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Emerging New Lipid-Lowering Therapies in the Statin Era

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Emerging New Lipid-Lowering Therapies in the Statin Era Cardiometab Syndr J. 2021 Mar;1(1):66-75 https://doi.org/10.51789/cmsj.2021.1.e5 pISSN 2734-1143·eISSN 2765-3749 View Point Emerging New Lipid-Lowering Therapies in the Statin Era Albert Youngwoo Jang , MD1, Sang-Ho Jo , MD, PhD2, and Kwang Kon Koh, MD, PhD1 1Division of Cardiovascular Disease, Gachon Cardiovascular Research Institute, Gachon University Gil Hospital, Incheon, Korea 2Cardiovascular Center, Hallym University Sacred Heart Hospital, Anyang, Korea Received: Dec 18, 2020 Revised: Jan 12, 2021 ABSTRACT Accepted: Jan 17, 2021 Statins have become the backbone of lipid-lowering therapy today by dramatically improving Correspondence to cardiovascular (CV) outcomes. Despite well-controlled low-density lipoprotein cholesterol Kwang Kon Koh, MD, PhD (LDL-C) through statins, up to 40% patients still experience CV diseases. New therapeutic Cardiometabolic Syndrome Unit, Division of Cardiology, Gachon University Gil Hospital, 774 agents to target such residual cholesterol risk by lowering not only LDL-C but triglyceride beon-gil 21, Namdong-daero, Namdong-gu, (TG), TG-rich lipoproteins (TRL), or lipoprotein(a) (Lp[a]) are being newly introduced. Incheon 21565, Korea. Proprotein convertase subtilisin/kexin type 9 (PCSK9) small interference RNA (siRNA) and E-mail: [email protected] bempedoic acid therapies adding to statin therapies have shown additional improvement Copyright © 2021. Korean Society of in CV outcomes. Recent trials investigating eicosapentaenoic acid to patients with high CardioMetabolic Syndrome TG despite statin therapy have also demonstrated significant CV benefit. Antisense This is an Open Access article distributed oligonucleotide (ASO) therapies with hepatocyte-specific targeting modifications are now under the terms of the Creative Commons being newly introduced with promising lipid-lowering effects. ASOs targeting TG/TRL, such Attribution Non-Commercial License (https:// as angiopoietin-like 3 or 4 (ANGPTL3 or ANGPTL4), apolipoprotein C-III (APOC3), or Lp(a) creativecommons.org/licenses/by-nc/4.0/) have effectively lowered the corresponding lipids without requiring high or frequent doses. which permits unrestricted non-commercial use, distribution, and reproduction in any Clinical outcomes from such novel therapeutics are yet to be proven. In this article, we review medium, provided the original work is properly emerging therapeutics targeting LDL-C, TG, TRL, and Lp(a) to reduce the residual risk. cited. Keywords: Dyslipidemia; Cardiovascular disease; Residual risk; Treatment ORCID iDs Albert Youngwoo Jang https://orcid.org/0000-0002-8802-268X Sang-Ho Jo INTRODUCTION https://orcid.org/0000-0002-2063-1542 Funding Many investigators have demonstrated the beneficial effects of low-density lipoprotein This work was supported by a grant from the cholesterol (LDL-C) lowering statins on reducing coronary artery disease (CAD) events Korean Society of CardioMetabolic Syndrome. in patients with or without CV disease (CVD).1,2 Despite significant improvement in CV outcomes since the advent of statins, up to 40% of statin-treated patients continue to suffer Conflict of Interest from life-threatening CV events even with adequately controlled LDL-C targets by intensive The authors have no financial conflicts of 3,4 interest. Dr. Koh holds a certificate of patent, statin treatment. The remaining CV risk in such patients is called the ‘residual risk.’ In 10-1579656 (pravastatin+valsartan). this article, we review emerging therapeutics targeting LDL-C, triglyceride (TG), TG-rich lipoproteins (TRL), and lipoprotein(a) (Lp[a]) for residual cholesterol risk reduction. Author Contributions Conceptualization: Koh KK, Jang AW; Writing - original draft: Koh KK, Jang AW; Writing - review & editing: Koh KK, Jang AW, Jo SH. https://e-cmsj.org 66 New Lipid-Lowering Therapies RESIDUAL CHOLESTEROL RISK DESPITE OF STATIN THERAPY Total cholesterol is composed of high-density lipoprotein cholesterol (HDL-C) and atherogenic lipoproteins (LDL-C and TRL cholesterol [TRL-C]), which contain apolipoprotein B100 molecule (apoB) (Figure 1). Among LDL-C, small dense LDL is characterized as cholesterol-depleted LDL particles. Lp(a) is also an atherogenic lipoprotein that contains apoB. Lp(a) consists of a covalent link between apoB-containing LDL-like particle and apolipoprotein (a) (apo[a]). Because the level of TG is significantly correlated with the amount of remnant cholesterol in TRLs, TG is a biomarker for circulating TRLs and their metabolic remnants.3,4 Recently, increased TRL-C levels were shown to be associated with increased CV risk.5,6 For these reasons, TRL-C may