Previous changes

April 2024 — reviewed. A literature search was conducted in February 2024 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of this topic. New sections were created describing important risk factors which may increase the risk of atherosclerotic cardiovascular disease in people with familial hypercholesterolaemia (FH), differential diagnoses which deserve consideration for people with suspected FH, and prescribing information for bempedoic acid and inclisiran. Other minor structural changes have been made to the topic to align with current evidence-based guidance and recommendations. 

December 2023 — minor update. Recommendations on follow-up updated in line with the updated NICE guideline Cardiovascular disease: risk assessment and reduction, including lipid modification.

April 2023— minor update. Adverse effects of statins were updated in line with the manufacturer's SPC as they have been found to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia. Treatment should be discontinued in case of aggravation or development of these symptoms. 

December 2022 — minor update. Immune-mediated necrotizing myopathy added as a possible adverse effect and ledipasvir/sofosbuvir added to list of possible drug interactions for atorvastatin in line with the manufacturer's updated SPC.

October 2022 — minor update. Information regarding interactions between ticagrelor and rosuvastatin added in line with the manufacturer's updated SPC.

August 2022 — minor update. Recommendations on offering inclisiran and bempedoic acid have been added in line with the NICE technology appraisals Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidemia and Bempedoic acid with ezetimibe for treating primary hypercholesterolaemia or mixed dyslipidaemia.

March 2022 — minor update. Minor text changes have been made to clarify the recommendation to offer a lipid-lowering drug. 

September 2020 — minor update. Ticagrelor added as a drug interaction with simvastatin in line with the updated Summary of Product Characteristics.

August 2020 — minor update. Broken URL links updated and adverse effects of simvastatin updated in line with manufacturer's revised SPC.

February 2019 — reviewed. A literature search was conducted in February 2019 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of this topic. Based on an update of the National Institute for Health and Care (NICE) guideline Familial hypercholesterolaemia: identification and management, the following key changes have been made to this CKS topic:

• Information on when to suspect familial hypercholesterolaemia (FH) has been amended.
• Information on how to identify people with FH has been added.
• The Dutch Lipid Clinic Network (DLCN) criteria has been included as an alternative to the Simon Broome criteria for making a clinical diagnosis of FH in primary care.
• Advice on the use of coronary heart disease (CHD) risk estimation tools has been amended: CHD risk estimation tools, such as QRISK and those based on the Framingham algorithm, should not be used because people with FH are already at a high risk of premature CHD.

December 2016 — minor update. The indications for ezetimibe have been updated in line with the manufacturer's Summary of Product Characteristics. 

October 2015 — minor update. Immune-mediated necrotizing myopathy (IMNM) has been included as a very rare adverse effect of some statins. 

July 2015 — minor updates:

• Following an update to the Summary of Product Characteristics (SPC) for rosuvastatin (Crestor^®), information on the interaction of rosuvastatin with simeprevir has been added to the Prescribing information section.  
• Minor text change to remove the percentage equivalents of HbA1c mmol/mol values, which are no longer commonly used to diagnose diabetes mellitus.

May 2015 — minor updates:

• Following an update to the SPC for colesevelam, information on the potential drug interaction of colesevelam with olmesartan, metformin, glimepiride, and glipizide has been added to the topic. The adverse effects section has also been updated to include intestinal obstruction as a possible adverse effect of colesevelam.
• Following an update to the SPC for atorvastatin, as advised by the European Medicines Agency, immune-mediated necrotizing myopathy has been added as a possible adverse effect during or after treatment with atorvastatin (and other statins).  

February 2015 — reviewed. A literature search was conducted in January 2015 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of this topic. No major changes to recommendations have been made; however, new sections have been added to the topic, including prescribing information sections for lipid-modifying drugs and a section on tests that should be implemented before starting lipid-modification treatment.

November 2012 — minor update. The links to the electronic medicines website (www.medicines.org.uk) have been updated.

December 2010 — minor update. Following the publication of the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, the Supporting evidence section has been updated. 

June 2010 — minor update. Following a review of the data from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial, the Medicines and Healthcare products Regulatory Agency (MHRA) has advised that simvastatin 80 mg should be considered only in patients with severe hypercholesterolaemia and high risk of cardiovascular complications who have not achieved their treatment goals on lower doses, when the benefits are expected to outweigh the potential risks. 

October 2009 — minor update. A reminder from the MHRA that aspirin is not licensed for use in primary prevention of vascular events has been added. 

November 2008 to March 2009 — this is a new CKS topic. The evidence base has been reviewed in detail, and recommendations are clearly justified and transparently linked to the supporting evidence.

New evidence

Evidence-based guidelines

• NICE (2024) Evinacumab for treating homozygous familial hypercholesterolaemia in people 12 years and over. National Institute for Health and Care Excellence. [Free Full-text]

HTAs (Health Technology Assessments)

• No new HTAs since 1 February 2024.

Economic appraisals

No new economic appraisals relevant to England since 1 February 2024.

Systematic reviews and meta-analyses

No new systematic reviews or meta-analysis which reach the CKS threshold for inclusion published since 1 February 2024.

Primary evidence

• Gaudet, D., Greber-Platzer, S., Reeskamp, L.F., et al. (2024) Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy. European Heart Journal. https://academic.oup.com/eurheartj [Free Full-text]

New policies

No new national policies or guidelines since 1 February 2024.

New safety alerts

No new safety alerts published since 1 February 2024.

