Existing and emerging therapies for the treatment of familial hypercholesterolemia

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.

Keywords: LDL; LDL receptor; angiopoietin-like protein 3; atherosclerotic cardiovascular disease; cholesterol-lowering therapies; familial hypercholesterolemia; genetics; lipoprotein (a); proprotein convertase subtilisin Kexin 9.

Fig. 1

Mechanism of action for LDL lowering with statins and proprotein convertase subtilisin Kexin type 9 (PCSK9) inhibitors. The lower left of the image shows that statins inhibit HMG-CoA reductase (HMGR), which is the rate limiting step in cholesterol biosynthesis. The top section shows binding of circulating PCSK9 by human monoclonal antibody inhibitors of PCSK9. After maturation, the LDLR anchors at the cell surface and binds LDL particles via apolipoprotein B. The ligand-receptor interaction initiates receptor-mediated endocytosis. The increased pH in the lysosome degrades LDL and releases the LDLR allowing the receptor to recycle dozens of times when PCSK9 is absent. However, when PCSK9 is present, the receptor is retained in the lysosome with LDL and cannot recycle (middle right of image). Decreased intracellular cholesterol level activates SREBP-2 in the endoplasmic reticulum (lower left of image), which initiates synthesis of LDLRs allowing for binding of circulating LDL, and PCSK9 synthesis. 1. Top of form. 2. Bottom of form.

Fig. 2

Angiopoietin-like protein 3 (ANGPTL3) inhibition lowers LDL-cholesterol. Schematic depicting the mechanism whereby ANGPTL3 inhibition lowers LDL-cholesterol. Upper panel: During homeostasis, ANGPTL3 diminishes the activity of vascular lipases lipoprotein lipase (LPL) and endothelial lipase (EL) and regulates APOB-containing lipoprotein turnover. Lower panel: Evinacumab unblocks the inhibitory effect of ANGPLT3 on both lipases, promoting VLDL remodeling and preferential removal of VLDL remnants from the circulation by hepatic remnant receptors, and reducing the pool for LDL. Thus, ANGPTL3 inhibition with a fully human monoclonal antibody lowers LDL-cholesterol by diminishing vascular LDL production. The effect of evinacumab on Apo B secretion require further study. APOB, apolipoprotein B.

Fig. 3

Clinical algorithm for LDL-cholesterol lowering in patients with homozygous familial hypercholesterolemia. ASCVD, atherosclerotic cardiovascular disease; PCSK9, proprotein convertase subtilisin Kexin type 9.

Fig. 4

Clinical algorithm for LDL-cholesterol lowering in patients with heterozygous familial hypercholesterolemia. PCSK9, PCSK9, proprotein convertase subtilisin Kexin type 9; SC, subcutaneously.