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Basic Information ⬇

AUTHOR: Fred F. Ferri, MD

Definition

Hypercholesterolemia refers to a blood cholesterol measurement ≥200 mg/dl.

Synonyms

Hyperlipidemia

Hypercholesteremia

Dyslipidemia

Type II familial hyperlipoproteinemia

ICD-10CM CODE
E78.0Pure hypercholesterolemia
Epidemiology & Demographics

  • More than 105 million (37% of) adults in the U.S. have total blood cholesterol levels higher than 200 mg/dl. Of this group, more than 36 million adults have extremely high-risk cholesterol levels over 240 mg/dl (13%).
  • For men over the age of 20, approximately 48% of White men, 45% of Black men, and 50% of Hispanic men have high blood cholesterol.
  • For women over the age of 20, approximately 50% of White women, 42% of Black women, and 50% of Hispanic women have hypercholesterolemia.
  • Prevalence of hypercholesterolemia increases with age.
  • According to National Health and Nutrition Examination Survey (NHANES) data approximately 47% of adults had at least one of three risk factors for cardiovascular disease-uncontrolled high blood pressure, uncontrolled high levels of low-density lipoproteins (LDL) cholesterol, or current smoking.
Physical Findings & Clinical Presentation

  • A detailed medication history should be performed because some medications may affect lipid levels (e.g., thiazides, corticosteroids, β-blockers, and estrogens).
  • The physical examination should include measurements of body mass index and blood pressure (BP), thyroid and liver assessments, and examining peripheral pulses including carotids for bruits.
  • Physical findings, particularly in the familial forms may include:
    1. Tendon xanthomas
    2. Xanthelasma
    3. Arcus corneae
    4. Arterial bruits (young adulthood)
Etiology
Primary

  • Genetics
  • Obesity
  • Dietary intake
Secondary

  • Hypothyroidism
  • Diabetes mellitus (DM)
  • Nephrotic syndrome
  • Obstructive liver disease: Hepatoma, extrahepatic biliary obstruction, primary biliary cirrhosis
  • Alcohol or tobacco use
  • Dysgammaglobulinemia (multiple myeloma, systemic lupus erythematosus)
  • Drugs: Oral contraceptives, progesterone, corticosteroids, thiazide diuretics, β-blockers, androgenic steroids, retinoic acid derivatives, protease inhibitors

Diagnosis ⬆ ⬇

Differential Diagnosis

  • Always consider underlying secondary causes for the elevated cholesterol.
  • Patients with very high LDL cholesterol usually have genetic forms of hypercholesterolemia (see “Hyperlipoproteinemia, Primary”). Early detection of these cases and family testing to identify similarly affected relatives is important.
  • Metabolic syndrome:
    1. A constellation of lipid and nonlipid risk factors of a metabolic origin
    2. Diagnosed when three or more of the following are present: Abdominal obesity (waist circumference >40 in for men and >35 in for women); fasting triglycerides >150 mg/dl; HDL <40 mg/dl in males and <50 mg/dl in females; systolic BP >130 mm Hg and diastolic BP >85 mm Hg; fasting glucose >110 mg/dl
Who Should be Screened

  • The American Association of Clinical Endocrinologists (AACE) recommends screening of patients >20 yr of age for elevated cholesterol every 5 yr, males >45 yr and females >55 yr of age every 1 to 2 yr, and >65 yr of age every yr up to 75 yr of age regardless of coronary artery disease (CAD) risk status. Patients above 75 yr of age with multiple CAD risk factors should continue to get screened annually.
  • The United States Preventive Services Task Force (USPSTF) supports routine screening for men aged >35 yr and women aged >45 yr by measurement of nonfasting total and HDL cholesterol alone.
  • In 2010 the USPSTF recommended routine screening for overweight and obese persons aged <20 yr.
  • In 2011, American College of Cardiology (ACC)/American Heart Association (AHA) recommended screening for hypertriglyceridemia by a nonfasting measurement. A nonfasting level of <200 mg/dl is commensurate with an optimal level of <100 mg/dl, and no further testing is required. However, a nonfasting level of >200 mg/dl warrants further testing with a fasting lipid profile.
Laboratory Tests