Changes in product availability

• New product, rosuvastatin 10mg/5ml Oral Solution, is licensed for the treatment of homozygous familial hypercholesterolaemia in adults, adolescents and children aged 6 years or older. See more here.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guideline Familial hypercholesterolaemia: identification and management [NICE, 2019b], and expert opinion in narrative review articles [McGowan, 2019; BMJ Best Practice, 2024].

Tendon xanthomata

• Tendon xanthomata are hard, non-tender, nodular enlargements of tendons most commonly found on the dorsum (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 eyelid xanthelasma) and premature corneal arcus may occur in people with FH, but these signs are less specific.

[Winder, 1998; Moruisi, 2006; DermNet NZ, 2020; BMJ Best Practice, 2024]

Causes of secondary hypercholesterolaemia

• The following conditions may cause hypercholesterolaemia (without hypertriglyceridaemia):
  • Hypothyroidism. See the CKS topic on Hypothyroidism for more information.
  • Cholestatic liver disease (such as primary biliary cirrhosis).
  • Nephrotic syndrome.
  • Cushing's syndrome.
  • Anorexia nervosa. See the CKS topic on Eating disorders for more information.
  • The use of certain drugs, including androgens and ciclosporin.
• The following conditions may also cause hypercholesterolaemia, but, usually, hypertriglyceridaemia would also be present:
  • Diabetes mellitus or obesity (although hypertriglyceridaemia alone is the more common presentation). See the CKS topics on Diabetes - type 1, Diabetes - type 2, and Obesity for more information.
  • Pregnancy.
  • Renal replacement therapy or end-stage chronic kidney disease. See the CKS topic on Chronic kidney disease for more information.
  • Monoclonal gammopathy.
  • Excess alcohol consumption. See the CKS topic on Alcohol - problem drinking for more information.
  • HIV infection. See the CKS topic on HIV infection and AIDS for more information.
  • The use of certain drugs, including thiazide diuretics, corticosteroids, retinoic acid derivatives, beta-blockers, and anti-retrovirals (protease inhibitors and nucleoside analogue reverse transcriptase inhibitors, such as stavudine).

[Bhatnagar, 2008; Herink, 2018; Yanai, 2021; BMJ Best Practice, 2024]

The Simon Broome and the Dutch Lipid Clinic Network criteria

• The Simon Broome criteria includes cholesterol concentrations, clinical characteristics, molecular diagnosis, and family history.
  • The criteria are presented in tables 1 and 2.

Table 1. Simon Broome criteria for 'definite' familial hypercholesterolaemia

Table 2. Simon Broome criteria for 'possible' familial hypercholesterolaemia

• Using the Dutch Lipid Clinic Network criteria, points are assigned for family history of hyperlipidaemia or heart disease, clinical characteristics (such as tendon xanthomata), elevated LDL cholesterol, and/or an identified mutation.
  • The higher the score, the higher the likelihood of the person having FH.
  • See Table 1 for more information.

Table 3. Dutch Lipid Clinic Network Criteria to diagnose familial hypercholesterolaemia.

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guidelines Identification and management of familial hypercholesterolaemia (Full guideline) [NICE, 2019a] and Familial hypercholesterolaemia: identification and management [NICE, 2019b], and expert opinion in narrative review articles [McGowan, 2019; Yanai, 2021; BMJ Best Practice, 2024].

Measuring low-density lipoprotein (LDL) cholesterol

• NICE recommends two measurements of LDL cholesterol because biological and analytical variability occurs between samples. The NICE guideline development group agreed that confirmation of the cholesterol concentration at diagnosis should be undertaken before considering people for further investigation and lifelong management for familial hypercholesterolaemia (FH).
• NICE guidance advises that recommendations regarding lipid measurements, concentrations and levels refer to the measurement of total cholesterol (TC), triglycerides (TGs), high-density lipoprotein (HDL) cholesterol, and LDL cholesterol. The guidance also states that LDL cholesterol is not usually measured directly, but calculated from the TC, TGs and HDL cholesterol, ideally using a fasting sample [NICE, 2019b].
• The collection of fasting blood lipid measurements in children can be problematic, expert opinion from a narrative review article is that non-fasting lipid testing may be used for initial screening [McGowan, 2019].

Excluding secondary causes of hypercholesterolaemia

• NICE recommends that secondary causes of hypercholesterolaemia should be excluded before a diagnosis of FH is considered [NICE, 2019b].
• The methods suggested for excluding secondary hypercholesterolaemia are based on NICE guidance [NICE, 2019b], expert opinion in narrative review articles [McGowan, 2019; Yanai, 2021; BMJ Best Practice, 2024], and on what CKS considers to be good clinical practice.

Using the Simon Broome or the Dutch Lipid Clinic Network (DLCN) criteria to make a clinical diagnosis of FH in primary care

• NICE recommends the Simon Broome diagnostic criteria because they are validated, their development was based on a UK population, and they are simpler to use than other criteria, with a comparable or better positive likelihood ratio [NICE, 2019b].
• The Dutch Lipid Clinic Network criteria are also recommended because they provide similar scores to the Simon Broome Register criteria [NICE, 2019b].
• The key difference between the two clinical scoring systems are that the Simon Broome criteria consider a molecular diagnosis sufficient evidence for a diagnosis of FH, while the Dutch Lipid Clinic Network criteria require one additional criterion to be met.

