Hyperlipidaemia

What is hyperlipidaemia?^{1 2}

Hyperlipidaemia is the term used to denote raised serum levels of one or more of total cholesterol (TChol), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), or both TChol and TG (combined hyperlipidaemia).

Dyslipidaemia is a wider term that also includes low levels of high-density lipoprotein cholesterol (HDL-C).^{1 2} Many types of hyperlipidaemias carry an increased risk of cardiovascular disease (CVD), but HDL-C confers protection. It is important as one of the three main modifiable risk factors for CVD (the others being smoking and hypertension).

Familial hyperlipidaemia (FH) is an inherited condition (autosomal dominant) in which the liver is much less able to remove excess LDL cholesterol. There are three main genes that can be involved in FH:

• LDL receptor genes: by far the most commonly affected genes.

• Apolipoprotein B (APOB) gene: LDL cholesterol does not bind well to LDL receptors.

• PCSK9 gene: LDL receptors are broken down in the liver so can’t take cholesterol out of the blood stream.

How common is hyperlipidaemia? (Epidemiology)³

• The UK population has one of the highest average serum cholesterol levels in the world. Two thirds of the UK population have a serum cholesterol level greater than 5.2 mmol/L.

• Low levels of HDL-C are often associated with raised TG levels (eg, in familial combined hyperlipidaemia and in dyslipidaemia in type 2 diabetes).

• Heterozygous familial hypercholesterolaemia (FH) is relatively common. Between 1 in 250 and 1 in 500 of the UK population have heterozygous FH.

• Homozygous FH is rare, with an incidence of about one case per one million. Symptoms first appear in childhood.

• Of the theoretical estimated prevalence of 1/500 for heterozygous familial hypercholesterolaemia, less than 1% are diagnosed in most countries.⁴

What causes hyperlipidaemia? (Aetiology)^{5 6 7}

See the separate Prevention of Cardiovascular Disease article.

Inherited disorders

• Familial dyslipidaemias.

• Familial hypercholesterolaemia

• Familial combined hyperlipidaemia.

• Apoprotein disorders.

Secondary causes

• Medical conditions - eg, hypothyroidism, obstructive jaundice, Cushing's syndrome, anorexia nervosa, nephrotic syndrome, diabetes mellitus, metabolic syndrome, HIV, polycystic ovary syndrome and chronic kidney disease.

• Drugs - eg, thiazide diuretics, glucocorticoids, immunosuppressive agents, antiretroviral therapy, beta-blockers, combined oral contraceptive pill, atypical antipsychotics, and retinoic acid derivatives.

• Pregnancy.

• Obesity.

• Alcohol abuse.

Assessment^{5 6}

For the estimation of cardiovascular risk, measure both total blood cholesterol and high-density lipoprotein (HDL) cholesterol. See also the separate Cardiovascular Risk Assessment and Prevention of Cardiovascular Disease articles.

Suspect familial hypercholesterolaemia (FH) in adults with:

• A total cholesterol level greater than 7.5 mmol/L and/or

• A personal or family history of premature coronary heart disease (CHD, an event before 60 years in an index person or first-degree relative [parents, siblings, children]).

Systematically search primary care records for people who are at highest risk of FH, including:

• People younger than 30 years of age with a total cholesterol concentration greater than 7.5 mmol/L and

• People aged 30 years or older with a total cholesterol concentration greater than 9.0 mmol/L.

• For people with a personal or family history of premature CHD (an event before 60 years in an index person or first-degree relative) whose total cholesterol is unknown, offer to measure their total cholesterol.

In children aged 0–10 years who are at risk of FH because of one affected parent, refer for a DNA test at the earliest opportunity. If testing of a child at risk has not been undertaken by the age of 10 years, offer an additional opportunity for a DNA test.

In children at risk of homozygous FH because of two affected parents or because of the presence of clinical signs, eg, cutaneous lipid deposits (xanthomata), low-density lipoprotein (LDL) cholesterol concentration should be measured before the age of 5 years or at the earliest opportunity thereafter.

If familial hypercholesterolaemia (FH) is suspected, consider referring children and young people [up to 15 years of age] to a specialist for the assessment to be carried out.

Take two measurements of low-density lipoprotein (LDL) cholesterol concentration.

• Consider a clinical diagnosis of homozygous FH in adults with LDL cholesterol concentration greater than 13 mmol/L.

• Consider a clinical diagnosis of homozygous FH in a child or young person (up to 15 years of age) with an LDL cholesterol concentration greater than 11 mmol/L.

Look for clinical signs of FH, such as tendon xanthomata, but be aware that the absence of clinical signs does not exclude a diagnosis of FH.

Use the Simon Broome criteria or the Dutch Lipid Clinic Network (DLCN) criteria to aid clinical diagnosis of FH in primary care (see below). Make a clinical diagnosis of FH in people who meet the Simon Broome criteria for 'possible' or 'definite' FH, or have a DLCN score greater than 5.
The Simon Broome criteria has different lipid concentration levels for adults and children.

Refer all people with a clinical diagnosis of FH (heterozygous or homozygous) to a specialist for confirmation of the diagnosis and initiation of cascade testing (which involves identification of affected relatives by DNA testing).

Tendon xanthomata

Tendon xanthomata are hard, non-tender, nodular enlargements of tendons most commonly found on the knuckles of the hands and in the Achilles tendons, but may rarely be present on the extensor hallucis longus and triceps tendons.

They feel hard because they are fibrotic, and may become inflamed in the Achilles tendons (sometimes presenting as chronic Achilles tenosynovitis, which may be exacerbated by a statin).
Because the overlying skin is of normal colour, they may be difficult to detect.

