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Dyslipidemia in Adults

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Synopsis
Terminology
Diagnosis
Treatment
Complications and Prognosis
Screening and Prevention

Dec.06.2023

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) ^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 ^r5
  - 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 ^c3^c4

Physical examination

Commonly there are no signs of dyslipidemia
Eyes
- Corneal arcus occurs in patients with familial and other types of hypercholesterolemia ^r6^c5
  - 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 ^r6^c10^c11^c12
- 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) ^c14^c15^c16
- 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 ^r7^r8^c18
    - 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 ^r9
  - Familial hypertriglyceridemia ^c25
  - Familial combined hyperlipidemia ^c26
  - Dysbetalipoproteinemia (from APOE variants) ^c27
  - Lipoprotein lipase deficiency (from LPL variants) ^c28
  - Apolipoprotein C2 deficiency (from APOC2 variants) ^c29
  - Apolipoprotein A5 deficiency (from APOA5 variants) ^c30
- Genetic causes of low HDL-C/apolipoprotein A1 ^r10
  - 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 ^c41^c42
Secondary causes of hypertriglyceridemia
- Diets very low in fat or with high proportion of refined carbohydrates ^c43^c44
- 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 ^c51^c52

Risk factors and/or associations

Age

Prevalence increases with age ^c53^c54

Genetics

Polygenic and/or epigenetic defects are most common ^r7^r8^c55
Inherited monogenic disorders are rare ^c56

Ethnicity/race

Prevalence is increased in racial and ethnic groups who adopt westernized lifestyle ^r11^c57

Other risk factors/associations

Drugs ^r12
- 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 ^c67^c68
- Some chemotherapy drugs (eg, asparaginase)
- Bile acid sequestrants (can worsen hypertriglyceridemia) ^r13
Dietary influences
- Fat intake above 40% of total calories ^r14^c69
- Saturated fat intake above 9% of total calories ^r14^c70
- Cholesterol intake higher than 300 mg/day ^r15^c71
- Excessive sugar and/or carbohydrate intake ^c72^c73
- 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 younger than 55 years and in female patients 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 ^r16
      - Thresholds in populations with Asian ethnicity are lower (90 cm or more for males and 80 cm or more for females) ^r16
    - 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) ^r17
  - 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 of 50 mg/dL or higher (125 nmol/L or higher)
      - 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
        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 ^r2^r19
    - 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 ^r19^r20
      - 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 ^c77^c78
- 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 ^r20^r21
  - 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; postulated by some to be better estimate of cardiovascular risk than LDL-C
High-sensitivity C-reactive protein test ^c79
- Marker for inflammation, which may contribute to atherosclerotic cardiovascular disease ^r23
- 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 ^r24
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 ^c84^d2
- 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 ^r25^c88
- 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 ^r26^r27

Other diagnostic tools

Several calculators of atherosclerotic risk are available ^r1^r28^c90
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) ^r1^r28
- Pooled cohort equations calculator assesses the following risk factors:
  - Age
  - Sex
  - Race
  - Cholesterol levels (total and HDL)
  - Systolic blood pressure level
  - Current medical treatment for hypertension
  - Diabetes diagnosis
  - Smoking status
Diagnosis of familial hypercholesterolemia
- Usually, but not always, characterized by: ^r6
  - Elevated LDL-C level ^c91^c92^c93
    - Suspect homozygous familial hypercholesterolemia if LDL-C level is above 400 mg/dL ^r6^r29^r30
    - Suspect heterozygous familial hypercholesterolemia if LDL-C level is 190 mg/dL or higher in adults or 160 mg/dL or higher in children ^r6^r29^r30
  - History of premature coronary artery disease ^c94^c95
  - 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 ^r1^r31^r32^r33

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,^r31 which sets specific targets for LDL-C levels as goals of therapy, depending on risk level calculated by Framingham risk score^r34 and National Lipid Association guideline^r35^r36^r37)

Extreme risk (American Association of Clinical Endocrinology guideline only): LDL-C levels below 55 mg/dL and non–HDL-C levels below 80 mg/dL
Very high risk: LDL-C levels below 70 mg/dL, non–HDL-C levels below 100 mg/dL
High risk: LDL-C levels below 100 mg/dL, non–HDL-C levels below 130 mg/dL
Moderate risk: LDL-C levels below 100 mg/dL, non–HDL-C levels below 130 mg/dL
Low risk: LDL-C levels below 130 mg/dL, non–HDL-C levels below 160 mg/dL