Cascade testing

• Cascade testing is a mechanism for identifying people at risk of a genetic condition by a process of family tracing. For FH the test employed is a DNA test where a disease-causing mutation has been identified in an person with suspected FH [NICE, 2019b].
• NICE recommends that all people with FH should be referred to a specialist with expertise in FH for confirmation of diagnosis and initiation of cascade testing. This is performed though DNA testing to identify affected first- and second- and, where possible, third-degree biological relatives of people with a genetic diagnosis of FH [NICE, 2019b].
• It has been demonstrated that the effectiveness of national cascade screening programmes varies considerably, both within the UK and internationally. The NHS Long Term Plan had set an ambitious target of identifying 25% of people with FH by 2024, but this will not be achieved. Electronic healthcare record screening combined with effective cascade screening has been suggested as the best strategy to improve national detection rates for FH [Page et al, 2023].

Genetic testing

• Genetic diagnosis of FH may involve testing for either known pathogenic variants in genes encoding the LDL receptor, apolipoprotein B (ApoB), and proprotein convertase subtilisin/kexin type 9 (PCSK9), or whole‐gene sequencing [McGowan, 2019].
• Although diagnosis of FH may be confirmed by genetic testing, a pathogenic mutation is only identified in 30% to 80% of individuals with clinical FH [McGowan, 2019; BMJ Best Practice, 2024]. The diagnosis cannot therefore be excluded in the absence of a causative mutation [McGowan, 2019].
• In cases where a pathogenic mutation is not identified, hypercholesterolemia may be secondary to an unidentified mutation or may be polygenic. However, polygenic hypercholesterolemia is not be expected to display an autosomal dominant pattern of inheritance typically observed in FH [McGowan, 2019].
• Genetic testing has also proven valuable in facilitating cascade screening of family members and for prognostic information [BMJ Best Practice, 2024].
  • It has been estimated that people with severe hypercholesterolaemia and an FH mutation have a 22-fold increase in the odds of atherosclerotic cardiovascular disease compared to those with a LDL cholesterol level <3.4 mmol/L, and 6-fold increase compared to those with severe hypercholesterolaemia and similar LDL cholesterol levels but no FH mutation [BMJ Best Practice, 2024].
  • It has also been estimated that the odds of developing atherosclerotic cardiovascular disease varies depending on the mutation detected (odds ratio of 1.8, 3.4, and 19.9, for LDL‐R, ApoB, and PCSK9 mutations, respectively) [McGowan, 2019].

Basis for recommendation

These recommendations are based on the National Institute for Health and Care Excellence (NICE) guidelines Identification and management of familial hypercholesterolaemia (Full guideline) [NICE, 2019a] and Familial hypercholesterolaemia: identification and management [NICE, 2019b], and expert opinion in narrative review articles [Heidemann, 2022; Loh, 2022].

How should I manage an adult with confirmed heterozygous familial hypercholesterolaemia?

Do not use coronary heart disease (CHD) risk assessment tools, such as QRISK and those based on the Framingham algorithm, to guide management as 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.
• For all other adults with confirmed heterozygous FH:
  • Consider organizing 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. For more information, see the CKS topics on Smoking cessation, Hypertension, and Obesity.
    • Offering individualized 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. People with FH should not routinely be recommended to take omega‑3 fatty acid supplements.
    • Identifying and managing secondary causes of hyperlipidaemia, such as excess alcohol consumption, uncontrolled diabetes mellitus, hypothyroidism, liver disease, nephrotic syndrome, and chronic kidney disease. For more information, see the CKS topics on Alcohol - problem drinking, Diabetes - type 1, Diabetes - type 2,  Hypothyroidism, Non-alcoholic fatty liver disease (NAFLD), and Chronic kidney disease.
    • Where possible, optimizing 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 more information, see the CKS topics on Atrial fibrillation, Rheumatoid arthritis, Psychosis and schizophrenia, and Bipolar disorder.
    • Recommend the NHS Live Well website for further advice about healthy living, including eating a balanced diet, healthy weight, exercise, quitting smoking and drinking less alcohol.
  • Offer a lipid-modifying drug after performing baseline blood tests to determine suitability.
• Provide written information on FH, for example:
  • HEART UK (www.heartuk.org.uk) has an educational booklet for people with FH.
• Offer advice on support groups, for example:
  • HEART UK (www.heartuk.org.uk, telephone 0845 450 5988) provides information and advice on preventing premature deaths caused by high cholesterol concentrations.

Which lipid-modifying drug should I offer an adult with heterozygous familial hypercholesterolaemia?

• 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. 
  • Before initiating treatment with a statin, perform baseline blood tests to ensure that lipid-modification treatment is appropriate.
  • 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).
    • For detailed information on prescribing statins, including contraindications and cautions, adverse effects, and drug interactions, see the section on Prescribing information.
  • Advise the person that lipid-modification treatment should be lifelong.
  • Follow up the person to assess the efficacy and tolerability of treatment.
• 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). For detailed information on prescribing ezetimibe, including contraindications and cautions, adverse effects, and drug interactions, see the section on Ezetimibe.
  • 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 (NICE) technology appraisal guidance on Alirocumab and Evolocumab for more information on these treatments. 

What follow up is recommended after initiation of lipid-modification treatment?

