Dyslipidemia

General Principles

  • Lipids are sparingly soluble macromolecules that include cholesterol, fatty acids, and their derivatives.
  • Plasma lipids are transported by lipoprotein particles composed of apolipoproteins, phospholipids, free cholesterol, cholesterol esters, and triglycerides.
  • Human plasma lipoproteins are separated into five major classes based on density:
    • Chylomicrons (least dense)
    • Very-low-density lipoproteins (VLDLs)
    • Intermediate-density lipoproteins
    • LDLs
    • HDLs
  • A sixth class, lipoprotein(a) [Lp(a)], resembles LDL in lipid composition and has a density that overlaps LDL and HDL.
  • Physical properties of plasma lipoproteins are summarized in Table 3-6.
    Table 3-6: Physical Properties of Plasma Lipoproteinsa
    LipoproteinLipid CompositionOriginApolipoproteins
    ChylomicronsTG, 85%; chol, 3%IntestineA-I, A-IV; B-48; C-I, C-II, C-III; E
    VLDLTG, 55%; chol, 20%LiverB-100; C-I, C-II, C-III; E
    IDLTG, 25%; chol, 35%Metabolic product of VLDLB-100; C-I, C-II, C-III; E
    LDLTG, 5%; chol, 60%Metabolic product of IDLB-100
    HDLTG, 5%; chol, 20%Liver, intestineA-I, A-II; C-I, C-II, C-III; E
    Lp(a)TG, 5%; chol, 60%LiverB-100; Apo(a)

    aRemainder of particle is composed of phospholipid and protein.

    Chol, cholesterol; HDL, high-density lipoprotein; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); TG, triglyceride; VLDL, very-low-
density lipoprotein.

  • Nearly 90% of patients with CHD have some form of dyslipidemia. Increased levels of LDL cholesterol (LDL-C), remnant lipoproteins, and Lp(a) and decreased levels of HDL cholesterol have all been associated with an increased risk of premature vascular disease.1,2 In addition, dyslipidemia is highly prevalent in children with nonalcoholic fatty liver disease and may play a role in its pathophysiology.3
  • Clinical dyslipoproteinemias
    • Most dyslipidemias are multifactorial in etiology and reflect the effects of genetic influences coupled with diet, inactivity, smoking, alcohol use, and comorbid conditions such as obesity and DM.
    • Differential diagnosis of the major lipid abnormalities is summarized in Table 3-7.
      Table 3-7: Differential Diagnosis of Major Lipid Abnormalities
      Lipid AbnormalityPrimary DisordersSecondary Disorders
      HypercholesterolemiaPolygenic, familial hypercholesterolemia, familial defective apo B-100; PCSK9 gain of function mutationHypothyroidism, nephrotic syndrome, anorexia nervosa
      HypertriglyceridemiaLipoprotein lipase deficiency, apo C-II deficiency, apo A-V deficiency, familial hypertriglyceridemia, dysbetalipoproteinemiaDiabetes mellitus, obesity, metabolic syndrome, alcohol use, oral estrogen, renal failure, hypothyroidism, retinoic acid, lipodystrophies
      Combined hyperlipidemiaFamilial combined hyperlipidemia, dysbetalipoproteinemiaDiabetes mellitus, obesity, metabolic syndrome, nephrotic syndrome, hypothyroidism, lipodystrophies
      Low HDLFamilial hypoalphalipoproteinemia, Tangier disease (ABCA1 deficiency), apoA1 mutations, lecithin–cholesterol acyltransferase deficiencyDiabetes mellitus, obesity, metabolic syndrome, hypertriglyceridemia, smoking, anabolic steroids

      apo, apolipoprotein; HDL, high-density lipoprotein.

    • The major genetic dyslipoproteinemias are reviewed in Table 3-8.4,5
      • Familial hypercholesterolemia (FH) and familial combined hyperlipidemia are disorders that contribute significantly to premature CVD.
        Table 3-8: Review of Major Genetic Dyslipoproteinemias
        Type of Genetic DyslipidemiaTypical Lipid ProfileType of Inheritance PatternPhenotypic FeaturesOther Information
        Familial hypercholesterolemia
        • Increased LDL cholesterol (>190 mg/dL)
        • Homozygous form or compound heterozygous form (rare) can have LDL cholesterol >500 mg/dL
        Autosomal dominant (prevalence of 1 in 200–250 for heterozygote form and 1 in 250,000 for homozygous form)
        • Premature CAD
        • Tendon xanthomas
        • Premature arcus corneae (full arc before age 40)
        • Homozygous form: planar and tendon xanthomas and CAD in childhood and adolescence
        Mutations of the LDL receptor, apolipoprotein B-100, and gain-of-function mutations of proprotein convertase/kexin subtype 9 (PCSK9) lead to impaired uptake and degradation of LDL
        Familial combined hyperlipidemia
        • High levels of VLDL, LDL, or both
        • LDL apo B-100 level >130 mg/dL
        Autosomal dominant (prevalence of 1–2%)
        • Premature CAD
        • Patients do not develop tendon xanthomas
        Genetic and metabolic defects are not established
        Familial dysbetalipoproteinemia
        • Symmetric elevations of cholesterol and triglycerides (300–500 mg/dL)
        • Elevated VLDL-to-triglyceride ratio (>0.3)
        Autosomal recessive
        • Premature CAD
        • Tuberous or tuberoeruptive xanthomas
        • Planar xanthomas of the palmar creases are essentially pathognomonic
        Mutation of ApoE gene
        Many homozygotes are normolipidemic, and emergence of hyperlipidemia often requires a secondary metabolic factor such as diabetes mellitus, hypothyroidism, or obesity
        Familial hypertriglyceridemia (can result in chylomicronemia syndrome)
        • Most patients have triglyceride levels in the range of 150–500 mg/dL
        • Clinical manifestations may occur when triglyceride levels exceed 1500 mg/dL
        • Familial hypertriglyceridemia is an autosomal dominant disorder caused by overproduction of VLDL triglycerides and manifests in adults
        • Eruptive xanthomas
        • Lipemia retinalis
        • Pancreatitis
        • Hepatosplenomegaly
        Patients may develop the chylomicronemia syndrome in the presence of secondary factors such as obesity, alcohol use, or diabetes
        Familial hyperchylomicronemia
        • Similar to familial hypertriglyceridemia
        • Onset before puberty indicates deficiency of lipoprotein lipase or apo C-II, both autosomal recessive
        • Similar to familial hypertriglyceridemia
        Homozygosity for mutations in apoAV, LMF, and GHIHBP1 also found (rare)