  • Obtain a lipid profile. A fasting lipid panel has been traditionally preferred over a nonfasting lipid profile; however, this recommendation has come into question, and expert consensus statements from Canada and Europe recommend nonfasting lipid testing as the new standard for lipid measurement. In nonfasting patients, triglyceride levels ≥175 mg/dl should be considered elevated as compared with <150 mg/dl for fasting panels. Fasting lipid panels are preferred for patients with triglycerides over 400 mg/dl.
  • Lipoprotein(a) [Lp(a)]: Current U.S. guidelines suggest that Lp(a) may be used as a “risk-enhancing factor” to support statin prescription, in concert with other factors and shared decision-making, among primary prevention patients aged 40 to 75 yr with an estimated 10-yr risk for atherosclerotic cardiovascular disease (ASCVD) of 5.0% to 19.9%.1
  • Perform a workup for secondary causes if clinically indicated, such as thyroid-stimulating hormone, metabolic profile, liver function tests (LFTs), and fasting glucose.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

  • First-line treatment: Dietary therapy can result in 5% to 15% reduction in LDL cholesterol level
  • Composition of the TLC diet:
    1. Total fat 25% to 30% of total calories
    2. Polyunsaturated fat up to 10% of total calories
    3. Monounsaturated fat up to 20% of total calories
    4. Saturated fats <7% of total calories
    5. Carbohydrate 50% to 60% of total calories
    6. Protein 15% of total calories
    7. No more than 200 mg/day of cholesterol
    8. Fiber 20 to 30 g/day
  • Increased physical activity: Encourage 30 min of moderately intense physical activity, four to six times a wk (e.g., brisk walking, riding stationary bike, water aerobics)
  • Maintenance of a healthy weight
  • Avoidance of tobacco products
  • Counseling on CAD risk factors (Table 1)
  • Plant-based diets (including stanol-containing margarines, oat bran, and nuts) have shown effectiveness in controlling lipids

TABLE 1 Risk Factors for Heart Disease

  1. Cigarette smoking
  2. Hypertension (BP ≥140/90 mm Hg or on medications)
  3. Low HDL cholesterol (<40 mg/dl)∗
  4. Family history of premature CHD (<55 yr in first-degree male relative or <65 yr in first-degree female relative)
  5. Age (men ≥45 yr, women ≥55 yr)

BP, Blood pressure; CHD, congenital heart disease; HDL, high-density lipoprotein cholesterol.

∗HDL cholesterol >60 mg/dl counts as a negative risk factor; its presence removes one risk factor from the total count.

