Hypercholesterolemia

Chapter: Hypercholesterolemia
McMaster Section Editor(s): P.J. Devereaux
Section Editor(s) in Interna Szczeklika: Andrzej Budaj, Wiktoria Leśniak
McMaster Author(s): Mirna Attalla, Greg Curnew
Author(s) in Interna Szczeklika: Barbara Cybulska, Longina Kłosiewicz-Latoszek, Wiktor Szostak
Additional Information

Definition, Etiology, PathogenesisTop

In healthy individuals a plasma/serum low-density lipoprotein cholesterol (LDL-C) level ≥3.0 mmol/L (115 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.

Classification:

1) Primary hypercholesterolemia:

a) Polygenic hypercholesterolemia (most common) involving environmental factors, such as diet.

b) Familial (monogenic) hypercholesterolemia (FH): Most often heterozygous familial hypercholesterolemia (HeFH) caused by a mutation affecting the LDL receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin type 9 (PCSK9) protease.

2) Secondary hypercholesterolemia: Hypercholesterolemia caused by medical conditions, including hypothyroidism, nephrotic syndrome, chronic kidney disease, liver disease with cholestasis, Cushing syndrome, anorexia nervosa, or drug induced (secondary to progestogens, glucocorticoids, protease inhibitors).

Clinical FeaturesTop

Clinical signs in patients with FH: Tendon xanthomas (of the Achilles tendon and tendon of the extensor digitorum muscle), corneal arcus.

ScreeningTop

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.

4) Aortic aneurysm.

5) Chronic obstructive pulmonary disease.

6) Hypertension.

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

8) Chronic kidney disease (CKD).

9) HIV.

10) Erectile dysfunction.

11) Clinical features of atherosclerosis.

12) Obesity.

13) Chronic inflammatory disease.

14) Active smokers.

15) Hypertensive disease in pregnancy.

DiagnosisTop

Diagnostic Criteria

Indirect evidence is provided by LDL-C levels >4.9 mmol/L (190 mg/dL) or signs of premature atherosclerosis (these can occur in childhood in homozygous patients) and first-degree relatives with FH. Detection of a mutation causing hypercholesterolemia confirms the diagnosis of FH but has no impact on the clinical management.

Differential Diagnosis

1. Familial combined hyperlipidemia (lower total cholesterol [TC] and higher triglyceride [TG] levels).

2. Polygenic hypercholesterolemia (lower TC levels, no 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.

TreatmentTop

General Considerations

Target LDL-C levels and indications (Table 3.12-1) depend on the patient’s total cardiovascular risk rather than on the absolute lipid level. In North America the risk of cardiovascular disease (CVD) is assessed using the Framingham risk score (see Table 3.15-1). 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 3.12-1).

Lifestyle Modifications

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 cumulative risk factors 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.

4. There is no evidence that improved sleep hygiene has beneficial effects.Evidence 4Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to heterogeneity. Kruisbrink M, Robertson W, Ji C, Miller MA, Geleijnse JM, Cappuccio FP. Association of sleep duration and quality with blood lipids: a systematic review and meta-analysis of prospective studies. BMJ Open. 2017 Dec 14;7(12):e018585. doi: 10.1136/bmjopen-2017-018585. Review. PubMed PMID: 29247105; PubMed Central PMCID: PMC5735405.

Pharmacotherapy

Agents and dosage: Table 3.12-2.

1. Statins are the first-line agents to lower LDL-C levels and have a moderate effect on TG and high-density lipoprotein cholesterol (HDL-C) concentrations.

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 transplantation, 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, and those in a perioperative period.

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 >4 × 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 <4 × 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 ≥4 × ULN (and <10 × ULN), you can continue statin treatment if the CK concentration is monitored.

2. Ezetimibe 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. Bile acid sequestrants (resins): 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 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.

4. Inhibitors of PCSK9: Evolocumab and alirocumab (subcutaneous injection once every 2-4 weeks). 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 high cost of medications. Indications include:

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

2) Very high cardiovascular risk in patients who have not reached the target LDL-C level despite using a statin at the maximum tolerated dose in combination with ezetimibe. Threshold serum LDL-C concentrations in qualifying for the initiation of a PCSK9 inhibitor:

a) In patients with atherosclerotic CVD without additional risk factors: >3.6 mmol/L (140 mg/dL).

b) In patients with atherosclerotic CVD with additional risk factors: >2.6 mmol/L (100 mg/dL).

c) In patients with FH without additional risk factors: >4.5 mmol/L (180 mg/dL).

d) In patients with FH with additional risk factors: >3.6 mmol/L (140 mg/dL).

5. Lomitapide (inhibitor of the microsomal TG transfer protein in hepatocytes): Usually authorized for reimbursement for homozygous FH treatment, which is very rare. Treatment should be conducted in specialized centers.

Other Approaches

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.

TablesTop

Table 3.12-1. Management targets for dyslipidemia

Risk category (10-year CVD risk)a

Serum target

High risk (FRS ≥20%)

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

or

Apolipoprotein B <0.8 g/L

or

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) Apolipoprotein B >1.2 g/L

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

LDL-C >5.0 mmol/L

>50% reduction in LDL-C

a See Table 3.15-1.

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

c 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.

CVD, cardiovascular disease; FRS, Framingham risk score; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol.

Table 3.12-2. Selected lipid-lowering agents

Agent

Dosage

Statins

Atorvastatin

10-80 mg once daily

Fluvastatin

20-80 mg once daily

Lovastatin

20-80 mg once daily

Rosuvastatin

5-40 mg once daily

Simvastatin

5-80 mga once daily

Bile acid sequestrants (resins)

Cholestyramine

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

Colesevelam

Monotherapy 1.875 g bid or 3.75 g once daily (max, 4.375 g/d)

Combination treatment 2.5-3.75 g/d (max, 3.75 g/d)

Fibrates

Ciprofibrate

100 mg once daily

Fenofibrate

 

Nonmicronized

Start from 100 mg tid; maintenance dose 200 mg/d

Micronized

145, 160, 200, 215, or 267 mg once daily

Other

Ezetimibe

10 mg once daily

PCSK9 inhibitors

Evolocumab

140 mg SC every 2 weeks or 420 mg once monthly

Alirocumab

75 mg SC every other week, then dose may be increased to 150 mg 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.

SC, subcutaneous.

 

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