Inclisiran-Silencing the Cholesterol, Speaking up the Prognosis

Abstract

The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%-20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.

Keywords: atherosclerosis; cardiovascular disease; hypercholesterolemia; inclisiran; siRNA.

Figure 1

Mechanism of native low-density lipoprotein-cholesterol (LDL-C) and oxidized LDL (ox-LDL) uptake by macrophages. Native LDL-C binds to LDL receptors on macrophages or undergoes oxidation. Ox-LDL binds to specific receptors: scavenger receptor class A (SR-A), scavenger receptor class B type I (SR-BI), cluster differentiating 36 (CD36), and lectin-like oxidized LDL receptor-1 (LOX-1) on macrophages as well. Macrophages accumulate cholesterol from both native LDL and ox-LDL, which results in the formation of foam cells. Figure created with BioRender.com (accessed on 12 May 2021).

Figure 2

Effects of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on the crucial cells participating in atherosclerosis development. VCAM-1, vascular cell adhesion molecule 1. Figure created with BioRender.com (accessed on 12 May 2021).

Figure 3

Mechanism of action of inclisiran. Inclisiran (sense + antisense strand connected with N-acetylgalactosamine) binds to a hepatocyte by means of an asialoglycoprotein receptor. The antisense strand is sliced by an RNA-induced silencing complex (RISC). The sense strand connects with mRNA of PCSK9, which leads to degradation of this complex. As a result, PCSK 9 synthesis in the Golgi apparatus and excretion are decreased. Less PCSK9 is available to bind LDL receptors, which leads to decreased degradation of LDL receptors in lysosomes. LDL receptors are not destroyed, which enables their re-exposure in the cell membrane and the uptake of more LDL cholesterol (LDL-C). Figure created with BioRender.com (accessed on 12 May 2021).

Figure 4

Compatible mechanisms of action of statins, ezetimibe, and inclisiran. Inclisiran inhibits PCSK9—proprotein convertase subtilisin-kexine type 9. LDL-C, low density lipoprotein cholesterol. Created with BioRender.com (accessed on 12 May 2021).