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    Dyslipidemia in Adults

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    Apr.10.2024

    Dyslipidemia in Adults

    Synopsis

    Key Points

    • Dyslipidemia is a heterogeneous group of disorders characterized by abnormal lipid and lipoprotein levels in the blood
    • Usually asymptomatic until serum cholesterol levels and/or serum triglyceride levels are severely elevated and well beyond range at which cardiovascular morbidity and mortality are increased
    • Lifestyle modifications (eg, weight loss, exercise, dietary changes) are key to long-term management; consider medications to lower lipids (eg, statins) if lifestyle modifications alone do not achieve lipid-lowering goals
    • Statins are drug of choice for elevated cholesterol levels
    • Treatment of hypertriglyceridemia is indicated when triglyceride levels exceed 500 mg/dL r1

    Urgent Action

    • Make aggressive attempts to lower triglyceride level when it exceeds 1000 mg/dL to prevent pancreatitis r1
    • Suspect rhabdomyolysis in patients taking statins who develop severe myopathy, myoglobinuria, and acute renal failure; rhabdomyolysis requires urgent evaluation and management in ICU

    Pitfalls

    • Elevated level of lipoprotein(a) is a risk factor for cardiovascular disease even with effective reduction of LDL-C and apoB100 lipoprotein r2
    • Nonstatin therapies are only for selected patients with certain indications, not for primary prevention generally, because in the latter context, they do not provide acceptable risk reduction benefit compared with their potential adverse effects
    • Do not prescribe bile acid sequestrants for patients whose baseline fasting triglyceride levels are elevated because severe hypertriglyceridemia may occur

    Terminology

    Clinical Clarification

    • Dyslipidemia is a heterogeneous group of disorders characterized by abnormal serum lipid and lipoprotein levels
      • Serves as major, modifiable risk factor for atherosclerosis and cardiovascular disease
    • Defined as elevated total cholesterol, triglyceride, LDL-C, apolipoprotein B, and/or lipoprotein(a) levels (in 90th percentile) along with lower HDL-C or apolipoprotein A1 levels (below 10th percentile) r1
    • Lipid lowering therapies are the most effective means of primary and secondary prevention of atherosclerotic cardiovascular disease; benefits are maximized when therapy begins earlier, is more intense, and is given persistently r3

    Classification

    • Can be classified according to Fredrickson classification scheme,r4 which follows traditional lipoprotein phenotype or primary or secondary causes
      • Fredrickson classification r4
        • Type I: elevated serum chylomicron level; triglyceride level above 99th percentile
        • Type IIa: elevated serum LDL-C level; total cholesterol level above 90th percentile
        • Type IIb: elevated serum LDL-C and VLDL-C levels; total cholesterol and/or triglyceride levels above 90th percentile
        • Type III: elevated serum VLDL-C remnants and chylomicron remnants; total cholesterol and triglyceride levels above 90th percentile
        • Type IV: elevated serum VLDL-C level, total cholesterol level normal or increased, triglyceride level above 90th percentile, and low to normal HDL-C and LDL-C levels
        • Type V: elevated serum VLDL-C and chylomicron levels; triglyceride level above 99th percentile
      • Cause classification
        • Primary: genetic basis, although specific defect is not typically sought or identified
        • Secondary: caused by another disorder (eg, diabetes, hypothyroidism, renal disease, liver disease)

    Diagnosis

    Clinical Presentation

    History

    • Asymptomatic except when complications occur c1
    • Symptoms resulting from complications
      • Abdominal pain may be present with pancreatitis, a complication of severe hypertriglyceridemia c2
      • Angina pectoris and chest pain can result from coronary artery disease c3c4

    Physical examination

    • Commonly there are no signs of dyslipidemia
    • Eyes
      • Corneal arcus occurs in patients with familial and other types of hypercholesterolemia r5c5
        • In a young person, corneal arcus is very suggestive of familial hypercholesterolemia c6
      • Xanthelasma may be found in patients with familial or common types of hypercholesterolemia c7
      • Lipemia retinalis, a creamy appearance within retinal blood vessels, can rarely be seen in patients with severe hypertriglyceridemia c8
    • Skin
      • Xanthomas
        • Eruptive xanthomas, which appear as small papules on buttocks and back, may occur in patients with severe hypertriglyceridemia c9
        • In familial hypercholesterolemia, xanthomas may appear on skin covering extensor tendons of hands, Achilles tendons, and insertions of patellar tendons; xanthelasma may also appear on skin around eyes r5c10c11c12
      • Orange palmar creases may occur with type III hyperlipoproteinemia c13
    • Other
      • Corneal opacification, with or without tonsillar hypertrophy and splenomegaly, may be seen with specific severe low HDL-C syndromes (eg, Tangier disease, lecithin–cholesterol acyltransferase deficiency) c14c15c16
      • Increased waist circumference (reflecting abdominal adiposity) correlates with high triglyceride level with or without low HDL-C level c17

    Causes and Risk Factors

    Causes

    • Primary
      • Most commonly caused by genetic factors, but diet, drugs, and certain diseases worsen dyslipidemia
      • Genetic causes of hypercholesterolemia
        • Familial r6r7c18
          • Variants in LDLR gene (LDL receptor) c19
          • Variants in PCSK9 gene (proprotein convertase subtilisin/kexin type 9) c20
          • Variants in APOB gene (apolipoprotein B) causing familial defective apolipoprotein B-100 c21
          • Variants in LDLRAP1 gene (LDL receptor adaptor protein 1) c22
        • Familial combined hyperlipidemia (autosomal dominant disorder characterized by elevations in LDL-C and triglyceride levels) c23
        • Hyperapobetalipoproteinemia c24
      • Genetic causes of hypertriglyceridemia r8
        • Familial hypertriglyceridemia (autosomal dominant, type IV hyperlipoproeinemia) c25
        • Familial combined hyperlipidemia (polygenic, type IIb hyperlipoproteinemia) c26
        • Dysbetalipoproteinemia (from APOE variants) (aka remnant removal disease, type III hyperlipoproteinemia) c27
        • Familial chylomicronemia syndrome (type 1 hyperlipoproteinemia)
          • Mongenic forms of hypertriglyceridemia, including:
            • Lipoprotein lipase deficiency (from LPL variants) c28
            • Apolipoprotein C2 deficiency (from APOC2 variants) c29
            • Apolipoprotein A5 deficiency (from APOA5 variants) c30
            • Lipase maturation factor 1 deficiency (from LMF1 variants)
            • Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 deficiency (from GPHIHB1 variants)
        • Multifactorial chylomicronemia syndrome (type V hyperlipoproteinemia) r8
          • Much more common and complex than familial chylomicronemia
          • Involves multiple genes that work in concert with non-genetic factors to cause hypertriglyceridemia
      • Genetic causes of low HDL-C/apolipoprotein A1 r9
        • Familial hypoalphalipoproteinemia/familial HDL deficiency (from variants in ABCA1 or APOA1) c31
        • Familial combined hypolipidemia c32
        • Lipoprotein lipase deficiency c33
    • Secondary causes of elevated LDL-C levels
      • Hypothyroidism c34
      • Lipodystrophy c35
      • Chronic renal failure c36
      • Nephrotic syndrome c37
      • Cholestatic disorders c38
      • Cushing syndrome c39
      • Dysproteinemias c40
      • Obesity or weight gain c41c42
    • Secondary causes of hypertriglyceridemia
      • Diets very low in fat or with high proportion of refined carbohydrates c43c44
      • Excessive alcohol intake c45
      • Uncontrolled diabetes mellitus type 2 c46
      • Nephrotic syndrome c47
      • Chronic renal failure c48
      • Lipodystrophy c49
      • Hypothyroidism c50
      • Obesity or weight gain c51c52