Tendon xanthomata appear in people with heterozygous familial hypercholesterolaemia (FH) from 20 years of age onwards (unless the person was started on a statin early in life), but are often evident in homozygous FH from childhood. They are highly suggestive of FH, but their absence does not exclude FH.

Other types of xanthomata (such as xanthelasmata on the eyelids) and premature corneal arcus may occur in people with FH, but they are less specific.

Triglycerides⁸

Greater than 20mmol/L:

• Refer to lipid clinic for urgent specialist review if not a result of excess alcohol or poor glycaemic control.

• At risk of acute pancreatitis.

10 - 20mmol/L:

• Repeat the TG measurement with a fasting test (after an interval of 5 days, but within 2 weeks) and review for potential secondary causes of hyperlipidaemia.

• Seek specialist advice if the TG concentration remains > 10mmol/litre.

• At risk of acute pancreatitis.

4.5 - 9.9mmol/L:

• If non-fasting triglycerides are greater than 4.5mmol/L, repeat with a fasting TG measurement.

• CVD risk may be underestimated by risk assessment tools.

• Optimise the management of other CVD risk factors present and seek specialist advice if non-HDL-C concentration is > 7.5 mmol/litre.

Diagnostic criteria

The Simon Broom diagnostic criteria

• Definite: familial hypercholesterolaemia is diagnosed if an individual has:

  • A TChol level in an adult of >7.5 mmol/L (>6.7 mmol/L in a child) and an LDL-C of >4.9 mmol/L (>4.0 mmol/L in a child); PLUS

  • Tendon xanthomata or evidence of these signs in a first-degree or second-degree relative; OR

  • DNA evidence of an LDL receptor mutation, familial defective apo-B-100 or a PCSK9 mutation.

• Possible: familial hypercholesterolaemia should be diagnosed if the cholesterol concentrations fit these criteria and the individual has at least one of the following:

  • A family history of myocardial infarction in a second-degree relative aged 50 years or younger, or in a first-degree relative aged 60 years or younger.

  • A family history of raised TChol greater than 7.5 mmol/L in adult first-degree or second-degree relatives or greater than 6.7 mmol/L in a child, brother or sister aged younger than 16 years.

The Dutch Lipid Clinic Network (DLCN) criteria
An alternative to the Simon Broom criteria, this method assesses whether a person has FH based on personal and family medical history, clinical signs, LDL‑C concentration and DNA testing. A score is attributed to each component; the higher the score, the higher the likelihood of the person having FH.

Familial combined hyperlipidaemia⁹

This is the most common genetic dyslipidaemia, occurring in about 1 in 100 people but is usually polygenic in origin (it is also sometimes called polygenic hypercholesterolaemia).

Lipid phenotypes in familial combined hyperlipidaemia vary considerably but suspect where:

• There is family history of hyperlipidaemia or premature CHD not due to familial hypercholesterolaemia.

• There is moderate-to-severe mixed hyperlipidaemia (typically TChol 6.5-8.0 mmol/L and TG 2.3-5.0 mmol/L).

Before considering pharmacological treatment of dyslipidaemias, always try to identify and correct/optimise any secondary or contributory causes.

Investigations^{5 8}

Lipid profile: includes TChol, LDL-C (or non-HDL-C), HDL-C and TGs.

To exclude secondary hypercholesterolaemia:

• An underlying cause can usually be detected from the history and examination and by checking thyroid stimulating hormone, HbA1c, renal function, electrolytes, and liver function.

• An underlying condition or drug may be exacerbating primary FH, and serum lipids should be rechecked (if possible) after the condition has resolved or the drug has been stopped.

Further investigations may be required if another underlying cause of hyperlipidaemia is suspected, such as Cushing's syndrome or polycystic ovary syndrome.

DNA testing⁵

People with a clinical diagnosis of familial hypercholesterolaemia should be offered a DNA test to increase the certainty of their diagnosis and to aid diagnosis among their relatives. Inform all people who have an identified mutation diagnostic of FH that they have an unequivocal diagnosis of FH even if their LDL‑C concentration does not meet the diagnostic criteria.

Children⁵

• In children at risk of familial hypercholesterolaemia because of one affected parent, the following diagnostic tests should be carried out by the age of 10 years or at the earliest opportunity:

  • A DNA test if the family mutation is known.

  • LDL-C concentration measurement if the family mutation is not known. When excluding a diagnosis of familial hypercholesterolaemia, a further LDL-C measurement should be repeated after puberty because LDL-C concentrations change during puberty.

• If a child at risk has not been DNA tested by the age of 10, offer a further opportunity for a test.

• In children at risk of homozygous FH because of two affected parents or because of the presence of clinical signs - for example, cutaneous lipid deposits (xanthomata) - LDL‑C concentration should be measured before the age of 5 years or at the earliest opportunity thereafter. If the LDL‑C concentration is greater than 11 mmol/Ll then a clinical diagnosis of homozygous FH should be considered.

Treatment and management of hyperlipidaemia^{5 6 8}

The aim of treating hyperlipidaemia is to prevent or reduce the risk and complications of CVD. Such risk reduction includes non-drug measures (such as addressing lifestyle factors) and drug treatment using lipid-lowering therapy.

See also the separate Prevention of Cardiovascular Disease and Lipid-regulating Drugs (including Statins) articles.

In addition to statins and other lipid-lowering drugs, the treatment of hyperlipidaemia may include:

• LDL apheresis should be considered for the treatment of adults and children/young people with homozygous FH.

• Liver transplantation should be considered as an option for the treatment of people with homozygous FH after treatment with lipid-modifying drug therapy and LDL apheresis.

