Elsevier

The Lancet

Volume 398, Issue 10312, 6–12 November 2021, Pages 1713-1725
The Lancet

Articles
Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)

https://doi.org/10.1016/S0140-6736(21)01122-3Get rights and content

Summary

Background

The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally.

Methods

Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases.

Findings

Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53·6%] women) from 56 countries were included in the study. Of these, 31 798 (75·4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84·2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46·2 years (IQR 34·3–58·0); median age at diagnosis of familial hypercholesterolaemia was 44·4 years (32·5–56·5), with 40·2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17·4% (2·1% for stroke and 5·2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81·1%) were receiving statins and 3691 (21·2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5·43 mmol/L (IQR 4·32–6·72) among patients not taking lipid-lowering medications and 4·23 mmol/L (3·20–5·66) among those taking them. Among patients taking lipid-lowering medications, 2·7% had LDL cholesterol lower than 1·8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin–kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1·8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p<0·001).

Interpretation

Familial hypercholesterolaemia is diagnosed late. Guideline-recommended LDL cholesterol concentrations are infrequently achieved with single-drug therapy. Cardiovascular risk factors and presence of coronary disease were lower among non-index cases, who were diagnosed earlier. Earlier detection and greater use of combination therapies are required to reduce the global burden of familial hypercholesterolaemia.

Funding

Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron.

Introduction

Recognition that familial hypercholesterolaemia is not an uncommon condition, whose clinical course can be improved through early detection and treatment, led to the 1998 WHO Report on familial hypercholesterolaemia,1 which advocated the need to address the challenge of familial hypercholesterolaemia worldwide through multiple approaches. Since then, there has been insufficient progress in the implementation of key aspects of those recommendations, which include making an early diagnosis, providing effective treatment, and raising awareness.2 Contemporary epidemiological and genetic studies now suggest that familial hypercholesterolaemia is approximately twice as common as previously thought, potentially affecting more than 25 million people worldwide.3 Yet, with no consensus on approaches for detection or screening, fewer than 5% of individuals potentially affected are estimated to have been diagnosed, with scarce data from many world regions.3, 4

Although different registries have been initiated in several countries to inform local policy independently, efforts to tackle the global burden of familial hypercholesterolaemia have been hampered by the lack of an integrated approach. The European Atherosclerosis Society (EAS) Familial Hypercholesterolaemia Studies Collaboration (FHSC)5 was established to create a global registry of patients with familial hypercholesterolaemia, creating a network of investigators (currently from 66 countries worldwide) for the purpose of providing a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of regional and national data. The FHSC aims to provide hitherto unavailable insights on the detection and management of familial hypercholesterolaemia on a global level, with potential implications for future public health strategies. In this study, we specifically aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and describe how it is detected and managed globally.

Research in context

Evidence before this study

We did a systematic search in PubMed for research articles published from inception to Feb 23, 2021, with no language restrictions. We included MeSH and free terms related to (“familial hypercholesterolaemia”) and (“registry”/“gender”/”sex”/“index case”), or variations of these terms thereof. We screened articles by title and abstract to identify relevant studies. Reference lists of eligible articles were also searched for additional studies. Articles that explored familial hypercholesterolaemia and registries to characterise familial hypercholesterolaemia and its burden, identification, and management were considered. We also reviewed the most recent guidelines and consensus statements on dyslipidaemias and familial hypercholesterolaemia.

In 2020, large meta-analyses showed that familial hypercholesterolaemia is a relatively common inherited condition, affecting about one in 300 individuals in the general population (approximately twice the prevalence historically estimated). Information on prevalence and burden of familial hypercholesterolaemia is scarce in many countries and regions. Low rates (<5–10%) of familial hypercholesterolaemia identification are consistently reported. Beyond opportunistic screening, family cascade screening and universal screening have been proposed; however, there is no consensus on the optimal strategy, and screening programmes are not widely implemented, with only few exceptions. Characterisation of index cases versus non-index cases could help inform optimal strategies, but information reported is insufficient. Familial hypercholesterolaemia increases the risk of (premature) cardiovascular disease, particularly of coronary disease, with data suggesting that outcomes could be prevented through early identification and intervention. However, undertreatment is consistently reported. Sex disparities in identification and management of familial hypercholesterolaemia have been suggested, but this requires additional characterisation.