Acute General Rx

No acute treatment needed

Chronic Rx

  • Box 1 summarizes the key recommendations for the treatment of blood cholesterol to reduce ASCVD risk in adults.
  • The guidelines identify four high-risk groups that benefit from statin therapy:
    1. Patients with clinical ASCVD (Table 2, Fig. 1)
    2. LDL ≥190 mg/dl
    3. DM aged 40 to 75 yr and LDL 70 to 189 mg/dl
    4. 10-yr risk for ASCVD ≥7.5% and LDL 70 to 189 mg/dl
  • The 10-yr risk of ASCVD is calculated with the risk calculator available at http://my.americanheart.org/cvriskcalculator.
  • ASCVD events are reduced by using the maximum tolerated statin intensity in the aforementioned groups shown to benefit the most (Tables 3 and 4).
  • Additional factors such as C-reactive protein >2 mg/L, primary LDL >160, genetic hyperlipidemias, family history of premature coronary heart disease (CHD), ankle-brachial index <0.9, and coronary artery calcium score (CAD) assessed with computed tomography may be used in patients who are not in one of four statin benefit groups and for whom a decision to initiate statin therapy is otherwise unclear. Statins are generally beneficial in patients at intermediate risk and selected patients with borderline risk who have a calcium score that is 100 or higher or who are in the 75th percentile or higher for their age, sex, and race. Statins should also be considered in persons with scores of 1 to 99, particularly if they are age 55 yr or older.
  • Percent reduction in LDL cholesterol is used as a guide to compliance and adherence to therapy in the 2018 AHA/ACC Revised Clinical Practice Guidelines (Fig. 2). Studies have shown that compared with less-intensive LDL-C lowering, more intensive lowering reduces all-cause mortality and cardiovascular mortality; patients with higher baseline LDL-C have greater benefit.
  • Moderate-intensity statin therapy should be continued for individuals >75 yr of age for secondary prevention. However, factors such as comorbidities, safety, and priorities of care should be considered before initiating statins for primary prevention of ASCVD.
  • Adherence to lifestyle and to statin therapy should be reiterated with patients before the addition of a nonstatin drug.
  • High-risk patients with a suboptimal response to statins who are unable to tolerate a recommended intensity or who are completely statin intolerant may benefit from the addition of a nonstatin cholesterol-lowering agent such as ezetimibe and/or Protein Convertase Subtilisin/Kexin 9 (PCSKS 9) inhibitor to reduce risk for major cardiovascular events.2 Combination therapies for LDL are summarized in Table 5.
  • Ezetimibe inhibits cholesterol absorption in the intestine, whereas statins inhibit cholesterol production primarily in the liver. Ezetimibe is not as effective as most statins, but will reduce LDL by 15% to 22%. It can reduce the risk of heart attacks and strokes when taken alongside a statin, but there is little evidence it can do this if used on its own.
  • PCSK9 binds to LDL receptors on hepatocytes, promotes receptor degradation, and prevents LDL-C clearance from the circulation thereby increasing serum concentrations of LDL-C. PCSK9 monoclonal antibody inhibitors alirocumab (Praluent), evolocumab (Repatha), and inclisiran (Leqvio), a PCSK9-directed small interfering RNA, are currently indicated as adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL cholesterol. PCSK9 inhibitors lower risk for ischemic cardiovascular events in persons with stable CAD and elevated atherogenic lipoproteins despite statin therapy. These medications are administered by subcutaneous injection and are expensive.
  • The management of metabolic syndrome includes weight reduction, increased physical activity, and treatment of hypertension, elevated triglycerides, and low HDL cholesterol.
  • According to recent studies, each 40 mg/dl reduction in LDL cholesterol by statin therapy confers a 20% reduction in ASCVD. In other words, a relative risk reduction of 30% in ASCVD by moderate-intensity therapy and 45% by high-intensity therapy has been approximated.
  • Recent trials have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces LDL cholesterol. The addition of bempedoic acid to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significant lowering of LDL cholesterol.
  • Recent trials have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces LDL cholesterol. The addition of bempedoic acid to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significant lowering of LDL cholesterol.
  • Table 6 summarizes oral drugs affecting lipoprotein metabolism.

