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General Principles

  • Lipids are sparingly soluble molecules 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 (IDLs)
    • Low-density lipoproteins (LDLs)
    • High-density lipoproteins (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.
  • Nearly 90% of patients with CHD have some form of dyslipidemia. Increased levels of LDL cholesterol, remnant lipoproteins, and Lp(a) and decreased levels of HDL cholesterol have all been associated with an increased risk of premature vascular disease (Circulation 1992;85:2025; Circulation 1998;97:2519).
    Table 3-6: Physical Properties of Plasma Lipoproteins
    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)

    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.

    aRemainder of particle is composed of phospholipid and protein.

  • 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-100Hypothyroidism, 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 (LCAT) 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 (Circulation 1974;49:476; J Lipid Res 1990;31:1337; Clin Invest 1993;71:362).
      • Familial hypercholesterolemia and familial combined hyperlipidemia are disorders that contribute significantly to premature cardiovascular disease.
      • Familial hypercholesterolemia is an underdiagnosed, autosomal co-dominant condition with a prevalence of 1 in 200 to 1 in 500 people that causes elevated LDL cholesterol levels from birth (Curr Opin Lipidol 2012;23:282; Eur Heart J 2013;34:3478). It is associated with significantly increased risk of early cardiovascular disease when untreated (J Clin Lipidol 2011;5:133).
      • 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 (J Clin Endocrinol Metab 2012;97:2969).
      Table 3-8: Review of Major Genetic Dyslipoproteinemias
      Type of Genetic DyslipidemiaTypical Lipid ProfileType of Inheritance PatternPhenotypic FeaturesOther Information
      Familial hypercholesterolemia (FH)
      • Increased LDL cholesterol (>190 mg/dL) cholesterol
      • Homozygous form or compound heterozygous form (rare) can have LDL cholesterol >500 mg/dL
      Autosomal dominant (prevalence of 1 in 200–500 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 (FCH)
      • 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 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.

  • Standards of care for hyperlipidemia
    • LDL cholesterol–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) (Lancet 1994;344:1383; N Engl J Med 1996;335:1001; N Engl J Med 1998;339:1349; Lancet 2002;360:7) or without (primary prevention) (Lancet 2002;360:7; N Engl J Med 1995;333:1301; JAMA 1998;279:1615; Lancet 2003;361:1149; Lancet 2004;364:685) known CHD.
    • Prevention of atherosclerotic cardiovascular disease (ASCVD) is the primary goal of the 2013 American College of Cardiology (ACC)/American Heart Association (AHA) Guidelines. These guidelines address risk assessment (Circulation 2014;129:S49), lifestyle modifications (Circulation 2014;129:S76), evaluation and treatment of obesity (Circulation 2014;129:S102), and evaluation and management of blood cholesterol (Circulation 2014;129:S1).



  • Screening for hypercholesterolemia should be done in all adults age 20 years or older (Circulation 2014;129:S49).
  • Screening is best performed with a lipid profile (total cholesterol, LDL cholesterol, 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 40–75 (Circulation 2014;129:S49).
  • 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 2013 guidelines identify four groups in whom the benefits of LDL cholesterol–lowering therapy with HMG-CoA reductase inhibitors (statins) clearly outweigh the risks (Circulation 2014;129:S1):
    • Patients with clinical ASCVD
    • Patients with LDL cholesterol ≥190 mg/dL
    • Patients with DM age 40–75 years with LDL cholesterol between 70–189 mg/dL
    • Patients with a calculated ASCVD risk ≥7.5%
  • For patients without clinical ASCVD or an LDL cholesterol ≥190 mg/dL, the guidelines advise 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 (Circulation 2014;129:S49).
  • The ACC/AHA risk calculator is available at http://my.americanheart.org/cvriskcalculator.
    • For patients of ethnicities other than African American or non-Hispanic white, risk cannot be as well assessed. 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 cholesterol ≥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.


  • The 2013 guidelines recognize lifestyle factors, including diet (Circulation 2014;129:S76) and weight management (Circulation 2014;129:S102) as an important component of risk reduction for all patients.
  • 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 (Circulation 2014;129:S76).

    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).

    From Circulation 2014;129:S76.

