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    Dyslipidemia in Adults

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    Jul.25.2022

    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

    • 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 use bile acid sequestrants in 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 levels of HDL-C or apolipoprotein A1 levels (below 10th percentile) r2

    Classification

    • Can be classified according to Fredrickson classification scheme,r3 which follows traditional lipoprotein phenotype or primary or secondary causes
      • Fredrickson classification r3
        • 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 r4
        • 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, rarely can be seen in patients with severe hypertriglyceridemia c8
    • Skin
      • Xanthomas
        • Eruptive xanthoma, 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 also may 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 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 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
      • Anabolic steroids c58
      • Retinoids c59
      • Oral contraceptives c60
      • Corticosteroids c61
      • Thiazide diuretics c62
      • Protease inhibitors c63
      • β-blockers c64
      • Transplant immunosuppressive therapy (eg, sirolimus) c65
      • Antipsychotics c66
      • Raloxifene or tamoxifen c67c68
    • Dietary influences
      • Fat intake above 40% of total calories r11c69
      • Saturated fat intake above 9% of total calories r11c70
      • Cholesterol intake higher than 300 mg/day r12c71
      • 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 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 generally are used to define abdominal obesity in North America and Europe r13
            • Thresholds in populations with Asian ethnicity are lower (90 cm or more for males and 80 cm or more for females) r13
          • 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) r14
        • 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)
            • Relative indication for taking this measurement is family history of premature atherosclerotic cardiovascular disease
            • European 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 r15
          • 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 in patients with diabetes, metabolic syndrome, obesity, or very low LDL-C level r15
          • Ankle-brachial index less than 0.9
          • Elevated high-sensitivity C-reactive protein level of 2 mg/L or higher
          • Coronary artery calcium score r15r16
            • Can provide additional information to guide treatment decisions in low- to moderate-risk patients if need for treatment remains uncertain after initial evaluation
          • Arterial plaque burden on carotid and/or femoral arterial ultrasonography r15
            • Can provide additional information to guide treatment decisions in 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 r16r17
        • Fasting levels are preferred in patients with significant nonfasting hypertriglyceridemia
      • Calculated LDL-C levels r18
        • Laboratory reports estimated 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
    • High-sensitivity C-reactive protein test c79
      • 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 r19
    • 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 r20c88
      • 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 in patients already treated with statins r1
      • Score = 0: risk of atherosclerotic cardiovascular disease is low. It may be reasonable to withhold statin therapy except in 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 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 r21r22

    Other diagnostic tools

    • Several calculators of atherosclerotic risk are available r1r23c90
    • 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, to estimate 10-year atherosclerotic cardiovascular disease risk r23
      • 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: r5
        • Elevated LDL-C level c91c92c93
          • Suspect homozygous familial hypercholesterolemia if LDL-C level is above 400 mg/dL r5r24r25
          • Suspect heterozygous familial hypercholesterolemia if LDL-C levels are 190 mg/dL or higher in adults or 160 mg/dL or higher in children r5r24r25
        • 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 r1r26r27r28
      • 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,r27 which sets specific targets for LDL-C levels as goals of therapy, depending on risk level calculated by Framingham risk scorer29 and National Lipid Association guideliner30r31r32)
        • 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.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 of non–HDL-C levels (according to National Institute for Health and Care Excellence guidelines) r28
        • 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: r33
      • 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

    Treatment Options

    Encourage all patients with dyslipidemia to make healthy lifestyle changes to help reduce risk of atherosclerotic cardiovascular disease events r34

