Lipid-lowering interventions targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): an emerging chapter in lipid-lowering therapy

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is mainly expressed in the liver but can also be found in the intestine and kidneys. PCSK9 promotes the degradation of low density lipoprotein receptors (LDLR) by reducing their recycling and targeting the receptors for lysosomal destruction, thereby decreasing the rate of removal of LDL-cholesterol from the circulation. Thus, interventions targeting PCSK9 by reducing its expression may lead to significant reductions of LDL-cholesterol and possibly decrease cardiovascular risk. The present review aims to present and discuss the current clinical and scientific data pertaining to lipid-lowering interventions targeting PCSK9.

Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia

“…Inclisiran is a long-acting, synthetic siRNA directed against PCSK9, which is conjugated to triantennary N -acetylgalactosamine carbohydrates. These carbohydrates bind to abundant liver-expressed asialoglycoprotein receptors, leading to the uptake of inclisiran specifically into the hepatocytes [ 20 , 21 ].…”

Research progress on alternative non-classical mechanisms of PCSK9 in atherosclerosis in patients with and without diabetes

“…The proprotein convertase subtilisin/kexin type 9 (PCSK9) has been reported to play an important role in the development of atherosclerosis; PCSK9 monoclonal antibodies (mAbs), including evolocumab and alirocumab, have been put into clinical use to decrease circulating PCSK9 [1,2]. In addition, a small interfering RNA (siRNA) molecule, inclisiran, decreases the hepatic production of PCSK9 [3]. PCSK9 secreted by the liver combines with the epidermal growth factor-like repeat A (EGF-A) domain of the LDL receptor (LDLR) to form the PCSK9-LDLR complex, which is internalized by endosomes and then undergoes a degradation process in lysosomes.…”

“…Circulating PCSK9 is secreted from hepatocytes and other cells. PCSK9 mAbs mainly decreases circulating PCSK9, while inclisiran targets hepatic production of PCSK9 [3]. Accordingly, the mechanisms of PCSK9 in atherosclerosis can be grouped into intracellular and extracellular mechanisms ( Table 1).…”

Targeting Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9): A New Promising Approach for the Management of Hypercholesterolemia

“…However, there are still cases in which patients fail to achieve the desired LDL-C goals or are intolerant to statins due to side effects (mostly myalgias). Thus, extensive research is being conducted to identify new LDL-C lowering drugs with a favorable side effect profile, which (used alone or in combination with statin therapy) would be able to produce significant LDL-C reductions and decrease cardiovascular risk [1,2].…”

“…However, there are still cases in which patients fail to achieve the desired LDL-C goals or are intolerant to statins due to side effects (mostly myalgias). Thus, extensive research is being conducted to identify new LDL-C lowering drugs with a favorable side effect profile, which (used alone or in combination with statin therapy) would be able to produce significant LDL-C reductions and decrease cardiovascular risk [1,2].Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease, which is expressed mainly in the liver but may also be found in the intestine and kidneys. The human PCSK9 gene is located in the human chromosome 1p32.3 and encodes a 692-amino acid inactive glycoprotein, which undergoes an intramolecular self-catalytic cleavage in the endoplasmic reticulum [3].…”