        CAD, coronary artery disease; GHIHBP1, glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein.

      • FH is an underdiagnosed, autosomal co-dominant condition with a prevalence of approximately 1 in 200 people that causes elevated LDL-C levels from birth.5,6 It is associated with significantly increased risk of early CVD.7
      • Familial combined hyperlipidemia has a prevalence of 1%–2% and typically presents in adulthood, although obesity and high dietary fat and sugar intake have led to increased presentation in childhood and adolescence.8
  • Standards of care for hyperlipidemia
    • LDL-C–lowering therapy, particularly with hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (commonly referred to as statins), lowers the risk of CHD-related death, morbidity, and revascularization procedures in patients with (secondary prevention) or without (primary prevention) known CHD.9,10,11,12,13,14,15,16 LDL lowering therapy has proven beneficial even in patients at low risk for vascular disease.17
    • Prevention of ASCVD is the primary goal of the 2018 ACC/AHA guidelines. These guidelines address risk assessment, lifestyle modifications, evaluation and treatment of obesity, and evaluation and management of blood cholesterol and aim for a more personalized and shared decision-making approach to risk management.18

Screening

  • Screening for hypercholesterolemia should be done in all adults age 20 years or older.18
  • Screening is best performed with a lipid profile (total cholesterol, LDL-C, HDL cholesterol, and triglycerides) obtained after a 12-hour fast.
  • If a fasting lipid panel cannot be obtained, total and HDL cholesterol should be measured. Non-HDL cholesterol ≥220 mg/dL may indicate a genetic or secondary cause. A fasting lipid panel is required if non-HDL cholesterol is ≥220 mg/dL or triglycerides are ≥500 mg/dL.
  • If the patient does not have an indication for LDL-lowering therapy, screening can be performed every 4–6 years between ages 40 and 75.18
  • Patients hospitalized for an acute coronary syndrome or coronary revascularization should have a lipid panel obtained within 24 hours of admission if lipid levels are unknown.
  • Individuals with hyperlipidemia should be evaluated for potential secondary causes, including hypothyroidism, DM, obstructive liver disease, chronic renal disease such as nephrotic syndrome, and medications such as estrogens, progestins, anabolic steroids/androgens, corticosteroids, cyclosporine, retinoids, atypical antipsychotics, and antiretrovirals (particularly protease inhibitors).

Risk Assessment

  • The 2018 guidelines emphasize risk stratification based on predicted future risk, with further stratification using risk-enhancing factors to identify groups in whom the benefits of LDL-C–lowering therapy with HMG-CoA reductase inhibitors (statins) clearly outweigh the risks and to aim for certain goals in the reduction of LDL-C. A key observation is that the more LDL-C is reduced, the greater the subsequent risk reduction.18

    In all individuals, a heart healthy lifestyle should be encouraged as it reduces ASCVD risk at all ages.

  • Areas in which treatment with statin therapy is recommended:
    • Patients with clinical ASCVD
    • Patients with LDL-C ≥190 mg/dL
    • Patients with DM age 40–75
    • Patients age 40–75 with a calculated ASCVD risk ≥7.5% if a discussion of treatment options favors statin therapy.
  • For patients without clinical ASCVD or an LDL-C ≥190 mg/dL, the guidelines advise having a clinician–patient risk discussion before starting statin therapy. This includes calculating a patient’s risk for ASCVD based on age, sex, ethnicity, total and HDL cholesterol, SBP (treated or untreated), presence of DM, and current smoking status in addition to the presence of risk-enhancing factors.18
  • The ACC/AHA risk calculator is available at tools.acc.org/ASCVD-Risk-Estimator-Plus/.
    • For patients of ethnicities other than African American or non-Hispanic white, risk cannot be well assessed with the risk calculator. Use of the non-Hispanic white risk calculation is suggested, with the understanding that risk may be lower than calculated in East Asian Americans and Hispanic Americans and higher in American Indians and South Asians.
    • Ten-year risk should be calculated beginning at age 40 in patients without ASCVD or LDL-C ≥190 mg/dL.
    • Lifetime risk may be calculated in patients age 20–39 and patients age 40–59 with a 10-year risk <7.5% to inform decisions regarding lifestyle modification.