    • 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 r1r35

    • Statins r1r28r36
      • Therapy of choice to treat elevated LDL-C levels and prevent primary and secondary atherosclerotic cardiovascular disease
      • 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
      • Indicated for adults who fall into 1 or more of the following 4 groups that are proven to benefit from statins: r1
        • Patients with clinical atherosclerotic cardiovascular disease (secondary prevention)
          • 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
            • Use high-intensity or maximally tolerated statin therapy for patients who are aged 75 years or younger
              • For patients who are at very high risk, use maximally tolerated statin therapy plus ezetimibe
                • Very high risk patients include those with history of multiple major atherosclerotic cardiovascular disease events (eg, acute coronary syndrome, myocardial infarction or ischemic stroke, symptomatic peripheral artery disease) or 1 major atherosclerotic cardiovascular disease event and multiple high-risk conditions
              • May add PCSK9 inhibitor to treatment for patients who are very high risk and are taking maximally tolerated LDL-C–lowering medication if either of the following:
                • LDL-C level is 70 mg/dL or higher
                • Non–HDL-C level is 100 mg/dL or higher
              • Use moderate-intensity statin therapy if patient cannot receive high-intensity therapy
            • In 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 r37
              • 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 r37
        • Patients 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
          • Consider PCSK9 inhibitor for patients with multiple risk factors for atherosclerotic cardiovascular disease whose LDL-C remains 100 mg/dL or higher with maximally tolerated statin therapy and ezetimibe
        • Patients with diabetes who are aged 40 to 75 years with LDL-C levels 70 to 189 mg/dL
          • Use moderate- or high-intensity statin therapy, depending on risk
        • Patients aged 40 to 75 years with LDL-C levels 70 to 189 mg/dL who have an estimated 10-year atherosclerotic cardiovascular disease risk of 7.5% or greater
          • Initiate high-intensity statin therapy in 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 in 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, evidence for benefit of statins for primary prevention in patients older than 75 years has been more limited r38r39r40
            • Guidelines suggest that statin therapy is reasonable to consider for primary prevention of atherosclerotic cardiovascular disease in patients aged 75 years or older without life-limiting disease according to risk of atherosclerotic cardiovascular disease r1r15
            • Recent studies support use of statins for primary prevention in those aged 75 years or older, finding reduced risk of cardiovascular events, cardiovascular mortality, and all-cause mortality in these patients r38r41
    • Nonstatin drug therapy r1
      • Other LDL-C–lowering agents include ezetimibe, bile acid sequestrants, PCSK9 inhibitors, and monoclonal antibodies r1
        • Ezetimibe is most commonly used nonstatin agent
        • Consider bile acid sequestrants only in the following patients: r42
          • Those with severe hypercholesterolemia when they are unable to tolerate ezetimibe
          • Those with baseline LDL-C level of 190 mg/dL or higher who achieve less than 50% reduction in LDL-C levels and have fasting triglycerides 300 mg/dL or lower while taking maximally tolerated statin and ezetimibe therapy r1
        • Monoclonal antibody evinacumab shows promising results in treatment of severe hypercholesterolemia that is refractory to treatment with maximally tolerated statins, ezetimibe, and PCSK9 inhibitors; its long-term efficacy and safety have not been established r43r44r45
      • Nonstatin therapies have not been proven to directly reduce cardiovascular mortality when used for primary prevention and are not recommended in this population r16

    Management of hypertriglyceridemia

    • Address and treat the following: r1
      • Lifestyle factors
      • Obesity and metabolic syndrome
      • Secondary causes
        • Diabetes mellitus
        • Chronic liver disease
        • Chronic kidney disease
        • Hypothyroidism
      • Medications that increase triglycerides
        • Oral estrogens
        • Tamoxifen
        • Raloxifene
        • Retinoids
        • Cyclosporine
        • Sirolimus
        • Tacrolimus
        • β-blockers
        • Interferon
        • Atypical antipsychotic drugs
        • Protease inhibitors
        • Thiazide diuretics
        • Glucocorticoids
        • Rosiglitazone
        • Bile acid sequestrants
        • Asparaginase
        • Cyclophosphamide
    • Major medication classes used to treat hypertriglyceridemia are statins, fibrates, and ω-3 fatty acids; niacin is rarely used and should be avoided in those 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 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
    • 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

