge D.J.
      • Durrington P.N.
      • et al.
      Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial.
      [EL 1; RCT];
      • Pedersen T.R.
      • Faergeman O.
      • Kastelein J.J.
      • et al.
      High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: the IDEAL study: a randomized controlled trial. (Erratum in: JAMA. 2005;28:3092).
      [EL 1; RCT];
      • Ray K.K.
      • Cannon C.P.
      • McCabe C.H.
      • et al.
      Early and late benefits of high-dose atorvastatin in patients with acute coronary syndromes: results from the PROVE IT-TIMI 22 trial.
      [EL 1; RCT];
      • Waters D.D.
      • LaRosa J.C.
      • Barter P.
      • et al.
      Effects of high-dose atorvastatin on cerebrovascular events in patients with stable coronary disease in the TNT (treating to new targets) study.
      [EL 1; RCT];
      • Ridker P.M.
      • MacFadyen J.G.
      • Fonseca F.A.
      • et al.
      Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER).
      [EL 1; RCT];
      • Ford I.
      • Murray H.
      • McCowan C.
      • Packard C.J.
      Long- Term Safety and Efficacy of Lowering Low-Density Lipoprotein Cholesterol With Statin Therapy: 20-Year Follow-Up of West of Scotland Coronary Prevention Study.
      [EL 2; PCS]), the focus of risk prediction and reduction has shifted toward LDL-C management in ASCVD and primary prevention in individuals with multiple risk factors (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      National Institutes of Health; National Heart Lung, and Blood Institute; 2002 National Cholesterol Education Program.
      [EL 4; NE]).

       Familial Hypercholesterolemia

      Familial hypercholesterolemia (FH) is caused by genetic mutations passed on by one (heterozygous, HeFH) or both parents (homozygous, HoFH) (
      • Zimmerman M.P.
      How do PCSK9 inhibitors stack up to statins for low-density lipoprotein cholesterol control?.
      [EL 4; NE]). A parental history of heart disease or MI has been established as an independent risk factor for ASCVD (
      • Barrett-Connor E.
      • Khaw K.
      Family history of heart attack as an independent predictor of death due to cardiovascular disease.
      [EL 3; CSS];
      • Shea S.
      • Ottman R.
      • Gabrieli C.
      • Stein Z.
      • Nichols A.
      Family history as an independent risk factor for coronary artery disease.
      [EL 3; CSS];
      • Sesso H.D.
      • Lee I.M.
      • Gaziano J.M.
      • Rexrode K.M.
      • Glynn R.J.
      • Buring J.E.
      Maternal and paternal history of myocardial infarction and risk of cardiovascular disease in men and women.
      [EL 3; SS]). It has been estimated that 77% of individuals with ASCVD and 54% of their first- and second-degree relatives express genetically linked dyslipidemia. Moreover, ASCVD risk is approximately 50% in siblings of individuals with premature ASCVD (
      • Superko H.R.
      Did grandma give you heart disease? The new battle against coronary artery disease.
      [EL 4; NE]). In addition, studies of asymptomatic individuals indicate that a positive family history of ASCVD increases the risk of subclinical atherosclerosis (CAC and CIMT) compared with risk of individuals without a positive family history (
      • Fornage M.
      • Lopez D.S.
      • Roseman J.M.
      • Siscovick D.S.
      • Wong N.D.
      • Boerwinkle E.
      Parental history of stroke and myocardial infarction predicts coronary artery calcification: The Coronary Artery Risk Development in Young Adults (CARDIA) study.
      [EL 3; CSS];
      • Nasir K.
      • Michos E.D.
      • Rumberger J.A.
      • et al.
      Coronary artery calcification and family history of premature coronary heart disease: sibling history is more strongly associated than parental history.
      [EL 3; CSS];
      • Juonala M.
      • Viikari J.S.
      • Räsänen L.
      • Helenius H.
      • Pietikäinen M.
      • Raitakari O.T.
      Young adults with family history of coronary heart disease have increased arterial vulnerability to metabolic risk factors: the Cardiovascular Risk in Young Finns Study.
      [EL 3; CSS]).
      HoFH is quite uncommon; although it was previously thought to affect 1 in 1 million people, recent prevalence estimates are between 1 in 160,000 and 1 in 250,000 (
      • Goldstein J.
      • Hobbs H.
