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.

Evinacumab for Pediatric Patients With Homozygous Familial Hypercholesterolemia

“…1 in 250 000 to 360 000 individuals worldwide and is characterized by severe hypercholesterolemia, with lowdensity lipoprotein cholesterol (LDL-C) levels generally >400 mg/dL (>10 mmol/L), 2 starting in utero. 4,5 HoFH includes patients with LDLR-defective (some residual activity; ranging between 2% and 15%), and with LDLRnegative (no activity [<2%]) pathogenic variants.…”

“…4,5 HoFH includes patients with LDLR-defective (some residual activity; ranging between 2% and 15%), and with LDLRnegative (no activity [<2%]) pathogenic variants. 2,[6][7][8][9][10][11] Elevated LDL-C levels lead to a roughly 20-fold or more increased risk of developing premature atherosclerotic cardiovascular disease complications, including coronary arterial atherosclerosis as well as valvular and supravalvular aortic stenosis, compromising the coronary ostia (that results from accumulation of lipids in the aortic root). 2 This pathology can lead to early myocardial infarction and other atherosclerotic cardiovascular disease events, resulting in disability or death during childhood and adolescence.…”

“…2,[6][7][8][9][10][11] Elevated LDL-C levels lead to a roughly 20-fold or more increased risk of developing premature atherosclerotic cardiovascular disease complications, including coronary arterial atherosclerosis as well as valvular and supravalvular aortic stenosis, compromising the coronary ostia (that results from accumulation of lipids in the aortic root). 2 This pathology can lead to early myocardial infarction and other atherosclerotic cardiovascular disease events, resulting in disability or death during childhood and adolescence. [12][13][14] The magnitude of LDL-C elevations in HoFH is primarily dependent on the gene involved, with pathogenic variants in LDLR associated with more severe phenotypes compared with pathogenic variants in APOB, PCSCK9, and LDLRAP1, and more severe outcomes associated with LDLR-negative variants compared with LDLR-defective variants.…”

“…[12][13][14] The magnitude of LDL-C elevations in HoFH is primarily dependent on the gene involved, with pathogenic variants in LDLR associated with more severe phenotypes compared with pathogenic variants in APOB, PCSCK9, and LDLRAP1, and more severe outcomes associated with LDLR-negative variants compared with LDLR-defective variants. 2 In the United States, approved standard-of-care lipid-lowering therapies (LLTs) used to reduce LDL-C in adult and pediatric patients with HoFH include statins, ezetimibe, PCSK9 inhibitors, and lipoprotein apheresis. 2,[15][16][17][18][19] LLTs solely approved for the treatment of adult patients with HoFH include bempedoic acid and lomitapide.…”

“…2 In the United States, approved standard-of-care lipid-lowering therapies (LLTs) used to reduce LDL-C in adult and pediatric patients with HoFH include statins, ezetimibe, PCSK9 inhibitors, and lipoprotein apheresis. 2,[15][16][17][18][19] LLTs solely approved for the treatment of adult patients with HoFH include bempedoic acid and lomitapide. 2,[19][20][21] Because the 4 main classes of LLTs (ie, statins, ezetimibe, bempedoic acid, and PCSK9 inhibitors) are LDLR-dependent, they have minimal efficacy in patients with HoFH and almost none in those with null/null variants.…”