Intended for healthcare professionals

  1. Education
  2. Familial...
  3. Familial hypercholesterolaemia
Practice Practice Pointer

Familial hypercholesterolaemia

BMJ 2023; 382 doi: https://doi.org/10.1136/bmj-2022-073280 (Published 10 July 2023) Cite this as: BMJ 2023;382:e073280

This article has a correction. Please see:

  1. Sarah McErlean, clinical academic fellow1,
  2. Balwani Mbakaya, associate professor2 3,
  3. Cormac Kennedy, consultant clinical pharmacologist and physician4 5
  1. 1Department of General Practice, UCD School of Medicine, University College Dublin, Dublin, Ireland
  2. 2Public Health Department, Faculty of Applied Sciences, University of Livingstonia, Malawi
  3. 3Biological Sciences Department, Faculty of Science, Technology and Innovation, Mzuzu University, Malawi
  4. 4Department of Pharmacology, School of Medicine, Trinity College Dublin, Ireland
  5. 5Department of Pharmacology and HRB Clinical Research Facility, St James's Hospital, Dublin 8, Ireland
  1. Correspondence to: S McErlean sarah.mcerlean{at}ucd.ie

What you need to know

  • Familial hypercholesterolaemia is a common genetic condition affecting 1 in 310 people, resulting in premature coronary artery disease due to elevated cholesterol levels from birth

  • If a parent has familial hypercholesterolaemia, there is a 50% chance their child will inherit the condition

  • Treatment is based on lowering low density lipoprotein (LDL) cholesterol concentration, with a target of at least 50% reduction from baseline

Heterozygous familial hypercholesterolaemia is the most common autosomal dominant genetic condition, affecting approximately 1 in 310 people around the world.12 It causes markedly elevated low density lipoprotein (LDL) cholesterol from birth.1234 It has a high penetrance, and elevated LDL cholesterol can begin in utero, with an LDL cholesterol concentration >4 mmol/L in children and >5 mmol/L in adults suggesting its presence.5

What is familial hypercholesterolaemia?

Familial hypercholesterolaemia is caused by a functional mutation that impairs LDL receptor-mediated uptake of the LDL particle, therefore resulting in higher LDL cholesterol in the bloodstream.67 Most of those affected (85-90%) have a mutation in the LDL receptor gene.68 Familial hypercholesterolaemia can be classified as heterozygous or homozygous depending on the presence of one or two affected gene alleles.9 However, the heterozygous form is common, whereas the homozygous form is very rare.

It is estimated that 25-35 million people worldwide inherit the condition but fewer than 10% are ever diagnosed and most remain untreated.1349 Most studies reporting the prevalence of familial hypercholesterolaemia in the general population are from Europe, North America, East Asia, and Australia, so it is unclear if the same underlying prevalence exists in different parts of the world and among different ethnicities.12 Some populations with founder effects have a higher prevalence of familial hypercholesterolaemia—for example, South African Afrikaners and Ashkenazi Jews have a prevalence of 1-1.5%.10 This happens when a subpopulation group is formed from a small number of ancestors, resulting in reduced genetic diversity.10 If one of the founder subjects carries a familial hypercholesterolaemia mutation then this can result in an unusually high proportion of subjects affected.

The global prevalence of premature coronary artery disease in those with familial hypercholesterolaemia is 11.3%, 20-fold higher than in the general population.29 The onset of premature coronary artery disease in midlife is directly related to the substantially increased cholesterol burden present from birth. If left untreated, 50% of men with heterozygous familial hypercholesterolaemia may develop coronary artery disease before the age of 50 years and 30% of women before age 60.1112

The condition is often overlooked in patients who have other risk factors for cardiovascular disease, and there is a lack of awareness of this condition in both primary and secondary care.12 Given that ischaemic heart disease is currently the leading cause of death across the world,13 improved detection and management of familial hypercholesterolaemia in all medical specialties has the potential for public health improvements.

This article aims to give an overview of the detection and management of familial hypercholesterolaemia for both non-specialists and general practitioners to ensure patients with familial hypercholesterolaemia are managed appropriately.

How can we screen for familial hypercholesterolaemia in primary care?