Lifestyle advice

Lifestyle modifications should be recommended for everyone, irrespective of cardiovascular risk, lipid levels or any comorbidities:

• Not smoking.

• Eating a balanced healthy diet.

• Maintaining a healthy weight.

• Getting regular exercise.

• Keeping alcohol intake within the recommended limits.

Primary prevention

• If lifestyle modification is ineffective or inappropriate offer statin treatment: atorvastatin 20 mg daily.

• Measure full lipid profile again after 3 months (non-fasting).

• High intensity statin treatment should achieve reduction of non-HDL-C > 40% from baseline. If not achieved after 3 months:

  • Discuss treatment adherence, timing of dose, diet and lifestyle

  • If at higher risk (based on comorbidities, risk score or clinical judgement) consider increasing the dose every 2-3 months up to a maximum dose of atorvastatin 80 mg daily.

• If patients on a high-intensity statin have side effects, offer a lower dose or an alternative statin.

• If maximum tolerated dose of statin does not achieve non-HDL-C reduction > 40% of baseline value after 3 months consider adding Ezetimibe 10 mg daily.¹⁰

• If statin treatment is contraindicated or not tolerated:

  • Ezetimibe 10 mg monotherapy may be considered. Assess response after 3 months.

  • Ezetimibe 10 mg/bempedoic acid 180 mg combination may be considered when ezetimibe alone does not control non-HDL-C/LDL-C well enough.¹¹

• If non-HDL-C reduction remains < 40% of baseline despite maximal tolerated lipid lowering therapy (including people with intolerances and contraindications) consider referral to specialist lipid management clinic according to local arrangements.

Secondary prevention

• Offer statin therapy to adults with CVD. Do not delay statin treatment if a person has acute coronary syndrome. Take a lipid sample on admission (within 24 hours).
  Identify and address all modifiable risk factors - smoking, diet, obesity, alcohol intake, physical activity, blood pressure and HbA1c. Do not delay statin treatment in secondary prevention while managing modifiable risk factors.

• Prescribe a high intensity statin: Atorvastatin 80 mg daily. Use a lower dose of atorvastatin if there is a potential drug interaction, high risk of or experiencing adverse effects, or patient preference. Offer atorvastatin 20 mg if CKD (people with GFR< 60 mL/min/1.73m2).

• Measure full lipid profile again after 3 months (non-fasting). High intensity statin treatment should achieve reduction of non-HDL-C > 40% from baseline. If not achieved after 3 months:

  • Discuss treatment adherence, timing of dose, diet and lifestyle measures.

  • If started on less than atorvastatin 80 mg and the person is judged to be at higher risk (based on comorbidities, risk score or clinical judgement), consider increasing to 80 mg atorvastatin.

• If non-HDL-C baseline value is not available, consider target non-HDL-C < 2.5mmol/L (approximately equivalent to LDL-C < 1.8mmol/L).¹

• If patients on a high-intensity statin have side effects, offer a lower dose or an alternative statin.

If maximum tolerated dose of statin does not control non-HDL-C/LDL-C well enough after 3 months confirm statin adherence, then consider the following options based on shared decision making with the patient:

• If statin intolerance is confirmed, consider:

• Ezetimibe 10 mg monotherapy. Assess response after 3 months.¹⁰

• Ezetimibe 10 mg/bempedoic acid 180 mg combination when ezetimibe alone does not control non-HDL-C sufficiently.¹¹

If non HDL-C remains > 2.5mmol/L despite other lipid lowering therapies consider injectable therapies (alirocumab, evolocumab or inclisiran). Arrange a fasting blood test and assess eligibility criteria. (^{14 15 16}

• If eligibility criteria not met, consider ezetimibe 10 mg daily (if not previously considered).

• Additional CV risk reduction considerations: - check fasting triglycerides levels and consider icosapent ethyl.

Type 1 Diabetes

NICE recommends considering statins in all adults with type 1 diabetes.

Chronic kidney disease

• Offer atorvastatin 20 mg for the primary or secondary prevention of CVD to people with CKD (eGFR less than 60 mL/min/1.73m² and/or albuminuria).

• Increase the dose if a greater than 40% reduction in non-HDL-C is not achieved and eGFR is 30 mL/min/1.73m² or more.

• Agree the use of higher doses with a renal specialist if eGFR is less than 30 mL/min/1.73m².

Severe hypercholesterolaemia

If TC>7.5mmol/L and/or LDL-C>4.9mmol/L and/or non-HDL-C >5.9mmol/L, a personal and/or family history of confirmed CHD (<60 years) and with no secondary causes:

• Suspect familial hypercholesterolaemia (possible heterozygous FH).

• Do not use QRISK risk assessment tool.

Diagnosis and referral

• Take fasting blood for repeat lipid profile to measure LDL-C.

• Use the Simon Broome or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH.

• Refer to Lipid Clinic for further assessment if clinical diagnosis of FH or if any of (regardless of family history) the following:

  • TC>9.0mmol/L.

  • LDL-C >6.5mmol/L.

  • Non-HDL-C >7.5mmol/L.

  • Fasting triglycerides > 10mmol/L.

Treatment targets in FH
If clinical diagnosis of FH and/or other risk factors present follow the recommended treatment management pathway for primary or secondary prevention as for non-FH, but aim to achieve at least a 50% reduction of LDL-C (or non-fasting non-HDL-C) from baseline.

Consider specialist referral for further treatment and/or consideration of injectable therapies (see above) if, despite maximal tolerated statin and ezetimibe therapy:

• They are assessed to be at very high risk of a coronary event (established coronary heart disease, or 2 or more other CVD risk factors).