    Risk factors and/or associations

    Age
    • Prevalence increases with age c53c54
    Genetics
    • Polygenic and/or epigenetic defects are most common r6r7c55
    • Inherited monogenic disorders are rare c56
    Ethnicity/race
    • Prevalence is increased in racial and ethnic groups who adopt westernized lifestyle r10c57
    Other risk factors/associations
    • Drugs r11
      • Anabolic steroids c58
      • Retinoids c59
      • Oral estrogens, including oral contraceptives c60
      • Corticosteroids c61
      • Thiazide diuretics c62
      • Protease inhibitors c63
      • β-Blockers c64
      • Some immunosuppressive agents (eg, cyclosporine, sirolimus, tacrolimus) c65
      • Atypical antipsychotics c66
      • Tamoxifen c67c68
      • Some chemotherapy drugs (eg, asparaginase)
      • Bile acid sequestrants (can worsen hypertriglyceridemia) r12
    • Dietary influences
      • Fat intake greater than 40% of total calories r13c69
      • Saturated fat intake greater than 9% of total calories r13c70
      • Cholesterol intake greater than 300 mg/day r14c71
      • Excessive sugar and/or carbohydrate intake c72c73
      • Excessive calorie intake c74
    • Lifestyle influences
      • Habitual excessive alcohol intake c75
      • Sedentary lifestyle c76

    Diagnostic Procedures

    Primary diagnostic tools r1

    • Obtain serum lipid profile
    • Exclude secondary causes of dyslipidemia by using thyroid, hepatic, and renal function tests
    • Determine patient's risk of clinical atherosclerotic cardiovascular disease to classify into risk category r1
      • Assess for diabetes mellitus, hypertension, and cigarette smoking
      • Evaluate for presence of risk-enhancing factors r1
        • Family history of premature atherosclerotic cardiovascular disease (ie, in male patients aged younger than 55 years and in female patients aged younger than 65 years)
        • Primary hypercholesterolemia: LDL-C level 160 to 189 mg/dL (4.1-4.8 mmol/L); non–HDL-C level 190 to 219 mg/dL (4.9-5.6 mmol/L)
        • Metabolic syndrome: 3 or more of the following:
          • Increased waist circumference
            • Threshold varies according to population and sex
            • Increased risk of metabolic complications is seen with waist circumferences of 94 cm or more in males and 80 cm or more in females, and risk is substantially increased at 102 cm or more in males and 88 cm or more in females; these higher thresholds are generally used to define abdominal obesity in North America and Europe r15
            • Thresholds in populations with Asian ethnicity are lower (90 cm or more for males and 80 cm or more for females) r15
          • Elevated triglyceride level (higher than 175 mg/dL)
          • Elevated blood pressure
          • Elevated glucose level
          • HDL-C level lower than 40 mg/dL in males and lower than 50 mg/dL in females
        • Chronic kidney disease: estimated GFR of 15 to 59 mL/minute/1.73 m² with or without albuminuria; not treated with dialysis or kidney transplant
        • Chronic inflammatory conditions (eg, psoriasis, rheumatoid arthritis, HIV/AIDS) r16
        • History of premature menopause (before age 40 years) and history of pregnancy-associated hypertension
        • High-risk race or ethnicity (eg, South Asian ancestry)
        • Persistently elevated triglyceride levels (175 mg/dL or higher, ideally on 3 or more occasions); primary hypertriglyceridemia
        • Other biomarkers if measured in selected patients
          • Elevated lipoprotein(a) level defined as greater than 30 mg/dL (75 nmol/L) in United States and greater than 50 mg/dL (125 nmol/L) in Europe r17
            • National Lipid Association guidelines recommend measuring this biomarker to improve risk assessment for the following: r18
              • Patients with first-degree relatives with premature atherosclerotic cardiovascular disease (aged younger than 55 years in males, 65 years in females)
              • Patients with premature atherosclerotic cardiovascular disease themselves
              • Patients with severe hypercholesterolemia (LDL-C level of 190 mg/dL or higher) or suspected familial hypercholesterolemia
            • Other guidelines recommend measuring at least once in a person's lifetime to identify those with very high levels, which confer lifetime risk of atherosclerotic cardiovascular disease equivalent to that of heterozygous familial hypercholesterolemia r2r19
              • Levels are greater than 90% genetically determined and vary little across time, hence repeat testing is not warranted
          • Elevated apolipoprotein B level of 130 mg/dL or higher
            • Relative indication for taking this measurement is triglyceride level of 200 mg/dL or higher
            • Also recommended to aid risk assessment for patients with diabetes, metabolic syndrome, obesity, or very low LDL-C level r19
          • Ankle-brachial index less than 0.9
          • Elevated high-sensitivity C-reactive protein level of 2 mg/L or higher
          • Coronary artery calcium score r19r20
            • Can provide additional information to guide treatment decisions for low- to moderate-risk patients if need for treatment remains uncertain after initial evaluation
          • Arterial plaque burden on carotid and/or femoral arterial ultrasonography r19
            • Can provide additional information to guide treatment decisions for low- to moderate-risk patients if need for treatment remains uncertain after initial evaluation
    • Test for conditions that may influence statin safety

    Laboratory

    • Lipid profile c77c78
      • Draw venous blood sample (ideally after at least 8-hour fast) to measure serum total cholesterol, HDL-C, and triglyceride levels r1
        • In most cases, nonfasting lipid levels are sufficient; equivalent to fasting levels in terms of risk prediction and more convenient for patients r20r21
        • Fasting levels are preferred for patients with significant nonfasting hypertriglyceridemia
      • Calculated LDL-C levels r22
        • Laboratory reports estimate LDL-C level based on the following equation:
          • LDL-C = total cholesterol − HDL-C − triglycerides × 0.2 (Friedewald formula)
        • Calculating LDL-C level is only accurate when triglyceride level is lower than 400 mg/dL; if triglyceride level is high, the only way to accurately determine LDL-C level is by direct measurement
        • If LDL-C level is less than 70 mg/dL, can obtain more accurate levels by direct measurement or by using a modified calculation (Martin-Hopkins method)
      • Calculate non–HDL-C level
        • Non–HDL-C level = total cholesterol − HDL-C
        • Non–HDL-C includes all cholesterol present in lipoprotein particles that is considered atherogenic, including LDL, lipoprotein(a), IDL (intermediate-density lipoprotein), and VLDL; levels relatively independent of non-fasting state r23
        • Postulated by some to be better estimate of cardiovascular risk than LDL-C and recommended as a co-primary treatment target r23
    • High-sensitivity C-reactive protein test c79
      • Marker for inflammation, which may contribute to atherosclerotic cardiovascular disease r24
      • Additional risk marker that may be used when treatment decisions are uncertain
      • C-reactive protein levels of 2 mg/L or higher signify increased atherosclerotic cardiovascular risk r25
    • Laboratory testing for diabetes, using 1 of 4 methods: d1
      • Fasting glucose measurement c80
      • 2-Hour 75-g oral glucose tolerance test c81
      • Hemoglobin A1C c82
      • Random blood glucose measurement c83
    • Tests to exclude secondary causes
      • TSH test
        • Screens for primary hypothyroidism; formal diagnosis requires additional thyroid hormone levels c84d2
      • Serum creatinine test
        • Detects chronic kidney disease as a cause of secondary dyslipidemia c85
      • Liver function tests
        • Detect cholestatic liver disease c86
        • Assess safety of statin therapy
      • Urinalysis
        • Detects proteinuria due to nephrotic syndrome c87

    Imaging

    • Coronary artery calcium score r26c88
      • Additional risk marker that may be used when treatment decisions are uncertain
      • Measurement of calcified plaque in coronary arteries as determined from cardiac CT scan
      • Measurement is not useful for patients already treated with statins r1
      • Score = 0: risk of atherosclerotic cardiovascular disease is low. It may be reasonable to withhold statin therapy except for patients who smoke cigarettes, have diabetes, or have strong family history of atherosclerotic cardiovascular disease. Consider remeasuring after 5 to 10 years r1
      • Score = 1 to 99: initiate statin therapy for patients aged 55 years or older r1
      • Score = 100 or higher or in 75th percentile or higher: initiate statin therapy r1

