New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins

Abstract

Statins are the cornerstone of the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD). However, even under optimal statin therapy, a significant residual ASCVD risk remains. Therefore, there has been an unmet clinical need for novel lipid-lowering agents that can target low-density lipoprotein cholesterol (LDL-C) and other atherogenic particles. During the past decade, several drugs have been developed for the treatment of dyslipidemia. Inclisiran, a small interfering RNA that targets proprotein convertase subtilisin/kexin type 9 (PCSK9), shows comparable effects to that of PCSK9 monoclonal antibodies. Bempedoic acid, an ATP citrate lyase inhibitor, is a valuable treatment option for the patients with statin intolerance. Pemafibrate, the first selective peroxisome proliferator-activated receptor alpha modulator, showed a favorable benefit-risk balance in phase 2 trial, but the large clinical phase 3 trial (PROMINENT) was recently stopped for futility based on a late interim analysis. High dose icosapent ethyl, a modified eicosapentaenoic acid preparation, shows cardiovascular benefits. Evinacumab, an angiopoietin-like 3 (ANGPTL3) monoclonal antibody, reduces plasma LDL-C levels in patients with refractory hypercholesterolemia. Novel antisense oligonucleotides targeting apolipoprotein C3 (apoC3), ANGPTL3, and lipoprotein(a) have significantly attenuated the levels of their target molecules with beneficial effects on associated dyslipidemias. Apolipoprotein A1 (apoA1) is considered as a potential treatment to exploit the athero-protective effects of high-density lipoprotein cholesterol (HDL-C), but solid clinical evidence is necessary. In this review, we discuss the mode of action and clinical outcomes of these novel lipid-lowering agents beyond statins.

Keywords: Angiopoietin-like protein 3; Apolipoprotein C-III; Apoprotein(a); Cardiovascular diseases; Dyslipidemias; Lipoprotein(a); Oligonucleotides, antisense.

Fig. 1

Sites and targets of new lipid-lowering agents. In the small intestine, lipids and apolipoprotein B48 (ApoB48) are packaged into chylomicron (CM) particles. In the liver, bempedoic acid inhibits an enzyme ATP citrate lyase (ACLY), which is responsible for the conversion of citrate and coenzyme A (CoA) to oxaloacetate and acetyl-CoA. Pemafibrates are selective peroxisome proliferator-activated receptor alpha (PPARα) modulators, which initiate β-oxidation, reduce triglyceride (TG) content, and enhance lipoprotein lipase (LPL) activity. Omega-3 fatty acids also exhibit their effects through the PPAR-mediated pathway. Recycling of low-density lipoprotein receptors (LDLRs) is increased by the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). In the plasma, TGs within the CM and very-low-density lipoprotein (VLDL) are hydrolyzed by LPL, inhibitors of which include apolipoprotein C3 (ApoC3) and angiopoietin-like 3 (ANGPTL3). Volanesorsen is an antisense oligonucleotide (ASO) targeting the ApoC3. Evinacumab is a monoclonal antibody which targets ANGPTL3. Vupanorsen is a triantennary N-acetylgalactosamine carbohydrates (GalNAc)-conjugated ASO which targets ANGPTL3 mRNA. Binding of apolipoprotein (a) (Apo(a)) to apolipoprotein B100 (ApoB100) an LDL-like moiety forms lipoprotein(a) (Lp(a)). IONIS-APO(a)_Rx and IONIS-APO(a)L_Rx are ASOs targeting the Apo(a). Olpasiran and SLN360 are small interfering RNAs (siRNAs) targeting the Apo(a). In the peripheral cells, apolipoprotein A1 (ApoA1) present in small high-density lipoprotein (HDL) mobilizes intracellular cholesterol (C) and is assisted by ATP-binding cassette protein A1 (ABCA1) and ATP-binding cassette protein G1 (ABCG1), after esterification by lecithin cholesterol acyl transferase (LCAT). ApoA1 peptide induces C efflux. CMR, chylomicron remnant; FA, fatty acid; HMGCR, 3-hydroxy3-methylglutaryl-coenzyme A reductase; IDL, intermediate-density lipoprotein.

Fig. 2

Diverse classes of lipid-lowering agents. ASO, antisense oligonucleotide; siRNA, small interfering RNA.