• Therapy is not tolerated.

• LDL-C remains >5mmol/L (primary prevention).

• LDL-C remains >3.5mmol/L (secondary prevention).

Triglycerides

Although statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration, they are less effective than fibrates in reducing triglyceride concentration. Fenofibrate may be added to statin therapy if triglycerides remain high even after the LDL-cholesterol concentration has been reduced adequately.¹⁷

Icosapent ethyl is recommended by NICE as an option for reducing the risk of cardiovascular events in adults. It is recommended if they have a high risk of cardiovascular events and raised fasting triglycerides (1.7 mmol/L or above) and are taking statins, but only if they have:¹⁸

• Established cardiovascular disease (secondary prevention), and

• Low-density lipoprotein cholesterol (LDL-C) levels above 1.04 mmol/L and below or equal to 2.60 mmol/L.

Icosapent ethyl¹⁸

• Check fasting triglycerides levels.

• Manage secondary causes of hypertriglyceridaemia.

• Consider icosapent ethyl if established cardiovascular disease (secondary prevention) and on statins and fasting TG ≥ 1.7mmol/L and LDL-C between 1.04 and ≤2.6mmol/L.

Familial hypercholesterolaemia⁵

Anyone with homozygous familial hyperlipidaemia should be referred to and managed in a specialist lipid clinic.

Do not use coronary heart disease (CHD) risk assessment tools to guide management because people with familial hypercholesterolaemia (FH) are already at a high risk of premature CHD.

• Refer people who are at very high risk of a coronary event to a specialist with expertise in FH. Very high risk is defined as the presence of any of the following:

  • Established CHD.

  • A family history of premature CHD (first-degree relative [parent, sibling, or child] before 60 years of age or second-degree relative [grandparent, uncle, or aunt] before 50 years of age).

  • Two or more other cardiovascular disease (CVD) risk factors (such as male gender, smoking, hypertension, or diabetes).

• Consider a routine referral to a cardiologist for evaluation for possible CHD if the person has a family history of CHD in early adulthood.

Confirmed heterozygous FH

• Consider doing a baseline electrocardiogram (ECG).

• Implement measures to reduce the risk of CVD, including:

  • Addressing other modifiable CVD risk factors, such as smoking, high blood pressure, and obesity.

  • Offering individualised nutritional advice from a dietician. Do not advise against the consumption of food products containing stanols and sterols. If people with FH wish to consume them, advise that such products cannot be prescribed, and they need to be taken consistently to be effective.

  • Identifying and managing secondary causes of hyperlipidaemia, such as excess alcohol consumption, uncontrolled diabetes mellitus, hypothyroidism, liver disease, nephrotic syndrome, and chronic kidney disease.

  • Where possible, optimising treatment of other conditions associated with an increased risk of CVD, including atrial fibrillation; rheumatoid arthritis, systemic lupus erythematosus, and other systemic inflammatory disorders; and serious mental health problems.

• For all adults with confirmed heterozygous familial hypercholesterolaemia (FH) who do not need to be referred, offer a high-intensity statin as the initial treatment, and aim to achieve at least a 50% reduction in low-density lipoprotein (LDL) cholesterol concentration from the baseline measurement.

• If appropriate, prescribe a daily dose of atorvastatin 20 mg or rosuvastatin 10 mg, unless statins are contraindicated (for example during pregnancy).

• Prescribe atorvastatin 20 mg (and not rosuvastatin 10 mg) for people with predisposing factors for rhabdomyolysis, such as being of Asian origin, concomitant use with an interacting drug, and stage 3 chronic kidney disease (estimated glomerular filtration rate 30–60 mL/minute/1.73 m²).

• If statins are contraindicated, consider one of the following options:

  • Prescribe ezetimibe 10 mg once daily (provided creatine kinase and liver function tests are normal and ezetimibe is not contraindicated).

  • Refer to a specialist with expertise in FH.

• If both statins and ezetimibe are contraindicated, refer to a specialist with expertise in FH. Secondary care treatment options include:

  • A bile acid sequestrant (resin) or a fibrate.

  • A proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (alirocumab or evolocumab). See the National Institute for Health and Care Excellence (NICE) technology appraisal guidance on Alirocumab and Evolocumab for more information on these treatments.

If clinical diagnosis of FH and/or other risk factors present, follow the recommended treatment management pathway for primary or secondary prevention as for non-FH. However, aim to achieve at least a 50% reduction of LDL-C (or non-fasting non-HDL-C) from baseline.

Further treatment and/or consideration of PCSK9i therapy should be considered if:

• Assessed to be at very high risk of a coronary event (established coronary heart disease, or two or more other CVD risk factors).

• Therapy is not tolerated.

• LDL-C remains above 5 mmol/L (primary prevention) or above 3.5 mmol/L (secondary prevention), despite maximal tolerated statin and ezetimibe therapy.

Complications and prognosis³

• Without treatment, heterozygous familial hypercholesterolaemia (FH) leads to a greater than 50% risk of coronary heart disease in men by the age of 50 years and at least 30% in women by the age of 60 years. Homozygous FH is associated with early death from CHD.

• If treatment is started early enough in life, people with FH will have the same life expectancy as the general population.

• People with familial combined hyperlipidaemia also have an increased risk of CHD, but CHD usually only presents after the age of 60 years.⁵

• Very severe hypertriglyceridaemia (more than 10 mmol/L) is a risk factor for pancreatitis.

