Year: 2021
Type: article
Abstract: Familial hypercholesterolemia (FH), an autosomal dominant disorder of LDL metabolism that is characterized by elevated LDL-cholesterol, is commonly encountered in patients with atherosclerotic coronary heart disease.Combinations of cholesterol-lowering therapies are often used to lower LDL-cholesterol in patients with FH; however, current treatment goals for LDL-cholesterol are rarely achieved in patients with homozygous FH (HoFH) and are difficult to achieve in patients with heterozygous FH (HeFH).Therapies that lower LDL-cholesterol through LDL receptor-mediated mechanisms have thus far been largely ineffective in patients with HoFH, particularly in those with negligible (<2%) LDL receptor activity.Among patients with HeFH who were at very high risk for atherosclerotic cardiovascular disease events, combined therapy consisting of a high dose of high-intensity statin, ezetimibe, and proprotein convertase subtilisin Kexin type 9 inhibitor failed to lower LDL-cholesterol to minimal acceptable goals in more than 50%.This article provides a framework for the use of available and emerging treatments that lower LDL-cholesterol in adult patients with HoFH and HeFH.A framework is provided for the use of angiopoietin-like protein 3 inhibitors in the treatment of HoFH and HeFH.Supplementary key words angiopoietin-like protein 3 • familial hypercholesterolemia • LDL • LDL receptor • lipoprotein (a) • proprotein convertase subtilisin Kexin 9 • cholesterol-lowering therapies • atherosclerotic cardiovascular disease • geneticsFamilial hypercholesterolemia (FH) is an autosomal dominant genetic disorder characterized by lifelong elevations in LDL-cholesterol (1).Because LDL is a causal and increscent risk factor for atherosclerotic cardiovascular disease (ASCVD) (2), individuals with FH have a high risk of early onset coronary heart disease (3-5).FHspecific guidelines recommend early detection of children and adults with FH in order to initiate LDLcholesterol-lowering therapy and prevent premature ASCVD and death (www.nice.org.uk/guidance/cg71)(6-10).Optimal care of patients with FH requires a model of care based on an integrated evidence-based system of health care services (11).Fundamental components of this framework comprise screening and detection, clinical and genetic testing, assessment of risk, and implementation of lifestyle, pharmacotherapies, and apheresis procedures.Effective care requires a patient-centered approach that encompasses organization of clinical services and education through regular outpatient visits emphasizing adherence to a healthy lifestyle and pharmacotherapy, treatment of nonlipid risk factors, and community support from patient networks (8,11).This review discusses the use of existing cholesterollowering therapies and the challenges in achieving minimal acceptable LDL-cholesterol goals with available therapies in adults with homozygous FH (HoFH) and heterozygous FH (HeFH).Special emphasis is devoted to the biology, genetics, and clinical studies with inhibitors of angiopoietin-like protein 3 (ANGPLT3). GENETICS OF FHFH is an autosomal dominant inherited disorder that results in elevations in LDL-cholesterol and increased risk for coronary heart disease (1).FH is caused mainly by mutations in LDLR, the gene encoding the LDL receptor (LDLR), and less often by mutations in APOB, the ligand for LDLR and proprotein convertase subtilisin Kexin type 9 (PCSK9), a protein that degrades LDLR (12).The variant frequency varies by race and ethnicity and the presence of founder genes.HoFH is characterized by two mutations in the same gene (true homozygotes) or two different genes (compound heterozygotes) (7), whereas HeFH results from a mutation in one gene (13).FH is associated with variable LDL-cholesterol levels that depend on the genetic variants contributing to the LDLR activity ( 14).The highest LDL-cholesterol levels occur in patients with virtually absent (null) or impaired (non-null) LDLR activity.LDL
Source: Journal of Lipid Research
Author: Robert S. Rosenson
Institution: Icahn School of Medicine at Mount Sinai
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,500
OpenAlex ID: W3137520281