There are no universally accepted diagnostic criteria for familial hypercholesterolaemia, leading to variations in prevalence from different studies.49 The UK National Institute for Health and Care Excellence (NICE) guidance uses total cholesterol and/or LDL cholesterol, whereas European, Canadian, and US guidelines use LDL cholesterol as the key biomarker for familial hypercholesterolaemia.381214

The 2019 NICE guidelines on familial hypercholesterolaemia encourages GPs to systematically search their records for those who may have the condition to improve diagnosis.11 Key points to consider are in box 1. NICE recommends that familial hypercholesterolaemia be considered in adults (aged >16 years) when lipid values are high (total cholesterol >7.5 mmol/L and/or LDL cholesterol >5 mmol/L) or if there is a personal or family history of premature coronary artery disease (event before 55 years of age in a man and before 60 years old in a woman). Currently, NICE does not have recommendations specific to children.11 The European, Canadian, and US guidelines recommend familial hypercholesterolaemia be considered in children if their LDL cholesterol level is >4 mmol/L.81416

Box 1

Guidance on identifying familial hypercholesterolaemia

  • If a patient has notably elevated total cholesterol and LDL cholesterol levels, exclude secondary causes of hypercholesterolaemia3111214

    • Hypothyroidism

    • Liver disease

    • Renal disease

    • Medications such as highly active antiretroviral drugs

    • Ketogenic diet

  • If hypertriglyceridaemia is present, further fasting measurements are indicated3

  • Take a detailed family history, identifying those with premature coronary artery disease and markedly elevated LDL cholesterol

  • Assess for clinical signs of familial hypercholesterolaemia such as tendon xanthomata (rarely found in general practice), corneal arcus, and xanthelasma (fig 1). The absence of these signs does not exclude disease.15

RETURN TO TEXT

Globally, the most commonly used diagnostic algorithm for familial hypercholesterolaemia is the Dutch Lipid Clinic Network (DLCN) score, which can be used to screen and identify adults >16 years old at risk in primary care and make a possible, probable, or definite clinical phenotypic diagnosis (table 1).91112 The Simon-Broome criteria are most commonly used in the UK (box 2) and are derived from the Simon Broome register of patients with familial hypercholesterolaemia which began in the UK in 1980.17 These criteria have LDL cholesterol cut-off values for both adults and children but may not be applicable in other groups such as Asian populations, who tend to have lower cholesterol levels.417 Both of these definitions rely on cutaneous findings, which are becoming increasingly rare in clinical practice. The Simplified Canadian Definition for Familial Hypercholesterolaemia has been proposed to better fit current practice.14 Other accepted diagnostic criteria included the Make Early Diagnosis–Prevent Early Death (MED-PED) criteria (which require extensive knowledge of family history, with cholesterol cut-off levels more specific for the US), Japanese criteria, and genetic diagnosis.1918

Table 1

Dutch Lipid Clinic Network Score for diagnosing familial hypercholesterolaemia

View this table:
Box 2

Simon Broome criteria for diagnosing familial hypercholesterolaemia

Definite familial hypercholesterolaemia

  • Required laboratory evidence of high cholesterol levels:

    • Adult = total cholesterol >290 mg/dL (7.5 mmol/L) or LDL cholesterol >190 mg/dL (4.9 mmol/L)

    • Child <16 years old = total cholesterol 260 mg/dL (6.7 mmol/L) or LDL cholesterol 155 mg/dL (4.0 mmol/L)

  • Plus at least one of:

    • Physical finding of tendon xanthomas or tendon xanthomas in first or second degree relative

    • DNA based evidence of an LDL-receptor mutation, familial defective apo B-11, or a PCSK9 mutation

Possible familial hypercholesterolaemia

  • Laboratory evidence of high cholesterol levels:

    • Adult = total cholesterol >290 mg/dL (7.5 mmol/L) or LDL cholesterol >190 mg/dL (4.9 mmol/L)

    • Child <16 years old = total cholesterol >260 mg/dL (6.7 mmol/L) or LDL cholesterol >155 mg/dL (4.0 mmol/L)

  • Plus at least one of:

    • Family history of myocardial infarction at:

      • Age ≤60 years in first degree relative

      • Age ≤50 years in second degree relative

      • OR

    • Family history of elevated total cholesterol

      • >290 mg/dL (7.5 mmol/L) in adult first or second degree relative

      • >260 mg/dL (6.7 mmol/L) in child, brother, or sister aged <16 years

RETURN TO TEXT
Fig 1
Fig 1

Signs of hypercholesterolaemia can include (left) xanthoma (of the Achilles tendons), (centre) corneal arcus, and (right) xanthelasma. (Credit: St James Hospital, Dublin; P Marazzi/SPL; ISM/SPL)

How can we manage familial hypercholesterolaemia in primary care?