    Procedures

    Ankle-brachial index c89
    General explanation
    • Comparison of blood pressure at ankle with that at brachial biceps to estimate relative burden of disease in lower extremities versus upper extremities
    • Additional risk marker that may be used when treatment decisions are uncertain
    Indication
    • Patients who do not fall into 1 of the 4 groups who should receive statin therapy (especially those whose estimated 10-year atherosclerotic cardiovascular disease risk is 5%-19.9%) r1
    Interpretation of results
    • Ankle-brachial index lower than 0.9 indicates impaired blood flow in lower extremities and enhanced atherosclerotic cardiovascular risk r27r28

    Other diagnostic tools

    • Several calculators of atherosclerotic risk are available r1r29c90
    • The following approach to risk stratification and treatment is based on pooled cohort equations, as suggested by American College of Cardiology and American Heart Association, and categorizes 10-year risk for atherosclerotic cardiovascular disease as low risk (less than 5%), borderline risk (5% to less than 7.5%), intermediate risk (7.5% to less than 20%), and high risk (20% or higher) r1r29
      • Pooled cohort equations calculator assesses the following risk factors:
        • Age
        • Sex
        • Race
        • Cholesterol levels (total, HDL, LDL)
        • Blood pressure
        • Current medical treatment for hypertension
        • Diabetes diagnosis
        • Smoking status
        • Current statin therapy
    • Diagnosis of familial hypercholesterolemia
      • Usually, but not always, characterized by: r5
        • Elevated LDL-C level c91c92c93
          • Suspect homozygous familial hypercholesterolemia if LDL-C level is higher than 400 mg/dL r5r30r31
          • Suspect heterozygous familial hypercholesterolemia if LDL-C level is 190 mg/dL or higher in adults or 160 mg/dL or higher in children r5r30r31
        • History of premature coronary artery disease c94c95
        • Family history of premature coronary artery disease or severe hypercholesterolemia c96
        • Corneal arcus
        • Xanthoma tendinosum (ie, nodules in tendons, ligaments, fascia, and periosteum, especially on hands, elbows, knees, or heels) c97

    Differential Diagnosis c98

    Treatment

    Goals

    • Reduce elevated levels of atherogenic cholesterol to prevent atherosclerotic cardiovascular disease and related cardiovascular events
    • Reduce elevated triglyceride levels in patients with severe hypertriglyceridemia to prevent acute pancreatitis
    • Treat patients who have known cardiovascular disease with statin therapy to reduce risk of myocardial infarction and ischemic stroke, regardless of baseline LDL-C levels r1
    • For primary prevention, most professional organizations recommend assessing risk of cardiovascular disease and treating patients at higher risk
    • Several professional organizations have issued treatment guidelines for dyslipidemia risk assessments and management; treatment goals are defined by level of atherosclerotic cardiovascular risk and may differ among them r1r32r33r34
      • Set by intensity of statin therapy for desired percentage of reduction of LDL-C levels (according to American College of Cardiology/American Heart Association guidelines) r1
        • High intensity: lower LDL-C levels by 50% or more
        • Moderate intensity: lower LDL-C levels by 30% to 49%
        • Low intensity: lower LDL-C levels by less than 30%
      • Set to specific LDL-C and non–HDL-C levels (according to American Association of Clinical Endocrinology guideline,r33 which sets specific targets for LDL-C levels as goals of therapy, depending on risk level calculated by Framingham risk scorer35 and National Lipid Association guideliner36r37r38)
        • Extreme risk (American Association of Clinical Endocrinology guideline only): LDL-C levels less than 55 mg/dL and non–HDL-C levels less than 80 mg/dL
        • Very high risk: LDL-C levels less than 70 mg/dL, non–HDL-C levels less than 100 mg/dL
        • High risk: LDL-C levels less than 100 mg/dL, non–HDL-C levels less than 130 mg/dL
        • Moderate risk: LDL-C levels less than 100 mg/dL, non–HDL-C levels less than 130 mg/dL
        • Low risk: LDL-C levels less than 130 mg/dL, non–HDL-C levels less than 160 mg/dL
        • American Association of Clinical Endocrinology risk category stratification and treatment targets.Data from Jellinger PS et al: American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 23(suppl 2):1-87, 2017, Table 6.
          Risk categoryRisk factorsTreatment target: LDL (mg/dL)Treatment target: non–HDL-C (mg/dL)Treatment target: apolipoprotein B (mg/dL)
          ExtremeProgressive atherosclerotic cardiovascular disease, including unstable angina, after achieving LDL level lower than 70 mg/dLLower than 55Lower than 80Lower than 70
          Established clinical cardiovascular disease in patients with diabetes, stage 3 or 4 chronic kidney disease, or heterozygous familial hypercholesterolemia
          History of premature atherosclerotic cardiovascular disease (younger than 55 years in males, younger than 65 years in females)
          Very highEstablished or recent hospitalization for acute coronary syndrome or carotid or peripheral vascular diseaseLower than 70Lower than 100Lower than 80
          Diabetes or stage 3 or 4 chronic kidney disease with 1 or more risk factors
          Heterozygous familial hypercholesterolemia
          High2 or more risk factors and 10-year risk of 10% to 20%Lower than 100Lower than 130Lower than 90
          Diabetes or stage 3 or 4 chronic kidney disease with no other risk factors
          Moderate2 or fewer risk factors and 10-year risk less than 10%Lower than 100Lower than 130Lower than 90
          Low0 risk factorsLower than 130Lower than 160Not recommended
      • Set to desired percentage of reduction in non–HDL-C levels (according to National Institute for Health and Care Excellence guidelines) r32
        • Aim for more than 40% reduction in non–HDL-C for all patients started on statin treatment after 3 months

    Disposition

    Recommendations for specialist referral

    • Refer the following patients to lipid specialist: r39
      • Patients with suspected primary or familial forms of dyslipidemia (ie, LDL-C level 190 mg/dL or higher) to define and/or treat specific type
      • Pregnant patients, to consider nonstatin therapies
      • Patients with previously diagnosed homozygous or severe heterozygous familial hypercholesterolemia for treatment intensification, as needed
      • Patients with severe hypertriglyceridemia
      • Patients with atherosclerotic cardiovascular disease and baseline LDL-C level of 190 mg/dL or higher who do not achieve LDL-C lowering of 50% or more from baseline and LDL-C level less than 70 mg/dL on maximally tolerated statin therapy in combination with nonstatin therapy r40
    • Consider referring patients with atherosclerotic cardiovascular disease and baseline LDL-C level of 190 mg/dL or higher or intolerance on at least 2 (preferably 3) statin therapies with 1 attempt at the lowest FDA-approved dose and a trial of an alternative statin dosing regimen r40

    Treatment Options

    Encourage all patients with dyslipidemia to make healthy lifestyle changes to help reduce risk of atherosclerotic cardiovascular disease events r41

    • Encourage them to attain and maintain BMI within reference range
    • Counsel them regarding healthy diet, physical exercise, and tobacco and alcohol use
    • Provide relevant information and referrals (eg, smoking cessation program, dietitian) d3

    Pharmacologic therapy chosen to lower LDL-C levels is based on actual LDL-C levels and assessment of atherosclerotic cardiovascular disease and acute pancreatitis risk r1r42