• Measure lipid levels 2 to 3 months after starting treatment. The aim of treatment is to achieve a greater than 50% reduction in baseline low-density lipoprotein (LDL) cholesterol levels.
  • If the target has not been reached:
    • Discuss adherence and timing of dose, and reinforce adherence to drug treatment, diet, and lifestyle measures.
    • Titrate the dose of the statin (atorvastatin or rosuvastatin) up to the maximum licensed or tolerated dose to achieve the target.
  • If statin monotherapy fails to achieve the target, consider one of the following two options:
    • Prescribing ezetimibe 10 mg once daily in addition to a statin. For detailed information on prescribing statins or ezetimibe, including contraindications and cautions, adverse effects, and drug interactions, see the section on Prescribing information.
    • Prescribing simvastatin 80 mg for people with severe hypercholesterolaemia and high risk of cardiovascular complications.
      • An increased risk of myopathy has been associated with simvastatin 80 mg. Use should only be considered where the benefits of treatment are expected to outweigh the potential risks. This includes people with severe hypercholesterolaemia at high risk of developing cardiovascular complications where treatment goals on alternative high-intensity statins have not been achieved.
  • If combined treatment with a statin and ezetimibe fails to achieve the target, or simvastatin 80 mg is not suitable, offer referral to a specialist with expertise in FH. Secondary care treatment options include:
    • Co-administration of a statin and other lipid-lowering drugs (for example, a bile acid sequestrant [resin] or a fibrate).
    • Trial of a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (alirocumab or evolocumab), alone or in combination with a statin and/or other lipid-lowering drugs. See the National Institute for Health and Care (NICE) technology appraisal guidance on alirocumab and evolocumab for more information on these treatments.
    • LDL-lowering apheresis may be considered in exceptional instances, such as when there is progressive, symptomatic coronary heart disease, despite maximal tolerated lipid-modifying drug therapy and optimal medical and surgical therapy.
  • For people taking ezetimibe monotherapy (if statins are contraindicated or not tolerated), consider ezetimibe with bempedoic acid if ezetimibe alone does not control low-density lipoprotein cholesterol well enough.
    • For detailed information on prescribing bempedoic acid, including contraindications and cautions, adverse effects, and drug interactions, see the section on Prescribing information.
  • Consider inclisiran as an option as an adjunct to diet if:
    • There is a history of any of the following cardiovascular events: acute coronary syndrome (such as myocardial infarction or unstable angina needing hospitalisation); coronary or other arterial revascularisation procedures; coronary heart disease; ischaemic stroke, or peripheral arterial disease, and
    • LDL-C concentrations are persistently 2.6 mmol/l or more, despite maximum tolerated lipid-lowering therapy (maximum tolerated statins with or without other lipid-lowering therapies or, other lipid-lowering therapies when statins are not tolerated or are contraindicated).
    • For detailed information on prescribing inclisiran, including the route of administration and dosing schedule, contraindications and cautions, adverse effects, and drug interactions, see the section on Prescribing information.
• Recheck liver function tests (LFTs) 2 to 3 months after starting treatment and again at 12 months. Further monitoring is not necessary unless clinically indicated (for example, if symptoms or signs of hepatotoxicity develop).
• Offer a regular structured review that is carried out at least annually. During an annual review:
  • Check medication adherence, and ask about possible adverse effects of treatment.
  • Ask about symptoms of coronary heart disease (CHD).
    • In adults, consider a baseline electrocardiogram (ECG) if this was not performed at diagnosis.
    • A low threshold for referral is recommended for evaluation of possible CHD symptoms.
  • Check fasting lipids and blood pressure, and consider checking HbA1c and renal function.
  • Consider whether any of the following are needed:
    • Smoking cessation or weight loss advice. See the CKS topics on Smoking cessation and Obesity.
    • Additional lifestyle advice.
    • Change to lipid-modifying drug.
    • Pregnancy or contraception advice.
    • Referral to a specialist with expertise in FH.
• Routinely monitor for adverse effects of statin treatment.
  • If unexplained muscle symptoms (such as pain, tenderness, or weakness) develop:
    • Check creatine kinase (CK) levels.
    • Stop statin treatment immediately if muscle symptoms are intolerable or if CK is five or more times the upper limit of normal.
  • If muscle pain develops but statin treatment was previously tolerated for more than 3 months, explore other possible causes of myalgia and raised CK, such as vigorous physical activity, hypothyroidism, infection, recent trauma, and drug or alcohol misuse.
    • If the statin is suspected to be the cause of muscle pain and CK is five or more times the upper limit of normal, stop statin treatment immediately.
  • If other adverse effects are reported, discuss the following possible strategies with the person:
    • Stopping statin treatment and trying again when the symptoms have resolved to check if the symptoms are related to statin use, or
    • Changing to an alternative high-intensity statin or ezetimibe, or
    • Referral to a specialist with expertise in FH for consideration of treatment with a bile acid sequestrant (resin) or a fibrate.

How should I manage an adult with confirmed homozygous familial hypercholesterolaemia?

• Provide written information on FH, for example: 
  • HEART UK (www.heartuk.org.uk) has online information for people with homozygous FH. 
• Ensure that all adults with confirmed homozygous familial hypercholesterolaemia (FH) are managed in secondary care by a specialist with expertise in FH.
  • Specialist management may include:
    • Drug treatment with bile acid sequestrants (resins), nicotinic acid, and/or fibrates (usually in addition to statins and/or ezetimibe).
    • Low-density lipoprotein (LDL) apheresis, which involves removal of blood (usually via an arterio-venous fistula) for treatment to clear LDL cholesterol.
    • Liver transplant.