General practice is central to the continuity of care for all patients with familial hypercholesterolaemia and their families, which includes advocacy, screening, diagnosis, prescribing and monitoring lipid-lowering medication, and managing comorbidities.19 A structured annual review is recommended for all people with familial hypercholesterolaemia. This creates an opportunity to assess lifestyle risk factors, smoking status, fasting lipid levels, symptoms of coronary artery disease, and the progress of cascade testing in family members.11 A medication review at this appointment includes possible side effects, if any changes to therapy are indicated to achieve the target LDL cholesterol level, and an emphasis on medication compliance.1115

Box 3 provides an approach using the SORT mnemonic (search the practice database; offer screening; risk assess and refer; treat where indicated).3811121420 A suggested treatment approach is presented in figure 2.

Box 3

Approach to recognition and identification of potential patients with familial hypercholesterolaemia using the SORT mnemonic

Search

Systematically search primary care records for:

  • Adults with an LDL cholesterol level >5 mmol/L

  • Children with LDL cholesterol >4 mmol/L

  • People with a personal or family history of premature coronary artery disease

Offer

Offer to measure lipid profile in:

  • People with a personal or family history of premature coronary heart disease (an event before 60 years)

  • Children or close relatives of patients with proven familial hypercholesterolaemia

  • People who have (or whose family members have) tendon xanthomata

Risk assess and refer

  • Identify family history of premature coronary artery disease

  • Use the Simon Broome criteria or DLCN score to identify potential cases

  • Refer people for further evaluation and family screening if they have a DLCN score >5 or possible or definite familial hypercholesterolaemia on Simon Broome criteria

  • Do not use standard risk assessment tools for cardiovascular disease (such as QRISK3) as these underestimate risk in people with suspected familial hypercholesterolaemia

Treat

  • Address lifestyle factors, especially avoidance of smoking

  • Start high intensity statin therapy aiming for ≥50% reduction in baseline LDL cholesterol concentration

  • Consider using ezetimibe or bempedoic acid if statins are not tolerated or contraindicated, or as add-on therapy

  • Consider additional therapies for those not reaching target LDL cholesterol level, including PCSK9 inhibitors or inclisiran

RETURN TO TEXT
Fig 2
Fig 2

Suggested treatment approach to familial hypercholesterolaemia. (LDL-C = low density lipoprotein cholesterol)

Lifestyle changes

Families with familial hypercholesterolaemia benefit from comprehensive education targeting smoking, diet, and physical activity.1221 A healthy diet low in saturated fats (focusing on wholegrains, vegetables, fruit, and fish) with regular exercise (30-60 minutes daily) are recommended.31221 The advantages of both diet and exercise can mitigate against the emergence of other cardiovascular risk factors such as hypertension, diabetes, and obesity.3

Lipid lowering therapy

Use of lipid lowering therapy, usually with high intensity statins, is the mainstay of treatment.3411 Table 2 outlines the impact of lipid lowering drugs on LDL cholesterol levels based on European Society of Cardiology guidance.

Table 2

Impact of lipid lowering treatment on LDL cholesterol levels in those with familial hypercholesterolaemia (adapted from Mach 20203)

View this table:

A 2008 cohort study conducted in the Netherlands observed a risk reduction of 76% (hazard ratio 0.24 (95% confidence interval 0.18 to 0.30)) for the development of ischaemic heart disease in patients with familial hypercholesterolaemia even with modest statin doses, and the risk of myocardial infarction approached that of the general population in these statin treated patients.22 Risk stratification tools such as QRISK3 are not valid for patients with familial hypercholesterolaemia as they are already at high risk of cardiovascular disease.11

  • Aim to reduce LDL cholesterol by ≥50% from baseline with high intensity statin therapy (such as atorvastatin 40-80 mg, rosuvastatin 20-40 mg).311

  • Treatment targets set by the European Society of Cardiology are LDL cholesterol <1.8 mmol/L with a lower goal of 1.4 mmol/L for those with confirmed coronary artery disease.3

  • Measure LDL cholesterol 8-12 weeks after starting statin therapy, and after each dose adjustment until the target LDL cholesterol level is reached.3

  • Once at target then LDL cholesterol can be measured annually.3

  • Consider adding ezetimibe if target LDL cholesterol is not achieved on maximally tolerated dose of statin.311 Based on randomised trial evidence, a combination of a high intensity statin with ezetimibe can achieve a 65% reduction in LDL cholesterol (table 2).32324

  • If a patient is unable to tolerate statin therapy, consider ezetimibe as monotherapy or in combination with bempedoic acid.31125

  • For those not achieving target cholesterol levels with the above strategies, PCSK9 inhibitors such as alirocumab or evolocumab should be considered.3111214

  • PCSK9 inhibitors are injectable drugs that can achieve substantial reductions in LDL cholesterol and can be used in combination with statins and/or ezetimibe.1112

