2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.

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HomeCirculationVol. 139, No. 252018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines Free AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessReview ArticlePDF/EPUB2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines Scott M. Grundy, MD, PhD, FAHA, Chair, Neil J. Stone, MD, FACC, FAHA, Vice Chair, Alison L. Bailey, MD, FACC, FAACVPR, Craig Beam, CRE, Kim K. Birtcher, MS, PharmD, AACC, FNLA, Roger S. Blumenthal, MD, FACC, FAHA, FNLA, Lynne T. Braun, PhD, CNP, FAHA, FPCNA, FNLA, Sarah de Ferranti, MD, MPH, Joseph Faiella-Tommasino, PhD, PA-C, Daniel E. Forman, MD, FAHA, Ronald Goldberg, MD, Paul A. Heidenreich, MD, MS, FACC, FAHA, Mark A. Hlatky, MD, FACC, FAHA, Daniel W. Jones, MD, FAHA, Donald Lloyd-Jones, MD, SCM, FACC, FAHA, Nuria Lopez-Pajares, MD, MPH, Chiadi E. Ndumele, MD, PhD, FAHA, Carl E. Orringer, MD, FACC, FNLA, Carmen A. Peralta, MD, MAS, Joseph J. Saseen, PharmD, FNLA, FAHA, Sidney C. Smith Jr, MD, MACC, FAHA, Laurence Sperling, MD, FACC, FAHA, FASPC, Salim S. Virani, MD, PhD, FACC, FAHA and Joseph Yeboah, MD, MS, FACC, FAHA Scott M. GrundyScott M. Grundy Search for more papers by this author , Neil J. StoneNeil J. Stone Search for more papers by this author , Alison L. BaileyAlison L. Bailey Search for more papers by this author , Craig BeamCraig Beam Search for more papers by this author , Kim K. BirtcherKim K. Birtcher Search for more papers by this author , Roger S. BlumenthalRoger S. Blumenthal Search for more papers by this author , Lynne T. BraunLynne T. Braun Search for more papers by this author , Sarah de FerrantiSarah de Ferranti Search for more papers by this author , Joseph Faiella-TommasinoJoseph Faiella-Tommasino Search for more papers by this author , Daniel E. FormanDaniel E. Forman Search for more papers by this author , Ronald GoldbergRonald Goldberg Search for more papers by this author , Paul A. HeidenreichPaul A. Heidenreich Search for more papers by this author , Mark A. HlatkyMark A. Hlatky Search for more papers by this author , Daniel W. JonesDaniel W. Jones Search for more papers by this author , Donald Lloyd-JonesDonald Lloyd-Jones Search for more papers by this author , Nuria Lopez-PajaresNuria Lopez-Pajares Search for more papers by this author , Chiadi E. NdumeleChiadi E. Ndumele Search for more papers by this author , Carl E. OrringerCarl E. Orringer Search for more papers by this author , Carmen A. PeraltaCarmen A. Peralta Search for more papers by this author , Joseph J. SaseenJoseph J. Saseen Search for more papers by this author , Sidney C. Smith JrSidney C. Smith Jr Search for more papers by this author , Laurence SperlingLaurence Sperling Search for more papers by this author , Salim S. ViraniSalim S. Virani Search for more papers by this author and Joseph YeboahJoseph Yeboah Search for more papers by this author Originally published10 Nov 2018https://doi.org/10.1161/CIR.0000000000000625Circulation. 2019;139:e1082–e1143is corrected byCorrection to: 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice GuidelinesOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: November 10, 2018: Ahead of Print Table of ContentsTop 10 Take-Home Messages to Reduce Risk of Atherosclerotic Cardiovascular Disease Through Cholesterol Management e1083Preamble e10841. Introduction e10851.1. Methodology and Evidence Review e10851.2. Organization of the Writing Committee e10861.3. Document Review and Approval e10861.4. Scope of the Guideline e10861.5. Class of Recommendation and Level of Evidence e10871.6. Abbreviations e10872. High Blood Cholesterol and ASCVD e10872.1. Serum Cholesterol, Lipoproteins, and ASCVD e10872.1.1. Cholesterol, Lipoproteins, and Apolipoprotein B e10872.1.2. Cholesterol, LDL-C, and ASCVD e10872.1.3. LDL-C and Other Risk Factors e10872.2. Measurements of LDL-C and Non–HDL-C e10882.3. Measurements of Apolipoprotein B and Lipoprotein (a) e10892.4. Monitoring Response of LDL-C to Statin Therapy e10903. Therapeutic Modalities e10903.1. Lifestyle