How should I manage a child or young person with confirmed familial hypercholesterolaemia?

• Ensure that all children with confirmed heterozygous or homozygous familial hypercholesterolaemia (FH) are managed in secondary care by a specialist with expertise in FH in children and young people. If unavailable locally, the child should be referred to a specialist with expertise in FH (usually at a lipid or metabolic clinic).
  • Specialist management for children and young people with homozygous FH includes:
    • Lipid-modifying drug treatment — this is usually started by the age of 10 years or at the earliest opportunity thereafter. 
    • Routine monitoring of growth and pubertal development.

What are the cautions and contraindications for atorvastatin, rosuvastatin, and simvastatin?

• Do not prescribe statins to:
  • People with active liver disease.
  • People with transaminase (alanine aminotransferase or aspartate aminotransferase) levels that are three or more times the upper limit of normal.
  • Inform all women and girls of childbearing age with familial hypercholesterolaemia (FH) that adequate contraception is required during treatment and for 1 month afterwards. See the CKS topic on Contraception - assessment for information on choosing a suitable method of contraception.
    • Interruption of lipid-modifying drug treatment may be appropriate for women with FH who wish to conceive, whereas some women, such as those at very high risk of cardiovascular events during pregnancy, may benefit from continued treatment.
    • Women using lipid-modifying drugs who are considering pregnancy or pregnant women with a new diagnosis of FH should be referred for pre-pregnancy planning and/or antenatal care by an obstetrician and, if she is not already under their care, a cardiology specialist with expertise in FH. Where considered appropriate, specialists may advise women with FH who are planning pregnancy to stop lipid-modifying drug treatment 3 months before attempting to conceive.
    • In the event of an unplanned pregnancy in a woman taking lipid-modifying drugs, consider stopping treatment (where appropriate) and refer urgently (to be seen within 14 days) to an obstetrician for fetal assessment and a cardiology specialist with expertise in FH.
  • Breastfeeding women — manufacturers advise to avoid (no information available).
• In addition:
  • Do not prescribe rosuvastatin to people with:
    • A personal or family history of hereditary muscular disorders.
    • Stage 4 or 5 chronic kidney disease (CKD, estimated glomerular filtration rate [eGFR] less than 30 mL/minute/1.73 m²).
  • Do not prescribe rosuvastatin 40 mg to people with predisposing factors for rhabdomyolysis, such as being of Asian origin, concomitant use with an interacting drug, stage 3 CKD (eGFR 30–60 mL/minute/1.73 m²), hypothyroidism, personal or family history of hereditary muscular disorders, previous history of muscular toxicity with another statin or a fibrate, and alcohol misuse. A maximum daily dose of 20 mg is recommended for this group of people.
• Prescribe statins with caution to:
  • People with history of liver disease.
  • People with predisposing factors for rhabdomyolysis.
    • Note that rosuvastatin 40 mg is contraindicated in this group of people (see above).
    • Muscle toxicity can occur with all statins. People at increased risk include the elderly, females, those with a personal or family history of muscular disorders (including muscular toxicity), unexplained persistent muscle pain, a history of liver disease, high alcohol intake, certain genetic polymorphisms, renal impairment, hypothyroidism, concomitant use of an interacting drug which may increase the plasma concentration of statins, or those who undertake strenuous exercise.
  • People with a history of haemorrhagic stroke, particularly those with inadequately controlled hypertension — seek specialist advice before initiating a statin in this group of people.

[EMC, 2022ca; EMC, 2023b; EMC, 2023c; UKTIS, 2023; BNF, 2024]

What are the adverse effects of atorvastatin, rosuvastatin, and simvastatin?

• Adverse effects of statins include:
  • Common or very common — arthralgia, asthenia, constipation, diarrhoea, dizziness, flatulence, gastrointestinal discomfort, headache, myalgia, nausea, sleep disorders, and thrombocytopenia.
  • Uncommon — alopecia, hepatic disorders, memory loss, pancreatitis, paraesthesia, sexual dysfunction, skin reactions, and vomiting.
  • Rare or very rare:
    • Peripheral neuropathy.
    • Tendinopathy.
    • Lupus-like syndrome.
    • Myopathy and rhabdomyolysis (incidences of 1.6 cases per 100,000 person-years and 5 cases per 100,000 person-years, respectively), muscle rupture, and immune-mediated necrotizing myopathy (IMNM) during or after treatment with some statins. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase, which persist even when statin treatment is discontinued.
    • Although myalgia has been reported commonly in people receiving statins, muscle toxicity truly attributable to statin use is rare. When a statin is suspected to be the cause of myopathy and creatine kinase (CK) concentration is markedly elevated, or if muscular symptoms are severe, treatment should be discontinued.
    • If symptoms resolve and CK concentrations return to normal, reintroduce the statin at a lower dose and monitor the person closely.
  • Frequency not known — depression, interstitial lung disease (characterized by dyspnoea, cough, and weight loss), and diabetes mellitus (in those at risk, including people with a history of hypertension, raised triglycerides, and a raised body mass index at baseline). Statins have also been found to induce de novo or aggravate pre-existing myasthenia gravis or ocular myasthenia, and treatment should be discontinued in case of aggravation or development of these symptoms.
    • Statins should not be discontinued if there is an increase in the blood-glucose concentration, as the benefits continue to outweigh the risks.
• In addition for atorvastatin:
  • Common or very common — epistaxis, hyperglycaemia, hypersensitivity, joint disorders, laryngeal pain, muscle complaints, nasopharyngitis, and pain.
  • Uncommon — appetite decreased, burping, chest pain, fever, hearing impairment, hypoesthesia, hypoglycaemia, malaise, numbness, peripheral oedema, taste altered, vision disorders, and weight increased.
  • Rare or very rare — angioedema, gynaecomastia, thrombocytopenia, and severe cutaneous adverse reactions (SCARs).
• In addition for rosuvastatin:
  • Rare or very rare — arthralgia, gynaecomastia, haematuria, polyneuropathy, and thrombocytopenia.
  • Frequency not known — cough, dyspnoea, oedema, proteinuria, Stevens-Johnson syndrome, and tendon disorders.
• In addition for simvastatin:
  • Rare or very rare — acute kidney injury, anaemia, blurred vision and visual impairment, gynaecomastia, lichenoid drug eruptions, muscle cramps, and muscle rupture.
  • Frequency not known — cognitive impairment and depression.