Treatment

  • The 2018 guidelines recognize lifestyle factors, including diet and weight management as an important component of risk reduction for all patients.18
  • Patients should be advised to adopt a diet that is high in fruits and vegetables, whole grains, fish, lean meat, low-fat dairy, legumes, and nuts, with lower intake of red meat, saturated and trans fats, sweets, and sugary beverages (Table 3-9). Saturated fat should comprise no more than 5%–6% of total calories.19
    Table 3-9: Nutrient Composition of the Therapeutic Lifestyle Change Diet
    NutrientRecommended Intake
    Saturated fata<5%–6% of total calories
    Polyunsaturated fatUp to 10% of total calories
    Monounsaturated fatUp to 20% of total calories
    Total fat25%–35% of total calories
    Carbohydrateb50%–60% of total calories
    Fiber20–30 g/d
    ProteinApproximately 15% of total calories
    Cholesterol<200 mg/d
    Total calories (energy)cBalance energy intake and expenditure to maintain desirable body weight/prevent weight gain

    aTrans fatty acids are another low-density lipoprotein–raising fat that should be kept at a low intake.

    bCarbohydrates should be derived predominantly from foods rich in complex carbohydrates, including grains (especially whole grains), fruits, and vegetables.

    cDaily energy expenditure should include at least moderate physical activity (contributing approximately 200 kcal/d).