Therapies e10903.1.1. Diet Composition, Weight Control, and Physical Activity e10903.1.2. Lifestyle Therapies and Metabolic Syndrome e10903.2. Lipid-Lowering Drugs e10903.2.1. Statin Therapy e10903.2.2. Nonstatin Therapies e10913.2.3. Nonstatin Add-on Drugs to Statin Therapy e10914. Patient Management Groups e10914.1. Secondary ASCVD Prevention e10914.2. Severe Hypercholesterolemia (LDL-C ≥190 mg/dL [≥4.9 mmol/L]) e10954.3. Diabetes Mellitus in Adults e10974.4. Primary Prevention e10994.4.1. Evaluation and Risk Assessment e10994.4.2. Primary Prevention Adults 40 to 75 Years of Age With LDL-C Levels 70 to 189 mg/dL (1.7 to 4.8 mmol/L) e11024.4.3. Monitoring in Response to LDL-C–Lowering Therapy e11064.4.4. Primary Prevention in Other Age Groups e11074.5. Other Populations at Risk e11114.5.1. Ethnicity e11114.5.2. Hypertriglyceridemia e11125. Statin Safety and Statin-Associated Side Effects e11176. Implementation e11207. Cost and Value Considerations e11217.1. Economic Value Considerations: PCSK9 Inhibitors e11218. Limitations and Knowledge Gaps e11228.1. Randomized Controlled Trials e11228.2. Risk Assessment e11228.2.1. Continuing Refinement of PCE e11238.2.2. Improvement in Lifetime Risk Estimate e11238.2.3. Refinement of Clinician–Patient Risk Discussion e11238.2.4. Monitoring and Adjustment of Treatment e11238.2.5. Prognostic Significance of CAC e1123References e1124Appendix 1: Author Relationships With Industry and Other Entities (Relevant)—2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol (August 2018) e1139Appendix 2: Reviewer Relationships With Industry and Other Entities (Comprehensive)—2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol (August 2018) e1141Top 10 Take-Home Messages to Reduce Risk of Atherosclerotic Cardiovascular Disease Through Cholesterol ManagementIn all individuals, emphasize a heart-healthy lifestyle across the life course. A healthy lifestyle reduces atherosclerotic cardiovascular disease (ASCVD) risk at all ages. In younger individuals, healthy lifestyle can reduce development of risk factors and is the foundation of ASCVD risk reduction. In young adults 20 to 39 years of age, an assessment of lifetime risk facilitates the clinician–patient risk discussion (see No. 6) and emphasizes intensive lifestyle efforts. In all age groups, lifestyle therapy is the primary intervention for metabolic syndrome.In patients with clinical ASCVD, reduce low-density lipoprotein cholesterol (LDL-C) with high-intensity statin therapy or maximally tolerated statin therapy. The more LDL-C is reduced on statin therapy, the greater will be subsequent risk reduction. Use a maximally tolerated statin to lower LDL-C levels by ≥50%.In very high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider addition of nonstatins to statin therapy. Very high-risk includes a history of multiple major ASCVD events or 1 major ASCVD event and multiple high-risk conditions. In very high-risk ASCVD patients, it is reasonable to add ezetimibe to maximally tolerated statin therapy when the LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L). In patients at very high risk whose LDL-C level remains ≥70 mg/dL (≥1.8 mmol/L) on maximally tolerated statin and ezetimibe therapy, adding a PCSK9 inhibitor is reasonable, although the long-term safety (>3 years) is uncertain and cost effectiveness is low at mid-2018 list prices.In patients with severe primary hypercholesterolemia (LDL-C level ≥190 mg/dL [≥4.9 mmol/L]), without calculating 10-year ASCVD risk, begin high-intensity statin therapy. If the LDL-C level remains ≥100 mg/dL (≥2.6 mmol/L), adding ezetimibe is reasonable. If the LDL-C level on statin plus ezetimibe remains ≥100 mg/dL (≥2.6 mmol/L) and the patient has multiple factors that increase subsequent risk of ASCVD events, a PCSK9 inhibitor may be considered, although the long-term safety (>3 years) is uncertain and economic value is uncertain at mid-2018 list prices.In patients 40 to 75 years of age with diabetes mellitus and LDL-C ≥70 mg/dL (≥1.8 mmol/L), start moderate-intensity statin therapy without calculating 