    Drug therapy

    • Statins (hydroxymethylglutaryl-CoA reductase inhibitors) c99
      • Therapy of choice for elevated LDL-C levels for most patients r1r35r46
        • Statin therapy is associated with reduced risk of all-cause mortality, cardiovascular mortality, stroke, and myocardial infarction r47r48
      • High-intensity statinsr49 (daily dose lowers LDL-C levels by 50% or more, on average) r1
        • Atorvastatin Calcium Oral tablet; Adults: 40 or 80 mg PO once daily. c100c101c102
        • Rosuvastatin Calcium Oral tablet; Adults: 20 or 40 mg PO once daily. c103c104c105
        • 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
      • Moderate-intensity statins (daily dose lowers LDL-C levels by 30%-49%, on average) r1
        • Atorvastatin Calcium Oral tablet; Adults: 10 or 20 mg PO once daily. c106c107c108
        • Rosuvastatin Calcium Oral tablet; Adults: 5 or 10 mg PO once daily. c109c110c111
        • Simvastatin Oral tablet; Adults: 20 or 40 mg PO once daily. c112c113c114
        • Pravastatin Sodium Oral tablet; Adults: 40 or 80 mg PO once daily. c115c116c117
        • Lovastatin Oral tablet; Adults: 40 or 80 mg PO once daily. c118c119c120
        • Fluvastatin Sodium Oral capsule; Adults: 40 mg PO twice daily. c121c122c123
        • Fluvastatin Sodium Oral tablet, extended-release; Adults: 80 mg PO once daily. c124
        • Pitavastatin Oral tablet; Adults: 1 to 4 mg PO once daily. c125c126c127
      • 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
        • Simvastatin Oral tablet; Adults: 10 mg PO once daily. c128
        • Pravastatin Sodium Oral tablet; Adults: 10 or 20 mg PO once daily. c129
        • Lovastatin Oral tablet; Adults: 20 mg PO once daily. c130
        • Fluvastatin Sodium Oral capsule; Adults: 20 or 40 mg PO once daily. c131
      • Statin safety recommendations r1r50
        • 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 upper reference limit
        • Use a moderate-intensity statin in patients for whom high-intensity statin would otherwise be recommended but who have any of the following characteristics, which predispose them to adverse effects: r51r52
          • 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 upper reference limit
          • Use of drugs that affect statin metabolism
          • Older than 75 years
      • Statin combination therapy
        • Several fixed-dose combinations are available
          • Atorvastatin plus ezetimibe c132c133
            • Ezetimibe, Atorvastatin Calcium Oral tablet; Adults: 10 mg ezetimibe/10 mg atorvastatin or 10 mg ezetimibe/20 mg atorvastatin PO once daily, initially, or 10 mg ezetimibe/40 mg atorvastatin 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 atorvastatin to 10 mg/day ezetimibe/80 mg/day atorvastatin. 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 (ezetimibe) c136c137
        • Block intestinal absorption of cholesterol by approximately 60% with subsequent mean reduction in LDL-C levels of approximately 18% r46
        • Indicated for patients who are intolerant of statins, those who require additional LDL-C lowering despite maximally tolerated statin therapy, or those who have sitosterolemiar53
        • Minimal effects on triglyceride or HDL levels
        • Ezetimibe
          • Ezetimibe Oral tablet; Adults: 10 mg PO once daily.
      • Proprotein convertase subtilisin/kexin type 9 (PCSK9) serine protease inhibitors c138
        • 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 in 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 in 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%) r54r55
          • 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, or coronary revascularization) when used as secondary prevention in persons with high risk who are already on lipid-lowering therapy r56
        • Evolocumab r54c139
          • Evolocumab Solution for injection; Adults: 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly.
        • Alirocumab r55c140
          • Alirocumab Solution for injection; Adults: 75 mg subcutaneously every 2 weeks or 300 mg subcutaneously every 4 weeks. Monitor LDL-C as clinically appropriate; the LDL-lowering effect may be measured as early as 4 weeks after starting therapy. Measure LDL-C just before next dose in patients receiving 300 mg subcutaneously every 4 weeks. May adjust dose to 150 mg subcutaneously every 2 weeks if response is inadequate.