  • Efforts should be made to replace dietary saturated fat with polyunsaturated and monounsaturated fats, as this has been shown to lower LDL-C and triglycerides. Polyunsaturated fat intake has been shown to promote atherosclerosis regression.20
  • Physical activity, including aerobic and resistance exercise, is recommended in all patients.19
  • For all obese patients (body mass index ≥30) and for overweight patients (body mass index ≥25) who have additional risk factors, sustained weight loss of 3%–5% or greater reduces ASCVD risk.20
  • Consultation with a registered dietitian nutritionist may be helpful to plan, start, and maintain a saturated fat–restricted and weight loss–promoting diet.
  • Prior to the start of treatment, there should be a risk discussion between the patient and the clinician. Topics for discussion include the following:
    • Potential for ASCVD risk reduction benefits
    • Potential for adverse effects and drug–drug interactions
    • Heart healthy lifestyle and management of other risk factors
    • Patient preferences
  • Clinical ASCVD
    • Clinical ASCVD includes acute coronary syndromes, history of MI, stable angina, arterial revascularization (coronary or otherwise), stroke, transient ischemic attack, or atherosclerotic peripheral arterial disease.
    • Secondary prevention is an indication for high-intensity statin therapy, which has been shown to reduce events more than moderate-intensity statin therapy. Statin regimens are listed in Table 3-10. Goal is reduction of LDL-C by >50%.
    • If high-dose statin therapy is contraindicated or poorly tolerated or there are significant risks to high-intensity therapy (including age >75 years), the maximally tolerated statin therapy is an option.
    • In very-high-risk ASCVD, use a LDL-C threshold of 70 mg/dL (1.8 mmol/L) to consider addition of nonstatins to statin therapy. If proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor is considered, add ezetimibe to maximal statin before adding PCSK9 inhibitor. Very high-risk ASCVD includes a history of multiple major ASCVD events or one major ASCVD event and multiple high-risk conditions (major ASCVD events are recent ACS [past 12 months], history of MI, history of ischemic stroke, symptomatic peripheral arterial disease).
    • High-risk conditions include age >65 years, heterozygous FH, history of prior coronary bypass surgery or percutaneous intervention outside the major ASCVD event, DM, hypertension, CKD (eGFR 15–59 mL/min/1.73 m), current smoking, persistently elevated LDL-C (>100 mg/dL) despite maximally tolerated statin therapy and ezetimibe, history of CHF.
  • LDL-C ≥190 mg/dL
    • These individuals have elevated lifetime risk because of long-term exposure to very high LDL-C levels, and the risk calculator does not account for this.
    • LDL-C should be reduced with high-intensity statin therapy. If high-intensity therapy is not tolerated, maximum tolerated intensity should be used.
    • If LDL-C on statin therapy remains >100 mg/dL (>2.6 mmol/L), adding ezetimibe is reasonable.
    • If the LDL-C level on statin plus ezetimibe remains >100 mg/dL (>2.6 mmol/L) and the patient has multiple factors that increase subsequent risk of ASCVD event, a PCSK9 inhibitor may be considered, although the long-term safety (>3 years) is uncertain.
    • LDL apheresis is an optional therapy in patients with homozygous FH and those with severe heterozygous FH with insufficient response to medication. Lomitapide, a microsomal triglyceride transfer protein inhibitor, and mipomersen, an apolipoprotein B antisense oligonucleotide, are medications indicated for the treatment of patients with homozygous FH.5
    • Because hyperlipidemia of this degree is often genetically determined, discuss screening of other family members (including children) to identify candidates for treatment. In addition, screen for and treat secondary causes of hyperlipidemia.6
  • Patients with diabetes, aged 40–75, LDL-C >70 mg/dL
    • Moderate-intensity statin therapy is indicated regardless of estimated 10-year ASCVD risk.
    • In patients with DM at higher risk, especially those with multiple risk factors or those aged 50–75, it is reasonable to use a high-intensity statin to reduce the LDL-C by >50%.
    • It is reasonable to assess the 10-year ASCVD risk and in adults with DM2 who have multiple ASCVD risk factors; it is reasonable to prescribe high-intensity statin therapy with the aim to reduce LDL-C levels by 50% or more.
    • Diabetes-specific risk enhancers: long duration (>10 years for DM2 or >20 years for DM1), albuminuria (>30 mcg of albumin/mg creatinine), eGFR <60 mL/min/1.73 m, retinopathy, neuropathy, ankle-brachial index (ABI) <0.9.
    • In adults with DM and 10-year ASCVD risk of 20% or higher, it may be reasonable to add ezetimibe to maximally tolerated statin therapy to reduce LDL-C by 50% or more.
    • In adults 20–39 years with DM that is of long duration (>10 years of DM2 or >20 years of DM1), albuminuria, eGFR <60 mL/min/1.73 m, retinopathy, neuropathy, or ABI (<0.9), it may be reasonable to initiate statin therapy.
  • Patients without diabetes, aged 40–75, LDL-C between 70 and 189 mg/dL
    • Using the AHA/ACC risk calculator, calculate 10-year risk of an ASCVD event in these patients (categories: >20%, ≥7.5%–<20%, 5.0%–7.5%, and <5.0%).
    • A 10-year risk ≥7.5%–<20% is an indication for moderate-intensity statin if a discussion of options favors statin therapy. Risk-enhancing factors favor statin therapy.
    • Risk-enhancing factors include family history of premature ASCVD, persistently elevated LDL-C levels (>160 mg/dL), metabolic syndrome, chronic kidney disease, history of pre-eclampsia or premature menopause (<40 years), chronic inflammatory disorders (e.g., rheumatoid arthritis, psoriasis, or chronic HIV), high-risk ethnic groups (e.g., South Asian), persistent elevations of triglycerides >175 mg/dL, and, if measured in selected individuals, apolipoprotein B >130 mg/dL, high-sensitivity C-reactive protein >2.0 mg/L, ABI <0.9, and lipoprotein (a) >50 mg/dL or 125 nmol/L.
    • If statins are indicated, reduce LDL-C levels by 30%, and if 10-year risk is >20%, reduce LDL-C levels by 50%.
    • In intermediate-risk adults in whom high-intensity statins are advisable to reach goal reduction, but not acceptable or tolerated, it is reasonable to add a nonstatin drug (ezetimibe or bile acid sequestrant) to moderate-intensity statin.