      • Brown M.
      Familial hypercholesterolemia.
      [EL 4; NE];
      • Bouhairie V.E.
      • Goldberg A.C.
      Familial hypercholesterolemia.
      [EL 4; NE]). Individuals with HoFH have extremely high LDL-C levels, above 500 mg/dL, and premature cardiovascular risk; many individuals with HoFH experience their first coronary event as children or adolescents (
      • Turgeon R.D.
      • Barry A.R.
      • Pearson G.J.
      Familial hypercholesterolemia: Review of diagnosis, screening, and treatment.
      [EL 4; NE]). HeFH is more common and also more frequently occurring than once believed. Recent data indicate that HeFH prevalence is 1 in 200 or 1 in 250, as opposed to 1 in 500 as previously reported (
      • Bouhairie V.E.
      • Goldberg A.C.
      Familial hypercholesterolemia.
      [EL 4; NE]). Individuals with HeFH can present with LDL-C levels ranging from 90 to 500 mg/dL. HeFH is also associated with premature ASCVD; on average, individuals with HeFH experience their first coronary event at age 42, which is about 20 years younger than the general population (
      • Turgeon R.D.
      • Barry A.R.
      • Pearson G.J.
      Familial hypercholesterolemia: Review of diagnosis, screening, and treatment.
      [EL 4; NE]).
      FH diagnostic criteria include lipid levels and family history, physical symptoms (if any), and genetic analysis (if available) (
      • Bouhairie V.E.
      • Goldberg A.C.
      Familial hypercholesterolemia.
      [EL 4; NE]). Three of the clinical diagnostic tools that are available are: the Simon Broome Register Diagnostic Criteria, the Dutch Lipid Clinic Network Diagnostic Criteria, and the US Make Early Diagnoses Prevent Early Deaths Program Diagnostic Criteria (MEDPED)
      • Haralambos K.
      • Ashfield-Watt P.
      • McDowell I.F.
      Diagnostic scoring for familial hypercholesterolaemia in practice.
      [EL 4; NE],
      • Turgeon R.D.
      • Barry A.R.
      • Pearson G.J.
      Familial hypercholesterolemia: Review of diagnosis, screening, and treatment.
      [EL 4; NE]). Factors that lead to an FH diagnosis include premature ASCVD, fasting LDL-C >190 mg/dL, the presence of tendon xanthomas, full corneal arcus in individuals younger than 40 years of age, or a family history of high cholesterol and/or premature ASCVD (
      • Bouhairie V.E.
      • Goldberg A.C.
      Familial hypercholesterolemia.
      [EL 4; NE]). Although it is an important risk factor, familial history is often overlooked during evaluations of individual cardiovascular risk. A family history of ASCVD, however, is both highly predictive and typically easy to determine by direct inquiry. While genetic testing may identify FH, it is not commonly used in the U.S. due to cost and lack of payer coverage (
      • Bouhairie V.E.
      • Goldberg A.C.
      Familial hypercholesterolemia.
      [EL 4; NE]).
      FH is due to mutations causing partial or full dysfunction of LDL receptor activity; this results in increased plasma LDL-C levels and increased ASCVD risk (
      • Shantha G.P.
      • Robinson J.G.
      Emerging innovative therapeutic approaches targeting PCSK9 to lower lipids.
      [EL 4; NE]). Individuals with HoFH often present with LDL-C levels >500 mg/dL, while individuals with HeFH typically present with LDL-C levels between 155 and 500 mg/dL (
      • Bouhairie V.E.
      • Goldberg A.C.
      Familial hypercholesterolemia.
      [EL 4; NE]). Early treatment is recommended for all individuals with FH, with a goal of reducing LDL-C levels by 50% from baseline (
      • Bouhairie V.E.
      • Goldberg A.C.
      Familial hypercholesterolemia.
      [EL 4; NE]).
      Clinical trial data indicate that the use of PCSK9 inhibitors can significantly lower LDL-C compared to placebo, by up to 61% in individuals with HeFH and 39% in individuals with HoFH (
      • Shantha G.P.
      • Robinson J.G.
      Emerging innovative therapeutic approaches targeting PCSK9 to lower lipids.
      [EL 4; NE];
      • Raal F.J.
      • Stein E.A.
      • Dufour R.
      • et al.
      PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
      [EL 1; RCT]) The use of PCSK9 inhibitors in combination with statins is recommended to lower LDL-C in individuals with HF (
      • Raal F.J.
      • Stein E.A.
      • Dufour R.
      • et al.
      PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial.
      [EL 1; RCT];
      • Farnier M.
      • Jones P.
      • Severance R.
      • et al.
      Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial.
      [EL 1; RCT];
      • Garber A.J.
      • Abrahamson M.J.
      • Barzilay J.I.
      • et al.
      Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm--2016 Executive Summary.
      [EL 4; NE]). Individuals with HeFH and a history of ASCVD or with a first-degree relative with premature ASCVD are considered at extreme risk and should have an LDL-C goal <55 mg/dL. (
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      [EL 1; RCT])

       Low HDL-C

      Low HDL-C is associated with hypertriglyceridemia, T2DM, having overweight or obesity, physical inactivity, cigarette smoking, very high carbohydrate intake, certain drugs (beta-adrenergic blockers, anabolic steroids, progestational agents), and genetic factors (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      National Institutes of Health; National Heart Lung, and Blood Institute; 2002 National Cholesterol Education Program.
      [EL 4; NE]). Low HDL-C can act synergistically with other lipid risk factors to increase ASCVD risk. For example, the ratio of total cholesterol or LDL-C to HDL-C may be a clinically valuable and potentially sensitive marker of ASCVD risk (
      • Castelli W.P.
      • Anderson K.
      • Wilson P.W.
      • Levy D.
      Lipids and risk of coronary heart disease.
      [EL 4; NE];
      • Kinosian B.
      • Glick H.
      • Garland G.
      Cholesterol and coronary heart disease: predicting risks by levels and ratios.
      [EL 2; PCS];
      • Natarajan S.
      • Glick H.
      • Criqui M.
      • Horowitz D.
      • Lipsitz S.R.
      • Kinosian B.
      Cholesterol measures to identify and treat individuals at risk for coronary heart disease.
      [EL 2; PCS]). A re-analysis of data from the Treating to New Targets (TNT) trial found that both ratios of total cholesterol to HDL-C and LDL-C to HDL-C were highly predictive of major cardiovascular event risk (
      • Barter P.
      • Gotto A.M.
      • LaRosa J.C.
      • et al.
      HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.
      [EL 1; RCT]), while a clinical study of 258 normotensive, nondiabetic individuals with overweight determined that a TG to HDL-C ratio 2.4 or higher was predictive of the presence of insulin resistance (
      • McLaughlin T.
      • Abbasi F.
      • Cheal K.
      • Chu J.
      • Lamendola C.
      • Reaven G.
      Use of metabolic markers to identify overweight individuals who are insulin resistant.
      [EL 3; CSS]). In addition, low HDL-C was a significant predictor of cardiovascular risk in all treatment groups, including individuals with the lowest (<70 mg/dL) LDL-C levels (
      • Barter P.
      • Gotto A.M.
      • LaRosa J.C.
      • et al.
      HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.
      [EL 1; RCT]).
      The atherogenicity of low HDL-C can depend on both genetic and environmental factors. For example, the apo AI Milano trait, first isolated in a small community in Northern Italy, is marked by very low HDL-C and high TG levels. Carriers of this trait do not show signs of atherosclerosis typically associated with this lipid profile (
      • Gualandri V.
      • Franceschini G.
      • Sirtori C.R.
      • et al.
      AIMilano apoprotein identification of the complete kindred and evidence of a dominant genetic transmission.
      [EL 3; SS];
      • Sirtori C.R.
      • Calabresi L.
      • Franceschini G.
      • et al.
      Cardiovascular status of carriers of the apolipoprotein A-I(Milano) mutant: the Limone sul Garda study.
      [EL 3; SS]). In fact, a normal apo AI level in an individual with low HDL-C may be an indication of less risk, as this suggests the presence of an adequate number of HDL-C particles that contain less cholesterol (
      • Rubenfire M.
      • Coletti A.T.
      • Mosca L.
      Treatment strategies for management of serum lipids: lessons learned from lipid metabolism, recent clinical trials, and experience with the HMG CoA reductase inhibitors.
      [EL 4; NE]).

