How to Cite This Chapter: Attalla M, Curnew G, Pare G, Cybulska B, Kłosiewicz-Latoszek L, Szostak W. Hypercholesterolemia. McMaster Textbook of Internal Medicine. Kraków: Medycyna Praktyczna. https://empendium.com/mcmtextbook/chapter/B31.II.2.4.1.?utm_source=nieznany&utm_medium=referral&utm_campaign=social-chapter-link Accessed June 17, 2024.
Last Updated: February 2, 2022
Last Reviewed: February 2, 2022
Chapter Information

Definition, Etiology, PathogenesisTop

Hypercholesterolemia: In healthy individuals a plasma/serum low-density lipoprotein cholesterol (LDL-C) level ≥3.0 mmol/L (115 mg/dL) or even ≥2.6 mmol/L (100 mg/dL) may be considered abnormal. Current guidelines are not specific on abnormal levels but rather correlate the LDL-C concentration with a risk category and recommend lifestyle changes or pharmacotherapy on this basis.

Severe hypercholesterolemia: Defined as LDL-C level >4.9 mmol/L.

Premature atherosclerosis: Defined as the presence of complications of atherosclerosis (myocardial infarction [MI], stroke, peripheral arterial disease) at a relatively young age (<55 years for men or <65 for women) in the absence of risk factors for accelerated atherosclerosis. This should raise the suspicion of familial hypercholesterolemia (FH).

Secondary causes of hypercholesterolemia: Hypothyroidism, nephrotic syndrome, primary biliary cirrhosis, medications (isotretinoin, glucocorticoids).


Consider screening patients with the following:

1) Men aged ≥40 years; women ≥40 years or after menopause.

2) Ethnic groups at increased risk (eg, South Asian, First Nations).

3) Diabetes mellitus (particularly in individuals aged 40-75 years).

4) Family history of early cardiovascular disease (men <55 years, women <65 years).

5) Chronic kidney disease (CKD).

6) HIV.

7) Hypothyroidism.

8) Nephrotic syndrome.

9) Metabolic syndrome.

10) Chronic inflammatory disease.

11) Smoking.

12) Hypertensive disease in pregnancy.

13) Use of certain drugs (progestogens, glucocorticoids, protease inhibitors).

14) Cushing syndrome.

15) Anorexia nervosa.

16) Liver disease.

17) Hypertension.

Screening criteria suggesting the presence of FH:

1) LDL-C level ≥5.0 mmol/L in individuals aged ≥40 years.

2) LDL-C level ≥4.5 mmol/L in individuals aged 18 to 39 years.

3) LDL-C level ≥4.0 mmol/L in individuals aged <18 years.


Diagnostic Criteria

Simon Broome diagnostic criteria for FM:

1) Major diagnostic criteria for FH (definite FH): Presence of any of the following:

a) DNA mutation in the LDLR, APOB, or PCSK9 genes.

b) Tendon xanthoma.

c) LDL-C level ≥8.5 mmol/L.

2) Minor diagnostic criteria for FH (probable FH):

a) A first-degree relative with elevated LDL-C concentration.

b) A proband or first-degree relative with atherosclerotic cardiovascular disease (CVD) aged <55 years (men) or <65 years (women).

A more complex and frequently used formal scoring system, the Dutch Lipid Clinic Network, uses the same categories: family history, clinical history, physical examination, LDL-C levels, and DNA analysis (Table 8 in Familial hypercholesterolaemia (‎FH): report of a second WHO consultation, Geneva, 4 September 1998 at who.int). Calculators are also available online (eg, at www.mdcalc.com).

Differential Diagnosis

1. FH: Most often caused by a mutation affecting the LDL receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 (PCSK9) protease. FH follows an autosomal dominant mode of inheritance.

2. Polygenic hypercholesterolemia: Lower total cholesterol (TC) levels, equivocal family history of high TC levels, no xanthomas.

Note that in most countries <1% of patients with heterozygous FH are diagnosed.Evidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Nordestgaard BG, Chapman MJ, Humphries SE, et al; European Atherosclerosis Society Consensus Panel. 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 Dec;34(45):3478-90a. doi: 10.1093/eurheartj/eht273. Epub 2013 Aug 15. PubMed PMID: 23956253; PubMed Central PMCID: PMC3844152.