    • A 10-year risk of >20% favors initiating statin therapy.
    • A 10-year risk between 5.0% and 7.5% and risk-enhancing factors may favor moderate-intensity statin therapy.
  • Other patient populations
    • If a 10-year ASCVD risk is >7.5%–19.9% and decision about statin therapy is uncertain, consider measuring coronary artery calcium (CAC) to help identify risk. If the CAC is zero, it is reasonable to withhold statin therapy and reassess in 5–10 years, as long as higher risk conditions are absent. If CAC score is 1–99, it is reasonable to initiate statin therapy for patients >55 years. If CAC score is >100 and/or greater than 75th percentile, it is reasonable to initiate statin therapy.
    • Patients with stage 3–5 CKD are high risk for ASCVD21 and the use of LDL-lowering therapy is indicated in patients with nondialysis-dependent CKD.22
    • Use of statin therapy should be individualized for patients older than 75. In randomized controlled trials, patients older than 75 continued to have benefit from statin therapy, particularly for secondary prevention.12,23 In addition, many ASCVD events occur in this age group, and patients without other comorbidities may benefit substantially from cardiovascular risk reduction.
    • In adults >75 years it may be reasonable to stop statin therapy when functional decline (physical or cognitive), multimorbidity, frailty, or reduced life expectancy limits the potential benefits of statin therapy.
    • In adults with advanced kidney disease that requires dialysis treatment who are currently on LDL-lowering therapy with a statin, it may be reasonable to continue the statin.
    • In adults with advanced kidney disease who require dialysis treatment, initiation of a statin is not recommended.
    • In patients with HF with reduced ejection fraction attributable to ischemic heart disease who have a reasonable life expectancy (3–5 years) and are not already on a statin because of ASCVD, clinicians may consider initiation of moderate-intensity statin therapy to reduce the occurrence of ASCVD events.18
  • Treatment beyond statin therapy
    • When statins are insufficient for LDL-C reduction, further therapy with nonstatins may be indicated. This would generally include ezetimibe, bile acid sequestrants, and PCSK9 monoclonal antibodies.24
  • Hypertriglyceridemia
    • Hypertriglyceridemia may be an independent cardiovascular risk factor.4,25,26,27
    • Hypertriglyceridemia is often observed in the metabolic syndrome,27 and there are many potential etiologies for hypertriglyceridemia, including obesity, DM, renal insufficiency, genetic dyslipidemias, and therapy with oral estrogen, glucocorticoids, β-blockers, tamoxifen, cyclosporine, antiretrovirals, and retinoids.
    • The classification of serum triglyceride levels is as follows: normal: <150 mg/dL; borderline high: 150–199 mg/dL; high: 200–499 mg/dL; and very high: ≥500 mg/dL.27 The Endocrine Society has added two further categories: severe: 1000–1999 mg/dL (greatly increases the risk of pancreatitis) and very severe: ≥2000 mg/dL.8
    • Treatment of hypertriglyceridemia depends on the degree of severity.
      • For patients with very high triglyceride levels, triglyceride reduction through a very low–fat diet (≤15% of calories), exercise, weight loss, and drugs (fibrates, ω-3 fatty acids) is the primary goal of therapy to prevent acute pancreatitis.
      • When patients have a lesser degree of hypertriglyceridemia, controlling the LDL-C level is the primary aim of initial therapy. Lifestyle changes are indicated to lower triglyceride levels.8
  • Low HDL cholesterol
    • Low HDL cholesterol is an independent ASCVD risk factor that is identified as a non–LDL-C risk and is included as a component of the ACC/AHA scoring algorithm.28
    • Etiologies for low HDL cholesterol include genetic conditions, physical inactivity, obesity, insulin resistance, DM, hypertriglyceridemia, cigarette smoking, high-carbohydrate (>60% of calories) diets, and certain medications (β-blockers, anabolic steroids/androgens, progestins). Acquired low HDL can also occur with plasma cell dyscrasias due to interference of paraproteins with the assay.29
    • Because therapeutic interventions for low HDL cholesterol are of limited efficacy, the guidelines recommend considering low HDL cholesterol as a component of overall risk, rather than a specific therapeutic target.
    • There are no clinical trial data showing a benefit of pharmacologic methods of elevating HDL cholesterol.
  • Starting and monitoring therapy
    • Before starting therapy, guidelines recommend checking alanine aminotransferase (ALT), hemoglobin A1C (if diabetes status is unknown), labs for secondary causes (if indicated), and creatine kinase (if indicated).
    • Evaluate for patient characteristics that increase the risk of adverse events from statins, including impaired hepatic and renal function, history of statin intolerance, history of muscle disorders, unexplained elevations of ALT >3× the upper limit of normal, drugs affecting statin metabolism, Asian ethnicity, and age >75 years.18
    • A repeat fasting lipid panel is indicated 4–12 weeks after starting therapy to assess adherence, with reassessment every 3–12 months as indicated.
    • In patients without the anticipated level of LDL-C reduction based on intensity of statin therapy (≥50% for high intensity, 30%–50% for moderate intensity), assess adherence to therapy and lifestyle modifications, evaluate for intolerance, and consider secondary causes. After evaluation, if the therapeutic response is still insufficient on maximally tolerated statin therapy, it is reasonable to consider adding a nonstatin agent.24
    • Creatine kinase should not be routinely checked in patients on statin therapy but is reasonable to measure in patients with muscle symptoms.
    • In 2012, the FDA stated that liver enzyme tests should be performed before starting statin therapy and only as clinically indicated thereafter. The FDA concluded that serious liver injury with statins is rare and unpredictable and that routine monitoring of liver enzymes does not appear to be effective in detecting or preventing serious liver injury. Elevations of liver transaminases 2–3× the upper limit of normal are dose-dependent, may decrease on repeat testing even with continuation of statin therapy, and are reversible with discontinuation of the drug.