• Decreased levels of serum HDL-C are also an independent risk factor for CHD.¹⁹

What is hyperlipidaemia?^{1 2}

Hyperlipidaemia is the term used to denote raised serum levels of one or more of total cholesterol (TChol), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), or both TChol and TG (combined hyperlipidaemia).

Dyslipidaemia is a wider term that also includes low levels of high-density lipoprotein cholesterol (HDL-C).^{1 2} Many types of hyperlipidaemia carry an increased risk of cardiovascular disease (CVD), but HDL-C confers protection. It is important as one of the three main modifiable risk factors for CVD (the others being smoking and hypertension).

Familial hyperlipidaemia (FH) is an inherited condition (autosomal dominant) in which the liver is much less able to remove excess LDL cholesterol. There are three main genes that can be involved in FH:

• LDL receptor genes: by far the most commonly affected genes.

• Apolipoprotein B (APOB) gene: LDL cholesterol does not bind well to LDL receptors.

• PCSK9 gene: LDL receptors are broken down in the liver so can’t take cholesterol out of the blood stream.

How common is hyperlipidaemia? (Epidemiology)³

• The UK population has one of the highest average serum cholesterol levels in the world. Two thirds of the UK population have a serum cholesterol level greater than 5.2 mmol/L.

• Low levels of HDL-C are often associated with raised TG levels (eg, in familial combined hyperlipidaemia and in dyslipidaemia in type 2 diabetes).

• Heterozygous familial hypercholesterolaemia (FH) is relatively common. Between 1 in 250 and 1 in 500 of the UK population have heterozygous FH.

• Homozygous FH is rare, with an incidence of about one case per one million. Symptoms first appear in childhood.

• Of the theoretical estimated prevalence of 1/500 for heterozygous familial hypercholesterolaemia, less than 1% are diagnosed in most countries.⁴

What causes hyperlipidaemia? (Aetiology)^{5 6 7}

See the separate Prevention of Cardiovascular Disease article.

Inherited disorders

• Familial dyslipidaemias.

• Familial hypercholesterolaemia

• Familial combined hyperlipidaemia.

• Apoprotein disorders.

Secondary causes

• Medical conditions - eg, hypothyroidism, obstructive jaundice, Cushing's syndrome, anorexia nervosa, nephrotic syndrome, diabetes mellitus, metabolic syndrome, HIV, polycystic ovary syndrome and chronic kidney disease.

• Drugs - eg, thiazide diuretics, glucocorticoids, immunosuppressive agents, antiretroviral therapy, beta-blockers, combined oral contraceptive pill, atypical antipsychotics, and retinoic acid derivatives.

• Pregnancy.

• Obesity.

• Alcohol abuse.

Assessment^{5 6}

For the estimation of cardiovascular risk, measure both total blood cholesterol and high-density lipoprotein (HDL) cholesterol. See also the separate Cardiovascular Risk Assessment and Prevention of Cardiovascular Disease articles.

Suspect familial hypercholesterolaemia (FH) in adults with:

• A total cholesterol level greater than 7.5 mmol/L and/or

• A personal or family history of premature coronary heart disease (CHD, an event before 60 years in an index person or first-degree relative [parents, siblings, children]).

Systematically search primary care records for people who are at highest risk of FH, including:

• People younger than 30 years of age with a total cholesterol concentration greater than 7.5 mmol/L and

• People aged 30 years or older with a total cholesterol concentration greater than 9.0 mmol/L.

• For people with a personal or family history of premature CHD (an event before 60 years in an index person or first-degree relative) whose total cholesterol is unknown, offer to measure their total cholesterol.

In children aged 0–10 years who are at risk of FH because of one affected parent, refer for a DNA test at the earliest opportunity. If testing of a child at risk has not been undertaken by the age of 10 years, offer an additional opportunity for a DNA test.

In children at risk of homozygous FH because of two affected parents or because of the presence of clinical signs, eg, cutaneous lipid deposits (xanthomata), low-density lipoprotein (LDL) cholesterol concentration should be measured before the age of 5 years or at the earliest opportunity thereafter.

If familial hypercholesterolaemia (FH) is suspected, consider referring children and young people [up to 15 years of age] to a specialist for the assessment to be carried out.

Take two measurements of low-density lipoprotein (LDL) cholesterol concentration.

• Consider a clinical diagnosis of homozygous FH in adults with LDL cholesterol concentration greater than 13 mmol/L.

• Consider a clinical diagnosis of homozygous FH in a child or young person (up to 15 years of age) with an LDL cholesterol concentration greater than 11 mmol/L.

Look for clinical signs of FH, such as tendon xanthomata, but be aware that the absence of clinical signs does not exclude a diagnosis of FH.

Use the Simon Broome criteria or the Dutch Lipid Clinic Network (DLCN) criteria to aid clinical diagnosis of FH in primary care (see below). Make a clinical diagnosis of FH in people who meet the Simon Broome criteria for 'possible' or 'definite' FH, or have a DLCN score greater than 5.
The Simon Broome criteria has different lipid concentration levels for adults and children.

Refer all people with a clinical diagnosis of FH (heterozygous or homozygous) to a specialist for confirmation of the diagnosis and initiation of cascade testing (which involves identification of affected relatives by DNA testing).

Tendon xanthomata

Tendon xanthomata are hard, non-tender, nodular enlargements of tendons most commonly found on the knuckles of the hands and in the Achilles tendons, but may rarely be present on the extensor hallucis longus and triceps tendons.

They feel hard because they are fibrotic, and may become inflamed in the Achilles tendons (sometimes presenting as chronic Achilles tenosynovitis, which may be exacerbated by a statin).
Because the overlying skin is of normal colour, they may be difficult to detect.