  • Physical activity, including aerobic and resistance exercise, is recommended in all patients (Circulation 2014;129:S76).
  • 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 (Circulation 2014;129:S102).
  • Consultation with a registered dietitian 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:
    • 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.
      Table 3-10: Statin Therapy Regimens by Intensity
      High Intensity (↓ LDL ≥50%)Medium Intensity (↓ LDL 30–50%)Low Intensity (↓ LDL <30%)
      Atorvastatin 40–80 mgAtorvastatin 10–20 mgFluvastatin 20–40 mg
      Rosuvastatin 20–40 mgFluvastatin 40 mg bid, 80 mg XLLovastatin 20 mg

      Lovastatin 40 mgPitavastatin 1 mg

      Pitavastatin 2–4 mgPravastatin 10–20 mg

      Pravastatin 40–80 mgSimvastatin 10 mg

      Rosuvastatin 5–10 mg

      Simvastatin 20–40 mg

      LDL, low-density lipoprotein; , decreased. Italicized doses have not been studied in randomized controlled trials but achieve this level of LDL reduction in clinical use.

      From Circulation 2014;129:S1.

    • If high-dose statin therapy is contraindicated or poorly tolerated or there are significant risks to high-intensity therapy (including age >75 years), moderate-intensity therapy is an option.
  • LDL cholesterol ≥190 mg/dL
    • These individuals have elevated lifetime risk because of long-term exposure to very high LDL cholesterol levels, and the risk calculator does not account for this.
    • LDL cholesterol should be reduced by at least 50%, primarily with high-intensity statin therapy. If high-intensity therapy is not tolerated, maximum tolerated intensity should be used.
    • Even high-intensity statin therapy may not be sufficient to reduce LDL cholesterol by 50%, and nonstatin therapies are often required to achieve this goal (J Clin Lipidol 2011;5:S18).
    • LDL apheresis is an optional therapy in patients with homozygous familial hypercholesterolemia and those with severe heterozygous familial hypercholesterolemia with insufficient response to medication. Lomitapide, a microsomal triglyceride transfer protein inhibitor, and mipomersen, an apolipoprotein B antisense oligonucleotide, are new medications indicated for the treatment of patients with homozygous familial hypercholesterolemia (Eur Heart J 2013;34:3478).
    • 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 (Curr Opin Lipidol 2012;23:282).
  • Patients with diabetes, aged 40–75, LDL cholesterol between 70–189 mg/dL
    • Using the AHA/ACC risk calculator, calculate 10-year risk of an ASCVD event in these patients (categories: ≥7.5% or <7.5%).
    • If the risk is ≥7.5%, consider high-intensity statin therapy. Otherwise, these patients have an indication for moderate-intensity statin therapy.
  • Patients without diabetes, aged 40–75, LDL cholesterol between 70–189 mg/dL
    • Using the AHA/ACC risk calculator, calculate 10-year risk of an ASCVD event in these patients (categories: ≥7.5%, between 5.0–7.5%, and <5.0%).
    • A 10-year risk ≥7.5% is an indication for moderate- or high-intensity statin therapy. The decision between moderate- and high-intensity therapy should be made with the patient based on anticipated individualized risks and benefits.
    • A 10-year risk between 5.0–7.5% is reasonable for moderate-intensity statin therapy.
  • Other patient populations
    • Some patients not described above may still benefit from statin therapy: if the decision on treatment is unclear, the guidelines offer assessment of family history, high-sensitivity C-reactive protein (hs-CRP), coronary artery calcium (CAC) score, or arterial-brachial index (ABI) as options to further define risk (Circulation 2014;129:S49; Circulation 2014;129:S1).
      • A family history of premature ASCVD is defined as an event in a first-degree male relative before age 55 or in a first-degree female relative before age 65.
      • Higher risk is also indicated by an hs-CRP ≥2 mg/L; CAC ≥300 Agatston units or ≥75th percentile for age, sex, and ethnicity; or ABI ≤0.9.
      • The role of other biomarkers in risk assessment remains uncertain.
      • Depending on patient preference and assessment of risks and benefits, lower LDL cholesterol levels can be considered for treatment (particularly LDL cholesterol ≥160 mg/dL).
      • Patients with diabetes younger than 40 or older than 75 are reasonable candidates for statin therapy based on individual evaluation.
    • 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 (Lancet 2002;360:7; Lancet 2002;360:1623). In addition, many ASCVD events occur in this age group, and patients without other comorbidities may benefit substantially from cardiovascular risk reduction.