       High HDL-C as a Negative Risk Factor

      An HDL-C concentration greater than 60 mg/dL is an independent negative risk factor in both sexes, and when HDL-C is greater than 60 mg/dL, 1 risk factor can be subtracted from an individual’s overall risk profile (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      National Institutes of Health; National Heart Lung, and Blood Institute; 2002 National Cholesterol Education Program.
      [EL 4; NE];
      • Wilson P.W.
      • Abbott R.D.
      • Castelli W.P.
      High density lipoprotein cholesterol and mortality.
      [EL 2; PCS];
      • Gordon D.J.
      • Probstfield J.L.
      • Garrison R.J.
      • et al.
      High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.
      [EL 2; MNRCT];
      • Wilson P.W.
      • D’Agostino R.B.
      • Levy D.
      • Belanger A.M.
      • Silbershatz H.
      • Kannel W.B.
      Prediction of coronary heart disease using risk factor categories.
      [EL 2; PCS]). An analysis of 4 large epidemiologic studies suggests that each 1 mg/dL increase in HDL-C is associated with a decrease in ASCVD risk of 2% in men and 3% in women (
      • Gordon D.J.
      • Probstfield J.L.
      • Garrison R.J.
      • et al.
      High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies.
      [EL 2; MNRCT]). The cardioprotective effect of HDL-C may be due to its role in reverse cholesterol transport and other mechanisms such as the ability of HDL-C to prevent LDL oxidation (
      • Mackness M.I.
      • Arrol S.
      • Abbott C.
      • Durrington P.N.
      Protection of low-density lipoprotein against oxidative modification by high-density lipoprotein associated paraoxonase.
      [EL 4; NE];
      • Harper C.R.
      • Jacobson T.A.
      New perspectives on the management of low levels of high-density lipoprotein cholesterol.
      [EL 4; NE]).
      Research shows a strong predictive link between HDL-C levels and longevity; healthy older individuals tend to have higher HDL-C levels than younger individuals, regardless of the younger individuals’ ASCVD status (
      • Schaefer E.J.
      • Moussa P.B.
      • Wilson P.W.
      • McGee D.
      • Dallal G.
      • Castelli W.P.
      Plasma lipoproteins in healthy octogenarians: lack of reduced high density lipoprotein cholesterol levels: results from the Framingham Heart Study.
      [EL 2; PCS];
      • Nikkilä M.
      • Heikkinen J.
      High-density lipoprotein cholesterol and longevity.
      [EL 3; CSS];
      • Nikkilä M.
      • Pitkäjärvi T.
      • Koivula T.
      • Heikkinen J.
      Elevated high-density-lipoprotein cholesterol and normal triglycerides as markers of longevity.
      [EL 3; CSS];
      • Barter P.
      HDL: a recipe for longevity.
      [EL 4; NE]). These results apply to the general population, though a high HDL-C concentration may not confer cardioprotec- tion for every individual (
      • Gotto Jr., A.M.
      Prognostic and therapeutic significance of low levels of high-density lipoprotein cholesterol: current perspectives.
      [EL 4; NE]).

       T2DM

      The presence of T2DM is considered an ASCVD risk equivalent; therefore, individuals with diabetes are considered to be at high, very high, or extreme risk. Approximately 65% of diabetes-related mortality is due to heart disease and CVA. In comparison with individuals who do not have diabetes, individuals with T2DM have a significantly increased risk of ASCVD. For example, individuals with diabetes plus a previous MI have been shown to have a 2.5-fold greater risk of subsequent ASCVD events than individuals with ASCVD but no diabetes (
      [EL 4; NE];
      • Haffner S.M.
      Management of dyslipidemia in adults with diabetes.
      [EL 4; NE]). Epidemiologic data from Finland similarly suggest that individuals with T2DM and no history of MI have cardiovascular risk (fatal MI, nonfatal MI, CVA, or overall cardiovascular mortality) equivalent to those without diabetes and a history of MI. This same study found that individuals with T2DM and previous MI were at the highest risk, with a 7-year fatal or nonfatal MI incidence of 45% (
      • Haffner S.M.
      • Lehto S.
      • Rönnemaa T.
      • Pyörälä K.
      • Laakso M.
      Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
      [EL 3; CSS]). The Emerging Risk Factors Collaboration (
      • Di Angelantonio E.
      • Kaptoge E.
      • et al.
      Emerging Risk Factors Collaboration
      Association of cardiometabolic multimorbidity with mortality.