      • Bile acid sequestrants r57r58
        • Promote LDL-C clearance from plasma but can increase serum triglyceride level
        • May be considered for pregnant patients with severe hypercholesterolemia, although most experts do not recommend use of any cholesterol-lowering drug therapy during pregnancy c141c142c143
        • Effective in combination with statins or ezetimibe r59
        • Use alone for patients with statin intolerance, or use in combination with statin for patients with severe hypercholesterolemia c144
        • Gastrointestinal adverse effects of constipation and bloating are common
        • Options include:
          • Cholestyramine c145c146c147
            • 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 c148c149c150
            • 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.
            • Colestipol Hydrochloride Oral suspension; Adults: 5 g PO 1 to 2 times daily, initially. Monitor lipid concentrations as clinically appropriate and adjust dose as needed. May increase dose by 5 g/day every 1 to 2 months. Max: 30 g/day.
          • Colesevelam c151c152c153
            • 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.
    • Fibric acid derivatives (fibrates)
      • First line therapy for severe hypertriglyceridemia (triglycerides higher than 500 mg/dL) r60c154
      • May be combined with statins to reduce mixed dyslipidemia (ie, high LDL-C level, high triglyceride level, and low HDL-C level)r61
      • Options include:
        • Gemfibrozil c155
          • 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.
          • Avoid in combination with statins owing to increased risk of myopathy
        • Fenofibrate c156
          • Do not use fenofibrate if GFR level 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 concentrations fall significantly below target goals
          • Fenofibrate tablet and capsule formulations are not bioequivalent
            • Lipofen capsules c157
              • Fenofibrate Oral capsule; Adults: 150 mg PO once daily. Monitor lipid concentrations periodically to establish the lowest effective dose; consider reducing dose if lipid concentrations fall significantly below target range. Discontinue therapy in patients who do not have a satisfactory response after 2 months with 150 mg/day.
            • Tricor tablets c158
              • Fenofibrate Oral tablet; Adults: 145 mg PO once daily. Monitor lipid concentrations periodically to establish the lowest effective dose; consider reducing dose if lipid concentrations fall significantly below target range. Discontinue therapy in patients who do not have a satisfactory response after 2 months with 145 mg/day.
            • Lofibra capsules c159
              • Fenofibrate, Micronized Oral capsule; Adults: 200 mg PO once daily. Monitor lipid concentrations periodically to establish the lowest effective dose; consider reducing dose if lipid concentrations fall significantly below target range. Discontinue therapy in patients who do not have a satisfactory response after 2 months with 200 mg/day.
              • Fenofibrate, Micronized Oral capsule; Geriatric: 67 mg PO once daily, initially. Monitor lipid concentrations periodically and adjust dose if needed; consider reducing dose if lipid concentrations fall significantly below target range. Max: 200 mg/day. Discontinue therapy in patients who do not have a satisfactory response after 2 months with 200 mg/day.
    • ω-3 polyunsaturated fatty acids (ie, ω-3 fatty acids, polyunsaturated fatty acids, fish oil) c160
      • Effective at lowering fasting triglyceride levels r62
      • 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
        • 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 r63c161
      • Effective in lowering both LDL-C and triglyceride levels r64
      • 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 statinsr65
      • 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 r66r67r68
      • 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.
    • Medications to reduce LDL-C and VLDL-C levels in homozygous familial hypercholesterolemia
      • Lomitapide c162
        • Small molecule inhibitor of microsomal triglyceride transfer protein
        • 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 alpha-linolenic acid (ALA), 110 mg eicosapentaenoic acid (EPA), and 80 mg docosahexaenoic acid (DHA). r69