Treatment of Elevated LDL Cholesterol

  • HMG-CoA reductase inhibitors (statins)
    • Statins (see Table 3-10) are the treatment of choice for elevated LDL-C and usually lower levels by 30%–50% with moderate-intensity and ≥50% with high-intensity statin therapy.18,30,31
      Table 3-10: Statin Therapy Regimens by Intensity
      High Intensity 
(↓ LDL ≥50%)Medium Intensity 
(↓ LDL 30%–49%)Low Intensity 
(↓ LDL <30%)
      Atorvastatin 40–80 mgAtorvastatin 10–20 mgFluvastatin 20–40 mg
      Rosuvastatin 20–40 mgFluvastatin 40 mg bid, 
80 mg XL
      Lovastatin 40 mg
      Pitavastatin 1–4 mg
      Pravastatin 40–80 mg
      Rosuvastatin 5–10 mg
      Simvastatin 20–40 mg
      Lovastatin 20 mg
      Pravastatin 10–20 mg
      Simvastatin 10 mg

      LDL, low-density lipoprotein; ↓, decreased.

    • The lipid-lowering effect of statins appears within the first week of use and becomes stable after approximately 4 weeks of use.
    • Statin therapy is effective in both men and women.32
    • Common side effects (5%–10% of patients) include gastrointestinal upset (e.g., abdominal pain, diarrhea, bloating, constipation) and muscle pain or weakness, which can occur without creatine kinase elevations. Other potential side effects include malaise, fatigue, headache, and rash.31,33,34,35
    • Myalgias are the most common cause of statin discontinuation and are often dose-dependent. They occur more often with increasing age and number of medications and decreasing renal function and body size.34,35,36
      • Discontinue statins in patients who develop muscle symptoms until they can be evaluated. For severe symptoms, a creatine kinase level can be measured.18
      • For mild to moderate symptoms, evaluate for conditions increasing the risk of muscle symptoms, including renal or hepatic impairment, hypothyroidism, vitamin D deficiency, rheumatologic disorders, and primary muscle disorders. Statin-induced myalgias are likely to resolve within 2 months of discontinuing the drug.
      • If symptoms resolve, the same or lower dose of the statin can be reintroduced.
      • If symptoms recur, use a low dose of a different statin and increase as tolerated.
      • If the cause of symptoms is determined to be unrelated, restart the original statin.
    • Statins have been associated with an increased incidence of DM. However, the total benefit of statin use usually outweighs the potential adverse effects from an increase in blood sugar.37
    • In a recent review of the use of statins, there was no aggregated evidence that statins have any negative impact on cognitive function.38
    • Because some statins undergo metabolism by the cytochrome P450 enzyme system, taking these statins in combination with other drugs metabolized by this enzyme system increases the risk of rhabdomyolysis.31,33,34 Among these drugs are fibrates (greater risk with gemfibrozil), itraconazole, ketoconazole, erythromycin, clarithromycin, cyclosporine, nefazodone, and protease inhibitors.34
    • Statins may also interact with large quantities of grapefruit juice to increase the risk of myopathy.
    • Simvastatin can increase the levels of warfarin and digoxin and has significant dose-limiting interactions with amlodipine, amiodarone, dronedarone, verapamil, diltiazem, and ranolazine. Rosuvastatin may also increase warfarin levels.
    • Because a number of drug interactions are possible depending on the statin and other medications being used, drug interaction programs and package inserts should be consulted.39
    • The use of statins is contraindicated during pregnancy and lactation.
  • Bile acid sequestrant resins
    • Currently available bile acid sequestrant resins include the following:
      • Cholestyramine: 4–24 g/d PO in divided doses before meals.
      • Colestipol: tablets, 2–16 g/d PO; granules, 5–30 g/d PO in divided doses before meals.
      • Colesevelam: 625 mg tablets, three tablets PO bid or six tablets PO daily (maximum of seven tablets daily) with food, or one packet of oral suspension daily.
    • Bile acid sequestrants typically lower LDL-C levels by 15%–30% and thereby lower the incidence of CHD.31,40
    • These agents should not be used as monotherapy in patients with triglyceride levels >250 mg/dL because they can raise triglyceride levels. They may be combined with nicotinic acid or statins.
    • Common side effects of resins include constipation, abdominal pain, bloating, nausea, and flatulence.
    • Bile acid sequestrants may decrease oral absorption of many other drugs, including warfarin, digoxin, thyroid hormone, thiazide diuretics, amiodarone, glipizide, and statins.
      • Colesevelam interacts with fewer drugs than do the older resins but can affect the absorption of thyroxine.
      • Other medications should be given at least 1 hour before or 4 hours after resins.
  • Nicotinic acid (niacin)
    • Niacin can lower LDL-C levels by ≥15%, lower triglyceride levels by 20%–50%, and raise HDL cholesterol levels by up to 35%.25,41 The use of niacin is limited by its side effect profile.
    • Crystalline niacin is given 1–3 g/d PO in two to three divided doses with meals. Extended-release niacin is dosed at night, with a starting dose of 500 mg PO, and the dose may be titrated monthly in 500 mg increments to a maximum of 2000 mg PO (administer dose with milk, applesauce, or crackers).
    • Common side effects of niacin include flushing, pruritus, headache, nausea, and bloating. Other potential side effects include elevation of liver transaminases, hyperuricemia, and hyperglycemia.
      • Flushing may be decreased with the use of aspirin 325 mg 30 minutes before the first few doses.
      • Hepatotoxicity associated with niacin is partially dose-dependent and appears to be more prevalent with some over-the-counter time-release preparations.
    • Avoid use of niacin in patients with gout, liver disease, active peptic ulcer disease, and uncontrolled DM.
      • Niacin can be used with care in patients with well-controlled DM (hemoglobin A1C level ≤7%).
      • Serum transaminases, glucose, and uric acid levels should be monitored every 6–8 weeks during dose titration and then every 4 months.
    • The use of niacin in patients with well-controlled LDL-C levels (with statins) has not been shown to be of benefit in clinical trials.42,43 Niacin can be useful as an additional agent in patients with severely elevated LDL-C levels.
  • Ezetimibe
    • Ezetimibe is currently the only available cholesterol-absorption inhibitor. It appears to act at the brush border of the small intestine and inhibits cholesterol absorption.
    • Ezetimibe may provide an additional 25% mean reduction in LDL-C when combined with a statin and provides an approximately 18% decrease in LDL-C when used as monotherapy.44,45,46,47
    • The recommended dosing is 10 mg PO once daily. No dosage adjustment is required for renal insufficiency and mild hepatic impairment or in elderly patients. It is not recommended for use in patients with moderate to severe hepatic impairment.
    • Side effects are infrequent and include gastrointestinal symptoms (e.g., diarrhea, abdominal pain) and myalgias.
    • In clinical trials, there was no excess of rhabdomyolysis or myopathy when compared with statin or placebo alone.
    • Liver enzymes should be monitored when used in conjunction with fenofibrate but are not required in monotherapy or with a statin.
    • A clinical outcome trial showed decreased reduction of cardiovascular events with the combination of simvastatin and ezetimibe compared with placebo in patients with chronic renal failure.48 The IMPROVE-IT trial showed a reduction in cardiovascular end points when ezetimibe was added to simvastatin in high-risk patients with already low LDL levels.49
    • Ezetimibe is useful in patients with FH who do not achieve adequate LDL-C reductions with statin therapy alone.50
  • PCSK9 inhibitors
    • Monoclonal antibodies have been developed that lower LDL-C. They work by inhibiting the PCSK9 enzyme, which is involved in breaking down the LDL-C receptor. Their use increases the number of available cell surface LDL receptors and subsequently remove more LDL from circulation. Major studies have shown significant reduction in LDL-C when PCSK9 inhibitors were added to statin therapy.51
    • These agents have shown great ability in further reducing LDL-C in high-risk patients and are approved for use as adjuncts in patients with clinical ASCVD and heterozygous FH and as monotherapy for homozygous FH.
    • Two PCSK9 inhibitors are approved for clinical use, evolocumab and alirocumab. Evolocumab is dosed at 140 mg subcutaneously every 2 weeks or 420 mg sc every 4 weeks. Alirocumab is dosed at 75 or 150 mg every 2 weeks or 300 mg every 4 weeks.
    • Evolocumab has been shown to decrease major cardiovascular events.51 Data on the outcome trial with alirocumab are pending publication.

Treatment of Hypertriglyceridemia

  • Nonpharmacologic treatment

    Nonpharmacologic treatments are important in the therapy of hypertriglyceridemia. 
Approaches include the following:

    • Changing oral estrogen replacement to transdermal estrogen;
    • Decreasing alcohol intake;
    • Encouraging weight loss and exercise;
    • Controlling hyperglycemia in patients with DM;
    • Avoiding simple sugars and very high–carbohydrate diets.8,27