      [EL 3; CSS]) is a larger, more recent study showing similar evidence of diabetes as a CV risk equivalent.
      In addition to hyperglycemia, individuals with T2DM commonly have other risk factors including hypertension; low HDL-C; hypertriglyceridemia; small, dense LDL-C; a procoagulant state; and/or a pro-inflammatory milieu (
      [EL 4; NE];
      • Haffner S.M.
      Management of dyslipidemia in adults with diabetes.
      [EL 4; NE];
      • Frohlich J.
      • Steiner G.
      Dyslipidaemia and coagulation defects of insulin resistance.
      [EL 4; NE];
      • Sowers J.R.
      • Epstein M.
      • Frohlich E.D.
      Diabetes, hypertension, and cardiovascular disease: an update. (Erratum in: Hypertension. 2001;37:1350).
      [EL 4; NE];
      • Stehouwer C.D.
      • Gall M.A.
      • Twisk J.W.
      • Knudsen E.
      • Emeis J.J.
      • Parving H.H.
      Increased urinary albumin excretion, endothelial dysfunction, and chronic low-grade inflammation in type 2 diabetes: progressive, interrelated, and independently associated with risk of death.
      [EL 2; PCS];
      • Targher G.
      • Bertolini L.
      • Zoppini G.
      • Zenari L.
      • Falezza G.
      Increased plasma markers of inflammation and endothelial dysfunction and their association with microvascular complications in Type 1 diabetic patients without clinically manifest macroangiopathy.
      [EL 3; CSS];
      • Boden G.
      • Rao A.K.
      Effects of hyperglycemia and hyperinsulinemia on the tissue factor pathway of blood coagulation.
      [EL 4; NE]). Based on this level of increased risk, the NCEP ATP III and ADA/ACC Consensus Statement consider individuals with T2DM to manifest an ASCVD equivalent (a 10-year risk of ASCVD events that is equal to that of individuals with established ASCVD) and therefore be at high risk (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      National Institutes of Health; National Heart Lung, and Blood Institute; 2002 National Cholesterol Education Program.
      [EL 4; NE];
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation.
      [EL 4; NE]). Furthermore, the ADA/ACC categorizes individuals with diabetes and 1 or more additional risk factor as “very high risk” (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation.
      [EL 4; NE]). Individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance), especially those with MetS, are considered to be at increased risk for ASCVD. Lipid treatment goals for these individuals should be the same as those with diabetes (
      • Garber A.J.
      • Handelsman Y.
      • Einhorn D.
      • et al.
      Diagnosis and management of prediabetes in the continuum of hyperglycemia: when do the risks of diabetes begin? A consensus statement from the American College of Endocrinology and the American Association of Clinical Endocrinologists.
      [EL 4; NE]).

       T1DM

      Approximately 90% of individuals with diabetes have T2DM; therefore most data on lipid disorders and diabetes relate to those with T2DM. However, T1DM is also associated with increased ASCVD risk, especially after 15 years’ duration (
      • Lehto S.
      • Rönnemaa T.
      • Pyörälä K.
      • Laakso M.
      Poor glycemic control predicts coronary heart disease events in patients with type 1 diabetes without nephropathy.
      [EL 3; CSS];
      • Nathan N.M.
      • Cleary P.A.
      • et al.
      Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) Study Research Group
      Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
      [EL 2; PCS];
      • Pambianco G.
      • Costacou T.
      • Ellis D.
      • Becker D.J.
      • Klein R.
      • Orchard T.J.
      The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience.
      [EL 2; PCS];
      • Nathan N.M.
      • Zinman B.
      • et al.
      Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group
      Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (1983-2005).
      [EL 2; PCS];
      • Secrest A.M.
      • Becker D.J.
      • Kelsey S.F.
      • Laporte R.E.
      • Orchard T.J.
      Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes.
      [EL 2; PCS];
      • de Ferranti S.D.
      • de Boer I.H.
      • Fonseca V.
      • et al.
      Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association.
      [EL 4; NE]). Individuals with T1DM often do not have insulin resistance or its features such as a low HDL-C level or high TG. In fact, their HDL-C levels are typically higher than those in the general population (
      • Nikkilä E.A.
      • Hormila P.
      Serum lipids and lipoproteins in insulin-treated diabetes. Demonstration of increased high density lipoprotein concentrations.