[MHRA, 2009; MHRA, 2012; EMC, 2022ca; EMC, 2023b; EMC, 2023c; BNF, 2024]

What key drug interactions are associated with atorvastatin, rosuvastatin, and simvastatin?

• The following drugs increase the risk of rhabdomyolysis when given with certain statins:
  • Amiodarone
    • Atorvastatin and simvastatin — manufacturers advise monitor and adjust statin dose.
  • Colchicine 
    • Atorvastatin, rosuvastatin, and simvastatin — use with caution and adjust statin dose. 
  • Ezetimibe — manufacturers advise monitoring for atorvastatin, rosuvastatin, and simvastatin.
  • Fibrates 
    • Atorvastatin — manufacturer advises monitor.
    • Rosuvastatin and simvastatin — manufacturers advise to adjust dose of the statin.
  • Fusidic acid — the Medicines and Healthcare products Regulatory Agency (MHRA) advises that systemic fusidic acid should not be given with statins. 
    • If fusidic acid is essential, statins should be discontinued. They may be restarted 7 days after the last dose of fusidic acid. In exceptional cases requiring prolonged systemic fusidic acid treatment, the need for a statin should be assessed on an individual basis and only undertaken with close medical supervision.
    • People on concurrent treatment with a statin and fusidic acid should be advised to seek medical advice immediately if they experience any symptoms of muscle weakness, pain, or tenderness [MHRA, 2011].
  • Gemfibrozil — manufacturers advise avoid for atorvastatin, rosuvastatin, and simvastatin.
  • Danazol — manufacturers advise avoid for simvastatin.
  • Ticagrelor and lomitapide — levels of simvastatin may be slightly increased. If both drugs are given concurrently, advise people to report any unexplained muscle pain, tenderness, or weakness. use a maximum, simvastatin dose of 40 mg daily. 
• The following drugs have been shown to lead to markedly increased concentrations of certain statins by cytochrome P450 enzyme or transporter protein inhibition, resulting in a greatly increased risk of myopathy or rhabdomyolysis:
  • Ciclosporin
    • Rosuvastatin and simvastatin — manufacturers advise avoid.
    • Atorvastatin — manufacturer advises monitor or adjust atorvastatin dose.
  • Clarithromycin and erythromycin
    • Simvastatin — manufacturer advises avoid.
    • Atorvastatin — manufacturer advises avoid or adjust dose and monitor for rhabdomyolysis.
  • Amlodipine, diltiazem and verapamil
    • Atorvastatin — manufacturer advises use with caution and consider giving a lower maximum dose.
    • Simvastatin — manufacturer advises not to exceed 20 mg simvastatin daily.
  • Fluconazole
    • Atorvastatin and simvastatin — manufacturers advise monitor and adjust dose.
    • Note that both fluconazole and statins can increase the risk of hepatotoxicity.
  • Grapefruit juice
    • Atorvastatin — advise against concomitant intake with large quantities (more than 1.2 L) of grapefruit juice.
    • Simvastatin — manufacturer advises avoid.
  • HIV protease inhibitors, including atazanavir, ritonavir, ledipasvir, lopinavir, saquinavir, sofosbuvir, indinavir, velpatasvir, voxilaprevir, and darunavir.
    • Atorvastatin and rosuvastatin — manufacturers advise avoid or adjust dose and monitor for rhabdomyolysis.
    • Simvastatin — manufacturer advises avoid.
  • Azole antifungals, including itraconazole, fluconazole, ketoconazole, posaconazole, and voriconazole.
    • Atorvastatin — manufacturer advises avoid or adjust dose and monitor for rhabdomyolysis.
    • Simvastatin — manufacturer advises avoid.
    • Note that both itraconazole and statins can increase the risk of hepatotoxicity.
  • Miconazole
    • Atorvastatin — use with caution and adjust atorvastatin dose. 
    • Simvastatin — manufacturer advises avoid.
  • Hepatitis C antivirals 
    • Atorvastatin — manufacturer advises avoid concomitant use with glecaprevir and pibrentasvir.
    • Simvastatin — manufacturer advises the maximum dose of simvastatin should not exceed 20 mg daily with concomitant use of elbasivir or grazoprevir.
• Other interactions include:
  • Warfarin — rosuvastatin possibly enhances the effects of warfarin, and simvastatin use 20-40 mg daily may potentiate the effect of coumarin anticoagulants.
    • If concurrent use is necessary, monitor the international normalised ratio (INR) closely.
  • Combined oral contraceptives (COCs) — although COCs are not contraindicated in women with familial hypercholesterolaemia (FH), other methods of contraception should be considered because of the potential increased risk of cardiovascular events with COC use. See the section on Multiple risk factors for cardiovascular disease in the CKS topic on Contraception - assessment for information on choice of contraception for people with cardiovascular disease risk factors.
    • The National Institute for Health and Care Excellence (NICE) recommends that prescribers should refer to the manufacturers' Summaries of Product Characteristics (SPCs) for individual drugs regarding potential interactions. However, evidence from one small study of concomitant use of rosuvastatin and a third generation combined oral contraceptives showed no decrease in contraceptive efficacy or lipid-lowering efficacy [NICE, 2019a].
  • Ticagrelor
    • Levels of simvastatin may be slightly increased. If both drugs are given concurrently, advise people to report any unexplained muscle pain, tenderness, or weakness. Use a maximum simvastatin dose of 40 mg daily.
    • Renal excretion of rosuvastatin may be affected, increasing the risk for rosuvastatin accumulation. In some cases concomitant use of ticagrelor and rosuvastatin has led to renal function decrease, increased creatine phosphokinase levels and rhabdomyolysis.
• For a complete list of possible drug interactions of all statins, see the electronic Medicines Compendium (eMC) or the British National Formulary (BNF).