General Considerations

Target LDL-C levels and indications (Table 1) depend on the patient’s total cardiovascular risk rather than on the absolute lipid level. In North America the risk of CVD is assessed using the Framingham risk score (Table 1 in Prevention of Cardiovascular Diseases). The Framingham Heart Study website provides numerous ways of calculating the 10-year CVD risk. Canadian guidelines consider a probability of cardiovascular complications over 10 years that is >20% as high risk and a probability between 10% and 19% as intermediate risk. Cardiovascular complications include coronary death, myocardial infarction, coronary insufficiency, angina, ischemic stroke, hemorrhagic stroke, transient ischemic attack, peripheral artery disease, and heart failure.

According to Canadian guidelines, indications for statins include high and intermediate risk categories and are also based on the presence of certain clinical conditions (see Prevention of Cardiovascular Diseases). Treatment targets are similar with the exception of lower LDL-C in patients with acute coronary syndrome in the last 3 months (Table 1).

Lifestyle Modifications (Recommended for General Population)

1. The Mediterranean diet, characterized by a high consumption of vegetables and olive oil with a moderate consumption of protein (including nuts), can reduce the risk of cardiovascular events.Evidence 2Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and heterogeneity. Rees K, Takeda A, Martin N, et al. Mediterranean-style diet for the primary and secondary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2019 Mar 13;3:CD009825. doi: 10.1002/14651858.CD009825.pub3. PubMed PMID: 30864165; PubMed Central PMCID: PMC6414510. Suggestions include replacement of saturated fats with polyunsaturated fats; restriction of fatty acids to <7% of caloric requirements (<15 g/d with a caloric intake of 2000 kcal/d) by partial substitution with polyunsaturated fatty acids or complex carbohydrates (optimally high-fiber products); restricted intake of trans-unsaturated fatty acids (hard margarines, ready-made pastries, instant soups); limiting cholesterol to <300 mg/d.

2. Exercise reduces individual risk factors. However, its effect on the cumulative risk remains unclear.

3. Smoking cessation may improve the lipid profile.Evidence 3Low Quality of Evidence (low confidence that we know true effects of the intervention). Quality of Evidence lowered due to the observational nature of data. Gepner AD, Piper ME, Johnson HM, Fiore MC, Baker TB, Stein JH. Effects of smoking and smoking cessation on lipids and lipoproteins: outcomes from a randomized clinical trial. Am Heart J. 2011 Jan;161(1):145-51. doi: 10.1016/j.ahj.2010.09.023. PubMed PMID: 21167347; PubMed Central PMCID: PMC3110741.


Agents and dosage: Table 2.

1. Statins are the first-line agents to lower LDL-C levels and have a weak effect on TG and high-density lipoprotein cholesterol (HDL-C) concentrations. Statins should be initiated at a high intensity. Dosage can be reduced if the patient experiences adverse effects.

Indications for the initiation of statins: Dyslipidemia, particularly with LDL-C levels persistently >3.5 mmol/L and presence of other risk factors for CVD; established atherosclerotic CVD, such as coronary artery disease; CKD; aortic aneurysm; severe hypercholesterolemia (LDL-C >4.9 mmol/L); diabetes mellitus.

Contraindications: Pregnancy, breastfeeding, active liver disease (alanine aminotransferase [ALT] or aspartate aminotransferase [AST] levels >3 × upper limit of normal [ULN]; a smaller increase is not an absolute contraindication but requires close monitoring and control after 4-6 weeks). Certain liver conditions are not absolute contraindications: chronic liver disease or stable cirrhosis, nonalcoholic fatty liver, liver transplant, autoimmune (nonchronic) hepatitis.

Significant adverse effects:

1) Patients at increased risk of adverse events include those with any of the following: >80 years of age, renal failure, hypothyroidism, inflammatory diseases of the muscles, those in a perioperative period, and those of Asian ethnicity.