    • Statins are the therapy of choice to treat elevated LDL-C levels and for primary and secondary atherosclerotic cardiovascular disease prevention r1r32r43
      • Statin therapy is associated with reduced risk of all-cause mortality, cardiovascular mortality, stroke, and myocardial infarction r44
      • Depending on risk level, use statin therapy that is either high intensity (achieves 50% or more reduction in baseline LDL-C level) or moderate intensity (achieves 30%-49% reduction in baseline LDL-C level) r1
      • Statin therapy is indicated for adults who fall into 1 or more of the following 4 groups that are proven to benefit: r1
        • Patients aged 20 years and older with clinical atherosclerotic cardiovascular disease (for secondary prevention)
          • Treat all patients who have known cardiovascular disease with statin therapy to reduce risk of myocardial infarction and ischemic stroke, regardless of baseline LDL-C level r1
          • Use high-intensity or maximally tolerated statin therapy for patients aged 75 years or younger
            • The following patients are considered to be at very high risk and should be treated with maximally tolerated statin therapy plus ezetimibe from the outset r40r45r46
              • Patients with history of multiple major atherosclerotic cardiovascular disease events (eg, acute coronary syndrome, myocardial infarction or ischemic stroke, symptomatic peripheral artery disease)
              • Patients with a history of 1 major atherosclerotic cardiovascular disease event and more than 1 of the following high-risk conditions:
                • Age 65 years or older
                • Heterozygous familial hypercholesterolemia
                • History of prior coronary artery bypass surgery or percutaneous coronary intervention (separate from the major atherosclerotic cardiovascular disease event)
                • Comorbid diabetes, hypertension, chronic kidney disease, or congestive heart failure
                • Current smoking
                • Persistently elevated LDL-C level of 100 mg/dL or greater despite maximally tolerated statin therapy and ezetimibe
            • Some experts suggest that all patients with atherosclerotic cardiovascular disease should receive upfront combination therapy with a statin and at least ezetimibe, with few exceptions such as advanced age r3r45
            • May add PCSK9 inhibitor (proprotein convertase subtilisin/kexin type 9) to treatment for patients who are at very high risk and are taking maximally tolerated LDL-C–lowering medication and have either of the following:
              • LDL-C level of 70 mg/dL or higher
              • Non–HDL-C level of 100 mg/dL or higher
          • Use moderate-intensity statin therapy if patient cannot receive high-intensity therapy
            • Of note, combination of moderate-intensity statin with ezetimibe was found to be noninferior to high-intensity statin monotherapy for the 3-year composite outcome of cardiovascular death, major cardiovascular events, and nonfatal stroke r47
          • For patients older than 75 years, initiate or continue either moderate- or high-intensity statin therapy after considering potential reduction in risk, adverse effects, and interactions and general status
            • In healthy older adults aged 75 to 85 years, benefits of statin therapy generally outweigh the risks, especially when used for secondary prevention r48
            • For older adults with frailty, multiple complex comorbidities, and limited life expectancy, it may be appropriate to discontinue statin therapy; however, there is no consensus on criteria for doing so r48
        • Patients aged 20 years and older with severe primary hypercholesterolemia (LDL-C levels 190 mg/dL or higher)
          • Initiate high-intensity or maximally tolerated statin therapy regardless of atherosclerotic cardiovascular disease risk
          • Consider adding ezetimibe if LDL-C level remains 100 mg/dL or higher with maximally tolerated statin therapy; upfront combination treatment with ezetimibe is recommended by European guidelinesr46
          • Consider PCSK9 inhibitor for patients with multiple risk factors for atherosclerotic cardiovascular disease whose LDL-C level remains 100 mg/dL or higher with maximally tolerated statin therapy and ezetimibe
        • Patients aged 40 to 75 years with LDL-C levels of 70 to 189 mg/dL who have 1 or more atherosclerotic cardiovascular disease risk factors (ie, dyslipidemia, diabetes, hypertension, or smoking) and an estimated 10-year atherosclerotic cardiovascular disease risk of 7.5% or greater (for primary prevention of atherosclerotic cardiovascular disease) r44
          • Evidence of net benefit is greatest for those with an estimated 10-year cardiovascular disease risk of 10% or more r44
          • Initiate high-intensity statin therapy for patients with high risk of atherosclerotic cardiovascular disease (more than 20%)
          • If risk enhancers are present and risk estimate favors statin therapy, initiate moderate-intensity statin therapy for those with intermediate risk of atherosclerotic cardiovascular disease (more than 7.5%-19.9%); may also consider this therapy for patients with risk-enhancing factors and borderline atherosclerotic cardiovascular disease risk (more than 5%-7.4%)
          • Although statin therapy significantly reduces major cardiovascular events in all age groups, the USPSF (US Preventive Services Task Force) found insufficient evidence to assess the net benefit of statins for primary prevention in adults older than 75 years r44r49r50r51
            • Guidelines suggest that statin therapy is reasonable to consider for primary prevention of atherosclerotic cardiovascular disease for patients older than 75 years without life-limiting disease according to risk of atherosclerotic cardiovascular disease r1r19r52
            • Recent studies support use of statins for primary prevention for those aged 75 years or older, finding reduced risk of cardiovascular events, cardiovascular mortality, and all-cause mortality in these patients r49r53
        • Patients aged 40 to 75 years with diabetes without other atherosclerotic cardiovascular disease risk factors and LDL-C level less than 190 mg/dL r40
          • Most patients aged 40 to 75 years with diabetes have elevated 10-year arteriosclerotic cardiovascular disease risk and/or high-risk features or diabetes-specific risk enhancers and should receive high-intensity statin therapy to reduce LDL-C level by 50% or more
          • Treat the small proportion of patients who have 10-year predicted arteriosclerotic cardiovascular disease risk of less than 7.5% and no additional high-risk features with moderate-intensity statin therapy
        • Statin safety recommendations r1r54
          • Measure baseline hepatic function to assess for potential adverse effects that may occur with statin use
          • Modify intensity of statin drug therapy if serum ALT level is more than 3 times the upper reference limit
          • Use a moderate-intensity statin for patients for whom a high-intensity statin would otherwise be recommended but who have any of the following characteristics, which predispose them to adverse effects: r55
            • Multiple or serious comorbidities, including impaired renal or hepatic function
            • History of previous statin intolerance or muscle disorders
            • Unexplained serum ALT elevations to more than 3 times the upper reference limit
            • Use of drugs that affect statin metabolism
            • Older than 75 years
    • Nonstatin drug therapy may be used as an adjunct to maximally tolerated statin therapy if that fails to achieve LDL-C targets or as an alternative for patients unable to take statins r1r40
      • Nonstatin LDL-C–lowering agents include ezetimibe, PCSK9 inhibitors, inclisiran, evinacumab, bempedoic acid, and bile acid sequestrants r1r40
        • Ezetimibe and PCSK9 inhibitors incrementally reduce LDL-C levels in patients in whom LDL-C remains at or above 70 mg/dL on maximally tolerated statin therapy and have been shown to improve cardiovascular outcomes for patients at high or very high cardiovascular risk r56
          • The addition of these agents yielded little or no benefit among patients at moderate or low cardiovascular risk r57
      • American College of Cardiology has published treatment algorithms to guide use of nonstatin therapies for LDL-C lowering in the management of atherosclerotic cardiovascular disease risk r40
        • Intent is to provide interim recommendations while awaiting results of ongoing cardiovascular outcomes trials and their incorporation into evidence-based guidelines
      • Do not reduce the statin dose when adding ezetimibe or PCSK9 inhibitors to high-intensity statin therapy unless there are unacceptable statin-related side effects r3
      • Available nonstatin agents
        • Ezetimibe
          • The most commonly used nonstatin agent
          • Blocks intestinal absorption of cholesterol by approximately 60% with subsequent mean reduction in LDL-C levels of approximately 18% r58
          • Indicated for patients who are intolerant of statins, those who require additional LDL-C lowering despite maximally tolerated statin therapy, and those who have sitosterolemiar59
          • Minimal effects on triglyceride or HDL levels
          • Combination of a statin and ezetimibe is the first line treatment for very-high-risk patients with elevated LDL-C, patients with elevated LDL-C that is refractory to maximally tolerated statin therapy, and patients with familial hypercholesterolemia r40r46
        • PCSK9 inhibitors r60r61r62
          • Monoclonal antibodies that inhibit PCSK9 action of LDL-receptor degradation; net effect is to increase LDL-receptor density and to lower LDL-C level
          • Approved as adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C level
          • Also approved for use in combination with other LDL-C–lowering therapies for patients with homozygous familial hypercholesterolemia who require additional lowering of LDL-C levels
          • Effectiveness
            • Dramatically reduce LDL-C levels more than statin therapy alone (both approximately 60%) r60r61
            • A randomized trial of evolocumab showed 15% relative risk reduction (composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, and coronary revascularization) when used as secondary prevention for persons with high risk who are already on lipid-lowering therapy r62
            • Alirocumab added to high-intensity statin therapy in patients with familial hypercholesterolemia for 78 weeks resulted in significant regression of coronary plaque burden r63
        • Inclisiran
          • siRNA (small interfering RNA) that inhibits production of PCSK9 at an intracellular level
          • May be used as an adjunct to diet and maximally tolerated statin therapy for patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease who require additional lowering of LDL-C r40
            • Effect on cardiovascular morbidity and mortality has not been determined
        • Evinacumab r40r64r65r66
          • ANGPTL3 (angiopoietin-like protein 3) inhibitor
          • Fully human monoclonal antibody inhibitor of ANGPTL3 approved for use for patients with homozygous familial hypercholesterolemia as an adjunct to other LDL-C–lowering treatment
          • Effectively lowers LDL-C in patients with homozygous familial hypercholesterolemia and other causes of hypercholesterolemia; however, the effects on cardiovascular morbidity and mortality have not been studied
          • May be useful for severe hypercholesterolemia that is refractory to maximally tolerated statins, ezetimibe, and PCSK9 inhibitors
        • Bempedoic acid r67
          • An inhibitor of the enzyme adenosine triphosphate citrate lyase, which is upstream of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statin target) in the cholesterol biosynthesis pathway
          • Lowers LDL-C and other atherogenic proteins and was associated with reduction in risk of major cardiovascular events among statin-intolerant patients who had or have high risk for atherosclerotic cardiovascular disease; may be used for statin-intolerant patients who require modest lipid lowering
          • Uniquely reduces high-sensitivity C-reactive protein by 27% to 40% r3
          • Improves glycemic control in patients with diabetes and dyslipidemia r3
        • Bile acid sequestrants r40
          • Promote LDL-C clearance from plasma but can increase serum triglyceride level
          • Effective in combination with statins or ezetimibe r68
          • Use alone for patients with statin intolerance or use in combination with statin for patients with severe hypercholesterolemia when they are unable to tolerate ezetimibe c99
          • Add for patients with baseline LDL-C level of 190 mg/dL or higher who achieve less than 50% reduction in LDL-C levels and have fasting triglyceride levels of 300 mg/dL or lower while taking maximally tolerated statin and ezetimibe therapy r1
          • Adverse gastrointestinal effects of constipation and bloating are common
        • Lomitapide
          • Small molecule inhibitor of microsomal triglyceride transfer protein indicated for lowering of LDL-C and VLDL-C in homozygous familial hypercholesterolemia