Tendon xanthomata appear in people with heterozygous familial hypercholesterolaemia (FH) from 20 years of age onwards (unless the person was started on a statin early in life), but are often evident in homozygous FH from childhood. They are highly suggestive of FH, but their absence does not exclude FH.

Other types of xanthomata (such as xanthelasmata on the eyelids) and premature corneal arcus may occur in people with FH, but they are less specific.

Triglycerides⁸

Greater than 20mmol/L:

• Refer to lipid clinic for urgent specialist review if not a result of excess alcohol or poor glycaemic control.

• At risk of acute pancreatitis.

10 - 20mmol/L:

• Repeat the TG measurement with a fasting test (after an interval of 5 days, but within 2 weeks) and review for potential secondary causes of hyperlipidaemia.

• Seek specialist advice if the TG concentration remains > 10mmol/litre.

• At risk of acute pancreatitis.

4.5 - 9.9mmol/L:

• If non-fasting triglycerides are greater than 4.5mmol/L, repeat with a fasting TG measurement.

• CVD risk may be underestimated by risk assessment tools.

• Optimise the management of other CVD risk factors present and seek specialist advice if non-HDL-C concentration is > 7.5 mmol/litre.

Diagnostic criteria

The Simon Broom diagnostic criteria

• Definite: familial hypercholesterolaemia is diagnosed if an individual has:

  • A TChol level in an adult of >7.5 mmol/L (>6.7 mmol/L in a child) and an LDL-C of >4.9 mmol/L (>4.0 mmol/L in a child); PLUS

  • Tendon xanthomata or evidence of these signs in a first-degree or second-degree relative; OR

  • DNA evidence of an LDL receptor mutation, familial defective apo-B-100 or a PCSK9 mutation.

• Possible: familial hypercholesterolaemia should be diagnosed if the cholesterol concentrations fit these criteria and the individual has at least one of the following:

  • A family history of myocardial infarction in a second-degree relative aged 50 years or younger, or in a first-degree relative aged 60 years or younger.

  • A family history of raised TChol greater than 7.5 mmol/L in adult first-degree or second-degree relatives or greater than 6.7 mmol/L in a child, brother or sister aged younger than 16 years.

The Dutch Lipid Clinic Network (DLCN) criteria
An alternative to the Simon Broom criteria, this method assesses whether a person has FH based on personal and family medical history, clinical signs, LDL‑C concentration and DNA testing. A score is attributed to each component; the higher the score, the higher the likelihood of the person having FH.

Familial combined hyperlipidaemia⁹

This is the most common genetic dyslipidaemia, occurring in about 1 in 100 people but is usually polygenic in origin (it is also sometimes called polygenic hypercholesterolaemia).

Lipid phenotypes in familial combined hyperlipidaemia vary considerably but suspect where:

• There is family history of hyperlipidaemia or premature CHD not due to familial hypercholesterolaemia.

• There is moderate-to-severe mixed hyperlipidaemia (typically TChol 6.5-8.0 mmol/L and TG 2.3-5.0 mmol/L).

Before considering pharmacological treatment of dyslipidaemias, always try to identify and correct/optimise any secondary or contributory causes.

Investigations^{5 8}

Lipid profile: includes TChol, LDL-C (or non-HDL-C), HDL-C and TGs.

To exclude secondary hypercholesterolaemia:

• An underlying cause can usually be detected from the history and examination and by checking thyroid stimulating hormone, HbA1c, renal function, electrolytes, and liver function.

• An underlying condition or drug may be exacerbating primary FH, and serum lipids should be rechecked (if possible) after the condition has resolved or the drug has been stopped.

Further investigations may be required if another underlying cause of hyperlipidaemia is suspected, such as Cushing's syndrome or polycystic ovary syndrome.

DNA testing⁵

People with a clinical diagnosis of familial hypercholesterolaemia should be offered a DNA test to increase the certainty of their diagnosis and to aid diagnosis among their relatives. Inform all people who have an identified mutation diagnostic of FH that they have an unequivocal diagnosis of FH even if their LDL‑C concentration does not meet the diagnostic criteria.

Children⁵

• In children at risk of familial hypercholesterolaemia because of one affected parent, the following diagnostic tests should be carried out by the age of 10 years or at the earliest opportunity:

  • A DNA test if the family mutation is known.

  • LDL-C concentration measurement if the family mutation is not known. When excluding a diagnosis of familial hypercholesterolaemia, a further LDL-C measurement should be repeated after puberty because LDL-C concentrations change during puberty.

• If a child at risk has not been DNA tested by the age of 10, offer a further opportunity for a test.

• In children at risk of homozygous FH because of two affected parents or because of the presence of clinical signs - for example, cutaneous lipid deposits (xanthomata) - LDL‑C concentration should be measured before the age of 5 years or at the earliest opportunity thereafter. If the LDL‑C concentration is greater than 11 mmol/Ll then a clinical diagnosis of homozygous FH should be considered.

Treatment and management of hyperlipidaemia^{5 6 8}

The aim of treating hyperlipidaemia is to prevent or reduce the risk and complications of CVD. Such risk reduction includes non-drug measures (such as addressing lifestyle factors) and drug treatment using lipid-lowering therapy.

See also the separate Prevention of Cardiovascular Disease and Lipid-regulating Drugs (including Statins) articles.

In addition to statins and other lipid-lowering drugs, the treatment of hyperlipidaemia may include:

• LDL apheresis should be considered for the treatment of adults and children/young people with homozygous FH.

• Liver transplantation should be considered as an option for the treatment of people with homozygous FH after treatment with lipid-modifying drug therapy and LDL apheresis.