  • Pharmacologic treatment
    • Pharmacologic treatment of severe hypertriglyceridemia consists of fibric acid derivative (fibrates), niacin, or ω-3 fatty acids.
    • Patients with severe hypertriglyceridemia (>1000 mg/dL) should be treated with pharmacotherapy in addition to reduction of dietary fat, alcohol, and simple carbohydrates to decrease the risk of pancreatitis.
    • Statins may be effective for patients with mild to moderate hypertriglyceridemia and concomitant LDL-C elevation.8,27,52
    • Fibric acid derivatives
      • Currently available fibric acid derivatives include the following:
        • Gemfibrozil: 600 mg PO bid before meals
        • Fenofibrate: available in several forms, dosage typically 48–145 mg/d PO
      • Fibrates generally lower triglyceride levels by 30%–50% and increase HDL cholesterol levels by 10%–35%. They can lower LDL-C levels by 5%–25% in patients with normal triglyceride levels but may actually increase LDL-C levels in patients with elevated triglyceride levels.52,53
      • Common side effects include dyspepsia, abdominal pain, cholelithiasis, rash, and pruritus.
      • Fibrates may potentiate the effects of warfarin.31 Gemfibrozil given in conjunction with statins may increase the risk of rhabdomyolysis.34,54,55,56
    • ω-3 Fatty acids
      • High doses of ω-3 fatty acids from fish oil can lower triglyceride levels.57,58
      • The active ingredients are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
      • To lower triglyceride levels, 1–6 g of ω-3 fatty acids, either EPA alone or with DHA, is needed daily.
      • Main side effects are burping, bloating, and diarrhea.
      • Prescription forms of ω-3 fatty acids are available and are indicated for triglyceride levels >500 mg/dL. One preparation contains EPA and DHA; four tablets contain about 3.6 g of ω-3 acid ethyl esters and can lower triglyceride levels by 30%–40%. Other preparations contain only EPA or contain unesterified EPA and DHA.
      • In practice, ω-3 fatty acids are being used as an adjunct to statins or other drugs in patients with moderately elevated triglyceride levels.
      • Large cardiovascular outcomes trials with ω-3 fatty acids are in progress.
      • In addition, EPA and DHA may help preserve physical function in CAD patients.59
      • The combination of ω-3 fatty acids plus a statin has the advantage of avoiding the risk of myopathy seen with statin–fibrate combinations.60,61

Treatment of Low HDL Cholesterol

  • Low HDL cholesterol often occurs in the setting of hypertriglyceridemia and metabolic syndrome. Management of accompanying high LDL-C, hypertriglyceridemia, and the metabolic syndrome may result in improvement of HDL cholesterol.62
  • Nonpharmacologic therapies are the mainstay of treatment, including the following:
    • Smoking cessation
    • Exercise
    • Weight loss
  • In addition, medications known to lower HDL levels, such as β-blockers (except carvedilol), progestins, and androgenic compounds, should be avoided.
  • No clinical outcomes trials have shown a clear benefit to pharmacologic treatment for raising HDL cholesterol.

