2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance

Abstract

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.

Keywords: Clinical guidance; Diagnosis; Genetics; Homozygous familial hypercholesterolaemia; Treatment; Women.

Graphical Abstract

Homozygous familial hypercholesterolaemia is a rare autosomal semi-dominant disease affecting males and females equally, characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) from conception and accelerated atherosclerotic cardiovascular disease, often resulting in early death. Homozygous familial hypercholesterolaemia is diagnosed late and undertreated; both established and novel therapies offer hope to patients, but treatment inequity exacerbates poorer outcomes in less affluent countries.APOB, apolipoprotein B gene; CI, confidence interval; HR, hazard ratio; LDLR, low-density lipoprotein receptor gene; LDLRAP1, low-density lipoprotein adaptor protein 1 gene; PCSK9, proprotein conertase subtilisin/kexin type 9 gene.

Figure 1

Estimated global prevalence of homozygous familial hypercholesterolaemia by United Nations world region, based on 2020 population data and estimates of homozygous familial hypercholesterolaemia prevalence ranging from 1:250 000 to 1:360 000.^,

Figure 2

Identification and treatment of homozygous familial hypercholesterolaemia. (A) Algorithm for identification of phenotypic homozygous familial hypercholesterolaemia when clinically suspected in the absence of genetic data. (B) Treatment algorithm for homozygous familial hypercholesterolaemia (bi-allelic). ANGPTL3, angiopoietin-like 3; ASCVD, atherosclerotic cardiovascular disease; LALD, lysosomal acid lipase deficiency; LDL-C, low-density lipoprotein cholesterol; NGS, next-generation DNA sequencing; PCSK9, proprotein convertase subtilisin/kexin type 9.

Figure 3

Response to statin, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors is dependent on the degree of residual low-density lipoprotein receptor activity; however, for lomitapide, angiopoietin-like protein 3 (ANGPLT3)-directed therapy and lipoprotein apheresis, response is independent of low-density lipoprotein receptor function. Reproduced with permission from Mohamed et al..

Figure 4

As shown for high-income countries in the HoFH International Clinical Collaborators registry, multidrug therapy substantially improved low-density lipoprotein cholesterol- lowering. More than 50% of the few patients on five lipid-lowering therapies attained low-density lipoprotein cholesterol goal (defined as <2.5 mmol/L in primary prevention or <1.8 mmol/L in secondary prevention). Adapted with permission from Tromp et al.