10-year ASCVD risk. In patients with diabetes mellitus at higher risk, especially those with multiple risk factors or those 50 to 75 years of age, it is reasonable to use a high-intensity statin to reduce the LDL-C level by ≥50%.In adults 40 to 75 years of age evaluated for primary ASCVD prevention, have a clinician–patient risk discussion before starting statin therapy. Risk discussion should include a review of major risk factors (eg, cigarette smoking, elevated blood pressure, LDL-C, hemoglobin A1C [if indicated], and calculated 10-year risk of ASCVD); the presence of risk-enhancing factors (see No. 8); the potential benefits of lifestyle and statin therapies; the potential for adverse effects and drug–drug interactions; consideration of costs of statin therapy; and patient preferences and values in shared decision-making.In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL (≥1.8 mmol/L), at a 10-year ASCVD risk of ≥7.5%, start a moderate-intensity statin if a discussion of treatment options favors statin therapy. Risk-enhancing factors favor statin therapy (see No. 8). If risk status is uncertain, consider using coronary artery calcium (CAC) to improve specificity (see No. 9). If statins are indicated, reduce LDL-C levels by ≥30%, and if 10-year risk is ≥20%, reduce LDL-C levels by ≥50%.In adults 40 to 75 years of age without diabetes mellitus and 10-year risk of 7.5% to 19.9% (intermediate risk), risk-enhancing factors favor initiation of statin therapy (see No. 7). Risk-enhancing factors include family history of premature ASCVD; persistently elevated LDL-C levels ≥160 mg/dL (≥4.1 mmol/L); metabolic syndrome; chronic kidney disease; history of preeclampsia or premature menopause (age <40 years); chronic inflammatory disorders (eg, rheumatoid arthritis, psoriasis, or chronic HIV); high-risk ethnic groups (eg, South Asian); persistent elevations of triglycerides ≥175 mg/dL (≥1.97 mmol/L); and, if measured in selected individuals, apolipoprotein B ≥130 mg/dL, high-sensitivity C-reactive protein ≥2.0 mg/L, ankle-brachial index <0.9 and lipoprotein (a) ≥50 mg/dL or 125 nmol/L, especially at higher values of lipoprotein (a). Risk-enhancing factors may favor statin therapy in patients at 10-year risk of 5-7.5% (borderline risk).In adults 40 to 75 years of age without diabetes mellitus and with LDL-C levels ≥70 mg/dL to 189 mg/dL (≥1.8-4.9 mmol/L), at a 10-year ASCVD risk of ≥7.5% to 19.9%, if a decision about statin therapy is uncertain, consider measuring CAC. If CAC is zero, treatment with statin therapy may be withheld or delayed, except in cigarette smokers, those with diabetes mellitus, and those with a strong family history of premature ASCVD. A CAC score of 1 to 99 favors statin therapy, especially in those ≥55 years of age. For any patient, if the CAC score is ≥100 Agatston units or ≥75th percentile, statin therapy is indicated unless otherwise deferred by the outcome of clinician–patient risk discussion.Assess adherence and percentage response to LDL-C–lowering medications and lifestyle changes with repeat lipid measurement 4 to 12 weeks after statin initiation or dose adjustment, repeated every 3 to 12 months as needed. Define responses to lifestyle and statin therapy by percentage reductions in LDL-C levels compared with baseline. In ASCVD patients at very high-risk, triggers for adding nonstatin drug therapy are defined by threshold LDL-C levels ≥70 mg/dL (≥1.8 mmol/L) on maximal statin therapy (see No. 3).PreambleSince 1980, the American College of Cardiology (ACC) and American Heart Association (AHA) have translated scientific evidence into clinical practice guidelines with recommendations to improve cardiovascular health. These guidelines, which are based on systematic methods to evaluate and classify evidence, provide a foundation for the delivery of quality cardiovascular care. The ACC and AHA sponsor the development and publication of clinical practice guidelines without commercial support, and members volunteer their time to the writing and review efforts.Clinical practice guidelines provide recommendations applicable to patients with or at risk of developing cardiovascular disease (CVD). The focus is on medical practice in the United States, but these guidelines are relevant to patients throughout the world. Although guidelines may be used to inform regulatory or payer decisions, the intent is to improve quality of care and align with patients’ interests. Guidelines are intended to define practices meeting the needs of patients in most, but not all, circumstances, and should not replace clinical judgment.Recommendations for guideline-directed management and therapy, which encompasses clinical evaluation, diagnostic testing, and both pharmacological and procedural treatments, are effective only when followed by both practitioners and patients. Adherence to recommendations can be enhanced by shared decision-making between clinicians and patients, with patient engagement in selecting interventions on the basis of individual values, preferences, and associated conditions and comorbidities.The ACC/AHA Task Force on Clinical Practice Guidelines strives to ensure that the guideline writing committee both contains requisite expertise and is representative of the broader medical community by selecting experts from a broad array of backgrounds, representing different geographic regions, sexes, races, ethnicities, intellectual perspectives/biases, and scopes of clinical practice, and by inviting organizations and professional societies with related interests and expertise to participate as partners or collaborators. The ACC and AHA have rigorous policies and methods to ensure that documents are developed without bias or improper influence. The complete policy on relationships with industry and other entities (RWI) can be found online.Beginning in 2017, numerous modifications to the guidelines have been and continue to be implemented to make guidelines shorter and enhance “user friendliness.” Guidelines are written and presented in a modular knowledge chunk format, in which each chunk includes a table of recommendations, a brief synopsis, recommendation-specific supportive text and, when appropriate, flow diagrams or additional tables. Hyperlinked references are provided for each modular knowledge chunk to facilitate quick access and review. More structured guidelines—including word limits (“targets”) and a web guideline supplement for useful but noncritical tables and figures—are 2 such changes. This Preamble is an abbreviated version, with the detailed version available online.Glenn N. Levine, MD, FACC, FAHAChair, ACC/AHA Task Force on Clinical Practice Guidelines1. Introduction1.1. Methodology and Evidence ReviewThe recommendations listed in the present guideline are, whenever possible, evidence based. An initial extensive evidence review, which included literature derived from research involving human subjects, published in English, and indexed in MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to the present guideline, was conducted from May 1980 to July 2017. Key search words included but were not limited to the following: hyperlipidemia, cholesterol, LDL-C, HDL-C, ezetimibe, bile acid sequestrants, PCSK9 inhibitors, lifestyle, diet, exercise, medications, child, adolescent, screening, primary prevention, secondary prevention, cardiovascular disease, coronary artery calcium, familial hypercholesterolemia. ASCVD risk-enhancing factors, statin therapy, diabetes mellitus, women, adherence, Hispanic/Latino, South Asian, African American. Additional relevant studies published through August 2018 during the guideline writing process, were also considered by the writing committee and added to the evidence tables when appropriate. The final evidence tables are included in the Online Data Supplement and summarize the evidence used by the writing committee to formulate recommendations. References selected and published in the present document are representative and not all-inclusive.As noted in the detailed version of the Preamble, an independent evidence review committee was commissioned to perform a formal systematic review of critical clinical questions related to cholesterol (Table 1), the results of which were considered by the writing committee for incorporation into the present guideline. Concurrent with this process, writing committee members evaluated study data relevant to the rest of the guideline. The findings of the evidence review committee and the writing committee members were formally presented and discussed, and then recommendations were developed. The systematic review for the 2018 Cholesterol Clinical Practice GuidelinesS1.1-1 is published in conjunction with the present guideline, and includes its respective data supplements.Table 1. ERC QuestionsQuestionSection NumberIn adults ≥20 years of age with clinical atherosclerotic disease (eg, CHD, peripheral artery disease, or CVD) or at high-risk of ASCVD, what are the magnitude of benefit (absolute reduction; NNT) in individual endpoints and composite ischemic events (eg, fatal cardiovascular event, nonfatal MI, nonfatal stroke, unstable angina/revascularization) and magnitude of harm (absolute increase; NNH) in terms of adverse events (eg, cancer, rhabdomyolysis, diabetes mellitus) derived from LDL-C lowering in large RCTs (>1 000 participants and originally designed to last >12 months) with statin therapy plus a second lipid-modifying agent compared with statin alone?4.1Clinical atherosclerotic cardiovascular disease (ASCVD) includes acute coronary syndrome (ACS), those with history of myocardial infarction (MI), stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack (TIA), or peripheral artery disease (PAD) including aortic aneurysm, all of atherosclerotic origin.ASCVD indicates atherosclerotic cardiovascular disease; CHD, coronary heart disease; CVD, cardiovascular disease; ERC, Evidence Review Committee; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NNH, number needed to harm; NNT number needed to treat; and RCT, randomized controlled trial.Numerical values for triglycerides, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non–HDL-C are given in both mg/dL and mmol/L. To convert to mmol/L, the values in mg/dL for TC, LDL-C, HDL-C, and non–HDL-C were divided by 38.6 and for triglycerides, by 88.6.On May 10, 2018 a writing committee member discussed their participation in an industry-supported, multicenter study, which they had thought was not relevant to this prevention guideline. However, when this was reviewed using specific ACC/AHA criteria it was considered to represent a relevant relationship with industry. Given the current policy that a prevention guideline writing committee member must be free of any relevant relationships with industry, this member was removed from the committee. The 2 sections authored by the writing committee member were removed and replaced by new material written by the guideline chairs, and the revised sections reviewed and approved by all remaining writing committee members. The writing committee member did not participate in any further guideline discussions or review of the manuscript or recommendations.1.2. Organization of the Writing CommitteeThe writing committee consisted of medical experts including cardiologists, internists, interventionalists, a nurse practitioner, pharmacists, a physician assistant, a pediatrician, a nephrologist, and a lay/patient representative. The writing committee included representatives from the American Heart Association (AHA), American College of Cardiology (ACC), American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR), American Association Academy of Physician Assistants (AAPA), Association of Black Cardiologists (ABC), American College of Preventive Medicine (ACPM), American Diabetes Association (ADA), American Geriatrics Society (AGS), American Pharmacists Association (APhA), American Society for Preventive Cardiology (ASPC), National Lipid Association (NLA), and Preventive Cardiovascular Nurses Association (PCNA). Appendix 1 of the present document lists writing committee members’ relevant relationships with industry and other entities. For the purposes of full transparency, the writing committee members’ comprehensive disclosure information is available online.1.3. Document Review and ApprovalThis document was reviewed by 21 official reviewers each nominated by the ACC, AHA, AAPA, ABC, ACPM, ADA, AGS, APhA, ASPC, NLA, and PCNA, as well as 27 individual content reviewers. Reviewers’ RWI information was distributed to the writing committee and is published in this document (Appendix 2).This document was approved for publication by the governing bodies of the AHA, the ACC, AAPA, ABC, ACPM, ADA, AGS, APhA, ASPC, NLA, and PCNA.1.4. Scope of the GuidelineThe purpose of the present guideline is to address the practical management of patients with high blood cholesterol and related disorders. The writing committee reviewed previously published guidelines, evidence reviews, and related statements. Table S1 in the Web Supplement contains a list of publications and statements deemed pertinent. The primary sources of evidence are randomized controlled trials (RCTs). Most RCTs in this area have been performed with statins as the only cholesterol-lowering drug.S1.4-1–S1.4-3 Since the 2013 ACC/AHA cholesterol guideline,S1.4-4 newer cholesterol-lowering agents (nonstatin drugs) have been introduced and subjected to RCTs. They include ezetimibe and PCSK9 inhibitors, and their use is limited mainly to secondary prevention in patients at very high-risk of new atherosclerotic cardiovascular disease (ASCVD) events. Most other patients with ASCVD are treated with statins alone. In primary prevention, statins are recommended for patients with severe hypercholesterolemia and in adults 40 to 75 years of age either with diabetes mellitus or at higher ASCVD risk. Throughout these guidelines similar to the 2013 guidelines, consistent attention is given to a clinician–patient risk discussion for making shared decisions. Besides major risk factors of the pooled cohort equations (PCE), the clinician–patient risk discussion can include other risk-enhancing factors, and when risk status is uncertain, a coronary artery calcium (CAC) score is an option to facilitate decision-making in adults ≥40 years of age. In children, adolescents, and young adults, identifying those with familial hypercholesterolemia (FH) is a priority. However, most attention is given to reducing lifetime ASCVD risk through lifestyle therapies.1.5. Class of Recommendation and Level of EvidenceRecommendations are designated with both a class of recommendation (COR) and a level of evidence (LOE). The class of recommendation indicates the strength of recommendation, encompassing the estimated magnitude and certainty of benefit in proportion to risk. The level of evidence rates the quality of scientific evidence supporting the intervention on the basis of the type, quantity, and consistency of data from clinical trials and other sources (Table 2).S1.5-1Table 2. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015)Table 2. Applying Class of Recommendation and Level of Evidence to Clinical Strategies, Interventions, Treatments, or Diagnostic Testing in Patient Care* (Updated August 2015)1.6. AbbreviationsAbbreviationMeaning/PhraseABIankle-brachial indexACSacute coronary syndromeAIDSacquired immunodeficiency syndromeapoBapolipoprotein BARRabsolute risk reductionASCVDatherosclerotic cardiovascular diseaseCACcoronary artery calciumCHDcoronary heart diseaseCKcreatine kinaseCKDchronic kidney diseaseCORClass of RecommendationCTTCholesterol Treatment TrialistsCVDcardiovascular diseaseeGFRestimated glomerular filtration rateFHfamilial hypercholesterolemiaHDLhigh-density lipoproteinHFheart failureHIVhuman immunodeficiency virusLDL-Clow-density lipoprotein cholesterolLOELevel of EvidenceLp(a)lipoprotein (a)MImyocardial infarctionPCEpooled cohort equationsQALYquality-adjusted life-yearRArheumatoid arthritisRCTrandomized controlled trialsRRRrelative risk reductionRWIrelationships with industry and other entitiesSAMSstatin-associated muscle symptomsSRsystematic reviewTCtotal cholesterolVLDLvery low-density lipoproteinVLDL-Cvery low-density lipoprotein cholesterol2. High Blood Cholesterol and