  • PCSK9 inhibitors are expensive, and access can be limited and restricted. In many European countries reimbursement is limited to select groups of patients for specific indications.26

  • Newer approaches to lipid lowering therapy include inclisaran (a small interfering RNA that inhibits synthesis of PCSK9) and obicetrapib (a cholesterol ester transfer protein inhibitor).2728

  • The ORION trials demonstrated the ability of inclisaran to lower LDL cholesterol, but widespread clinical outcome data are not available.29

  • NICE has recommended that, subject to a commercial arrangement, inclisaran be prescribed as secondary prevention for patients with a history of cardiovascular events who do not achieve their LDL cholesterol target with statins and ezetimibe.27

Challenges with treating familial hypercholesterolaemia

The undertreatment of familial hypercholesterolaemia is consistently reported worldwide.912223031 Women are more likely to be underdiagnosed and undertreated than men,932 while childhood is the ideal time to identify familial hypercholesterolaemia on the basis of LDL cholesterol because of minimal dietary or hormonal influence at that age (box 4).16 The Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry found the mean age at diagnosis was 44.4 years, with only 2.1% of individuals diagnosed in childhood or adolescence.9 At entry into the FHSC registry, only 59.5% of individuals were taking lipid lowering drugs.9 Of these, about 80% were taking statins, but fewer than 20% were on the highest dose, 21% were taking combination therapy, and only 2.7% of patients achieved a target LDL cholesterol level lower than 1.8 mmol/L.9

Box 4

Special considerations for women and children

Key points to note about women

  • On average, women are 2.5 years older than men at age of diagnosis of familial hypercholesterolaemia9

  • Women are less likely to be

    • Diagnosed with familial hypercholesterolaemia after hospital admission with a cardiovascular event33

    • Taking maximum statin therapy932

    • Taking combination therapy932

  • Advise women to stop taking statins and ezetimibe three months before conceiving, during pregnancy, and while breast feeding34

  • The loss of treatment years during pregnancy and breast feeding among women with familial hypercholesterolaemia results in a higher LDL burden over their lifetime and potential increased cardiovascular risk34

  • Women may benefit from aggressive treatment in the years before pregnancy to reduce complication rates while pregnant35

  • Treatment can be restarted postpartum or on completion of breast feeding32

  • If available, involve a multidisciplinary team including cardio-obstetrics32

  • Routine cholesterol measurement during pregnancy is not recommended11

Key points to note about children

  • Diagnosis in children ideally occurs before the age of 10 years, with statin treatment starting at this age too31116

  • Statins are effective and safe to use in children36

  • In children <10 years old, aim to reduce LDL cholesterol levels by 50% from baseline16

  • In children >10 years, aim for an LDL cholesterol level of 3.5 mmol/L16

  • Ezetimibe or a bile acid sequestrant may be needed if this target is not achieved16

  • PCSK9 inhibitors are recommended for children >10 years old whose LDL cholesterol level is not controlled with statin and/or ezetimibe therapy37

  • PCSK9 inhibitors have shown to be safe in children, with a statistically significant reduction in LDL cholesterol of 2 mmol/L over a 6 month period37

RETURN TO TEXT

Statins are generally well tolerated, but widely publicised unblinded observational studies have contributed to the public belief that statins cause muscle pain.38 However, a recent meta-analysis of randomised double blinded controlled trials has shown that statin induced muscle symptoms are rare.35 This meta-analysis included a subgroup analysis of high intensity statin use, which showed that statins are not the cause of muscle symptoms in >90% of patients who report them (rate ratio 1.08 (95% CI 1.04 to 1.13)), especially if the statin therapy has been well tolerated for a year.35 Statin use in low and middle income countries is still poor, with only 10% of those who are eligible taking a statin for primary prevention of coronary artery disease, highlighting lack of access to these drugs.39 Within Europe, access can also be limited as some countries require a specialist to prescribe both statins and ezetimibe.26

Integrated care between specialist centres and general practice is probably the best way to manage these patients effectively.43031 Continuity of care in general practice can facilitate identification of family members, timely follow-up, ongoing support, treatment, and referral.43031

When to refer to a specialist

Referral to specialist services is required for DNA testing to confirm suspected familial hypercholesterolaemia. Box 5 lists indications for referral. GPs can discuss the inheritance of familial hypercholesterolaemia with patients in primary care and offer to measure cholesterol levels in their first degree relatives. As familial hypercholesterolaemia is an autosomal dominant condition, half of first degree relatives of the index case will be affected. Once a clinical or genetic diagnosis of familial hypercholesterolaemia is confirmed, cascade testing of close family members can be initiated.11