    Management of hypertriglyceridemia

    • Address the following: r1
      • Lifestyle factors
      • Obesity and metabolic syndrome
      • Secondary causes r12
        • Diabetes mellitus
        • Chronic liver disease
        • Chronic kidney disease
        • Hypothyroidism
        • Medications associated with elevated triglycerides (eg, thiazides, β-blockers, estrogens, corticosteroids, bile acid–binding resins, protease inhibitors, and some immunosuppressants and antipsychotics)
        • Excess alcohol intake
    • Major medication classes used to treat hypertriglyceridemia are statins, fibrates, and ω-3 fatty acids; niacin is rarely used and should be avoided for patients on statins with LDL-C levels lower than 100 mg/dL r1
    • In adults with moderate hypertriglyceridemia (fasting or nonfasting triglycerides 150-499 mg/dL), use nonpharmacologic measures when possible r1
    • In adults aged 40 to 75 years with moderate or severe hypertriglyceridemia and atherosclerotic cardiovascular disease risk of 7.5% or higher, first address lifestyle and secondary factors, then reevaluate atherosclerotic cardiovascular disease risk. Consider persistently elevated triglyceride level as a factor favoring statin therapy r1
    • In adults with severe hypertriglyceridemia (ie, fasting triglyceride level of 500 mg/dL or higher that is persistent or increasing or any fasting triglyceride level of 1000 mg/dL or higher), recommend very-low-fat diet, avoidance of refined carbohydrates and alcohol, and ω-3 fatty acids or fibrate therapy to prevent acute pancreatitis r1
      • Most patients with severe hypertriglyceridemia have multiple atherosclerotic cardiovascular disease risk factors and are also candidates for statin therapy
    • Fibric acid derivates (fibrates) are first line therapy for severe hypertriglyceridemia (triglycerides higher than 500 mg/dL) r69c100
      • May be combined with statins to reduce mixed dyslipidemia (ie, high LDL-C level, high triglyceride level, and low HDL-C level)r70
      • Avoid in combination with statins owing to increased risk of myopathy
      • Systematic reviews found that fibrates reduce major adverse cardiovascular events by 12% to 16% compared to placebo r71
    • ω-3 Polyunsaturated fatty acids (ie, ω-3 fatty acids, polyunsaturated fatty acids, fish oil)
      • Effective at lowering fasting triglyceride levels r72
      • Reasonable first line therapy for patients with severe hypertriglyceridemia (triglyceride level more than 500 mg/dL)
      • Marine ω-3 fatty acids may raise LDL-C levels in some patients
    • Nicotinic acid
      • Effective in lowering both LDL-C and triglyceride levels r73
      • Most effective HDL-C medication currently approved but not demonstrated to confer definite cardiovascular benefits
      • Not recommended routinely but may be considered for patients at very high risk for cardiovascular events who have contraindications to statinsr74
      • Considered third line option for lowering triglyceride levels
      • Adverse effects are frequent and can include:
        • Cutaneous flushing
        • Dyspepsia
        • Worsening of esophageal reflux or peptic ulcer disease
        • Mild elevations in serum liver transaminase levels
        • Increases in uric acid level and precipitation of gouty attacks in susceptible patients
        • Acanthosis nigricans
      • Combination of slow- or extended-release nicotinic acid and statin therapy in patients with low HDL levels has been shown to slow progression of atherosclerosis in patients with coronary artery disease but has not been shown to reduce cardiovascular events r75r76r77

    Management of hyperlipoproteinemia(a)

    • Guidelines cite the current lack of randomized study evidence to support lipoprotein(a) levels as a specific target of therapy r1r2r19
    • Traditional therapies including aspirin, niacin, ezetimibe, and PCSK-9 inhibitors all decrease lipoprotein(a) levels by less than 50%; statins increase levels r17
    • Apheresis is most effective treatment for lowering lipoprotein(a), though levels return to baseline within 2 weeks r2r78
    • Studies on more effective lipoprotein(a) lowering agents and effects on cardiovascular outcomes are ongoing r17