2) Increased serum ALT or AST levels occur in 0.5% to 2% of patients, are dose-dependent, and usually return to baseline values after reducing the statin dose. An increase in AST or ALT may not have clinical implications and further liver assessment may be of value (albumin, international normalized ratio [INR], bilirubin). Measure serum transaminase levels within the first 3 months. In patients with ALT >3 × ULN, discontinue statins and measure the ALT level again after 4 to 6 weeks. Restarting statins in lower doses may be considered after the ALT concentration returns to normal.

3) Muscle discomfort may be present in up to 10% to 15% of patients.

4) Myopathy develops in <0.2% of patients. It manifests with pain, muscle weakness or tenderness (or both), and increased serum creatine kinase (CK) levels. Very rarely, myopathy may lead to rhabdomyolysis; this may occur at any time of statin therapy. Measurement of CK is advised prior to treatment initiation. Subsequent monitoring in patients with no muscle pain is not necessary. However, CK must be measured in all patients who develop muscle pain, tenderness, weakness, or brownish urine (all patients should be advised to report such symptoms immediately).

In patients with CK levels >3 × ULN, discontinue statins immediately and measure CK (if >10 × ULN, measure CK and creatinine every 2 weeks). Remember to review drugs for interactions (eg, fibrates [particularly gemfibrozil], azole antifungal agents [fluconazole, itraconazole, ketoconazole], macrolide antibiotics, other drugs inhibiting the metabolism of statins). If there is an attempt to restart statins, you can try to use atorvastatin or rosuvastatin in a low dose every other day or 1 to 2 days per week in combination with ezetimibe; in patients at very high cardiovascular risk who have not reached the target LDL-C level, subsequently consider a PCSK9 inhibitor as the third drug. If the patient does not tolerate statins even at a low dose, use ezetimibe and, if justified by the risk, possibly a PCSK9 inhibitor.

In patients with a CK level <3 × ULN, monitor CK and symptoms every 6 weeks. If the discomfort persists, stop the statin. If symptoms resolve after 2 to 4 weeks, you can try another statin while monitoring muscle aches and CK activity.

If CK measurement is performed in a patient with no muscle symptoms and the level is ≥3 × ULN (and <10 × ULN), you can continue statin treatment if the CK concentration is monitored.

Note that statins may increase the risk for developing diabetes among people at high risk of that condition.Evidence 4Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness. Crandall JP, Mather K, Rajpathak SN, et al. Statin use and risk of developing diabetes: results from the Diabetes Prevention Program. BMJ Open Diabetes Res Care. 2017 Oct 10;5(1):e000438. doi: 10.1136/bmjdrc-2017-000438. Erratum in: BMJ Open Diabetes Res Care. 2017 Oct 25;5(1):e000438corr1. PMID: 29081977; PMCID: PMC5652620.

2. Ezetimibe is second-line therapy and should be used primarily in combination with a statin in patients with significant hypercholesterolemia to achieve target LDL-C levels. Ezetimibe may be useful as monotherapy in patients with intolerance of statins, but it has lower effectiveness.

3. Inhibitors of PCSK9 are third-line therapy. Evolocumab and alirocumab (subcutaneous injection once every 2-4 weeks) are the available options. Generally the absolute benefit is proportional to cholesterol loweringEvidence 5High Quality of Evidence (high confidence that we know true effects of the intervention). Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of Proprotein Convertase Subtilisin/Kexin Type 9 Antibodies in Adults With Hypercholesterolemia: A Systematic Review and Meta-analysis. Ann Intern Med. 2015 Jul 7;163(1):40-51. doi: 10.7326/M14-2957. Review. PubMed PMID: 25915661.; the major limitation is the high cost of these medications in some jurisdictions (this may be >$5000 per year).

Indications include:

1) Homozygous FH or heterozygous FH with high LDL-C levels despite using a statin at the maximum tolerated dose.

2) Patients with a significantly high cardiovascular risk who have not reached the target LDL-C level despite using a statin at the maximum tolerated dose in combination with ezetimibe, or those who do not tolerate statins. Threshold serum LDL-C concentrations in qualifying for the initiation of a PCSK9 inhibitor:

a) LDL-C levels ≥2.0 mmol/L on a statin at the maximum tolerated dose + ezetimibe therapy.

b) Patients aged 30 to 75 years with heterozygous FH: LDL-C concentration ≥2.6 mmol/L while on a statin at the maximum tolerated dose + ezetimibe therapy.