Box 5

When to refer to a specialist

  • Possible or definite familial hypercholesterolaemia on Simon Broome criteria

  • DLCN score >5

  • All children

  • Women considering pregnancy

  • Patients with difficulty achieving LDL cholesterol targets

  • Patients with intolerance to lipid lowering therapy

  • Patients with symptoms of coronary artery disease11

  • Patients with established coronary artery disease, family history of premature coronary artery disease, or ≥2 risk factors for coronary artery disease

RETURN TO TEXT

A precise molecular diagnosis will enable efficient case-finding among family members, improve patient motivation and compliance, allow identification of those at highest risk of coronary artery disease (such as compound heterozygotes), and in some countries such as Ireland and the UK enable access to restricted lipid lowering treatments such as PCSK9 inhibitors.412152140

Approximately 20% of patients who meet the clinical criteria for probable or definite familial hypercholesterolaemia do not have a causative mutation identified.36712 These patients likely have a polygenic basis for their elevated LDL cholesterol levels without contributions from the classic genes for familial hypercholesterolaemia.6712 Such patients still require intensive LDL cholesterol lowering and cascade screening of family members. The cumulative burden of hypercholesterolaemia highlights the importance of early diagnosis and early treatment.12 This is particularly true for those with homozygous familial hypercholesterolaemia, who typically have cardiovascular complications in their teenage years.40

Assess all patients with familial hypercholesterolaemia diagnosed for symptoms of coronary artery disease such as exertional chest pain, as they will require urgent referral to cardiology for review.1112 There is no consensus on the use or frequency of non-invasive cardiovascular imaging such as computed tomography coronary angiography, carotid ultrasound, or coronary artery calcium scoring for asymptomatic screening.31214

Education into practice

  • Audit suggestion: search primary care database for

    • Adults with LDL cholesterol concentration >5 mmol/L

    • Children with LDL cholesterol >4 mmol/L

    • Family history of premature coronary artery disease

  • Use the Simon Broome Criteria or DLCN score to identify potential cases

How patients were involved in the creation of this article

A patient attending primary care was interviewed by SMc and reviewed an early draft of the manuscript. They highlighted the following, which were then included in the article:

  • The prevalence of CVD globally

  • The importance of lifestyle modifications

  • Statin compliance

  • The role and benefits of monitoring in primary care

  • The frequency of review

  • The implications of having a genetic disease would have for close family members. They emphasised that earlier diagnosis for future generations would be extremely beneficial.

How this article was made

We reviewed the most recent NICE guidelines on familial hypercholesterolaemia (updated 2019), the 2019 ESC/EAS guidelines for the management of dyslipidaemias, the 2021 ESC guidelines on cardiovascular disease prevention, the Canadian Society of Cardiology position statement on familial hypercholesterolaemia (2018), and the American Heart Association guidelines on the diagnosis and treatment of familial hypercholesterolaemia (2019).

We used the search term “familial hypercholesterolaemia” on the Cochrane Database and evaluated three relevant review papers. The search terms “familial hypercholesterolaemia” and “primary care” were used on the PubMed database. We reviewed references contained within high quality review articles. Expert input, patient input and collective experience were also used to write this article.

Footnotes

  • Contributors: All authors made substantial contributions to this article and were involved in drafting, revision, and approval of the final manuscript. All authors accept responsibility for the accuracy and integrity of the work. SMc is the guarantor.

  • Competing interests: The BMJ has judged that there are no disqualifying financial ties to commercial companies. The authors declare the following other interests: none. Further details of The BMJ policy on financial interests is here: https://www.bmj.com/sites/default/files/attachments/resources/2016/03/16-current-bmj-education-coi-form.pdf

References

  1. ↵
    1. Hu P,
    2. Dharmayat KI,
    3. Stevens CAT,
    4. et al
    . Prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Circulation2020;141:1742-59. doi:10.1161/CIRCULATIONAHA.119.044795. pmid:32468833
    OpenUrlCrossRefPubMed
  2. ↵
    1. Beheshti SO,
    2. Madsen CM,
    3. Varbo A,
    4. Nordestgaard BG
    . Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects. J Am Coll Cardiol2020;75:2553-66. doi:10.1016/j.jacc.2020.03.057. pmid:32439005
    OpenUrlCrossRefPubMed
  3. ↵
    1. Mach F,
    2. Baigent C,
    3. Catapano AL,
    4. et al.,
    5. ESC Scientific Document Group
    . 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J2020;41:111-88. doi:10.1093/eurheartj/ehz455 pmid:31504418
    OpenUrlCrossRefPubMed
  4. ↵
    1. Wilemon KA,
    2. Patel J,
    3. Aguilar-Salinas C,
    4. et al.,
    5. Representatives of the Global Familial Hypercholesterolemia Community
    . Reducing the clinical and public health burden of familial hypercholesterolemia: a global call to action. JAMA Cardiol2020;5:217-29. doi:10.1001/jamacardio.2019.5173. pmid:31895433
    OpenUrlCrossRefPubMed
  5. ↵
    1. Gidding SS,
    2. Champagne MA,
    3. de Ferranti SD,
    4. et al.,
    5. American Heart Association Atherosclerosis, Hypertension, and Obesity in Young Committee of Council on Cardiovascular Disease in Young, Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology, and Council on Lifestyle and Cardiometabolic Health
    . The agenda for familial hypercholesterolemia: a scientific statement from the American Heart Association. Circulation2015;132:2167-92. doi:10.1161/CIR.0000000000000297 pmid:26510694
    OpenUrlFREE Full Text
  6. ↵
    1. Futema M,
    2. Whittall RA,
    3. Kiley A,
    4. et al.,
    5. Simon Broome Register Group
    . Analysis of the frequency and spectrum of mutations recognised to cause familial hypercholesterolaemia in routine clinical practice in a UK specialist hospital lipid clinic. Atherosclerosis2013;229:161-8. doi:10.1016/j.atherosclerosis.2013.04.011. pmid:23669246
    OpenUrlCrossRefPubMedWeb of Science
  7. ↵
    1. Santos RD,
    2. Gidding SS,
    3. Hegele RA,
    4. et al.,
    5. International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel
    . Defining severe familial hypercholesterolaemia and the implications for clinical management: a consensus statement from the International Atherosclerosis Society Severe Familial Hypercholesterolemia Panel. Lancet Diabetes Endocrinol2016;4:850-61. doi:10.1016/S2213-8587(16)30041-9. pmid:27246162
    OpenUrlCrossRefPubMed
  8. ↵
    1. McGowan MP,
    2. Hosseini Dehkordi SH,
    3. Moriarty PM,
    4. Duell PB
    . Diagnosis and treatment of heterozygous familial hypercholesterolemia. J Am Heart Assoc2019;8:e013225. doi:10.1161/JAHA.119.013225. pmid:31838973
    OpenUrlCrossRefPubMed
  9. ↵
    1. Vallejo-Vaz AJ,
    2. De Marco M,
    3. Stevens CAT,
    4. et al.,
    5. EAS Familial Hypercholesterolaemia Studies Collaboration,
    6. EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) Investigators
    . Overview of the current status of familial hypercholesterolaemia care in over 60 countries - The EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC). Atherosclerosis2018;277:234-55. doi:10.1016/j.atherosclerosis.2018.08.051. pmid:30270054
    OpenUrlCrossRefPubMed
  10. ↵
    1. Austin MA,
    2. Hutter CM,
    3. Zimmern RL,
    4. Humphries SE
    . Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review. Am J Epidemiol2004;160:407-20. doi:10.1093/aje/kwh236. pmid:15321837
    OpenUrlCrossRefPubMedWeb of Science
  11. ↵
    National Institute for Health and Care Excellence. Familial hypercholesterolaemia: identification and management (clinical guideline CG71). 2019. www.nice.org.uk/guidance/cg71
  12. ↵
    1. Nordestgaard BG,
    2. Chapman MJ,
    3. Humphries SE,
    4. et al.,
    5. European Atherosclerosis Society Consensus Panel
    . Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J2013;34:3478-90a. doi:10.1093/eurheartj/eht273. pmid:23956253
    OpenUrlCrossRefPubMedWeb of Science
  13. ↵
  14. ↵
    1. Brunham LR,