    Drug therapy

    • Statins (hydroxymethylglutaryl-coenzyme A reductase inhibitors) c101
      • High-intensity statinsr79 (daily dose lowers LDL-C levels by 50% or more, on average) r1
        • Atorvastatin c102c103c104
          • Atorvastatin Calcium Oral tablet; Adults: 80 mg PO once daily. May decrease dose to 40 mg PO once daily if unable to tolerate the higher dose.
        • Rosuvastatin c105c106c107
          • Rosuvastatin Calcium Oral tablet; Adults: 20 or 40 mg PO once daily.
      • Moderate-intensity statins (daily dose lowers LDL-C levels by 30%-49%, on average) r1
        • Atorvastatin c108c109c110
          • Atorvastatin Calcium Oral tablet; Adults: 10 or 20 mg PO once daily.
        • Fluvastatin c111c112c113
          • Immediate-release c114
            • Fluvastatin Sodium Oral capsule; Adults: 40 mg PO twice daily.
          • Extended-release
            • Fluvastatin Sodium Oral tablet, extended-release; Adults: 80 mg PO once daily.
        • Lovastatin c115c116c117
          • Lovastatin Oral tablet; Adults: 40 or 80 mg PO once daily.
        • Pitavastatin c118c119c120
          • Pitavastatin Calcium Oral tablet; Adults: 1 to 4 mg PO once daily.
        • Pravastatin c121c122c123
          • Pravastatin Sodium Oral tablet; Adults: 40 or 80 mg PO once daily.
        • Rosuvastatin c124c125c126
          • Rosuvastatin Calcium Oral tablet; Adults: 5 or 10 mg PO once daily.
        • Simvastatin c127c128c129
          • Simvastatin Oral tablet; Adults: 20 or 40 mg PO once daily.
      • Low-intensity statins (daily dose lowers LDL-C levels by less than 30%, on average; usually reserved for patients who do not tolerate high- or moderate-intensity statins) r1
        • Fluvastatin c130
          • Fluvastatin Sodium Oral capsule; Adults: 20 or 40 mg PO once daily.
        • Lovastatin c131
          • Lovastatin Oral tablet; Adults: 20 mg PO once daily.
        • Pravastatin c132
          • Pravastatin Sodium Oral tablet; Adults: 10 or 20 mg PO once daily.
        • Simvastatin c133
          • Simvastatin Oral tablet; Adults: 10 mg PO once daily.
      • High-, moderate-, and low-intensity statins.Data from Grundy SM et al: 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. J Am Coll Cardiol. 73(24):e285-350, 2019, Table 3.
        Generic nameHigh intensityModerate intensityLow intensity
        Atorvastatin40 to 80 mg10 to 20 mg
        Rosuvastatin20 to 40 mg5 to 10 mg
        Simvastatin20 to 40 mg10 mg
        Pravastatin40 to 80 mg10 to 20 mg
        Lovastatin40 to 80 mg20 mg
        Fluvastatin80 mg daily (extended-release) or 40 mg twice daily20 to 40 mg
        Pitavastatin1 to 4 mg
    • Statin combination therapy
      • Fixed-dose combinations include:
        • Rosuvastatin plus ezetimibe
          • Rosuvastatin Calcium, Ezetimibe Oral tablet; Adults: 5 mg rosuvastatin/10 mg ezetimibe to 40 mg rosuvastatin/10 mg ezetimibe PO once daily. Monitor lipid concentrations after starting therapy or adjusting dose within 2 or more weeks and adjust dose if needed. Max: 40 mg/day rosuvastatin/10 mg/day ezetimibe. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Rosuvastatin Calcium, Ezetimibe Oral tablet; Asian Adults: 5 mg rosuvastatin/10 mg ezetimibe PO once daily, initially. Monitor lipid concentrations after starting therapy or adjusting dose within 2 or more weeks and adjust dose if needed. Max: 20 mg/day rosuvastatin/10 mg/day ezetimibe. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • Simvastatin plus ezetimibe c134c135
          • Ezetimibe, Simvastatin Oral tablet; Adults: 10 mg ezetimibe/10 mg simvastatin to 10 mg ezetimibe/20 mg simvastatin PO once daily, initially, or 10 mg ezetimibe/40 mg simvastatin PO once daily for patients requiring a larger reduction in LDL-C. Monitor lipid concentrations after starting therapy or adjusting dose within 2 or more weeks and adjust dose if needed. Usual dose: 10 mg/day ezetimibe/10 mg/day simvastatin to 10 mg/day ezetimibe/40 mg/day simvastatin. Max: 10 mg/day ezetimibe/80 mg/day simvastatin; restrict use to patients who have been taking 10 mg/day ezetimibe/80 mg/day simvastatin chronically without evidence of muscle toxicity. Do not titrate patients unable to achieve their LDL-C goal with 10 mg/day ezetimibe/40 mg/day simvastatin to 10 mg/day ezetimibe/80 mg/day simvastatin but place on alternative LCL-C-lowering therapy. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Nonstatin therapies to reduce LDL-C
      • Cholesterol absorption inhibitors c136c137
        • Ezetimibe
          • Ezetimibe Oral tablet; Adults: 10 mg PO once daily.
      • PCSK9 serine protease inhibitors c138
        • Evolocumab c139
          • Evolocumab Solution for injection; Adults: 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly.
        • Alirocumab c140
          • Alirocumab Solution for injection; Adults: 75 mg subcutaneously every 2 weeks or 300 mg subcutaneously every 4 weeks. May adjust dose to 150 mg subcutaneously every 2 weeks if response is inadequate.
      • siRNA directed to PCSK9 mRNA
        • Inclisiran
          • Inclisiran Solution for injection; Adults: 284 mg subcutaneously every 3 months for 2 doses, then 284 mg subcutaneously every 6 months.
      • ANGPTL3 inhibitor
        • Evinacumab
          • Evinacumab Solution for injection; Adults: 15 mg/kg/dose IV every 4 weeks.
      • ACL (adenosine triphosphate–citrate lyase) inhibitor
        • Bempedoic acid
          • Bempedoic Acid Oral tablet; Adults: 180 mg PO once daily.
      • Bile acid sequestrants c141c142c143
        • Cholestyramine c144c145c146
          • Cholestyramine Powder for Oral suspension; Adults: 4 g PO 1 to 2 times daily, initially. Monitor lipid/lipoprotein concentrations at intervals of not less than every 4 weeks and adjust dose as needed. Usual dose: 4 to 8 g PO twice daily. May administer in 1 to 6 doses/day. Max: 24 g/day.
        • Colestipol c147c148c149
          • Colestipol Hydrochloride Oral tablet; Adults: 2 g PO 1 to 2 times daily, initially. Monitor lipid concentrations as clinically appropriate and adjust dose as needed. May increase dose by 2 to 4 g/day every 1 to 2 months. Max: 16 g/day.
        • Colesevelam c150c151c152
          • Colesevelam Hydrochloride Oral tablet; Adults: 1.875 g PO twice daily or 3.75 g PO once daily.
          • Colesevelam Hydrochloride Powder for Oral suspension; Adults: 3.75 g PO once daily.
      • Lomitapide c153
        • Lomitapide Oral capsule; Adults: 5 mg PO once daily, initially. May increase dose to 10 mg PO once daily after at least 2 weeks, then 20 mg PO once daily after at least 4 weeks, then 40 mg PO once daily after at least 4 weeks, then 60 mg PO once daily after at least 4 weeks. Measure transaminases prior to initiation of therapy and before any dose increase. Max: 60 mg/day. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
        • To reduce the risk of developing a fat-soluble nutrient deficiency, patients treated with lomitapide should take daily supplements containing 400 international units vitamin E and at least 200 mg linoleic acid, 210 mg ALA (alpha-linolenic acidA), 110 mg EPA (eicosapentaenoic acid), and 80 mg DHA (docosahexaenoic acid) r80
    • Fibric acid derivatives (fibrates)
      • Gemfibrozil c154
        • Gemfibrozil Oral tablet; Adults: 600 mg PO twice daily. Monitor lipid concentrations periodically. Discontinue gemfibrozil if lipid response is inadequate after 3 months of therapy.
      • Fenofibrate c155
        • Do not use fenofibrate if GFR is below 30 mL/minute
        • Monitor renal status before initiating fenofibrate, within 3 months after initiation, and every 6 months thereafter
        • Consider reducing dosage if serum lipid levels fall significantly below target goals
        • Fenofibrate tablet and capsule formulations are not bioequivalent
        • Lipofen capsules c156
          • Fenofibrate Oral capsule; Adults: 150 mg PO once daily. Consider dose reduction if lipid concentrations fall significantly below target range. Discontinue if lack of satisfactory response after 2 months. Max: 150 mg PO once daily.
        • Lofibra capsules c157
          • Fenofibrate, Micronized Oral capsule; Adults: 200 mg PO once daily. Consider dose reduction if lipid concentrations fall significantly below target range. Discontinue if lack of satisfactory response after 2 months. Max: 150 mg PO once daily.
        • Tricor tablets c158
          • Fenofibrate Oral tablet; Adults: 145 mg PO once daily. Consider dose reduction if lipid concentrations fall significantly below target range. Discontinue if lack of satisfactory response after 2 months. Max: 145 mg PO once daily.
    • ω-3 Polyunsaturated fatty acids (ie, ω-3 fatty acids, polyunsaturated fatty acids, fish oil) c159
      • Omega-3-Acid Ethyl Esters, Eicosapentaenoic Acid (EPA), Docosahexaenoic Acid (DHA) Oral capsule, liquid filled; Adults: 4 g PO once daily or 2 g PO twice daily.
    • Nicotinic acid r81c160
      • Niacin Oral tablet, extended-release; Adults: 500 mg PO once daily at bedtime for 4 weeks, then 1,000 mg PO once daily at bedtime for 4 weeks. May increase dose by 500 mg/day every 4 weeks if needed. Usual dose: 1,000 to 2,000 mg/day. Max: 2,000 mg/day.