      [EL 4; NE];
      • Taskinen M.R.
      Quantitative and qualitative abnormalities in diabetes mellitus.
      [EL 4; NE]). Nonetheless, individuals with T1DM tend to develop atherosclerosis earlier than otherwise healthy individuals; have accelerated progression of coronary events, CVA, and peripheral arterial disease; and have higher associated mortality (
      • Valsania P.
      • Zarich S.W.
      • Kowalchuk G.J.
      • Kosinski E.
      • Warram J.H.
      • Krolewski A.S.
      Severity of coronary artery disease in young patients with insulin-dependent diabetes mellitus.
      [EL 3; CSS];
      • Chun B.Y.
      • Dobson A.J.
      • Heller R.F.
      The impact of diabetes on survival among patients with first myocardial infarction.
      [EL 3; SS];
      • Rozenman Y.
      • Sapoznikov D.
      • Mosseri M.
      • et al.
      Long-term angiographic follow-up of coronary balloon angioplasty in patients with diabetes mellitus: a clue to the explanation of the results of the BARI study. Balloon Angioplasty Revascularization Investigation.
      [EL 2; RCCS];
      • Miettinen H.
      • Lehto S.
      • Salomaa V.
      • et al.
      Impact of diabetes on mortality after the first myocardial infarction. The FINMONICA Myocardial Infarction Register Study Group.
      [EL 3; SS];
      • Savage M.P.
      • Krolewski A.S.
      • Kenien G.G.
      • Lebeis M.P.
      • Christlieb A.R.
      • Lewis S.M.
      Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor.
      [EL 3; CCS];
      • Dabelea D.
      • Kinney G.
      • Snell-Bergeon J.K.
      • et al.
      Effect of type 1 diabetes on the gender difference in coronary artery calcification: a role for insulin resistance? The Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study. (Erratum in: Diabetes. 2004;53:2177).
      [EL 3; CSS];
      • Libby P.
      • Nathan D.M.
      • Abraham K.
      • et al.
      Report of the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus.
      [EL 4; NE]). The Pittsburgh Epidemiology of Diabetes Complications Study and EURODIAB study found a similarly high prevalence of ASCVD among individuals with T1DM in both the U.S. (8.0% in men, 8.5% in women) and Europe (8.6% in men, 7.4% in women) (
      • Pambianco G.
      • Costacou T.
      • Ellis D.
      • Becker D.J.
      • Klein R.
      • Orchard T.J.
      The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience.
      [EL 2; PCS];
      • Nathan N.M.
      • Zinman B.
      • et al.
      Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group
      Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (1983-2005).
      [EL 2; PCS];
      • Savage M.P.
      • Krolewski A.S.
      • Kenien G.G.
      • Lebeis M.P.
      • Christlieb A.R.
      • Lewis S.M.
      Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor.
      [EL 3; CSS]). Several studies of individuals with T1DM have suggested other factors that may increase risk for ischemic ASCVD:
      • Albuminuria (
        • Borch-Johnsen K.
        • Kreiner S.
        Proteinuria: value as predictor of cardiovascular mortality in insulin dependent diabetes mellitus.
        [EL 2; PCS]),
      • Late-onset T1DM (older than 30 years) without nephropathy, but with:
      • Initiation of intensive control more than 5 years after diagnosis (
        • Nathan N.M.
        • Cleary P.A.
        • et al.
        Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) Study Research Group
        Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
        [EL 2; PCS]; [EL 2; PCS]),
      • Duration of disease greater than 15 years (
        • Lehto S.
        • Rönnemaa T.
        • Pyörälä K.
        • Laakso M.
        Poor glycemic control predicts coronary heart disease events in patients with type 1 diabetes without nephropathy.
        [EL 3; CSS];
        • Nathan N.M.
        • Cleary P.A.
        • et al.
        Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) Study Research Group
        Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
        [EL 2; PCS];
        • Pambianco G.
        • Costacou T.
        • Ellis D.
        • Becker D.J.
        • Klein R.
        • Orchard T.J.
        The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience.
        [EL 2; PCS];
        • Nathan N.M.
        • Zinman B.
        • et al.
        Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group
        Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (1983-2005).
        [EL 2; PCS];
        • Secrest A.M.
        • Becker D.J.
        • Kelsey S.F.
        • Laporte R.E.
        • Orchard T.J.
        Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes.