    2. Ruel I,
    3. Aljenedil S,
    4. et al
    . Canadian Cardiovascular Society position statement on familial hypercholesterolemia: update 2018. Can J Cardiol2018;34:1553-63. doi:10.1016/j.cjca.2018.09.005. pmid:30527143
    OpenUrlCrossRefPubMed
  15. ↵
    1. Brett T,
    2. Arnold-Reed D
    . Familial hypercholesterolaemia: A guide for general practice. Aust J Gen Pract2019;48:650-2. doi:10.31128/AJGP-04-19-4910 pmid:31476827
    OpenUrlCrossRefPubMed
  16. ↵
    1. Wiegman A,
    2. Gidding SS,
    3. Watts GF,
    4. et al.,
    5. European Atherosclerosis Society Consensus Panel
    . Familial hypercholesterolaemia in children and adolescents: gaining decades of life by optimizing detection and treatment. Eur Heart J2015;36:2425-37. doi:10.1093/eurheartj/ehv157. pmid:26009596
    OpenUrlCrossRefPubMed
  17. ↵
    1. Simon Broome Register Group
    . Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ1991;303:893-6. doi:10.1136/bmj.303.6807.893 pmid:1933004
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Abdul-Razak S,
    2. Rahmat R,
    3. Mohd Kasim A,
    4. et al
    . Diagnostic performance of various familial hypercholesterolaemia diagnostic criteria compared to Dutch lipid clinic criteria in an Asian population. BMC Cardiovasc Disord2017;17:264. doi:10.1186/s12872-017-0694-z. pmid:29037163
    OpenUrlCrossRefPubMed
  19. ↵
    1. Brett T,
    2. Radford J,
    3. Heal C,
    4. et al
    . Implications of new clinical practice guidance on familial hypercholesterolaemia for Australian general practitioners. Aust J Gen Pract2021;50:616-21. doi:10.31128/AJGP-02-21-5836 pmid:34462766
    OpenUrlCrossRefPubMed
  20. ↵
    1. Lui DTW,
    2. Lee ACH,
    3. Tan KCB
    . Management of familial hypercholesterolemia: current status and future perspectives. J Endocr Soc2020;5:a122. doi:10.1210/jendso/bvaa122 pmid:33928199
    OpenUrlCrossRefPubMed
  21. ↵
    1. Broekhuizen K,
    2. Jelsma JG,
    3. van Poppel MN,
    4. Koppes LL,
    5. Brug J,
    6. van Mechelen W
    . Is the process of delivery of an individually tailored lifestyle intervention associated with improvements in LDL cholesterol and multiple lifestyle behaviours in people with familial hypercholesterolemia?BMC Public Health2012;12:348. doi:10.1186/1471-2458-12-348. pmid:22583789
    OpenUrlCrossRefPubMed
  22. ↵
    1. Versmissen J,
    2. Oosterveer DM,
    3. Yazdanpanah M,
    4. et al
    . Efficacy of statins in familial hypercholesterolaemia: a long term cohort study. BMJ2008;337:a2423. doi:10.1136/bmj.a2423. pmid:19001495
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Ballantyne CM,
    2. Houri J,
    3. Notarbartolo A,
    4. et al.,
    5. Ezetimibe Study Group
    . Effect of ezetimibe coadministered with atorvastatin in 628 patients with primary hypercholesterolemia: a prospective, randomized, double-blind trial. Circulation2003;107:2409-15. doi:10.1161/01.CIR.0000068312.21969.C8. pmid:12719279
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Ballantyne CM,
    2. Weiss R,
    3. Moccetti T,
    4. et al.,
    5. EXPLORER Study Investigators
    . Efficacy and safety of rosuvastatin 40 mg alone or in combination with ezetimibe in patients at high risk of cardiovascular disease (results from the EXPLORER study). Am J Cardiol2007;99:673-80. doi:10.1016/j.amjcard.2006.10.022. pmid:17317370
    OpenUrlCrossRefPubMedWeb of Science
  25. ↵
    National Institute for Health and Care Excellence. Bempedoic acid with ezetimibe for treating primary hypercholesterolaemia or mixed dyslipidaemia (technology appraisal guidance TA694). 2021. https://www.nice.org.uk/guidance/ta694.
  26. ↵
    1. Banach M,
    2. Penson PE,
    3. Vrablik M,
    4. et al.,
    5. ACS EuroPath Central & South European Countries Project
    . Optimal use of lipid-lowering therapy after acute coronary syndromes: A Position Paper endorsed by the International Lipid Expert Panel (ILEP). Pharmacol Res2021;166:105499. doi:10.1016/j.phrs.2021.105499. pmid:33607265
    OpenUrlCrossRefPubMed
  27. ↵
    National Institute for Health and Care Excellence. Inclisiran for treating primary hypercholesterolaemia or mixed dyslipidaemia (technology appraisal guidance TA733). 2021. www.nice.org.uk/guidance/ta733