    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 c163c164
      • Diet r34
        • 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
        • Replacing saturated fat with polyunsaturated and possibly monounsaturated fats may help lower risk of cardiovascular disease r70r71
        • 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 r27
        • Adapt diet to patient 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) r72c165
        • Offer icosapent ethyl to patients receiving statins for secondary prevention who have fasting triglyceride levels persistently greater than 1.7 mmol/L (150 mg/dL) r16r73
      • Physical activity r34r74
        • 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 r34
          • 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 r34c166d3
      • Weight loss c167
        • Counsel adults who are overweight or obese; recommend that they restrict calories to aid weight loss r34
        • Sustained weight loss from 5% to 10% provides meaningful reduction of triglyceride level r75
        • Sustained weight loss of more than 10% improves LDL-C and HDL-C levels and reduces need for medication to control lipids r76
    • Use of OTC ω-3 polyunsaturated fatty acid supplements is not recommended to reduce risk for cardiovascular disease r77
    Procedures
    LDL apheresis c168
    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 risk that may affect treatment decisions include:
      • Diabetes mellitus c169
      • Hypertension c170
      • Obesity c171
      • Chronic kidney disease c172
      • Chronic inflammatory conditions c173

    Special populations

    • Patients with familial hypercholesterolemia r25
      • Medications to reduce LDL-C and VLDL-C levels in homozygous familial hypercholesterolemia include statins, ezetimibe, PCSK9 inhibitors, and lomitapider79
      • 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
      • Designated a coronary heart disease risk equivalent;r80 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 atherosclerotic cardiovascular disease, use moderate-intensity statin therapy r1r26
        • May consider high-intensity therapy for those with additional atherosclerotic cardiovascular disease risk factors or calculated 10-year atherosclerotic cardiovascular disease risk of 20% or more using the pooled cohort equations
      • In patients with known atherosclerotic cardiovascular disease, use high-intensity statin therapy
        • Consider adding 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 r26r81
      • In 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 r82
      • In 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 in 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 r27
        • Treatment targets are defined by assessed atherosclerotic cardiovascular disease risk, as calculated by Framingham Risk Scorer29
        • 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 at 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 r31
      • 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 r31
      • 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 r81
      • 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 r81
      • Consider LDL apheresis in pregnant patients with homozygous or severe heterozygous familial hypercholesterolemia and LDL-C levels of 300 mg/dL or higher r81
      • After patients stop breastfeeding, they can resume statin and ezetimibe therapy r31
    • 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% r53
    • 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 with LDL-C target of 70 mg/dL or greater r83
        • Recommendations are based upon results of 2 randomized controlled trials, SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Level) and TST (Treat Stroke to Target), that examined effects of lipid-lowering therapy in patients after ischemic stroke r84r85
        • 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 r86c174
    • American College of Cardiology/American Heart Association joint guidelines
      • Measure lipid profile 4 to 12 weeks after initiating statin 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 r86
        • Reinforce lifestyle changes and medication use r81c175
        • Increase to high-intensity or maximally tolerated statin therapy, if not already taking r81
          • If additional LDL-C lowering is clinically indicated in high or very high risk patients, consider adding nonstatin lipid-lowering therapy r81

    Complications and Prognosis

    Complications

    • Disease-associated complications
      • Atherosclerotic cardiovascular disease r87c176
        • Myocardial infarction c177
        • Stroke or transient ischemic attacks c178
      • Acute pancreatitis c179
        • Can occur with severe hypertriglyceridemia (level higher than 1000 mg/dL)
        • Patient presents with symptoms of abdominal pain, nausea, and vomiting
    • Statin-associated complications r50r51r52r88c180c181c182c183c184
      • 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 myoglobinuria
        • 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% patients; may result in arrhythmia, disseminated intravascular coagulation, or death r51r52
        • Defined as severe myonecrosis with myoglobinuria (reflecting acute kidney injury)
        • Marked elevation of creatine kinase level, greater than 10-fold r89
        • 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;r90r91 however, absolute risk is low and benefits of statin therapy outweigh risk
      • Statin-associated autoimmune myopathy r1
        • Rare
      • Memory/cognitive effects r1c185
        • 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 r46
    • 10% relative risk reduction in mortality (all causes) per mmol/L reduction in LDL-C levels r46

    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: r27

    • 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) r92
      • 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 in 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 c186
      • 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 r93

    • Maintain healthy weight (BMI 18.5-24.9 kg/m²) r94c187
    • Engage in regular exercise c188
    • Consume diet low in saturated fat (less than 7% of total calories) r93c189
    • Limit alcohol; no more than 2 drinks per day for males and no more than 1 drink per day for females r95c190
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