Added value of this study

The Familial Hypercholesterolaemia Studies Collaboration provides an integrated approach to assess the global burden of familial hypercholesterolaemia by bringing together multiple sources and registries, which are standardised, harmonised, and merged into a single global Registry. The study included over 42 000 adults with heterozygous familial hypercholesterolaemia from 56 countries. Although familial hypercholesterolaemia occurs across all WHO regions, some regional variations exist. Familial hypercholesterolaemia is detected late, on average when individuals are in their 40s, with only about 40% of cases diagnosed before age 40 years. Prevalence of cardiovascular disease and cardiovascular risk factors increased with age of diagnosis, suggesting that late diagnosis potentially misses out on opportunities to address other future determinants of health in addition to LDL cholesterol. However, for non-index cases, who appeared to be diagnosed at an earlier age than index cases, the prevalence of cardiovascular disease and risk factors was lower, supporting the role of screening from index cases. Only 2·7% of patients receiving lipid-lowering medications achieved LDL cholesterol lower than 1·8 mmol/L, with low use of combination therapy. Goal attainment improved incrementally with the number of therapies used, particularly when including PCSK9 inhibitors. We observed important differences by sex, with implications for screening and treatment.

Implications of all the available evidence

Identification of familial hypercholesterolaemia needs to be improved to detect individuals affected much earlier in their life course. Greater use of combination therapy is probably required to improve familial hypercholesterolaemia management and reduce the gap between guideline recommendations and clinical practice. This point raises challenges about accessibility and cost, particularly in low-income and middle-income countries. Sex disparities in familial hypercholesterolaemia detection and management seem to be present, with potential implications for care and outcomes.

Section snippets

Study design and population

The FHSC draws upon data from an international consortium of investigators with access to patients managed in specialist clinics that serve as national, regional, or local registries of familial hypercholesterolaemia. Individual data from these diverse sources are standardised to a common data dictionary, harmonised, and merged into a single global registry.5 Additional details of methods and data management are described in the appendix (pp 15–18) and in the published protocol.5

The protocol

Results

Of the 61 612 individuals in the FHSC registry, 42 167 were aged 18 years or older with probable or definite heterozygous familial hypercholesterolaemia and were included in our study (appendix p 18). Most individuals (31 798 [75·4%]) were diagnosed with the DLCN criteria (either clinical criteria alone or both clinical and genetic criteria). Of the remaining individuals, 605 (1·4%) were diagnosed with Simon-Broome criteria and 2527 (6·0%) with MEDPED, 6563 (15·6%) were diagnosed with genetic

Discussion

Registries are a valuable tool to help assess current practices, monitor patients, identify gaps in care (including guideline implementation), and ultimately inform policy.2 Although familial hypercholesterolaemia registries are available in many countries, aimed at research or to audit quality standards, no integrated approach exists globally. Variability in such segregated approaches has complicated efforts to harmonise and integrate information from diverse sources, impeding reliable

Data sharing

Data collected in the FHSC registry cannot be shared with third parties owing to clauses in data sharing agreements with data suppliers that do not allow this. Data ownership for the data shared with the FHSC registry remains the property of the data suppliers.

Declaration of interests

CAA-S reports grants from Amgen, during the conduct of the study. FAl reports grants from National Science, Technology and Innovation Plan (MAARIFAH) of Saudi Arabia (08-BIO34-10), during the conduct of the study; and personal fees from Amgen, Amryt Pharma, and Algorithma Pharma, outside the submitted work. RA reports personal fees and non-financial support from Tecnofarma, and personal fees from Novo Nordisk, Abbott, Saval, and Teva, outside the submitted work. KA-R reports personal fees from

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