        [EL 2; PCS];
        • de Ferranti S.D.
        • de Boer I.H.
        • Fonseca V.
        • et al.
        Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association.
        [EL 4; NE]),
      • Previous history of MI, or
      • Poorly controlled A1C (
        • Lehto S.
        • Rönnemaa T.
        • Pyörälä K.
        • Laakso M.
        Poor glycemic control predicts coronary heart disease events in patients with type 1 diabetes without nephropathy.
        [EL 3; CSS]),
      • Insulin resistance or MetS (
        • Alexander C.M.
        • Landsman P.B.
        • Teutsch S.M.
        • Haffner S.M.
        Third National Health and Nutrition Examination Survey (NHANES III); National Cholesterol Education Program (NCEP). NCEP-defined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older.
        [EL 3; SS]), and
      • An hsCRP concentration greater than 3.0 mg/L (
        • Mackness B.
        • Hine D.
        • McElduff P.
        • Mackness M.
        High C-reactive protein and low paraoxonase1 in diabetes as risk factors for coronary heart disease.
        [EL 3; CSS])
      Given the risks associated with T1DM and ASCVD, dyslipidemia in this population must not be overlooked and should be treated aggressively. Recommended optimal lipid levels for these individuals are outlined in Table 12 (
      • Brunzell J.D.
      • Davidson M.
      • Furberg C.D.
      • et al.
      Lipoprotein management in patients with cardiometabolic risk: consensus statement from the American Diabetes Association and the American College of Cardiology Foundation.
      [EL 4; NE];
      • Weiner D.E.
      • Tighiouart H.
      • Amin M.G.
      • et al.
      Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies.
      [EL 2; MNRCT];
      Heart Protection Study Collaborative Group
      MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial.
      [EL 1; RCT];
      • Shepherd J.
      • Blauw G.J.
      • Murphy M.B.
      • et al.
      Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial.
      [EL 1; RCT];
      • Sever P.S.
      • Dahlöf B.
      • Poulter N.R.
      • et al.
      Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
      [EL 1; RCT];
      • Ridker P.M.
      • Morrow D.A.
      • Rose L.M.
      • Rifai N.
      • Cannon C.P.
      • Braunwald E.
      Relative efficacy of atorvastatin 80 mg and pravastatin 40 mg in achieving the dual goals of low-density lipoprotein cholesterol <70 mg/dl and C-reactive protein <2 mg/l: an analysis of the PROVE-IT TIMI-22 trial.
      [EL 1; RCT];
      • Barter P.J.
      • Ballantyne C.M.
      • Carmena R.
      • et al.
      Apo B versus cholesterol in estimating cardiovascular risk and in guiding therapy: report of the thirty-person/ten-country panel.
      [EL 4; NE];
      • Boekholdt S.M.
      • Hovingh G.K.
      • Mora S.
      • et al.
      Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials.
      [EL 1; MRCT];
      • Cannon C.P.
      • Blazing M.A.
      • Giugliano R.P.
      • et al.
      Ezetimibe added to statin therapy after acute coronary syndromes.
      [EL 1; RCT];
      • Baigent C.
      • Keech A.
      • Kearney P.M.
      • et al.
      Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.
      [EL 1; MRCT]).
      Individuals with T1DM for more than 15 years or with 2 or more CV risk factors should be treated as if they had T2DM (
      • Lehto S.
      • Rönnemaa T.
      • Pyörälä K.
      • Laakso M.
      Poor glycemic control predicts coronary heart disease events in patients with type 1 diabetes without nephropathy.
      [EL 3; CSS];
      • Nathan N.M.
      • Cleary P.A.
      • et al.
      Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/ EDIC) Study Research Group
      Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
      [EL 2; PCS];
      • Pambianco G.
      • Costacou T.
      • Ellis D.
      • Becker D.J.
      • Klein R.
      • Orchard T.J.
      The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience.
      [EL 2; PCS];
      • Nathan N.M.
      • Zinman B.
      • et al.
      Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Research Group
      Modern-day clinical course of type 1 diabetes mellitus after 30 years’ duration: the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications and Pittsburgh Epidemiology of Diabetes Complications Experience (1983-2005).
      [EL 2; PCS];
      • Secrest A.M.
      • Becker D.J.
      • Kelsey S.F.
      • Laporte R.E.
      • Orchard T.J.
      Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes.