In adults who are 20 years of age or older and not on lipid-lowering therapy, measurement of either a fasting or a nonfasting plasma lipid profile is effective in estimating ASCVD risk and documenting baseline LDL-C.

In adults who are 20 years of age or older and in whom an initial nonfasting lipid profile reveals a triglycerides level of 400 mg/dL or higher (≥4.5 mmol/L), a repeat lipid profile in the fasting state should be performed for assessment of fasting triglyceride levels and baseline LDL-C.

For adults with an LDL-C level less than 70 mg/dL (<1.8 mmol/L), measurement of direct LDL-C or modified LDL-C estimate is reasonable to improve accuracy over the Friedewald formula.

In adults who are 20 years of age or older and without a personal history of ASCVD, but with a family history of premature ASCVD or genetic hyperlipidemia, measurement of a fasting plasma lipid profile is reasonable as part of an initial evaluation to aid in the understanding and identification of familial lipid disorders.

In patients who are 75 years of age or younger with clinical ASCVD*, high-intensity statin therapy should be initiated or continued with the aim of achieving a 50% or greater reduction in LDL-C levels [*Clinical ASCVD includes acute coronary syndrome, those with history of myocardial infarction, stable or unstable angina or coronary or other arterial revascularization, stroke, transient ischemic attack, or peripheral artery disease including aortic aneurysm, all of atherosclerotic origin].

In patients with clinical ASCVD in whom high-intensity statin therapy is contraindicated or who experience statin-associated side effects, moderate-intensity statin therapy should be initiated or continued with the aim of achieving a 30% to 49% reduction in LDL-C levels.

In patients with clinical ASCVD who are judged to be very high risk and considered for PCSK9 inhibitor therapy, maximally tolerated LDL-C lowering therapy should include maximally tolerated statin therapy and ezetimibe.

In patients with clinical ASCVD who are judged to be very high risk and who are on maximally tolerated LDL-C lowering therapy with LDL-C 70 mg/dL or higher (≥1.8 mmol/L) or a non–HDL-C level of 100 mg/dL or higher (≥2.6 mmol/L), it is reasonable to add a PCSK9 inhibitor following a clinician–patient discussion about the net benefit, safety, and cost.

In patients with clinical ASCVD who are on maximally tolerated statin therapy and are judged to be at very high risk and have an LDL-C level of 70 mg/dL or higher (≥1.8 mmol/L), it is reasonable to add ezetimibe therapy.

At mid-2018 list prices, PCSK9 inhibitors have a low cost value (>$150,000 per quality-adjusted life-year) compared to good cost value (<$50,000 per quality-adjusted life-year) [Value Statement: Low Value].

In patients older than 75 years of age with clinical ASCVD, it is reasonable to initiate moderate- or high-intensity statin therapy after evaluation of the potential for ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences.

In patients older than 75 years of age who are tolerating high-intensity statin therapy, it is reasonable to continue high-intensity statin therapy after evaluation of the potential for ASCVD risk reduction, adverse effects, and drug-drug interactions, as well as patient frailty and patient preferences.

In patients with clinical ASCVD who are receiving maximally tolerated statin therapy and whose LDL-C level remains 70 mg/dL or higher (≥1.8 mmol/L), it may be reasonable to add ezetimibe.

In patients with heart failure with reduced ejection fraction attributable to ischemic heart disease who have a reasonable life expectancy (3 to 5 years) and are not already on a statin because of ASCVD, clinicians may consider initiation of moderate-intensity statin therapy to reduce the occurrence of ASCVD events.

In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L), maximally tolerated statin therapy is recommended.

In patients 20 to 75 years of age with an LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L) who achieve less than a 50% reduction in LDL-C while receiving maximally tolerated statin therapy and/or have an LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L), ezetimibe therapy is reasonable.

In patients 20 to 75 years of age with a baseline LDL-C level of 190 mg/dL or higher (≥4.9 mmol/L), who achieve less than a 50% reduction in LDL-C levels and have fasting triglycerides 300 mg/dL or lower (≤3.4 mmol/L), while taking maximally tolerated statin and ezetimibe therapy, the addition of a bile acid sequestrant may be considered.

In patients 30 to 75 years of age with heterozygous familial hypercholesterolemia and with an LDL-C level of 100 mg/dL or higher (≥2.6 mmol/L) while taking maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.

In patients 40 to 75 years of age with a baseline LDL-C level of 220 mg/dL or higher (≥5.7 mmol/L) and who achieve an on-treatment LDL-C level of 130 mg/dL or higher (≥3.4 mmol/L) while receiving maximally tolerated statin and ezetimibe therapy, the addition of a PCSK9 inhibitor may be considered.

Among patients with familial hypercholesterolemia without evidence of clinical ASCVD taking maximally tolerated statin and ezetimibe therapy, PCSK9 inhibitors provide uncertain value at mid-2018 US list prices [Value Statement: Uncertain Value].

In adults 40 to 75 years of age with diabetes mellitus, regardless of estimated 10-year ASCVD risk, moderate-intensity statin therapy is indicated.

In adults 40 to 75 years of age with diabetes mellitus and an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it is reasonable to assess the 10-year risk of a first ASCVD event by using the race and sex-specific pooled cohort equation to help stratify ASCVD risk.

In adults with diabetes mellitus who have multiple ASCVD risk factors, it is reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C levels by 50% or more.

In adults older than 75 years of age with diabetes mellitus and who are already on statin therapy, it is reasonable to continue statin therapy.

In adults with diabetes mellitus and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C levels by 50% or more.

In adults older than 75 years with diabetes mellitus, it may be reasonable to initiate statin therapy after a clinician–patient discussion of potential benefits and risks.

In adults 20 to 39 years of age with diabetes mellitus that is either of long duration (≥10 years of type 2 diabetes mellitus, ≥20 years of type 1 diabetes mellitus), albuminuria (≥30 mcg of albumin/mg creatinine), estimated glomerular filtration rate (eGFR) less than 60 mL/min/1.73 m², retinopathy, neuropathy, or ankle-brachial index (ABI; <0.9), it may be reasonable to initiate statin therapy.

In adults at intermediate-risk, statin therapy reduces risk of ASCVD, and in the context of a risk discussion, if a decision is made for statin therapy, a moderate-intensity statin should be recommended.

In intermediate-risk patients, LDL-C levels should be reduced by 30% or more, and for optimal ASCVD risk reduction, especially in high-risk patients, levels should be reduced by 50% or more.

For the primary prevention of clinical ASCVD in adults 40 to 75 years of age without diabetes mellitus and with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), the 10-year ASCVD risk of a first “hard” ASCVD event (fatal and nonfatal myocardial infarction or stroke) should be estimated by using the race- and sex-specific pooled cohort equation, and adults should be categorized as being at low risk (<5%), borderline risk (5% to <7.5%), intermediate-risk (≥7.5% to <20%), and high-risk (≥20%).

Clinicians and patients should engage in a risk discussion that considers risk factors, adherence to healthy lifestyle, the potential for ASCVD risk-reduction benefits, and the potential for adverse effects and drug–drug interactions, as well as patient preferences, for an individualized treatment decision.

In intermediate-risk adults, risk-enhancing factors favor initiation or intensification of statin therapy.

In intermediate-risk or selected borderline-risk adults, if the decision about statin use remains uncertain, it is reasonable to use a coronary artery calcium score in the decision to withhold, postpone, or initiate statin therapy.

In intermediate-risk adults or selected borderline-risk adults in whom a coronary artery calcium score is measured for the purpose of making a treatment decision, AND if the coronary calcium score is zero, it is reasonable to withhold statin therapy and reassess in 5 to 10 years, as long as higher risk conditions are absent (diabetes mellitus, family history of premature CHD, cigarette smoking); if coronary artery calcium score is 1 to 99, it is reasonable to initiate statin therapy for patients ≥55 years of age; if coronary artery calcium score is 100 or higher or in the 75th percentile or higher, it is reasonable to initiate statin therapy.

In intermediate-risk adults who would benefit from more aggressive LDL-C lowering and in whom high-intensity statins are advisable but not acceptable or tolerated, it may be reasonable to add a nonstatin drug (ezetimibe or bile acid sequestrant) to a moderate-intensity statin.

In patients at borderline risk, in risk discussion, the presence of risk-enhancing factors may justify initiation of moderate-intensity statin therapy.

Adherence to changes in lifestyle and effects of LDL-C–lowering medication should be assessed by measurement of fasting lipids and appropriate safety indicators 4 to 12 weeks after statin initiation or dose adjustment and every 3 to 12 months thereafter based on need to assess adherence or safety.

In adults 75 years of age or older with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), initiating a moderate-intensity statin may be reasonable.

In adults 75 years of age or older, it may be reasonable to stop statin therapy when functional decline (physical or cognitive), multimorbidity, frailty, or reduced life-expectancy limits the potential benefits of statin therapy.

In adults 76 to 80 years of age with an LDL-C level of 70 to 189 mg/dL (1.7 to 4.8 mmol/L), it may be reasonable to measure coronary artery calcium to reclassify those with a coronary artery calcium score of zero to avoid statin therapy.

In children and adolescents with lipid disorders related to obesity, it is recommended to intensify lifestyle therapy, including moderate caloric restriction and regular aerobic physical activity.

In children and adolescents with lipid abnormalities, lifestyle counseling is beneficial for lowering LDL-C.

In children and adolescents 10 years of age or older with an LDL-C level persistently 190 mg/dL or higher (≥4.9 mmol/L) or 160 mg/dL or higher (4.1 mmol/L) with a clinical presentation consistent with familial hypercholesterolemia and who do not respond adequately with 3 to 6 months of lifestyle therapy, it is reasonable to initiate statin therapy.

In children and adolescents with a family history of either early CVD* or significant hypercholesterolemia,† it is reasonable to measure a fasting or nonfasting lipoprotein profile as early as age 2 years to detect familial hypercholesterolemia or rare forms of hypercholesterolemia [*Family history of early CVD is defined here as MI, documented angina, or atherosclerosis by angiography in parents, siblings, grandparents, aunts, or uncles (<55 years of age for men, <65 years of age for women). †TC ≥240 mg/dL (≥6.2 mmol/L), LDL-C ≥190 mg/dL (≥4.9 mmol/L), non-HDL-C ≥220 mg/dL (≥5.7 mmol/L), or known primary hypercholesterolemia].

In children and adolescents found to have moderate or severe hypercholesterolemia, it is reasonable to carry out reverse-cascade screening of family members, which includes cholesterol testing for first-, second-, and when possible, third-degree biological relatives, for detection of familial forms of hypercholesterolemia.

In children and adolescents with obesity or other metabolic risk factors, it is reasonable to measure a fasting lipid profile to detect lipid disorders as components of the metabolic syndrome.

In children and adolescents without cardiovascular risk factors or family history of early CVD, it may be reasonable to measure a fasting lipid profile or nonfasting non-HDL-C once between the ages of 9 and 11 years, and again between the ages of 17 and 21 years, to detect moderate to severe lipid abnormalities.

For clinical decision-making in adults of different race/ethnicities, it is reasonable for clinicians to review race/ethnic features that can influence ASCVD risk, so as to adjust choice of statin or intensity of treatment.

In adults 20 years of age or older with moderate hypertriglyceridemia (fasting or nonfasting triglycerides 175 to 499 mg/dL [2.0 to 5.6 mmol/L]), clinicians should address and treat lifestyle factors (obesity and metabolic syndrome), secondary factors (diabetes mellitus, chronic liver or kidney disease and/or nephrotic syndrome, hypothyroidism), and medications that increase triglycerides.

In adults 40 to 75 years of age with moderate or severe hypertriglyceridemia and ASCVD risk of 7.5% or higher, it is reasonable to reevaluate ASCVD risk after lifestyle and secondary factors are addressed and to consider a persistently elevated triglyceride level as a factor favoring initiation or intensification of statin therapy.

In adults 40 to 75 years of age with severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL [≥5.6 mmol/L]) and ASCVD risk of 7.5% or higher, it is reasonable to address reversible causes of high triglyceride and to initiate statin therapy.

In adults with severe hypertriglyceridemia (fasting triglycerides ≥500 mg/dL [≥5.7 mmol/L]), and especially fasting triglycerides ≥1000 mg/dL (11.3 mmol/L)), it is reasonable to identify and address other causes of hypertriglyceridemia), and if triglycerides are persistently elevated or increasing, to further reduce triglycerides by implementation of a very low-fat diet, avoidance of refined carbohydrates and alcohol, consumption of omega-3 fatty acids, and, if necessary to prevent acute pancreatitis, fibrate therapy.

Clinicians should consider conditions specific to women, such as premature menopause (age <40 years) and history of pregnancy-associated disorders (hypertension, preeclampsia, gestational diabetes mellitus, small-for-gestational-age infants, preterm deliveries), when discussing lifestyle intervention and the potential for benefit of statin therapy.

Women of childbearing age who are treated with statin therapy and are sexually active should be counseled to use a reliable form of contraception.