TABLE 6 Drugs Affecting Lipoprotein Metabolism

Drug ClassAgents and Daily DosesLipid/Lipoprotein EffectsSide EffectsContraindications
HMG-CoA reductase inhibitors (statins)Lovastatin (10-40 mg)
Pravastatin (10-80 mg)
Simvastatin† (5-80 mg)
Fluvastatin (20-40 mg)
Atorvastatin (10-80 mg)
Rosuvastatin (5-40 mg)
Pitavastatin (2-4 mg)		LDL↓ 20%-60%
HDL↑ 5%-15%
TG↓ 7%-30%		Myalgias, myositis
Increased liver enzymes
New-onset diabetes (with intensive therapy)
Unproven concerns about memory loss		Active or chronic liver disease
Pregnancy
Concomitant use of certain drugs∗
Bile acid sequestrantsColestipol (5-20 g)
Colesevelam‡ (2.6-3.8 g)
Cholestyramine (4-16 g)		LDL↓ 15%-30%
HDL↑ 3%-5%
TG No change or increase		Gastrointestinal distress, constipation, drug interaction, hypertriglyceridemia
Decreased absorption of fat-soluble vitamins		TG >300 mg/dl
GI motility disorder
Omega-3 fatty acidsFish oils (4-6 g)TG↓ 45%
HDL↑ 13%		Increased bleeding time
Nausea		Caution with anticoagulant therapy
Nicotinic acidImmediate release (niacin) (1.5-3 g)
Extended release (Niaspan) (1-2 g)		LDL↓ 5%-25%
HDL↑ 15%-35%
TG↓ 20%-50%		Flushing
Hyperglycemia
Hyperuricemia (or gout)
Upper GI distress
Hepatotoxicity		Chronic liver disease
Severe gout
Diabetes
Peptic ulcer disease
Pregnancy/lactation
Fibric acidsGemfibrozil (600 mg bid)
Fenofibrate (45-145 mg)		LDL↓ 5%-20%
HDL↑ 10%-20%
TG↓ 20%-50%		Dyspepsia
Gallstones
Myopathy (especially with concomitant use of gemfibrozil and statins)		Severe renal disease (dose adjustment for fenofibrate)
Severe hepatic disease
Caution with statins
Can worsen LDL cholesterol
Ezetimibe (cholesterol absorption inhibitor)Ezetimibe (10 mg)LDL↓ 18%
HDL↑ 1%
TG↓ 8%		Abdominal pain; myalgiasLiver disease
Avoid with resins and fibrates

GI, Gastrointestinal; HDL, high-density lipoprotein; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; LDL, low-density lipoprotein; TG, triglyceride.

∗Cyclosporine, macrolide antibiotics, various antifungal agents, and cytochrome P-450 inhibitors (fibrates and niacin should be used with appropriate caution).

† Dosages of simvastatin 80 mg are no longer recommended. Potential interactions with amlodipine and ranolazine warrant doses ≤2 mg daily.

‡ Colesevelam reduces glucose and A1c ∼0.5% and has been approved for treatment of diabetes with dyslipidemia.

Modified from The National Cholesterol Education Program, JAMA 285:2486, 2001. In Boyden TF et al: Implementing new guidelines in the management of blood cholesterol, Am J Med 127:705, 2014.

TABLE 5 Combination Therapies for LDL

Statin plus ezetimibeEzetimibe added to a statin may further reduce LDL by 20% or more and reduce triglycerides by 7%-13%.
The combination provides equivalent LDL reduction to a fourfold increase in statin dose.
Daily ezetimibe added to a low-dose statin given 2-3 times/wk can improve tolerance. Combination pills containing statin and ezetimibe are available.
Most common side effects reflect those of the individual drugs.
Combination ezetimibe and simvastatin has been shown to decrease cardiovascular events in patients with renal disease and acute coronary syndrome.
Statin and PCSK9 inhibitorsThis combination is the most effective known treatment for hypercholesterolemia.
There are no known negative interactions between these two therapies.
This combination reduces CHD events more than statin alone.
Statin plus bile acid sequestrantsBile acid sequestrants in combination with statins further decrease LDL from 24% to 60%.Cholestyramine and colestipol can interfere with the absorption of statins. Colesevelam does not affect statin absorption.
The statin-colesevelam combination is not ideal for patients with high triglycerides but may be useful in those with type 2 diabetes mellitus because colesevelam reduces glycemia.
Statin plus niacinAdding niacin to a statin can lower LDL by 10% to 20%, in addition to beneficial effects on triglycerides. When used in combination with a statin, the maximum dose of niacin should be 2000 mg/day.
This combination in subjects with already low LDL levels did not reduce CHD events.
Bile acid sequestrants plus niacinBefore the availability of statins, bile acid sequestrants plus niacin were used to lower LDL in high-risk patients.
The availability of colesevelam and extended-release niacin has made this combination tolerable for many patients who are unable to use statins.
Ezetimibe plus bile acid sequestrantsEzetimibe inhibits cholesterol absorption, and sequestrants enhance cholesterol excretion through conversion to bile acids. The combination can have additive effects.
This combination is useful for patients who cannot take statins.