  28. ↵
    1. Nicholls SJ,
    2. Ditmarsch M,
    3. Kastelein JJ,
    4. et al
    . Lipid lowering effects of the CETP inhibitor obicetrapib in combination with high-intensity statins: a randomized phase 2 trial. Nat Med2022;28:1672-8. doi:10.1038/s41591-022-01936-7. pmid:35953719
    OpenUrlCrossRefPubMed
  29. ↵
    1. Wright RS,
    2. Ray KK,
    3. Raal FJ,
    4. et al.,
    5. ORION Phase III Investigators
    . Pooled patient-level analysis of inclisiran trials in patients with familial hypercholesterolemia or atherosclerosis. J Am Coll Cardiol2021;77:1182-93. doi:10.1016/j.jacc.2020.12.058. pmid:33663735
    OpenUrlCrossRefPubMed
  30. ↵
    1. Benn M,
    2. Watts GF,
    3. Tybjaerg-Hansen A,
    4. Nordestgaard BG
    . Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab2012;97:3956-64. doi:10.1210/jc.2012-1563. pmid:22893714
    OpenUrlCrossRefPubMedWeb of Science
  31. ↵
    1. Bucholz EM,
    2. Rodday AM,
    3. Kolor K,
    4. Khoury MJ,
    5. de Ferranti SD
    . Prevalence and predictors of cholesterol screening, awareness, and statin treatment among US adults with familial hypercholesterolemia or other forms of severe dyslipidemia (1999-2014). Circulation2018;137:2218-30. doi:10.1161/CIRCULATIONAHA.117.032321. pmid:29581125
    OpenUrlAbstract/FREE Full Text
  32. ↵
    1. Balla S,
    2. Ekpo EP,
    3. Wilemon KA,
    4. Knowles JW,
    5. Rodriguez F
    . Women living with familial hypercholesterolemia: challenges and considerations surrounding their care. Curr Atheroscler Rep2020;22:60. doi:10.1007/s11883-020-00881-5. pmid:32816232
    OpenUrlCrossRefPubMed
  33. ↵
    1. Mundal L,
    2. Veierød MB,
    3. Halvorsen T,
    4. et al
    . Cardiovascular disease in patients with genotyped familial hypercholesterolemia in Norway during 1994-2009, a registry study. Eur J Prev Cardiol2016;23:1962-9. doi:10.1177/2047487316666371. pmid:27558979
    OpenUrlCrossRefPubMed
  34. ↵
    1. Klevmoen M,
    2. Bogsrud MP,
    3. Retterstøl K,
    4. et al
    . Loss of statin treatment years during pregnancy and breastfeeding periods in women with familial hypercholesterolemia. Atherosclerosis2021;335:8-15. doi:10.1016/j.atherosclerosis.2021.09.003. pmid:34520888
    OpenUrlCrossRefPubMed
  35. ↵
    1. Reith C,
    2. Baigent C,
    3. Blackwell L,
    4. et al.,
    5. Cholesterol Treatment Trialists’ Collaboration
    . Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials. Lancet2022;400:832-45. doi:10.1016/S0140-6736(22)01545-8. pmid:36049498
    OpenUrlCrossRefPubMed
  36. ↵
    1. Vuorio A,
    2. Kuoppala J,
    3. Kovanen PT,
    4. et al
    . Statins for children with familial hypercholesterolemia. Cochrane Database Syst Rev2017;7:CD006401. doi:10.1002/14651858.CD006401.pub4. pmid:28685504
    OpenUrlCrossRefPubMed
  37. ↵
    1. Santos RD,
    2. Ruzza A,
    3. Hovingh GK,
    4. et al.,
    5. HAUSER-RCT Investigators
    . Evolocumab in pediatric heterozygous familial hypercholesterolemia. N Engl J Med2020;383:1317-27. doi:10.1056/NEJMoa2019910. pmid:32865373
    OpenUrlCrossRefPubMed
  38. ↵
    1. Herrett E,
    2. Williamson E,
    3. Brack K,
    4. et al.,
    5. StatinWISE Trial Group
    . Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials. BMJ2021;372:n135. doi:10.1136/bmj.n135. pmid:33627334
    OpenUrlAbstract/FREE Full Text
  39. ↵
    1. Marcus ME,
    2. Manne-Goehler J,
    3. Theilmann M,
    4. et al
    . Use of statins for the prevention of cardiovascular disease in 41 low-income and middle-income countries: a cross-sectional study of nationally representative, individual-level data. Lancet Glob Health2022;10:e369-79. doi:10.1016/S2214-109X(21)00551-9. pmid:35180420
    OpenUrlCrossRefPubMed
  40. ↵
    1. Tromp TR,
    2. Hartgers ML,
    3. Hovingh GK,
    4. et al.,
    5. Homozygous Familial Hypercholesterolaemia International Clinical Collaborators
    . Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet2022;399:719-28. doi:10.1016/S0140-6736(21)02001-8. pmid:35101175
    OpenUrlCrossRefPubMed
Back to top