    • No official recommendation was made in the guidelines regarding initiation or continuation of statin therapy in patients on maintenance hemodialysis or with New York Heart Association class II–IV ischemic systolic HF. Evidence from randomized controlled trials has not shown a benefit from statin therapy in these subpopulations (Circulation 2014;129:S1).
  • Hypertriglyceridemia
    • Hypertriglyceridemia may be an independent cardiovascular risk factor (Circulation 2007;115:450; Ann Intern Med 2007;147:377; Circulation 2011;123:2292).
    • Hypertriglyceridemia is often observed in the metabolic syndrome (Circulation 2011;123:2292), 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 (Circulation 2011;123:2292): normal: <150 mg/dL; borderline high: 150–199 mg/dL; high: 200–499 mg/dL; and very high: ≥500 mg/dL. 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 (J Clin Endocrinol Metab 2012;97:2969).
    • 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, niacin, 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 cholesterol level is the primary aim of initial therapy. Lifestyle changes are indicated to lower triglyceride levels (J Clin Endocrinol Metab 2012;97:2969).
  • Low HDL cholesterol
    • Low HDL cholesterol is an independent ASCVD risk factor that is identified as a non-LDL cholesterol risk and is included as a component of the ACC/AHA scoring algorithm (Circulation 2014;129:S49).
    • 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).
    • 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 (Circulation 2014;129:S1).
    • 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 contrast to previous guidelines, therapeutic targets are not recommended because specific targets and a “treat to target” strategy have not been evaluated in randomized controlled trials.
    • In patients without the anticipated level of LDL cholesterol 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.
    • 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 cholesterol and usually lower levels by 30–50% with moderate-intensity and ≥50% with high-intensity statin therapy (J Clin Lipidol 2011;5:S18; N Engl J Med 1999;341:498; Circulation 2014;129:S1).
    • The lipid-lowering effect of statins appears within the first week of use and becomes stable after approximately 4 weeks of use.
    • 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 (N Engl J Med 1999;341:498; Ann Pharmacother 2002;36:1907; Circulation 2002;106:1024).
    • 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 (Circulation 2002;106:1024; Endocrinol Metab Clin North Am 2009;38:121).
      • The AHA/ACC guidelines recommend discontinuing statins in patients who develop muscle symptoms until they can be evaluated. For severe symptoms, evaluate for rhabdomyolysis (Circulation 2014;129:S1).
      • 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 (Lancet 2010;375:735).
    • Statins have very rarely been associated with reversible cognitive impairment and have not been associated with irreversible or progressive dementia.
    • Because some of the 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 (N Engl J Med 1999;341:498; Ann Pharmacother 2002;36:1907; Circulation 2002;106:1024). Among these drugs are fibrates (greater risk with gemfibrozil), itraconazole, ketoconazole, erythromycin, clarithromycin, cyclosporine, nefazodone, and protease inhibitors (Circulation 2002;106:1024).
    • 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 (J Clin Lipidol 2014;8:S30).
    • 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 cholesterol levels by 15–30% and thereby lower the incidence of CHD (N Engl J Med 1999;341:498; JAMA 1984;251:351).
    • 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 cholesterol levels by ≥15%, lower triglyceride levels by 20–50%, and raise HDL cholesterol levels by up to 35% (Circulation 2007;115:450; Arch Intern Med 1994;154:1586).
    • 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 cholesterol levels (with statins) has not been shown to be of benefit in clinical trials (N Engl J Med 2011;365:2255; Eur Heart J 2013;34:1279). Niacin can be useful as an additional agent in patients with severely elevated LDL cholesterol 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 cholesterol when combined with a statin and provides an approximately 18% decrease in LDL cholesterol when used as monotherapy (Am J Cardiol 2002;90:1092; Eur Heart J 2003;24:729; Am J Cardiol 2002;90:1084; Mayo Clin Proc 2004;79:620).
    • 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 to placebo in patients with chronic renal failure (Lancet 2011;377:2181). The recently completed 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 (American Heart Association Scientific Sessions 2014).
    • Ezetimibe is useful in patients with familial hypercholesterolemia who do not achieve adequate LDL cholesterol reductions with statin therapy alone (J Clin Lipidol 2011;5:S38).

