Lipid Target in Very High-Risk Cardiovascular Patients: Lesson from PCSK9 Monoclonal Antibodies

Abstract

The role of low-density lipoproteins (LDLs) as a major risk factor for cardiovascular disease has been demonstrated by several epidemiological studies. The molecular basis for LDLs in atherosclerotic plaque formation and progression is not completely unraveled yet. Pharmacological modulation of plasma LDL-C concentrations and randomized clinical trials addressing the impact of lipid-lowering interventions on cardiovascular outcome have clearly shown that reducing plasma LDL-C concentrations results in a significant decrease in major cardiovascular events. For many years, statins have represented the most powerful pharmacological agents available to lower plasma LDL-C concentrations. In clinical trials, it has been shown that the greater the reduction in plasma LDL-C concentrations, the lower the rate of major cardiovascular events, especially in high-risk patients, because of multiple risk factors and recurrent events. However, in a substantial number of patients, the recommended LDL target is difficult to achieve because of different factors: genetic background (familial hypercholesterolemia), side effects (statin intolerance), or high baseline plasma LDL-C concentrations. In the last decade, our understanding of the molecular mechanisms involved in LDL metabolism has progressed significantly and the key role of proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged. This protein is an enzyme able to bind the LDL receptors (LDL-R) on hepatocytes, favoring their degradation. Blocking PCSK9 represents an intriguing new therapeutic approach to decrease plasma LDL-C concentrations, which in recent studies has been demonstrated to also result in a significant reduction in major cardiovascular events.

Inclisiran: A New Promising Agent in the Management of Hypercholesterolemia

“…The siRNA molecule has been used recently to decrease PCSK9 levels. The siRNA molecules follow the natural pathway of RNA interference (RNAi) by binding intracellularly to the RNA-induced silencing complex (RISC), thus enabling it to cleave messenger RNA (mRNA) molecules specifically encoding PCSK9 [ 19 ].…”

Evolving Concepts of the SCORE System: Subtracting Cholesterol from Risk Estimation: A Way for a Healthy Longevity?

“…The new therapeutic options currently available aim to improve therapeutic adherence and reach target LDL-C levels more easily. Among these, in addition to ezetimibe and/or bempedoic acid, which are able to reduce LDL-C levels by 18% [ 69 ] and 24% [ 36 ], respectively, an important role is now played by PCSK 9 inhibition through monoclonal antibodies (alirocumab and evolocumab) [ 70 ] and siRNA (inclisiran) [ 39 , 71 ]. Blocking the PCSK9 protein results in increased recirculation of the LDL-C receptor on the cell surface, thus improving its function [ 70 ].…”

RNA Therapeutics - Research and Clinical Advancements

“…Therefore, it is essential to block PCSK9 to stimulate LDL-R recycling to lower blood LDL concentrations. (Ciccarelli et al, 2018) A subcutaneous injection of inclisiran, a formulation of phosphorothioate, 2′-O-methyl nucleotide, and 2′-fluoro nucleotide modified-siRNA directed against PCSK9 conjugated to triantennary N-acetylgalactosamine carbohydrates, has demonstrated to target and lower PCSK9 levels and LDL cholesterol levels in patients with high cardiovascular risk. (Ray et al, 2017;Raal et al, 2020) Many studies conducted using siRNA for choroidal neovascularization caused due to age-related macular degeneration (CNV-AMD) to target vascular endothelial growth factor receptor-1 (VEGFR1) or RTP801, have shown promising results in various phases of clinical trials.…”