    Nondrug and supportive care

    Lifestyle management to reduce cardiovascular risk

    • Recommended for all patients with dyslipidemia, regardless of whether these efforts are accompanied by drug therapy c161c162
      • Diet r41r82
        • Consume healthy diet that emphasizes vegetables, fruits, nuts, whole grains, lean vegetable or animal protein, and fish and minimizes trans fats, processed meats, refined carbohydrates, and sweetened beverages
        • Replace saturated fat with polyunsaturated and monounsaturated fats: reduce dietary cholesterol intake and avoid trans fat r41r83r84r85
        • Increase intake of fiber-rich foods r84
        • Consume minimally processed foods instead of ultra-processed foods r86
        • Aim for approximately 2 g/day of plant stanols/sterols and 10 to 25 g/day of soluble fiber for those who require additional lowering of LDL-C level r33
        • Adapt diet to patient's caloric requirements, cultural food preferences, and nutrition therapy for other medical conditions
        • Recommend moderation of alcohol consumption (up to 1 drink per day for females, up to 2 drinks per day for males) r87c163
      • Dietary supplements r46
        • Encourage daily consumption of whole foods such as nuts, legumes, oat cereal, psyllium, and foods supplemented with plant sterols or stanols: daily servings in combination can lower LDL-C equivalent to low-dose statin therapy
        • Several LDL-C–lowering nutraceuticals have been studied, including plant sterols or stanols, red yeast rice with monacolin K (a natural form of lovastatin), berberine, soy derivatives, and policosanol
          • Most evidence exists for plant sterols/stanols (2-3 g/day doses lower LDL-C by 9%-12%) and red yeast rice with monacolin K (3-10 mg/day doses lower LDL-C by 15%-25%)
          • Studies have not demonstrated benefit with regard to cardiovascular end points and there may be questions surrounding long-term safety and variable purity of some preparations
        • LDL-C–lowering nutraceuticals may have a role in the following: r46
          • Patients with only mild to moderately elevated LDL-C levels and low risk for cardiovascular disease who are not receiving pharmacologic therapy
          • Patients on statin therapy who are unwilling or unable to increase the statin dose or add nonstatin therapy to meet LDL-C targets
          • Patients who decline pharmacologic therapy
        • High-dose ω-3 fatty acids
          • Icosapent ethyl, a purified EPA (eicosapentaenoic acid) ethyl ester, lowered triglyceride levels and was associated with reduced cardiovascular events in one study; however, a study involving a different formulation of EPA plus DHA (docosahexaenoic acid) showed no cardiovascular benefit with a similar degree of triglyceride lowering r46
            • Both studies showed the incidence of atrial fibrillation was higher with ω-3 fatty acid treatment
          • Offer icosapent ethyl to patients receiving statins for secondary prevention who have fasting triglyceride levels persistently higher than 1.7 mmol/L (150 mg/dL) r20r88
      • Physical activity r41r89
        • Has greater impact on reducing triglyceride levels than on reducing LDL-C levels
        • Engage in at least 150 minutes per week of accumulated moderate-intensity physical activity or 75 minutes per week of vigorous-intensity physical activity r41
          • For adults unable to meet these physical activity recommendations, engaging in some moderate- or vigorous-intensity physical activity, even if less than this recommended amount, can be beneficial
      • Smoking cessation r41c164d3
      • Weight loss c165
        • Counsel adults with overweight or obesity; recommend that they restrict calories to aid weight loss r41
        • Sustained weight loss from 5% to 10% provides meaningful reduction of triglyceride level r90
        • Sustained weight loss of more than 10% improves LDL-C and HDL-C levels and reduces need for medication to control lipids r91
    • Use of OTC ω-3 polyunsaturated fatty acid supplements is not recommended to reduce risk of cardiovascular disease r92
    Procedures
    LDL apheresis c166
    General explanation
    • Selective removal of apolipoprotein B–containing lipoproteins from blood via extracorporeal LDL-C precipitation using heparin or dextran sulfate
    Indication r5
    • Coronary heart disease, severe hypercholesterolemia, and LDL-C level above 200 mg/dL despite tolerating maximum extent of drug therapy
    • No coronary heart disease, severe hypercholesterolemia, and LDL-C level above 300 mg/dL despite tolerating maximum extent of drug therapy
    Contraindications
    • Active infection
    • Hemodynamic instability
    • Thrombocytopenia
    Interpretation of results
    • Results in average LDL-C reduction of approximately 40% after 1 week r5
    • Observational studies suggest apheresis leads to reduction in major adverse coronary events r78

    Comorbidities

    • Other disorders associated with increased atherosclerotic cardiovascular disease risk that may affect treatment decisions include:
      • Diabetes mellitus c167
      • Hypertension c168
      • Obesity c169
      • Chronic kidney disease c170
      • Chronic inflammatory conditions c171