ASCVD2.1. Serum Cholesterol, Lipoproteins, and ASCVD2.1.1. Cholesterol, Lipoproteins, and Apolipoprotein BSerum cholesterol and its lipoprotein carriers (LDL, very low-density lipoprotein [VLDL], and HDL) are known to be related to ASCVD. LDL-C is the dominant form of atherogenic cholesterol. VLDL is the chief carrier of triglycerides, and VLDL cholesterol (VLDL-C) is also atherogenic. HDL-C is seemingly not atherogenic. Chylomicrons transport dietary fat; chylomicron atherogenicity is uncertain. The combination of LDL-C and VLDL-C is called non–HDL-C and is more atherogenic than either lipoprotein alone. The main protein embedded in LDL and VLDL is apolipoprotein B (apoB), and like non–HDL-C, apoB is a stronger indicator of atherogenicity than LDL-C alone.2.1.2. Cholesterol, LDL-C, and ASCVDEvidence that serum cholesterol contributes to ASCVD comes from several sources: animal studies, genetic forms of hypercholesterolemia, epidemiological studies, and RCTs. US population studiesS2.1.2-1,S2.1.2-2 suggest that optimal total cholesterol levels are about 150 mg/dL (3.8 mmol/L), which corresponds to an LDL-C level of about 100 mg/dL (2.6 mmol/L). Adult populations with cholesterol concentrations in this range manifest low rates of ASCVD.S2.1.2-3 RCTs of cholesterol-lowering drugs in high-risk patients confirm that LDL-C lowering produces marked reductions in ASCVD. This confirms the general principle that “lower is better” for LDL-C.S2.1.2-4–S2.1-6 The present guideline looks to evidence from new RCTs to aid in the translation of RCT data to the individual patient to provide net benefit.S2.1.2-72.1.3. LDL-C and Other Risk FactorsAlthough LDL-C is a primary cause of atherosclerosis, other risk factors contribute, as well. The major risk factors include cigarette smoking, hypertension, dysglycemia, and other lipoprotein abnormalities. Because atherosclerosis progresses with advancing age, a person’s age also counts as a risk factor. By combining all major risk factors into a prediction equation, an individual’s probability of developing ASCVD can be estimated. The Framingham Heart StudyS2.1.3-1 took the lead in creating risk-prediction equations. These were improved in the 2013 ACC/AHA cholesterol guidelinesS2.1.3-2 by compiling data from 5 community-based cohorts that were broadly representative of the US population. These so-called population cohort equations have been validated in a large community-based US population.S2.1.3-3 Initially, data from the Women’s Health Initiative, a contemporary multiethnic cohort of postmenopausal women, appeared to indicate that these pooled cohort equations overestimated ASCVD risk. However, when event surveillance was improved by data from Centers for Medicare & Medicaid Services, the authors found that the equations discriminated risk well.S2.1.3-4Several other factors associate with ASCVD, and in the present document these are called risk-enhancing factors. Projections of future risk derived from major risk factors and risk-enhancing factors can be used to adjust the intensity of LDL-lowering therapy.2.2. Measurements of LDL-C and Non–HDL-CSynopsisThe standard calculation method for LDL-C is the Friedewald formula: LDL-C=(TC)–(triglycerides/5)– (HDL-C). When triglyceride levels are not elevated, this equation is sufficiently accurate. In hypertriglyceridemia, however, Friedewald-calculated LDL-C can be erroneous. After normal food intake, LDL-C differs minimally with time.S2.2-10 Fasting and nonfasting TC and HDL-C levels appear to have fairly similar prognostic value and associations with CVD outcomes.S2.2-1–S2.2-6,S2.2-11 Thus, nonfasting samples can be used for risk assessment in primary prevention and for assessment of baseline LDL-C levels before the initiation of a statin in primary and secondary prevention. If more precision is necessary, fasting lipids can be measured, but a nonfasting sample is reasonable for most situations. The unreliability of the Friedewald-calculated LDL-C levels appears to be greatest at lower levels of LDL-C, particularly <70 mg/dL (<1.8 mmol/L).S2.2-7 Martin