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 (Circulation 2011;123:2292; J Clin Endocrinol Metab 2012;97:2969)

  • Pharmacologic treatment
    • Pharmacologic treatment of severe hypertriglyceridemia consists of a 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 cholesterol elevation (Circulation 2011;123:2292; J Clin Endocrinol Metab 2012;97:2969; N Engl J Med 2007;357:1009).
    • 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 cholesterol levels by 5–25% in patients with normal triglyceride levels but may actually increase LDL cholesterol levels in patients with elevated triglyceride levels (N Engl J Med 2007;357:1009; Lancet 2005;366:1849).
      • Common side effects include dyspepsia, abdominal pain, cholelithiasis, rash, and pruritus.
      • Fibrates may potentiate the effects of warfarin (N Engl J Med 1999;341:498). Gemfibrozil given in conjunction with statins may increase the risk of rhabdomyolysis (Circulation 2002;106:1024; Am J Med 2004;116:408; Am J Cardiol 2004;94:935; Am J Cardiol 2005;95:120).
    • ω-3 Fatty acids
      • High doses of ω-3 fatty acids from fish oil can lower triglyceride levels (J Clin Invest 1984;74:82; J Lipid Res 1990;31:1549).
      • 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, are 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.
      • The combination of ω-3 fatty acids plus a statin has the advantage of avoiding the risk of myopathy seen with statin–fibrate combinations (Am J Cardiol 2008;102:429; Am J Cardiol 2008;102:1040).

Treatment of Low HDL Cholesterol

  • Low HDL cholesterol often occurs in the setting of hypertriglyceridemia and metabolic syndrome. Management of accompanying high LDL cholesterol, hypertriglyceridemia, and the metabolic syndrome may result in improvement of HDL cholesterol (Circulation 2001;104:3046).
  • 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.


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Williams, Dominique, et al., editors. "Dyslipidemia." Washington Manual of Medical Therapeutics, 35th ed., Wolters Kluwer Health, 2016. Washington Manual, www.unboundmedicine.com/washingtonmanual/view/Washington-Manual-of-Medical-Therapeutics/602104/all/Dyslipidemia.
Dyslipidemia. In: Williams D, Ramgopal R, Gdowski M, et al, eds. Washington Manual of Medical Therapeutics. 35th ed. Wolters Kluwer Health; 2016. https://www.unboundmedicine.com/washingtonmanual/view/Washington-Manual-of-Medical-Therapeutics/602104/all/Dyslipidemia. Accessed May 19, 2019.
Dyslipidemia. (2016). In Williams, D., Ramgopal, R., Gdowski, M., Dretler, A., & Bhat, P. (Eds.), Washington Manual of Medical Therapeutics. Available from https://www.unboundmedicine.com/washingtonmanual/view/Washington-Manual-of-Medical-Therapeutics/602104/all/Dyslipidemia
Dyslipidemia [Internet]. In: Williams D, Ramgopal R, Gdowski M, Dretler A, Bhat P, editors. Washington Manual of Medical Therapeutics. Wolters Kluwer Health; 2016. [cited 2019 May 19]. Available from: https://www.unboundmedicine.com/washingtonmanual/view/Washington-Manual-of-Medical-Therapeutics/602104/all/Dyslipidemia.
* Article titles in AMA citation format should be in sentence-case
TY - ELEC T1 - Dyslipidemia ID - 602104 ED - Williams,Dominique, ED - Ramgopal,Rajeev, ED - Gdowski,Mark, ED - Dretler,Alexandra, ED - Bhat,Pavat, BT - Washington Manual of Medical Therapeutics UR - https://www.unboundmedicine.com/washingtonmanual/view/Washington-Manual-of-Medical-Therapeutics/602104/all/Dyslipidemia PB - Wolters Kluwer Health ET - 35 DB - Washington Manual DP - Unbound Medicine ER -