CHD, Coronary heart disease; LDL, low-density lipoprotein; PCSK9, proprotein convertase subtilisin/kexin type 9.

From Melmed S et al: Williams textbook of endocrinology, ed 14, St Louis, 2019, Elsevier.

Figure 2 A and B, Summary of 2018 ACC/AHA Cholesterol Guideline Recommendations for Statin and Nonstatin Therapy

Background Color Denotes Class and Level of Evidence: Green = Class I (Strong) Recommendation; Yellow = Class Iia (Reasonable) Recommendation; Blue = Grade A (High) Level of Evidence; Orange = Grade B (Moderate) Level of Evidence. Ascvd, Atherosclerotic Cardiovascular Disease; Cac, Coronary Artery Calcium; LDL-C, Low-Density Lipoprotein Cholesterol.

From Goldman L, Shafer AI: Goldman’s Cecil medicine, ed 26, St Louis, 2019, Elsevier.

TABLE 3 Statin Benefit Groups and Recommended Therapy

Statin Benefit GroupHigh IntensityModerate IntensityAdditional Testing
Clinical ASCVDYesConsider†None
Primary LDL-C >190 mg/dlYesConsider†None
Diabetes without ASCVD and 10-yr risk ≥7.5%∗YesConsider†None
Diabetes without ASCVD and 10-yr risk <7.5%∗Consider‡YesCase-by-case
Primary prevention and 10-yr risk ≥7.5%∗Consider‡YesCase-by-case
Primary prevention and 10-yr risk <7.5%∗Consider‡Consider‡Case-by-case

ASCVD, Atherosclerotic cardiovascular disease; LDL-C, low-density lipoprotein cholesterol.

∗Based on Pooled Cohort Risk Equations.

† If age >75 yr or not candidate for high intensity.

‡ If abnormal high-sensitivity C-reactive protein, coronary artery calcium, ankle-brachial index, lifetime risk.

From Boyden TF et al: Implementing new guidelines in the management of blood cholesterol, Am J Med 127:705, 2014.

TABLE 4 High-, Moderate-, and Low-Intensity Statin Therapy∗

Statin TherapyDaily Dose
High Intensity†
↓LDL-C ≥50%		Moderate Intensity‡
↓LDL-C 30<50%		Low Intensity§
↓LDL-C <30%
Atorvastatin(40||)-80 mg10(20)mg
Rosuvastatin20(40)mg(5)10 mg
Simvastatin20-40 mg10 mg
Pravastatin40(80)mg10-20 mg
Lovastatin40 mg20 mg
Fluvastatin80 mg (Fluvastatin XL)20-40 mg
Fluvastatin40 mg∗∗
Pitavastatin2-4 mg1 mg

FDA, U.S. Food and Drug Administration; LDL-C, low-density lipoprotein cholesterol; XL, extended-release.

∗Individual responses to statin therapy varied in randomized, controlled trials and vary in clinical practice. A less-than-average response may have a biologic basis. Statins and dosages in bold were reduced in major cardiovascular events in randomized, controlled trials. Statins and doses in italics were approved by the FDA but were not tested in randomized, controlled trials.

† Daily dose decreases LDL-C levels by an average of ≥50%.

‡ Daily dose decreases LDL-C levels by an average of 30 to <50%.