    Special populations

    • Patients with familial hypercholesterolemia r30
      • Are ideally managed in a lipid specialist center r93r94
      • Medications to reduce LDL-C and VLDL-C levels in homozygous familial hypercholesterolemia include statins, ezetimibe, PCSK9 inhibitors, evinacumab,r40 and lomitapider95
        • Guidelines recommend initial therapy with high intensity statins plus ezetimibe; most patients will require addition of a third agent (eg, PCSK9 inhibitor) to attain treatment goals r93r94
      • LDL-C–lowering dietary supplements may be helpful but do not replace pharmacotherapy r46
      • For patients with familial hypercholesterolemia and LDL-C levels 300 mg/dL or higher, despite maximal tolerated LDL-C–lowering therapy, consider initiating LDL apheresis r94
    • Patients with diabetes
      • Diabetes is designated a coronary heart disease risk equivalent;r96 suggested intensity of therapy for dyslipidemia is similar to that used for patients with established atherosclerotic cardiovascular disease
      • For patients aged 40 to 75 years without known atherosclerotic cardiovascular disease or additional atherosclerotic cardiovascular disease risk factors, use moderate-intensity statin therapy r1r34
        • High-intensity statin therapy to reduce LDL-C by 50% or more from baseline and to an LDL-C level of less than 70 mg/dL is recommended for those with additional atherosclerotic cardiovascular disease risk factors r34
          • It is reasonable to add a nonstatin agent (eg, ezetimibe or PCSK9 inhibitor) if LDL-C target levels below 70 mg/dL are not met with maximally tolerated statin therapy
      • For patients with known atherosclerotic cardiovascular disease, use high-intensity statin therapy to reduce LDL-C by 50% or more from baseline and to an LDL-C level of less than 55 mg/dL r34
        • Add a nonstatin agent (eg, ezetimibe or PCSK9 inhibitor) if LDL-C target levels are not met with maximally tolerated statin therapy
      • For adults aged 20 to 39 years, it may be reasonable to initiate statin therapy if any of the following risk-enhancing factors are present; moderate-intensity therapy is recommended r1
        • Long duration of diabetes mellitus: type 2, 10 years or more; type 1, 20 years or more
        • Albuminuria (30 mcg or more of albumin per milligram of creatinine)
        • Estimated GFR less than 60 mL/minute/1.73 m²
        • Retinopathy
        • Neuropathy
        • Ankle-brachial index lower than 0.9
      • For patients older than 75 years with diabetes and atherosclerotic cardiovascular disease, it is reasonable to continue high-intensity statins or highest-intensity statin tolerated after evaluation of net clinical benefit, potential adverse effects, and significant comorbidities potentially limiting life expectancy r97
      • For patients who are intolerant of high-intensity statin therapy, use a combination of moderate-intensity statin plus ezetimibe (a cholesterol absorption inhibitor)
        • Adding ezetimibe to simvastatin modestly reduces risk of cardiovascular events in secondary prevention, particularly for patients with type 2 diabetes
      • Fibrates and high-dose ω-3 fatty acids may be added for specific lipid profiles (ie, very-high triglyceride level, very-low HDL-C level)
      • American Association of Clinical Endocrinology guideline considers people with diabetes to be at high, very high, or extreme risk for arteriosclerotic cardiovascular disease; it sets treatment targets, according to risk level, for LDL-C, non–HDL-C, and apolipoprotein B levels r33
        • Treatment targets are defined by assessed atherosclerotic cardiovascular disease risk, as calculated by Framingham Risk Scorer35
        • Statin therapy is first line therapy
        • Can consider combination therapy to further lower LDL-C level even beyond established targets for patients with diabetes because they are considered high, very high, or extreme risk
    • Pregnant patients or those planning for pregnancy
      • Pregnant patients: advise to discontinue all lipid-lowering therapy, except bile acid sequestrants, immediately r38
      • Patients taking lipid-lowering drugs and planning to become pregnant: advise to discontinue those drugs, with exception of bile acid sequestrants, at least 1 month and preferably 3 months before attempting to become pregnant r38
      • Counsel patients who were using lipid-lowering therapy to treat clinical atherosclerotic cardiovascular disease or whose baseline LDL-C level is 190 mg/dL or higher about intensive lifestyle modifications; consider referring to lipid specialist r40
      • Monitor LDL-C levels throughout pregnancy in patients who were taking lipid-lowering drugs before pregnancy and have either diabetes or elevated 10-year atherosclerotic cardiovascular disease risk r40
      • Consider LDL apheresis for pregnant patients with homozygous or severe heterozygous familial hypercholesterolemia and LDL-C levels of 300 mg/dL or higher r40
      • Consider LDL apheresis for pregnant patients with familial hypercholesterolemia and atherosclerotic cardiovascular disease with LDL-C levels of 190 mg/dL or higher r40
      • After patients stop breastfeeding, they can resume statin and ezetimibe therapy r38
    • Patients with sitosterolemia r98
      • Rare autosomal recessive disorder caused by variants in either ABCG5 or ABCG8 genes
      • Characterized by increased intestinal absorption and decreased hepatic excretion of plant sterols, producing elevated serum levels of sitosterol and campersterol and premature atherosclerosis
      • First line therapy includes a plant sterol–restricted diet plus ezetimibe and/or bile acid sequestrants to inhibit intestinal absorption
    • Patients with history of stroke
      • Patients with history of ischemic stroke are at high risk because they have prevalent atherosclerotic cardiovascular disease
      • American Heart Association recommends high-intensity statin therapy for all patients with history of stroke; if LDL-C remains at 70 mg/dL or greater on maximally tolerated statin therapy, it may be reasonable to add ezetimibe and then a PCSK-9 inhibitor r99
        • Recommendations are based on results of 2 randomized controlled trials, SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Level) and TST (Treat Stroke to Target), which examined effects of lipid-lowering therapy in patients after ischemic stroke r100r101
        • Both trials found significant benefit from cholesterol-lowering therapy in preventing vascular events and confirmed superiority of LDL-C target less than 70 mg/dL

    Monitoring

    • Recommended intervals for follow-up lipid testing vary across professional society guidelines r102c172
    • American College of Cardiology/American Heart Association joint guidelines
      • Measure lipid profile 4 to 12 weeks after initiating statin therapy and every 3 to 12 months thereafter r1
        • Assess whether anticipated LDL-C level reduction has been achieved (30%-49% and 50% or more with moderate- and high-intensity statin therapy, respectively)
      • If treatment effect is judged inadequate, alter therapy to achieve desired percentage reduction of LDL-C levels r102
        • Reinforce lifestyle changes and medication use r40c173
        • Increase to high-intensity or maximally tolerated statin therapy, if not already taking r40
          • If additional LDL-C lowering is clinically indicated for patients at high or very high risk, consider adding nonstatin lipid-lowering therapy r40

    Complications and Prognosis

    Complications

    • Disease-associated complications
      • Atherosclerotic cardiovascular disease r103c174
        • Myocardial infarction c175
        • Stroke or transient ischemic attacks c176
      • Acute pancreatitis c177
        • Can occur with severe hypertriglyceridemia (level higher than 1000 mg/dL)
        • Patient presents with symptoms of abdominal pain, nausea, and vomiting
    • Statin-associated complications r54r55r104c178c179c180c181c182
      • Statin-associated myalgias
        • Occur in 3% to 5% of patients taking statins
        • Promptly discontinue statin and address possibility of rhabdomyolysis by measuring levels of creatine kinase, creatinine, and myoglobin
        • If muscle symptoms resolve and no contraindications are present, administer low dose of a different statin; when low dose is tolerated, gradually increase dose
      • Statin-associated myopathy
        • Occurs in 0.1% to 0.2% of patients
        • Defined by diffuse muscle symptoms (ie, myalgia, weakness, stiffness, cramps) that accompany elevation of plasma creatine kinase activity to 10 times higher than upper reference limit
      • Rhabdomyolysis d4
        • Rare, very serious adverse event occurring in 0.01% of patients; may result in arrhythmia, disseminated intravascular coagulation, or death r55
        • Defined as severe myonecrosis with myoglobinuria (reflecting acute kidney injury)
        • Marked elevation of creatine kinase level, greater than 10-fold r105
        • If condition is suspected, urgent evaluation in emergency department is indicated, and ICU admission may follow that
      • Hepatotoxicity
      • New-onset diabetes mellitus
        • Slightly increased risk of development of diabetes mellitus;r106r107 however, absolute risk is low, and benefits of statin therapy outweigh risk
      • Statin-associated autoimmune myopathy r1
        • Rare
      • Memory/cognitive effects r1c183
        • Rare

    Prognosis

    • Degree to which LDL-C levels are lowered with statins directly correlates with benefits achieved
    • Approximately 20% relative risk reduction in major vascular events per mmol/L reduction in LDL-C levels r58
    • 10% relative risk reduction in mortality (all causes) per mmol/L reduction in LDL-C levels r58

    Screening and Prevention

    Screening

    Screen to identify candidates who may benefit from lifestyle or pharmacologic interventions (lipid-lowering therapy) aimed at reducing cardiovascular risk

    American College of Cardiology/American Heart Association guideline recommends screening once every 4 to 6 years after age 20 years as part of overall cardiovascular risk assessment r1

    American Association of Clinical Endocrinology guideline recommends the following: r33

    • Screen male patients aged 20 to 45 years and female patients aged 20 to 55 years once every 5 years as part of overall risk assessment
    • Screen male patients aged 45 to 65 years and female patients aged 55 to 65 years every 1 to 2 years at minimum; screen patients more frequently if atherosclerotic cardiovascular disease risk factors are present
    • Annually screen male and female patients older than 65 years
    • Annually screen all patients with diabetes mellitus

    At-risk populations

    • Risk factors for atherosclerotic cardiovascular disease that affect recommended screening age or interval include the following:
      • Family history of premature cardiovascular disease (younger than 55 years in male relatives or younger than 65 years in female relatives) r108
      • Tobacco use
      • Diabetes mellitus
      • Hypertension
      • Obesity

    Screening tests

    • Measurement of either fasting or nonfasting plasma lipid profile is effective in estimating atherosclerotic cardiovascular disease risk and documenting baseline LDL-C for most patients r1
      • If initial nonfasting triglyceride level is 400 mg/dL or higher (4.5 mmol/L or higher), obtain lipid profile after 12-hour fast c184
      • If LDL-C level is lower than 70 mg/dL (lower than 1.8 mmol/L), measurement of direct LDL-C or modified LDL-C estimate may improve accuracy over Friedewald formula
    • Measurement of fasting plasma lipid profile is recommended for patients with family history of premature atherosclerotic cardiovascular disease or genetic hyperlipidemia r1

    Prevention r109

    • Maintain healthy weight c185
    • Engage in regular exercise c186
    • Consume diet low in saturated fat (less than 7% of total calories) r109c187
    • Limit alcohol; no more than 2 drinks per day for males and no more than 1 drink per day for females r110c188
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