[EMC, 2022ca; EMC, 2023b; EMC, 2023c; BNF, 2024; Preston, 2024]

What monitoring is recommended for statins?

• Before initiating a statin, perform baseline blood tests to ensure that lipid-modification treatment is appropriate.
• After initiating a statin, follow up the person to assess the effectiveness and tolerability of treatment.
  • Follow up should include:
    • Repeat liver function tests (LFTs) within 3 months of starting treatment, and again at 12 months. Statin therapy does not need to be routinely excluded unless the serum transaminases are raised above 3 times the upper limit of the reference range.
    • Checking creatine kinase (CK) if unexplained muscle symptoms (such as pain, tenderness, or weakness) develop.

[NICE, 2023; BNF, 2024]

What advice should I give to a person taking a statin?

• Emphasize the importance of adherence to treatment (as well as compliance with lifestyle and dietary advice).
• Advise the person:
  • To seek medical advice if they develop adverse effects such as:
    • Unexplained muscle symptoms (pain, tenderness, or weakness).
    • Presenting features of interstitial lung disease such as dyspnoea, non-productive cough, and deterioration in general health (for example fatigue, weight loss, and fever).
  • That some foods (for example grapefruit juice) and supplements (for example St John's wort) may interact with statins. They should seek advice from their GP or pharmacist when starting other drugs or supplements.
  • To remember to restart the statin if stopped because of drug interactions (for example with a macrolide antibiotic prescribed for an acute infection) or to treat intercurrent illnesses.
  • That atorvastatin can be taken at any time of the day.
  • Simvastatin should only be taken in the evening.
• Advise women of childbearing potential on the need for appropriate contraception due to the potential teratogenic risk of statins. See the CKS topic on Contraception - assessment for information on choosing a suitable method of contraception.

[EMC, 2022ca; EMC, 2023b; EMC, 2023c; NICE, 2023]

What are the contraindications and cautions for ezetimibe?

• Do not prescribe ezetimibe to:
  
  • Breastfeeding women — it is not known if ezetimibe is secreted into human breast milk, but studies on rats have shown that it is secreted into breast milk.
  • People who are also taking a statin and:
    • Are pregnant or breastfeeding.
    • Have active liver disease or unexplained persistent elevations in serum transaminases.
• Prescribe ezetimibe with caution to:
  • Pregnant women — the manufacturer advises use only if potential benefit outweighs risk as there are no clinical data on the use of ezetimibe during pregnancy. However, animal studies have shown no evidence of direct or indirect harmful effects on pregnancy, embryofetal development, birth, or postnatal development.
  • People with predisposing factors for rhabdomyolysis, such as concomitant use with an interacting drug, CKD, hypothyroidism, and personal or family history of hereditary muscular disorders.
  • People with predisposing factors for rhabdomyolysis, including the elderly, females, those with a personal or family history of muscular disorders (including muscular toxicity), unexplained persistent muscle pain, a history of liver disease, high alcohol intake, certain genetic polymorphisms, renal impairment, hypothyroidism, concomitant use of an interacting drug which may increase the plasma concentration of ezetimibe, or those who undertake strenuous exercise.
  • Hepatic impairment.

[EMC, 2022cb]

What are the adverse effects of ezetimibe?

• Common or very common adverse effects of ezetimibe include asthenia, diarrhoea, gastrointestinal discomfort, gastrointestinal disorders, headache.
• Other adverse effects include:
  • Uncommon — appetite decreased, arthralgia, chest pain, cough, dry mouth, dyspepsia, gastro-oesophageal reflux disease, hot flush, hypertension, muscle complaints, nausea, pain, and paraesthesia.
  • Frequency not known — cholelithiasis, cholecystitis, constipation, depression, dizziness, dyspnoea, hepatitis, myopathy, pancreatitis, paraesthesia, skin reactions, and thrombocytopenia.

[EMC, 2022cb; BNF, 2024] 

What drug interactions are associated with ezetimibe?