American Association of Clinical Endocrinology risk category stratification and treatment targets.
Risk category	Risk factors	Treatment target: LDL (mg/dL)	Treatment target: non–HDL-C (mg/dL)	Treatment target: apolipoprotein B (mg/dL)
Extreme	Progressive atherosclerotic cardiovascular disease, including unstable angina, after achieving LDL level lower than 70 mg/dL	Lower than 55	Lower than 80	Lower 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 high	Established or recent hospitalization for acute coronary syndrome or carotid or peripheral vascular disease	Lower than 70	Lower than 100	Lower than 80
	Diabetes or stage 3 or 4 chronic kidney disease with 1 or more risk factors
	Heterozygous familial hypercholesterolemia
High	2 or more risk factors and 10-year risk of 10% to 20%	Lower than 100	Lower than 130	Lower than 90
	Diabetes or stage 3 or 4 chronic kidney disease with no other risk factors
Moderate	2 or fewer risk factors and 10-year risk less than 10%	Lower than 100	Lower than 130	Lower than 90
Low	0 risk factors	Lower than 130	Lower than 160	Not 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: ^r38
- 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 ^r39
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 ^r39

Treatment Options

Encourage all patients with dyslipidemia to make healthy lifestyle changes to help reduce risk of atherosclerotic cardiovascular disease events ^r40

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 ^r1^r41

Statins are the therapy of choice to treat elevated LDL-C levels and for primary and secondary atherosclerotic cardiovascular disease prevention ^r1^r32^r42
- Statin therapy is associated with reduced risk of all-cause mortality, cardiovascular mortality, stroke, and myocardial infarction ^r43^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 of age 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 ^r39^r45^r46
        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 ^r45
      - 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 guidelines^r46
    - 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) ^r49
    - Evidence of net benefit is greatest for those with an estimated 10-year cardiovascular disease risk of 10% or more ^r49
    - 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 ^r49^r50^r51^r52
      - 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 ^r1^r19^r53
      - 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 ^r51^r54
  - Patients aged 40 to 75 years with diabetes without other atherosclerotic cardiovascular disease risk factors and LDL-C level less than 190 mg/dL ^r39
    - 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 ^r1^r55
    - 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: ^r56^r57
      - 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 ^r1^r39
- Nonstatin LDL-C–lowering agents include ezetimibe, PCSK9 inhibitors, inclisiran, evinacumab, bempedoic acid, and bile acid sequestrants ^r1^r39
  - 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 ^r58
    - The addition of these agents yielded little or no benefit among patients at moderate or low cardiovascular risk ^r59
- 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 ^r39
  - Intent is to provide interim recommendations while awaiting results of ongoing cardiovascular outcomes trials and their incorporation into evidence-based guidelines
- 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% ^r60
    - Indicated for patients who are intolerant of statins, those who require additional LDL-C lowering despite maximally tolerated statin therapy, and those who have sitosterolemia^r61
    - 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 ^r39^r46
  - PCSK9 inhibitors ^r62^r63^r64
    - 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%) ^r62^r64
      - Outcome data for cardiovascular events are focus of ongoing trials. One randomized trial has shown 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 ^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 ^r39
      - Effect on cardiovascular morbidity and mortality has not been determined
  - Evinacumab ^r39^r65^r66^r67
    - ANGPTL3 inhibitor (angiopoietin-like protein 3)
    - 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 ^r68
    - 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
  - Bile acid sequestrants ^r69
    - Promote LDL-C clearance from plasma but can increase serum triglyceride level
    - Effective in combination with statins or ezetimibe ^r70
    - 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 ^r13
  - 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) ^r71^c100
- May be combined with statins to reduce mixed dyslipidemia (ie, high LDL-C level, high triglyceride level, and low HDL-C level)^r72
- Avoid in combination with statins owing to increased risk of myopathy
ω-3 Polyunsaturated fatty acids (ie, ω-3 fatty acids, polyunsaturated fatty acids, fish oil)
- Effective at lowering fasting triglyceride levels ^r73
- 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 ^r74
- 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 statins^r75
- 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 ^r76^r77^r78