§ Daily dose decreases LDL-C levels by an average of <30%.

|| Evidence from 1 randomized, controlled trial only; down-titration if patient is unable to tolerate atorvastatin, 80 mg.

Although simvastatin, 80 mg, was evaluated in randomized, controlled trials, the FDA recommends against initiation of or titration to 80 mg of simvastatin because of increased risk for myopathy and rhabdomyolysis.

∗∗Twice daily.

Reprinted with permission of the authors: Stone NJ et al: 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol 63(25, Part B):2889-2934, 2014.

Figure 1 Initiating statin therapy in individuals with clinical ASCVD.

!!flowchart!!

∗Fasting lipid panel is preferred. In a nonfasting individual, a nonfasting non-HDL-C >220 mg/dl may indicate genetic hypercholesterolemia that requires further evaluation or a secondary etiology. If nonfasting triglycerides are >500 mg/dl, a fasting lipid panel is required.†It is reasonable to evaluate the potential for ASCVD benefits and for adverse effects and to consider patient preferences in initiating or continuing a moderate- or high-intensity statin in individuals with ASCVD >75 yr of age. ALT, Alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; CK, creatine kinase; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; ULN, upper limit of normal.

Modified from Stone NJ et al: 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol, 2013. In Mann DL et al: Braunwald’s heart disease, ed 10, Philadelphia, 2015, Elsevier.

TABLE 2 Atherosclerotic Cardiovascular Disease

  1. Coronary heart disease: Acute coronary syndromes, history of myocardial infarction, stable or unstable angina, coronary or other arterial revascularization
  2. Stroke or transient ischemic attack
  3. Peripheral arterial disease

BOX 1 2013 ACC/AHA Summary of Key Recommendations for the Treatment of Blood Cholesterol to Reduce ASCVD Risk in Adults