Adverse effects: Injection-site reactions (usually mild).

Monitoring: Check the LDL-C level 4 to 8 weeks after initiating therapy. A maximum dose should be used at initiation.

4. Bile acid sequestrants (resins) are fourth-line therapy: cholestyramine, colestipol, colesevelam. These are used as monotherapy in patients with contraindications to or intolerance of statins and in combination treatment when the efficacy of statins is suboptimal. Colesevelam is used in pregnant women.

Contraindications: High serum triglyceride (TG) levels (>5.6 mmol/L [500 mg/dL] or, according to some experts, >3.4 mmol/L [300 mg/dL]).

Adverse effects: Troublesome gastrointestinal symptoms, including constipation, eructation (belching), abdominal pain, flatulence (except for colesevelam); malabsorption of fat-soluble vitamins and other drugs, such as beta-blockers, thiazide diuretics, thyroxine, digoxin, and oral anticoagulants. All other drugs should be administered 1 hour before or 4 hours after a bile acid sequestrant.

Other Approaches

1. Emerging treatments such as inclisiran and bempedoic acid are approved in many jurisdictions, with data on patient-important outcome measures not yet fully available.

2. Lomitapide (inhibitor of the microsomal TG transfer protein in hepatocytes): Usually authorized for homozygous FH treatment. Treatment should be conducted in specialized centers.

3. LDL-C apheresis (extracorporeal removal of LDL-C) in homozygotic FH (TC usually 18-31 mmol/L) or severe heterozygotic FH in patients with CVD. The procedure is repeated every 2 weeks and the patient should be also treated with high-dose potent statins (eg, atorvastatin 80 mg/d or rosuvastatin 40 mg/d). It is a rare treatment conducted in specialized centers only.


Table 3.12-1. Management targets for dyslipidemia

Risk category (10-year CVD risk)a

Serum target

Very high risk

LDL-C <70 mg/dL (<1.8 mmol/L)b

High risk (FRS ≥20%)

LDL-C <2.0 mmol/L or reduce by >50%d


ApoB <0.8 g/L


Non–HDL-C <2.6 mmol/L

Intermediate risk (FRS 10%-19%) and ≥1 of:

1) LDL-C ≥3.5 mmol/L

2) Non–HDL-C ≥4.3 mmol/L

3) ApoB >1.2 g/L

4) Men >50 years, women >60 years (only with +1 additional CVD risk factor)c

LDL-C >5.0 mmol/L

>50% reduction in LDL-C

a See table 3.16-1.

b History of multiple major ASCVD events (recent ACS within the past 12 months, history of MI or ischemic stroke, symptomatic PAD) or 1 major ASCVD event and multiple high-risk conditions.

c Low HDL-C, impaired fasting glucose, high waist circumference, active smoker, hypertension.

d LDL-C <1.8 mmol/L in patients with acute coronary syndrome in the last 3 months.

Based on Can J Cardiol. 2016;32(11):1263-1282.

ApoB, apolipoprotein B; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; FRS, Framingham risk score; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; PAD, peripheral artery disease.

Table 3.12-2. Selected lipid-lowering agents





10-80 mg once daily


20-80 mg once daily


20-80 mg once daily


5-40 mg once daily


5-80 mga once daily

Pitavastatin (not used in Canada)

1-4 mg once daily

Bile acid sequestrants (resins)


Start from 4 g once daily to bid, then titrate up to 4 g/d (max, 24 g/d in divided doses)


1.875 g bid or 3.75 g once daily



10 mg once daily

PCSK9 inhibitors


140 mg SC every 2 weeks or 420 mg once monthly


75 mg SC every other week, 150 mg SC every 2 weeks, or 300 mg every 4 weeks

a Note: The US Food and Drug Administration does not recommend the use of simvastatin at a dose of 80 mg/d because of increased incidence of myopathy.

PCSK9, proprotein convertase subtilisin/kexin type 9; SC, subcutaneous.

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