Homozygous familial hypercholesterolaemia (HoFH), the most severe form of this high cholesterol disorder, affecting about one in 300,000 people, is poorly managed worldwide.1 -3 To address this, the European Atherosclerosis Society (EAS) has updated clinical guidance for HoFH care to improve early diagnosis and treatment, ensuring better outcome for all patients. This statement is an important step forward and should help to ensure that all HoFH patients receive effective treatment as soon as possible.
With very high levels of low-density lipoprotein (LDL) cholesterol from birth, early diagnosis of HoFH is crucial to avoid any delay in starting lipid-lowering therapy and reduce severe cardiovascular complications. This EAS statement recommends that LDL cholesterol is the key discriminator, with an LDL cholesterol level >10 mmol/L or >400 mg/dL suggestive of HoFH requiring further evaluation.
Novel genetic insights: What do we understand now by ‘homozygous FH’?
Co-Chair Professor Robert A. Hegele (Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada) discusses the impact of next generation DNA sequencing in defining what is meant by homozygous FH.Commentary by Prof Robert Hegele
In almost a decade since the last EAS statement on HoFH,4 there have been important advances in understanding the genetics of HoFH with improved terminology. According to Co-Chair Professor Robert A. Hegele, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada: ‘Next generation DNA sequencing has shown that what clinicians previously referred to as “homozygous FH” is remarkably complicated at the genetic level, with four main causal genes, different combinations of pathogenic variants and various inheritance patterns. Our new genetic classification system reflects how results now appear on genetic laboratory reports. We suggest the umbrella term “phenotypic homozygous FH”, which provides a clinical shorthand but also emphasises the priority of phenotype over genotype.’
A global approach to homozygous FH management: recognising treatment inequity
Co-Chair Prof. Derick Raal (University of the Witwatersrand, Parktown, Johannesburg, South Africa) discusses the impact of limitations in access to lipid-lowering therapies. These have been taken into account in the new treatment algorithm in the 2023 consensus statement.Commentary by Prof Derick Raal
Novel therapies such as lomitapide and the angiopoietin like-3 (ANGPTL3) inhibitor evinacumab, enable the possibility of achieving LDL cholesterol goal in HoFH patients. In real-world practice, however, these new treatments are mainly used in high-income countries. The statement recognises this with a treatment algorithm indicating less costly alternatives where access to new therapies is problematic. Co-Chair Professor Frederick J. Raal, University of the Witwatersrand, Parktown, Johannesburg, South Africa said: ‘Multiple lipid-lowering drug therapies, often in combination with lipoprotein apheresis, are required to lower markedly elevated LDL cholesterol levels seen in HoFH. However, as we have shown with the global HoFH International Clinical Collaboration registry,3 part-funded by the EAS, patients in less affluent countries are less likely to receive combination lipid-lowering therapy and have almost no access to newer therapies. As a result, these patients have a cardiovascular event such as a heart attack almost a decade earlier than those in high-income countries. We have a long way to go to ensure that all HoFH patients, particularly those living in less affluent countries, have access to newer treatments, essential to improve the quality of life and reduce both morbidity and mortality of our HoFH patients.’
Family planning discussion: integral to homozygous FH care
Co-Chair Dr. Marina Cuchel (Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA) discusses how advances in lipid-lowering treatment of homozygous FH have prolonged life expectancy, meaning that family planning discussions are essential to patient management.Commentary by Prof Marina Cuchel
Another new feature of this 2023 statement is a detailed discussion on family planning and pregnancy in HoFH patients. According to Co-Chair Dr. Marina Cuchel, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA: ‘The tremendous advances in lipid-lowering treatment for HoFH are prolonging life expectancy well into the reproductive years. For HoFH women of child-bearing potential, timely discussion of adequate contraception is essential to prevent unplanned pregnancy. Although associated with increased cardiovascular risk, and potentially life-threatening, pregnancy could be considered, especially if adequate treatment is initiated early in life. Key to this are acceptable results from a detailed cardiovascular evaluation , and a multidisciplinary team to manage the patient before, during and after pregnancy. Importantly, family planning discussion should include screening the partner and access to genetic counselling.’
The recommendations of this new EAS statement are fundamental to improving HoFH care in all regions of the world. Education programmes to improve awareness, screening programmes to improve early identification, and registries linked to outcome are all essential to improve health policy globally. EAS President, Professor Kausik K. Ray, Imperial College London, UK commented: ‘The EAS has led the way over the last decade to reduce the burden of cardiovascular disease resulting from HoFH. This latest update of the consensus paper brings under one umbrella all available data on genetics, implications of current practice and clinical management. We have worked with policy groups within the European Union and World Heart Federation to push forward screening for inherited lipid disorders including in childhood. We look forward to disseminating the current consensus globally and working with stakeholders globally to implement our recommendations.’
Cuchel M, Raal FJ, Hegele RA, Al-Rasadi K, Arca M, Averna M, Bruckert E, Freiberger T, Gaudet D, Harada-Shiba M, Hudgins LC, Kayikcioglu M, Masana L, Parhofer KG, Roeters van Lennep JE, Santos RD, Stroes ESG, Watts GF, Wiegman A, Stock JK, Tokgözoğlu LS, Catapano AL, Ray KK. 2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: New Treatments and Clinical Guidance. Eur Heart J 2023; doi: https://doi.org/10.1093/eurheartj/ehad197
- Hu P, Dharmayat KI, Stevens CAT, et al. Prevalence of familial hypercholesterolemia among the general population and patients with atherosclerotic cardiovascular disease: a systematic review and meta-analysis. Circulation 2020;141:1742–59.
- Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG. Worldwide prevalence of familial hypercholesterolemia: meta-analyses of 11 million subjects. J Am Coll Cardiol 2020;75:2553–66.
- Tromp TR, Hartgers ML, Hovingh GK, et al. Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study. Lancet
- Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J 2014;35:2146-57.