account, at least in part, for the residual cholesterol risk. Mendelian randomization studies demonstrated that genetic variants that mimic LDL-C- and TG- lowering therapies were associated with the same extent of reduction in atherosclerotic cardiovascular disease (ASCVD) risk as long as the per-unit decrease in apoB concentration was similar, regardless of the type of variant.2 These data strongly suggest that the risk of ASCVD is determined by the total concentration of circulating apoB particles irrespective of the lipid content they carry. Accordingly, the clinical benefit of any lipid-lowering therapy should be proportional to the absolute achieved reduction in apoB concentration regardless Artery lumen Artery wall LDL ApoB ApoB Lipolysis Trigger :LPL VLDL TRLs macrophage ApoB CE CETP TG Foam cell Production of nascent HDL Lipid exchange and formation and HDL Dysfunctional delivery of HDL inflammation→ HDL constituents atherosclerosis Endothelial junction Lipolysis :LPL ApoB TRLs Chylomicron ApoB Figure 1. The production of TRLs, remnant cholesterol which induce formation of atherosclerosis. Because TG can be degraded by most cells, but cholesterol cannot be degraded by any cell, the cholesterol content of TRLs is more likely to be the cause of atherosclerosis and cardiovascular disease rather than raised TG per se. Indeed, remnant lipoproteins like LDL can enter the arterial intima. LPL activity at the surface of remnant particles, either at the surface of vascular endothelium or within the intima, leads to liberation of free fatty acids, monoacylglycerols, and other molecules for energy use and storage. Some apoB lipoproteins in LDL and TRLs can become trapped in the artery wall and cause local injury and inflammation. High triglyceride concentrations are a marker for raised TRLs, remnant cholesterol which, upon entrance into the intima, leads to low-grade inflammation, foam cell formation, atherosclerotic plaques, and ultimately cardiovascular disease and increased mortality. apoB = apolipoprotein B100 molecule; CE = cholesterol ester; CETP = cholesteryl ester transfer protein; HDL = high-density lipoprotein; IDL = intermediate- density lipoprotein; LDL = low-density lipoprotein; LPL = lipoprotein lipase; VLDL = very low-density lipoprotein; TG = triglyceride; TRL = triglyceride rich lipoprotein.Reprinted with permission from Jang et al.19 https://e-cmsj.org https://doi.org/10.51789/cmsj.2021.1.e5 67 New Lipid-Lowering Therapies of the corresponding decrease in LDL-C or TGs. In other words, targeting TRL-C and non- HDL-C is essential in patients with CV risk factors because it can be as effective as lowering LDL-C to very low concentrations for residual CV risk reduction.3,4,7 EMERGING LDL-C-LOWERING THERAPIES PCSK9 small interference RNA The proprotein convertase subtilisin-kexin type 9 (PCSK9) small interference RNA (siRNA) decreases atherogenic lipoprotein levels, particularly LDL-C, through attenuation of LDL-C receptor degradation. Inclisiran is a newly developed drug using siRNA technology designed to inhibit PCSK9 production through neutralizing the messenger RNA of the PCSK9 gene (Table 1).8 Inclisiran is siRNAs conjugated to a triantennary N-acetylgalactosamine (GalNAc), designed to deliver the drug specifically to liver cells PCSK9 is mainly produced. Thus, a much lower amount of drug is required for liver cell-targeting therapeutics, maximizing drug efficacy and durability while reducing side effects.9 The impact of the drug is persisted for at least 180 days after initiation of treatment. This enables inclisiran to be administration every 3 or 6 months, compared with the PCSK9 mAbs injected every 2 or 4 weeks, although the LDL-C lowering effects are similar. Inclisiran successfully lowered LDL-C levels by 40 to 50% over 1.5 years in subjects with familial hypercholesterolemia (FH)10 or elevated LDL-C levels without FH.11 Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo; such reactions were generally mild, and none were severe or persistent. Phase 3 outcome studies are currently underway (ClinicalTrials.gov NCT03705234). Bempedoic acid Bempedoic acid also reduces LDL-C levels by attenuating ATP citrate lyase, an enzyme upstream of HMG-CoA reductase, crucial in the biosynthesis of cholesterol. The Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Harmony trial, enrolled Table 1. A summary of clinical trials targeted on lowering LDL-C Trial name Drug and dose Sample Inclusion Duration Primary endpoint LDL-C reduction Outcome (95% CI) size (yr) (mg/dL) ORION-910 Inclisiran 284 mg SC n=482 FH patients on 1.5 1. Percent change from baseline in 58.7 58.7%* (PCSK9 siRNA) injection on day 1, maximal statin dose LDL-C at day 510 90, 270, and 450 with or without 2. Time-adjusted percent change 37.7%
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