Lifestyle advice

Lifestyle modifications should be recommended for everyone, irrespective of cardiovascular risk, lipid levels or any comorbidities:

• Not smoking.

• Eating a balanced healthy diet.

• Maintaining a healthy weight.

• Getting regular exercise.

• Keeping alcohol intake within the recommended limits.

Primary prevention

• If lifestyle modification is ineffective or inappropriate offer statin treatment: atorvastatin 20 mg daily.

• Measure full lipid profile again after 3 months (non-fasting).

• High intensity statin treatment should achieve reduction of non-HDL-C > 40% from baseline. If not achieved after 3 months:

  • Discuss treatment adherence, timing of dose, diet and lifestyle

  • If at higher risk (based on comorbidities, risk score or clinical judgement) consider increasing the dose every 2-3 months up to a maximum dose of atorvastatin 80 mg daily.

• If patients on a high-intensity statin have side effects, offer a lower dose or an alternative statin.

• If maximum tolerated dose of statin does not achieve non-HDL-C reduction > 40% of baseline value after 3 months consider adding Ezetimibe 10 mg daily.¹⁰

• If statin treatment is contraindicated or not tolerated:

  • Ezetimibe 10 mg monotherapy may be considered. Assess response after 3 months.

  • Ezetimibe 10 mg/bempedoic acid 180 mg combination may be considered when ezetimibe alone does not control non-HDL-C/LDL-C well enough.¹¹

• If non-HDL-C reduction remains < 40% of baseline despite maximal tolerated lipid lowering therapy (including people with intolerances and contraindications) consider referral to specialist lipid management clinic according to local arrangements.

Secondary prevention

• Offer statin therapy to adults with CVD. Do not delay statin treatment if a person has acute coronary syndrome. Take a lipid sample on admission (within 24 hours).
  Identify and address all modifiable risk factors - smoking, diet, obesity, alcohol intake, physical activity, blood pressure and HbA1c. Do not delay statin treatment in secondary prevention while managing modifiable risk factors.

• Prescribe a high intensity statin: Atorvastatin 80 mg daily. Use a lower dose of atorvastatin if there is a potential drug interaction, high risk of or experiencing adverse effects, or patient preference. Offer atorvastatin 20 mg if CKD (people with GFR< 60 mL/min/1.73m2).

• Measure full lipid profile again after 3 months (non-fasting). High intensity statin treatment should achieve reduction of non-HDL-C > 40% from baseline. If not achieved after 3 months:

  • Discuss treatment adherence, timing of dose, diet and lifestyle measures.

  • If started on less than atorvastatin 80 mg and the person is judged to be at higher risk (based on comorbidities, risk score or clinical judgement), consider increasing to 80 mg atorvastatin.

• If non-HDL-C baseline value is not available, consider target non-HDL-C < 2.5mmol/L (approximately equivalent to LDL-C < 1.8mmol/L).¹

• If patients on a high-intensity statin have side effects, offer a lower dose or an alternative statin.

If maximum tolerated dose of statin does not control non-HDL-C/LDL-C well enough after 3 months confirm statin adherence, then consider the following options based on shared decision making with the patient:

• If statin intolerance is confirmed, consider:

• Ezetimibe 10 mg monotherapy. Assess response after 3 months.¹⁰

• Ezetimibe 10 mg/bempedoic acid 180 mg combination when ezetimibe alone does not control non-HDL-C sufficiently.¹¹

If non HDL-C remains > 2.5mmol/L despite other lipid lowering therapies consider injectable therapies (alirocumab, evolocumab or inclisiran). Arrange a fasting blood test and assess eligibility criteria. (^{14 15 16}

• If eligibility criteria not met, consider ezetimibe 10 mg daily (if not previously considered).

• Additional CV risk reduction considerations: - check fasting triglycerides levels and consider icosapent ethyl.

Type 1 Diabetes

The National Institute for Health and Care Excellence (NICE) recommends considering statins in all adults with type 1 diabetes.

Chronic kidney disease

• Offer atorvastatin 20 mg for the primary or secondary prevention of CVD to people with CKD (eGFR less than 60 mL/min/1.73m² and/or albuminuria).

• Increase the dose if a greater than 40% reduction in non-HDL-C is not achieved and eGFR is 30 mL/min/1.73m² or more.

• Agree the use of higher doses with a renal specialist if eGFR is less than 30 mL/min/1.73m².

Severe hypercholesterolaemia

If TC>7.5mmol/L and/or LDL-C>4.9mmol/L and/or non-HDL-C >5.9mmol/L, a personal and/or family history of confirmed CHD (<60 years) and with no secondary causes:

• Suspect familial hypercholesterolaemia (possible heterozygous FH).

• Do not use QRISK risk assessment tool.

Diagnosis and referral

• Take fasting blood for repeat lipid profile to measure LDL-C.

• Use the Simon Broome or Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH.

• Refer to Lipid Clinic for further assessment if clinical diagnosis of FH or if any of (regardless of family history) the following:

  • TC>9.0mmol/L.

  • LDL-C >6.5mmol/L.

  • Non-HDL-C >7.5mmol/L.

  • Fasting triglycerides > 10mmol/L.

Treatment targets in FH
If clinical diagnosis of FH and/or other risk factors present follow the recommended treatment management pathway for primary or secondary prevention as for non-FH, but aim to achieve at least a 50% reduction of LDL-C (or non-fasting non-HDL-C) from baseline.

Consider specialist referral for further treatment and/or consideration of injectable therapies (see above) if, despite maximal tolerated statin and ezetimibe therapy:

• They are assessed to be at very high risk of a coronary event (established coronary heart disease, or 2 or more other CVD risk factors).