• Drug interactions associated with ezetimibe include:
  • Ciclosporin — plasma concentration of both drugs may increase when ezetimibe is given with ciclosporin.
    • Concurrent use should be done cautiously, and ciclosporin concentrations should be monitored.
  • Fibrates — predicted to increase the risk of gallstones when given with ezetimibe.
    • Manufacturer advises discontinue if gallstones develop.
  • Statins — Although studies do not demonstrate an increased risk of myopathy when ezetimibe is combined with statins compared with statins alone, safety reports have described cases of myopathy (ezetimibe and atorvastatin), creatine kinase increases (ezetimibe and fluvastatin) and rhabdomyolysis (ezetimibe and simvastatin).
    • Monitor concurrent use closely.
  • Warfarin — there have been post-marketing reports of increased international normalized ratio (INR) in people who had ezetimibe added to warfarin.
    • If concurrent use is necessary, monitor INR closely.
• For a complete list of possible drug interactions of ezetimibe, see the electronic Medicines Compendium (eMC) or the British National Formulary (BNF).

[EMC, 2022cb; BNF, 2024; Preston, 2024]

What are the contraindications and cautions for bempedoic acid?

• Do not prescribe bempedoic acid to:
  • Pregnant women — there are no data to inform on the safety of bempedoic acid use in human pregnancy. Animal studies conducted in rats have shown reproductive toxicity (decreased foetal viability and skeletal abnormalities). Because bempedoic acid decreases cholesterol synthesis, the manufacturer advises use should be discontinued prior to conception or as soon as pregnancy is recognized.
  • Breastfeeding women — it is not known if bempedoic acid is secreted into human breast milk.
  • People who are taking simvastatin > 40 mg daily — bempedoic acid can increase the plasma concentrations of statins, and may increase the risk of adverse reactions (such as myopathy).
• Prescribe bempedoic acid with caution to:
  • People with increased serum uric acid — manufacturer advises treatment should be discontinued if hyperuricaemia accompanied with symptoms of gout appear.
  • People with renal impairment.
  • People with hepatic impairment.
  • People with rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption — manufacturer advises avoid as bempedoic acid contains lactose.

[EMC, 2022a]

What are the adverse effects of bempedoic acid?

• Common or very common adverse effects of bempedoic acid include anaemia, gout, hyperuricaemia and pain in extremity.
• Other adverse effects include:
  • Uncommon — decreased haemoglobin, elevated liver enzymes (aspartate aminotransferase and/or alanine aminotransferase), increased serum creatinine, and decreased glomerular filtration rate (GFR).
  • Frequency unknown — diarrhoea, muscle spasms and nausea.
• The manufacturer advises that bempedoic acid treatment should be discontinued if:
  • Transaminase levels increase and persist at 3 times the upper limit of normal.
  • Hyperuricaemia accompanied with symptoms of gout occur.

[EMC, 2022a; BNF, 2024]

What drug interactions are associated with bempedoic acid?

• Drug interactions associated with bempedoic acid include:
  • Probenecid — plasma concentration of bempedoic acid and it's active metabolite may increase (up to approximately 1.7- and 1.9-fold). The manufacturer advises these elevations are not clinically meaningful and do not impact dosing recommendations.
  • Statins — increased plasma concentrations have been observed for simvastatin, atorvastatin, pravastatin and rosuvastatin, which may increase the risk of myopathy.
  • Ezetimibe — plasma concentration may increase up to 1.6-fold. The manufacturer advises these elevations are not clinically meaningful and do not impact dosing recommendations.

[EMC, 2022a]

What is the route of administration and dosing schedule for inclisiran?

• Inclisiran is administered by subcutaneous injection, and is usually injected into the abdomen or alternatively the thigh or upper arm.
  • Injections should not be given into areas of active skin disease or injury such as sunburns, skin rashes, inflammation or skin infections.
• The recommended dose is 284 mg for 1 dose, followed by 284 mg after 3 months for 1 dose, then 284 mg every 6 months.

[EMC, 2022b; BNF, 2024]

What are the contraindications and cautions for inclisiran?

• Do not prescribe inclisiran to:
  • Pregnant women — there are no data to inform on the safety of inclisiran use in human pregnancy. Although animal studies do not indicate direct or indirect harmful effects, the manufacturer recommends avoiding on a precautionary basis.
  • Breastfeeding women — there are no human data to inform on the safety of inclisiran use in breastfeeding. Animal studies have demonstrated the excretion of inclisiran in milk. The manufacturer recommends avoiding on a precautionary basis.
• Prescribe inclisiran with caution to:
  • People with hepatic impairment.
  • People with renal impairment.
  • People undergoing haemodialysis — the manufacturer advises that as inclisiran is renally eliminated, haemodialysis should not be performed for at least 72 hours after inclisiran dosing.

[EMC, 2022b; BNF, 2024]

What are the adverse effects of inclisiran?

• Common adverse effects of inclisiran include injection site reaction, injection site pain, injection site erythema, and injection site rash.
  • The manufacturer reports that these injection site adverse reactions were all mild or moderate in severity, transient and resolved without sequelae.

[EMC, 2022b]

What drug interactions are associated with inclisiran?

• No drug interactions have been identified for inclisiran.
  • Inclisiran is not a substrate for common drug transporters and is not anticipated to be a substrate for cytochrome P450. The manufacturer states that inclisiran is not expected to have clinically significant interactions with other medicinal products.

[EMC, 2022b; Preston, 2024]