New treatment possibilities of homozygous familial hypercholesterolemia

Overview

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extremely elevated low-density lipoprotein cholesterol (LDL-C) levels, and is associated with premature atherosclerotic cardiovascular disease (ACVD) in early childhood. A crucial therapeutic measure is to attempt aggressive and adequate reduction of LDL-C levels, thereby delaying the onset or manifestation of ASKVO. Therapeutic decisions are based on LDL-C levels. However, it is problematic how to achieve this goal in patients with HoFH, particularly where LDL-C levels are extremely high (often above > 10 mmol/L) or when there is an inadequate response to treatment with, for example, statins and other medications where the mechanism of action requires functional LDL receptors. Fortunately, the therapeutic options for HoFH have expanded rapidly in recent years. The mainstay is combined LDL-C lowering therapy – both pharmacological intervention and lipoprotein apheresis (LA), which additionally eliminates lipoprotein(a). Statins and ezetimibe remain the first-line drugs. The addition of new, effective therapies (i.e., subtilisin/kexin type 9 proprotein convertase inhibitors, followed by evinacumab and/or lomitapide) offers the potential to achieve LDL-C targets or reduce the need for LA. Combination therapy with bile acid sequestrants or bempedoic acid is also an option. The future of HoFH treatment, probably not too distant, will be gene therapy and gene editing using CRISPR/Cas-9 technology.

Keywords:

ANGPTL3 – ezetimibe – gene therapy – familial hypercholesterolemia –lipoprotein apheresis – lomitapide – PCSK9 inhibitors – statins