Women of childbearing age with hypercholesterolemia who plan to become pregnant should stop the statin 1 to 2 months before pregnancy is attempted, or if they become pregnant while on a statin, should have the statin stopped as soon as the pregnancy is discovered.

In adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL (1.7 to 4.8 mmol/L) who are at 10-year ASCVD risk of 7.5% or higher, chronic kidney disease not treated with dialysis or kidney transplantation is a risk-enhancing factor and initiation of a moderate-intensity statin or moderate-intensity statins combined with ezetimibe can be useful.

In adults with advanced kidney disease that requires dialysis treatment who are currently on LDL-lowering therapy with a statin, it may be reasonable to continue the statin.

In adults with advanced kidney disease who require dialysis treatment, initiation of a statin is not recommended.

In adults 40 to 75 years of age with LDL-C 70 to 189 mg/dL (1.7 to 4.8 mmol/L) who have a 10-year ASCVD risk of 7.5% or higher, chronic inflammatory disorders and HIV are risk-enhancing factors and in risk discussion favor moderate-intensity statin therapy or high-intensity statin therapy.

In patients with chronic inflammatory disorders or HIV, a fasting lipid profile and assessment of ASCVD risk factors can be useful as a) a guide to benefit of statin therapy and b) for monitoring or adjusting lipid-lowering drug therapy before and 4 to 12 weeks after starting inflammatory disease–modifying therapy or antiretroviral therapy.

In adults with rheumatoid arthritis who undergo ASCVD risk assessment with measurement of a lipid profile, it can be useful to recheck lipid values and other major ASCVD risk factors 2 to 4 months after the patient’s inflammatory disease has been controlled.

A clinician–patient risk discussion is recommended before initiation of statin therapy to review net clinical benefit, weighing the potential for ASCVD risk reduction against the potential for statin-associated side effects, statin-drug interactions, and safety, while emphasizing that side effects can be addressed successfully.

In patients with statin-associated muscle symptoms, a thorough assessment of symptoms is recommended, in addition to an evaluation for nonstatin causes and predisposing factors.

In patients with indication for statin therapy, identification of potential predisposing factors for statin-associated side effects, including new-onset diabetes mellitus and statin-associated muscle symptoms, is recommended before initiation of treatment.

In patients with statin-associated side effects that are not severe, it is recommended to reassess and to rechallenge to achieve a maximal LDL-C lowering by modified dosing regimen, an alternate statin or in combination with nonstatin therapy.

In patients with increased diabetes mellitus risk or new-onset diabetes mellitus, it is recommended to continue statin therapy, with added emphasis on adherence, net clinical benefit, and the core principles of regular moderate-intensity physical activity, maintaining a healthy dietary pattern, and sustaining modest weight loss.

In patients treated with statins, it is recommended to measure creatine kinase levels in individuals with severe statin-associated muscle symptoms, objective muscle weakness, and to measure liver transaminases (aspartate aminotransferase, alanine aminotransferase) as well as total bilirubin and alkaline phosphatase (hepatic panel) if there are symptoms suggesting hepatotoxicity.

In patients at increased ASCVD risk with chronic, stable liver disease (including non-alcoholic fatty liver disease) when appropriately indicated, it is reasonable to use statins after obtaining baseline measurements and determining a schedule of monitoring and safety checks.

In patients at increased ASCVD risk with severe statin-associated muscle symptoms or recurrent statin-associated muscle symptoms despite appropriate statin rechallenge, it is reasonable to use randomized clinical trial proven nonstatin therapy that is likely to provide net clinical benefit.

Coenzyme Q10 is not recommended for routine use in patients treated with statins or for the treatment of statin-associated muscle symptoms.

In patients treated with statins, routine measurements of creatine kinase and transaminase levels are not useful.

Interventions focused on improving adherence to prescribed therapy are recommended for management of adults with elevated cholesterol levels, including telephone reminders, calendar reminders, integrated multidisciplinary educational activities, and pharmacist-led interventions, such as simplification of the drug regimen to once-daily dosing.

Clinicians, health systems, and health plans should identify patients who are not receiving guideline-directed medical therapy and should facilitate the initiation of appropriate guideline-directed medical therapy, using multifaceted strategies to improve guideline implementation.

Before therapy is prescribed, a patient-clinician discussion should take place to promote shared decision-making and should include the potential for ASCVD risk-reduction benefit, adverse effects, drug-drug interactions, and patient preferences.