References

  1. Genest JJ, Martin-Munley SS, McNamara JR, et al. Familial lipoprotein disorders in patients with premature coronary artery disease. Circulation. 1992;85:2025-2033.  [PMID:1534286]
  2. Kugiyama K, Doi H, Motoyama T, et al. Association of remnant lipoprotein levels with impairment of endothelium-dependent vasomotor function in human coronary arteries. Circulation. 1998;97:2519-2526.  [PMID:9657472]
  3. Dowla S, Aslibekyan S, Goss A, et al. Dyslipidemia is associated with pediatric nonalcoholic fatty liver disease. J Clin Lipidol. 2018;12:981-987.  [PMID:29699915]
  4. Hegele RA, Ginsberg HN, Chapman MJ, et al. The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management. Lancet Diabetes Endocrinol. 2014;2:655-666.  [PMID:24731657]
  5. Nordestgaard BG, Chapman MJ, Humphries SE, et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease:consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013;34:3478-3490a.  [PMID:23956253]
  6. Haase A, Goldberg AC. Identification of people with heterozygous familial hypercholesterolemia. Curr Opin Lipidol. 2012;23:282-289.  [PMID:22801386]
  7. Goldberg AC, Hopkins PN, Toth PP, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association Expert Panel on Familial Hypercholesterolemia. J Clin Lipidol. 2011;5:133-140.  [PMID:21600517]
  8. Berglund L, Brunzell JD, Goldberg AC, et al. Evaluation and treatment of hypertriglyceridemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2012;97:2969-2989.  [PMID:22962670]
  9. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344:1383-1389.
  10. Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N Engl J Med. 1996;335:1001-1009.  [PMID:8801446]
  11. The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.
  12. Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360:7-22.
  13. Shepherd J, Cobbe SM, Ford I, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland coronary prevention study group. N Engl J Med. 1995;333:1301-1307.  [PMID:7566020]
  14. Downs JR, Clearfield M, Weis S, et al. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA. 1998;279:1615-1622.  [PMID:9613910]
  15. Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003;361:1149-1158.  [PMID:12686036]
  16. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364:685-696.  [PMID:15325833]
  17. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet. 2012;380:581-590.  [PMID:22607822]
  18. Grundy SM, Stone NJ, Bailey AL, et al. AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2018. In press.
  19. Eckel RH, Jakicic JM, Ard JD, et al. 2013 AHA/ACC guideline on lifestyle management to reduce cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2014;129:S76-S99.  [PMID:24222015]
  20. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines and the obesity society. Circulation. 2014;129:S102-S138.  [PMID:24222017]
  21. Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073-2081.  [PMID:20483451]
  22. Palmer SC, Navaneethan SD, Craig JC, et al. HMG CoA reductase inhibitors (statins) for people with chronic kidney disease not requiring dialysis. Cochrane Database Syst Rev. 2014:CD007784.  [PMID:24771351]
  23. Shepherd J, Blauw GJ, Murphy MB, et al. Pravastatin in elderly individuals at risk of vascular disease (PROSPER): a randomised controlled trial. Lancet. 2002;360:1623-1630.  [PMID:12457784]
  24. Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. 2017 Focused update of the 2016 ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology task force on expert consensus decision pathways. J Am Coll Cardiol. 2017;70:1785-1822.  [PMID:28886926]
  25. Sarwar N, Danesh J, Eiriksdottir G, et al. Triglycerides and the risk of coronary heart disease: 10,158 incident cases among 262,525 participants in 29 Western prospective studies. Circulation. 2007;115:450-458.  [PMID:17190864]
  26. Tirosh A, Rudich A, Shochat T, et al. Changes in triglyceride levels and risk for coronary heart disease in young men. Ann Intern Med. 2007;147:377-385.  [PMID:17876021]
  27. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2011;123:2292-2333.  [PMID:21502576]
  28. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. Circulation. 2014;129:S49-S73.  [PMID:24222018]
  29. van Gorselen EO, Diekman T, Hessels J, et al. Artifactual measurement of low serum HDL-cholesterol due to paraproteinemia. Clin Res Cardiol. 2010;99:599-602.  [PMID:20593189]
  30. Robinson JG, Goldberg AC. Treatment of adults with familial hypercholesterolemia and evidence for treatment: recommendations from the National Lipid association expert panel on familial hypercholesterolemia. J Clin Lipidol. 2011;5:S18-S29.  [PMID:21600526]
  31. Knopp RH. Drug treatment of lipid disorders. N Engl J Med. 1999;341:498-511.  [PMID:10441607]
  32. Fulcher J, O’Connell R, Voysey M, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet. 2015;385:1397-1405.  [PMID:25579834]
  33. Chong PH. Lack of therapeutic interchangeability of HMG-CoA reductase inhibitors. Ann Pharmacother. 2002;36:1907-1917.  [PMID:12452755]
  34. Pasternak RC, Smith SC, Bairey-Merz CN, et al. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation. 2002;106:1024-1028.  [PMID:12186811]
  35. Thompson PD, Panza G, Zaleski A, et al. Statin-associated side effects. J Am Coll Cardiol. 2016;67:2395-2410.  [PMID:27199064]
  36. Venero CV, Thompson PD. Managing statin myopathy. Endocrinol Metab Clin North Am. 2009;38:121-136.  [PMID:19217515]
  37. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375:735-742.  [PMID:20167359]
  38. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532-2561.  [PMID:27616593]
  39. Kellick KA, Bottorff M, Toth PP, et al. A clinician’s guide to statin drug-drug interactions. J Clin Lipidol. 2014;8:S30-S46.  [PMID:24793440]
  40. The lipid research clinics coronary primary prevention trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351-364.  [PMID:6694309]
  41. Illingworth DR, Stein EA, Mitchel YB, et al. Comparative effects of lovastatin and niacin in primary hypercholesterolemia. A prospective trial. Arch Intern Med. 1994;154:1586-1595.  [PMID:8031206]
  42. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255-2267.  [PMID:22085343]
  43. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J. 2013;34:1279-1291.
  44. Dujovne CA, Ettinger MP, McNeer JF, et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1092-1097.  [PMID:12423709]
  45. Knopp RH, Gitter H, Truitt T, et al. Effects of ezetimibe, a new cholesterol absorption inhibitor, on plasma lipids in patients with primary hypercholesterolemia. Eur Heart J. 2003;24:729-741.  [PMID:12713767]
  46. Gagne C, Bays HE, Weiss SR, et al. Efficacy and safety of ezetimibe added to ongoing statin therapy for treatment of patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1084-1091.  [PMID:12423708]
  47. Goldberg AC, Sapre A, Liu J, et al. Efficacy and safety of ezetimibe coadministered with simvastatin in patients with primary hypercholesterolemia: a randomized, double-blind, placebo-controlled trial. Mayo Clin Proc. 2004;79:620-629.  [PMID:15132403]
  48. Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181-2192.  [PMID:21663949]
  49. Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387-2397.  [PMID:26039521]
  50. Ito MK, McGowan MP, Moriarty PM. Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association expert panel on familial hypercholesterolemia. J Clin Lipidol. 2011;5:S38-S45.  [PMID:21600528]
  51. Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713-1722.  [PMID:28304224]
  52. Brunzell JD. Clinical practice. Hypertriglyceridemia. N Engl J Med. 2007;357:1009-1017.  [PMID:17804845]
  53. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849-1861.  [PMID:16310551]
  54. Rosenson RS. Current overview of statin-induced myopathy. Am J Med. 2004;116:408-416.  [PMID:15006590]
  55. Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates. Am J Cardiol. 2004;94:935-938.  [PMID:15464682]
  56. Jones PH, Davidson MH. Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin. Am J Cardiol. 2005;95:120-122.  [PMID:15619408]
  57. Nestel PJ, Connor WE, Reardon MF, et al. Suppression by diets rich in fish oil of very low density lipoprotein production in man. J Clin Invest. 1984;74:82-89.  [PMID:6736254]
  58. Harris WS, Connor WE, Illingworth DR, et al. Effects of fish oil on VLDL triglyceride kinetics in humans. J Lipid Res. 1990;31:1549-1558.  [PMID:2246608]
  59. Alfaddagh A, Elajami TK, Saleh M, et al. The effect of eicosapentaenoic and docosahexaenoic acids on physical function, exercise, and joint replacement in patients with coronary artery disease: a secondary analysis of a randomized clinical trial. J Clin Lipidol. 2018;12:937-947.e2.  [PMID:29752179]
  60. Maki KC, McKenney JM, Reeves MS, et al. Effects of adding prescription omega-3 acid ethyl esters to simvastatin (20 mg/day) on lipids and lipoprotein particles in men and women with mixed dyslipidemia. Am J Cardiol. 2008;102:429-433.  [PMID:18678300]
  61. Barter P, Ginsberg HN. Effectiveness of combined statin plus omega-3 fatty acid therapy for mixed dyslipidemia. Am J Cardiol. 2008;102:1040-1045.  [PMID:18929706]
  62. Ballantyne CM, Olsson AG, Cook TJ, et al. Influence of low high-density lipoprotein cholesterol and elevated triglyceride on coronary heart disease events and response to simvastatin therapy in 4S. Circulation. 2001;104:3046-3051.  [PMID:11748098]

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