Drug therapy

Statins (hydroxymethylglutaryl-coenzyme A reductase inhibitors) ^c101

High-intensity statins^r79 (daily dose lowers LDL-C levels by 50% or more, on average) ^r1
- Atorvastatin ^c102^c103^c104
  - 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 ^c105^c106^c107
  - 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 ^c108^c109^c110
  - Atorvastatin Calcium Oral tablet; Adults: 10 or 20 mg PO once daily.
- Fluvastatin ^c111^c112^c113
  - 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 ^c115^c116^c117
  - Lovastatin Oral tablet; Adults: 40 or 80 mg PO once daily.
- Pitavastatin ^c118^c119^c120
  - Pitavastatin Calcium Oral tablet; Adults: 1 to 4 mg PO once daily.
- Pravastatin ^c121^c122^c123
  - Pravastatin Sodium Oral tablet; Adults: 40 or 80 mg PO once daily.
- Rosuvastatin ^c124^c125^c126
  - Rosuvastatin Calcium Oral tablet; Adults: 5 or 10 mg PO once daily.
- Simvastatin ^c127^c128^c129
  - 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.
Generic name	High intensity	Moderate intensity	Low intensity
Atorvastatin	40 to 80 mg	10 to 20 mg
Rosuvastatin	20 to 40 mg	5 to 10 mg
Simvastatin		20 to 40 mg	10 mg
Pravastatin		40 to 80 mg	10 to 20 mg
Lovastatin		40 to 80 mg	20 mg
Fluvastatin		80 mg daily (extended-release) or 40 mg twice daily	20 to 40 mg
Pitavastatin		1 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 ^c134^c135
    - 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 ^c136^c137
  - 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 ^c141^c142^c143
  - Cholestyramine ^c144^c145^c146
    - 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 ^c147^c148^c149
    - 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 ^c150^c151^c152
    - 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 ^r81^c160
- 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 ^c161^c162
- Diet ^r40^r82
  - 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 ^r40^r83^r84^r85
  - 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 ^r31
  - 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) ^r87^c163
- 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) ^r20^r88
- Physical activity ^r40^r89
  - 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 ^r40
    - 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 ^r40^c164^d3
- Weight loss ^c165
  - Counsel adults with overweight or obesity; recommend that they restrict calories to aid weight loss ^r40
  - 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 ^r6

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 ^r6
Observational studies suggest apheresis leads to reduction in major adverse coronary events ^r93

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
- Medications to reduce LDL-C and VLDL-C levels in homozygous familial hypercholesterolemia include statins, ezetimibe, PCSK9 inhibitors, evinacumab,^r39 and lomitapide^r94
- 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 referring to lipid specialist and initiating LDL apheresis
Patients with diabetes
- Diabetes is designated a coronary heart disease risk equivalent;^r95 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 ^r1^r96
  - 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 ^r96
    - 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 ^r96
  - 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 ^r31
  - Treatment targets are defined by assessed atherosclerotic cardiovascular disease risk, as calculated by Framingham Risk Score^r34
  - 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 ^r36
- 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 ^r36
- 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 ^r98
- 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 ^r98
- Consider LDL apheresis for pregnant patients with homozygous or severe heterozygous familial hypercholesterolemia and LDL-C levels of 300 mg/dL or higher ^r98
- After patients stop breastfeeding, they can resume statin and ezetimibe therapy ^r36
Patients with sitosterolemia
- Rare autosomal recessive disorder characterized by hyperabsorption of dietary sterols, high plant cholesterol levels (sitosterol and campesterol), and premature atherosclerosis
- Treatment of choice is dietary cholesterol restriction and ezetimibe, which reduces plant sterol concentrations by approximately 20% ^r61
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 ^r100^r101
  - 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 ^r102^c172
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 ^r98^c173
  - Increase to high-intensity or maximally tolerated statin therapy, if not already taking ^r98
    - If additional LDL-C lowering is clinically indicated for patients at high or very high risk, consider adding nonstatin lipid-lowering therapy ^r98

Complications and Prognosis

Complications

Disease-associated complications
- Atherosclerotic cardiovascular disease ^r103^c174
  - 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 ^r55^r56^r57^r104^c178^c179^c180^c181^c182
- 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 ^r56^r57
  - 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;^r106^r107 however, absolute risk is low, and benefits of statin therapy outweigh risk
- Statin-associated autoimmune myopathy ^r1
  - Rare
- Memory/cognitive effects ^r1^c183
  - 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 ^r60
10% relative risk reduction in mortality (all causes) per mmol/L reduction in LDL-C levels ^r60

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: ^r31

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 (BMI 18.5-24.9 kg/m²) ^r110^c185
Engage in regular exercise ^c186
Consume diet low in saturated fat (less than 7% of total calories) ^r109^c187
Limit alcohol; no more than 2 drinks per day for males and no more than 1 drink per day for females ^r111^c188

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Dyslipidemia in Adults

Synopsis

Key Points

Urgent Action

Pitfalls

Terminology

Clinical Clarification

Classification

Diagnosis

Clinical Presentation

History

Physical examination

Causes and Risk Factors

Causes

Risk factors and/or associations

Age

Genetics

Ethnicity/race

Other risk factors/associations

Diagnostic Procedures

Primary diagnostic tools r1

Laboratory

Imaging

Procedures

Ankle-brachial index c89

General explanation

Indication

Interpretation of results

Other diagnostic tools

Differential Diagnosis c98

Treatment

Goals

Disposition

Recommendations for specialist referral

Treatment Options

Drug therapy

Nondrug and supportive care

Procedures

LDL apheresis c166

Comorbidities

Special populations

Monitoring

Complications and Prognosis

Complications

Prognosis

Screening and Prevention

Screening

At-risk populations

Screening tests

Prevention r109

Primary diagnostic tools ^r1

Ankle-brachial index ^c89

Differential Diagnosis ^c98

LDL apheresis ^c166

Prevention ^r109