  1. Heart-healthy lifestyle habits should be encouraged for all individuals
  2. The appropriate intensity of statin therapy should be initiated or continued
    1. Clinical ASCVD∗
      1. Age 75 yr or less and no safety concerns: High-intensity statin (class I, level A)
      2. Age 75 yr or safety concerns: Moderate-intensity statin (class I, level A)∗
    2. Primary prevention: Primary LDL-C 190 mg/dl or greater
      1. Rule out secondary causes of hyperlipidemia (class I, level B)
      2. Age 21 yr or older: High-intensity statin (class I, level B)
      3. Achieve at least a 50% reduction in LDL-C (class IIa, level B)
      4. LDL-C lowering nonstatin therapy may be considered to further reduce LDL-C (class IIb, level C)
    3. Primary prevention: Diabetes, 40 to 75 yr of age, and LDL-C 70 to 189 mg/dl
      1. Moderate-intensity statin (class I, level A)
      2. Consider high-intensity statin when 7.5% or greater 10-yr ASCVD risk using the Pooled Cohort Equations (class IIa, level B)‡
    4. Primary prevention: No diabetes, 40 to 75 yr of age, and LDL-C 70 to 189 mg/dl
      1. Estimate 10-yr ASCVD risk using the Risk Calculator based on the Pooled Cohort Equations in those not receiving a statin; estimate risk every 4 to 6 yr (class I, level B)
      2. To determine whether to initiate a statin, engage in a clinician-patient discussion of the potential for ASCVD risk reduction, adverse effects, drug-drug interactions, and patient preferences
      3. Reemphasize heart-healthy lifestyle habits and address other risk factors (class IIa, level C)
        1. 7.5% or greater 10-yr ASCVD risk: Moderate- or high-intensity statin (class I, level A)
        2. 5% to 7.5% 10-yr ASCVD risk: Consider moderate-intensity statin (class IIa, level B)
        3. Other factors may be considered: LDL-C 160 mg/dl or greater, family history of premature ASCVD, hs-CRP 2.0 mg/L or greater, CAC score 300 Agatston units or greater, ABI less than 0.9, or lifetime ASCVD risk (class IIb, level C)
    5. Primary prevention when LDL-C is less than 190 mg/dl and age is less than 40 or more than 75 yr, or less than 5% 10-yr ASCVD risk
      1. Statin therapy may be considered in selected individuals (class IIb, level C)
    6. Statin therapy is not routinely recommended for individuals with NYHA class II-IV heart failure or who are receiving maintenance hemodialysis
  3. Regularly monitor adherence to lifestyle and drug therapy with lipid and safety assessments
    1. Assess adherence, response to therapy, and adverse effects within 4 to 12 wk following statin initiation or change in therapy (class I, level A)
      1. Measure a fasting lipid panel (class I, level A)
      2. Do not routinely monitor ALT or CK unless symptomatic (class IIa, level C)
      3. Screen and treat type 2 diabetes according to current practice guidelines. Heart-healthy lifestyle habits should be encouraged to prevent progression to diabetes (class I, level B)
      4. Anticipated therapeutic response: Approximately 50% or greater reduction in LDL-C from baseline for high-intensity statin and 30% to 50% for moderate-intensity statin (class IIa, level B)
        1. Insufficient evidence for LDL-C or non-HDL-C treatment targets from RCTs
        2. For those with unknown baseline LDL-C, an LDL-C less than 100 mg/dl was observed in RCTs of high-intensity statin therapy
      5. Less than anticipated therapeutic response:
        1. Reinforce improved adherence to lifestyle and drug therapy (class I, level A)
        2. Evaluate for secondary causes of hyperlipidemia if indicated (class I, level A)
        3. Increase statin intensity, or if on maximally tolerated statin intensity, consider addition of nonstatin therapy in selected high-risk individuals (class IIb, level C)§
    2. Regularly monitor adherence to lifestyle and drug therapy every 3 to 12 mo once adherence has been established. continue assessment of adherence for optimal ASCVD risk reduction and safety (class I, level A)
  4. In individuals intolerant of the recommended intensity of statin therapy, use the maximally tolerated intensity of statin (class I, level B). If there are muscle or other symptoms, establish that they are related to the statin (class IIa, level B)

ABI, Ankle brachial index; ACC, American College of Cardiology; AHA, American Heart Association; ALT, alanine transaminase; ASCVD, atherosclerotic cardiovascular disease; CAC, coronary artery calcium; CK, creatine kinase; hs-CRP, high sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; NYHA, New York Heart Association; RCTs, randomized clinical trials; TIA, transient ischemic attack.From 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, J Am Coll Cardiol 63(25 Pt B):2889-2934, 2014.

Disposition & Follow-Up

  • Baseline LFT testing should be done before initiation of statin therapy and as clinically indicated thereafter.
  • Creatine kinase level monitoring is not recommended unless a patient reports muscle weakness or myalgias.
  • Statin therapy should be monitored by repeating a lipid profile within 4 to 12 wk after initiation of therapy.
  • Counseling about behavioral lifestyle changes and risk factors for CHD should be provided at every follow-up visit.
  • Adverse effects of statin-associated diabetes vary by statin intensity: One excess case of diabetes per 1000 treated individuals with moderate-intensity statin and three excess cases of diabetes per 1000 treated individuals with high-intensity statin per year has been reported. Myopathy and hemorrhagic stroke incidence is around one excess case per 10,000 treated individuals.
  • Per new guidelines, those who develop diabetes during statin therapy should be advised to continue moderate to high intensity statins to reduce their risk of ASCVD events and should adhere to a heart-healthy diet, engage in physical activity, cease tobacco use, and maintain a healthy body weight (Table 6).
  • Regarding choice of statin, Atorvastatin and Rosuvastatin are preferred in most patients with moderate to high; hypercholesterolemia for patients on simvastatin with moderate to high. Maintain patients on 80 mg daily of simvastatin only if they have been taking this dose for 12 or more mo without evidence of muscle toxicity. Do not start new patients on simvastatin 80 mg. Place patients who do not meet their LDL goal on simvastatin 40 mg on alternative LDL-C-lowering treatment(s) to reach goal.
Referral

Patients with rare lipid disorders, hyperlipoproteinemias, patients resistant to treatment, on complex regimens, and with evidence of disease progression despite treatment should be referred to a lipid specialist.