• Therapy is not tolerated.

• LDL-C remains >5mmol/L (primary prevention).

• LDL-C remains >3.5mmol/L (secondary prevention).

Triglycerides

Although statins are more effective than other lipid-regulating drugs at lowering LDL-cholesterol concentration, they are less effective than fibrates in reducing triglyceride concentration. Fenofibrate may be added to statin therapy if triglycerides remain high even after the LDL-cholesterol concentration has been reduced adequately.¹⁷

Icosapent ethyl is recommended by NICE as an option for reducing the risk of cardiovascular events in adults. It is recommended if they have a high risk of cardiovascular events and raised fasting triglycerides (1.7 mmol/L or above) and are taking statins, but only if they have:¹⁸

• Established cardiovascular disease (secondary prevention), and

• Low-density lipoprotein cholesterol (LDL-C) levels above 1.04 mmol/L and below or equal to 2.60 mmol/L.

Icosapent ethyl¹⁸

• Check fasting triglycerides levels.

• Manage secondary causes of hypertriglyceridaemia.

• Consider icosapent ethyl if established cardiovascular disease (secondary prevention) and on statins and fasting TG ≥ 1.7mmol/L and LDL-C between 1.04 and ≤2.6mmol/L.

Familial hypercholesterolaemia⁵

Anyone with homozygous familial hyperlipidaemia should be referred to and managed in a specialist lipid clinic.

Do not use coronary heart disease (CHD) risk assessment tools to guide management because people with familial hypercholesterolaemia (FH) are already at a high risk of premature CHD.

• Refer people who are at very high risk of a coronary event to a specialist with expertise in FH. Very high risk is defined as the presence of any of the following:

  • Established CHD.

  • A family history of premature CHD (first-degree relative [parent, sibling, or child] before 60 years of age or second-degree relative [grandparent, uncle, or aunt] before 50 years of age).

  • Two or more other cardiovascular disease (CVD) risk factors (such as male gender, smoking, hypertension, or diabetes).

• Consider a routine referral to a cardiologist for evaluation for possible CHD if the person has a family history of CHD in early adulthood.

Confirmed heterozygous FH

• Consider doing a baseline electrocardiogram (ECG).

• Implement measures to reduce the risk of CVD, including:

  • Addressing other modifiable CVD risk factors, such as smoking, high blood pressure, and obesity.

  • Offering individualised nutritional advice from a dietician. Do not advise against the consumption of food products containing stanols and sterols. If people with FH wish to consume them, advise that such products cannot be prescribed, and they need to be taken consistently to be effective.

  • Identifying and managing secondary causes of hyperlipidaemia, such as excess alcohol consumption, uncontrolled diabetes mellitus, hypothyroidism, liver disease, nephrotic syndrome, and chronic kidney disease.

  • Where possible, optimising treatment of other conditions associated with an increased risk of CVD, including atrial fibrillation; rheumatoid arthritis, systemic lupus erythematosus, and other systemic inflammatory disorders; and serious mental health problems.

• For all adults with confirmed heterozygous familial hypercholesterolaemia (FH) who do not need to be referred, offer a high-intensity statin as the initial treatment, and aim to achieve at least a 50% reduction in low-density lipoprotein (LDL) cholesterol concentration from the baseline measurement.

• If appropriate, prescribe a daily dose of atorvastatin 20 mg or rosuvastatin 10 mg, unless statins are contraindicated (for example during pregnancy).

• Prescribe atorvastatin 20 mg (and not rosuvastatin 10 mg) for people with predisposing factors for rhabdomyolysis, such as being of Asian origin, concomitant use with an interacting drug, and stage 3 chronic kidney disease (estimated glomerular filtration rate 30–60 mL/minute/1.73 m²).

• If statins are contraindicated, consider one of the following options:

  • Prescribe ezetimibe 10 mg once daily (provided creatine kinase and liver function tests are normal and ezetimibe is not contraindicated).

  • Refer to a specialist with expertise in FH.

• If both statins and ezetimibe are contraindicated, refer to a specialist with expertise in FH. Secondary care treatment options include:

  • A bile acid sequestrant (resin) or a fibrate.

  • A proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (alirocumab or evolocumab). See the National Institute for Health and Care Excellence (NICE) technology appraisal guidance on Alirocumab and Evolocumab for more information on these treatments.

If clinical diagnosis of FH and/or other risk factors present, follow the recommended treatment management pathway for primary or secondary prevention as for non-FH. However, aim to achieve at least a 50% reduction of LDL-C (or non-fasting non-HDL-C) from baseline.

Further treatment and/or consideration of PCSK9i therapy should be considered if:

• Assessed to be at very high risk of a coronary event (established coronary heart disease, or two or more other CVD risk factors).

• Therapy is not tolerated.

• LDL-C remains above 5 mmol/L (primary prevention) or above 3.5 mmol/L (secondary prevention), despite maximal tolerated statin and ezetimibe therapy.

Complications and prognosis³

• Without treatment, heterozygous familial hypercholesterolaemia (FH) leads to a greater than 50% risk of coronary heart disease in men by the age of 50 years and at least 30% in women by the age of 60 years. Homozygous FH is associated with early death from CHD.

• If treatment is started early enough in life, people with FH will have the same life expectancy as the general population.

• People with familial combined hyperlipidaemia also have an increased risk of CHD, but CHD usually only presents after the age of 60 years.⁵

• Very severe hypertriglyceridaemia (more than 10 mmol/L) is a risk factor for pancreatitis.

• Decreased levels of serum HDL-C are also an independent risk factor for CHD.¹⁹