∗Clinical ASCVD includes acute coronary syndromes, history of MI, stable or unstable angina, coronary or other arterial revascularization, stroke, TIA, or peripheral arterial disease presumed to be of atherosclerotic origin.

‡ These factors may include primary LDL-C of 160 mg/dl or greater or other evidence of genetic hyperlipidemias; family history of premature ASCVD with onset at less than 55 yr of age in a first-degree male relative or at less than 65 yr of age in a first-degree female relative; hs-CRP 2 mg/L or greater; CAC score 300 Agatston units or greater or 75th percentile or greater for age, sex, and ethnicity; ABI less than 0.9; or lifetime risk of ASCVD. Additional factors that might aid in individual risk assessment could be identified in the future.

§ High-risk individuals include those with clinical ASCVD, an untreated LDL-C 190 mg/dl or greater, suggesting genetic hypercholesterolemia, or individuals with diabetes 40 to 75 yr of age and LDL-C 70 to 189 mg/dl.

Pearls & Considerations ⬆ ⬇

Comments

  • New features in the 2018 clinical practice guidelines compared to the 2013 guidelines support the addition of nonstatin medications (ezetimibe or PCSK9 inhibitors) to statin therapy for secondary prevention in patients at very high risk. In primary prevention, a clinical patient risk discussion is strongly recommended before a decision is made about statin treatment. Among intermediate-risk patients, identification of risk-enhancing factors and coronary calcium testing is recommended when considering the use of a statin.
  • Familial hypercholesterolemia (FH) is characterized by elevated cholesterol concentrations early in life. Untreated FH is associated with premature cardiovascular disease in adulthood. Screening can detect FH in children, and lipid-lowering treatment in childhood can reduce lipid concentrations in the short term, with little evidence of harm. A 20-yr follow-up study of statin therapy has shown that initiation of statin therapy during childhood in patients with FH slows the progression of carotid intima media thickness and reduces the risk of cardiovascular disease in adulthood.
  • The American Academy of Pediatrics (AAP) guideline (Pediatrics 122:198, 2008) recommends consideration toward pharmacologic treatment for children with LDL >190 mg/dl or >160 mg/dl if other risk factors are present.
  • HDL cholesterol efflux capacity refers to the ability of HDL to accept cholesterol from macrophages, which is a key step in reverse cholesterol transport. It is inversely associated with the incidence of cardiovascular events and may be a useful biomarker when added to traditional risk factors.
  • There are currently no pharmacologic therapies approved to reduce Lp(a) and ASCVD risk. Although PCSK9 monoclonal antibodies reduce Lp(a), they are not approved for use among individuals who meet LDL cholesterol targets. Niacin modestly reduces Lp(a) but may not further reduce ASCVD risk in addition to statins.3,4
Related Content

High Cholesterol (Patient Information)

Coronary Artery Disease (Related Key Topic)

Hyperlipoproteinemia, Primary (Related Key Topic)

Statin-Induced Muscle Syndrome (Related Key Topic)

Related Content ⬆

    1. Grundy SM et al: 2018 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, Circulation 139(25):e1082-e1143, 2019.
    2. Ho Q et al: PCSK9 inhibitors and ezetimibe for reduction of cardiovascular events : a clinical practice guideline with risk stratified recommendations, BMJ 377:e069066. 2022.
    3. O’Donoghue M.L. : Lipoprotein(a), PCSK9 inhibition, and cardiovascular riskCirculation. ;139(12):1483-1492, 2019.
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