The dawn of a new era of targeted lipid-lowering therapies

Abstract

Lipid risk factors for cardiovascular disease depend in part on lifestyle, but optimum control of lipids often demands additional measures. Low-density lipoprotein (LDL) doubtless contributes causally to atherosclerosis. Recent human genetic findings have substantiated a number of novel targets for lipid-lowering therapy including apolipoprotein C-III, angiopoietin-like protein 3 and 4, apolipoprotein V, and ATP citrate lyase. These discoveries coupled with advances in biotechnology development afford new avenues for management of LDL and other aspects of lipid risk. Beyond LDL, new treatments targeting triglyceride-rich lipoproteins and lipoprotein(a) have become available and have entered clinical development. Biological and RNA-directed agents have joined traditional small-molecule approaches, which themselves have undergone considerable refinement. Innovative targeting strategies have increased efficacy of some of these novel interventions and markedly improved their tolerability. Gene-editing approaches have appeared on the horizon of lipid management. This article reviews this progress offering insight into novel biological and therapeutic discoveries, and places them into a practical patient care perspective.

Keywords: Angiopoietin-like proteins; Apolipoprotein C-III; Lipoprotein(a); Lipoproteins; RNA therapeutics; Triglycerides.

Graphical Abstract

The future evolution of lipid-lowering therapies. The quest for new lipid-lowering therapies enabling less frequent administration is continuing. Outcome trials to show cardiovascular event reduction will determine their clinical application. ASO, antisense oligonucleotide; CV, cardiovascular; IPE, icosapent ethyl; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); MoAb, monoclonal antibodies; siRNA, small-interfering RNA.

Figure 1

New targets for lipid-lowering therapies. Beyond low-density lipoprotein, lipoprotein(a) and triglyceride-rich lipoproteins or remnant lipoproteins have become actionable targets in lipid management. IDL, intermediate-density lipoprotein; VLDL, very low-density lipoprotein.

Figure 2

Multiple lines of evidence showing low-density lipoprotein cholesterol is causal for cardiovascular disease. Data that have accrued from observational data, human genetic analyses, randomized clinical trial results, and animal experimentation in multiple species, all concordantly support a causal contribution of low-density lipoprotein to atherosclerosis.

Figure 3

Selected mechanisms of targeted lipid therapies. Current approaches to interventions that modify lipid metabolism include targeting genomic DNA, messenger RNA, or proteins. The strategies available include various strategies ranging from traditional small-molecule medicinal chemistry approaches through biological agents such as monoclonal antibodies, RNA therapeutics, and, on the horizon, gene editing. ApoC-III, apolipoprotein C-III; Lp(a), lipoprotein(a); HMG-CoA, hydroxymethylglutaryl coenzyme A; PCSK9, proprotein convertase subtilisin/kexin type 9.

Figure 4

Lipoprotein lipase modifiers. The enzyme lipoprotein lipase (depicted by the ribbon structure) associates with the surface of endothelial cells by binding to proteoglycans. This enzyme trims triglyceride from triglyceride-rich lipoproteins which include remnants of chylomicrons produced by intestinal cells from dietary lipid and very low-density lipoproteins synthesized endogenously by the liver. Lipoprotein lipase-mediated hydrolysis yields free fatty acids and low-density lipoprotein and intermediate-density lipoproteins. The proteins named in red inhibit lipoprotein lipase, and thus raise blood triglyceride-rich lipoprotein concentrations by limiting triglyceride-rich lipoprotein catabolism. The novel therapeutic agents listed inhibit these inhibitors and thus lower triglyceride-rich lipoprotein levels. Apolipoprotein AV activates lipoprotein lipase (shown in green.) Very strong human genetic evidence support the causality of each of the modulatory proteins depicted in regulating triglyceride-rich lipoproteins. ANGPTL, angiopoietin-like protein.

Figure 5

Newer and emerging lipid-lowering therapies target different aspects of lipid metabolism. The statins target hydroxymethylglutaryl coenzyme A reductase. The newer and emerging agents target other aspects of lipid metabolism as shown here. B48 refers to the shorter form of apolipoprotein B produced by RNA editing in the intestine. B100 refers to the longer form produced in the liver. See the list for explanations of other abbreviations.

Figure 6

Current and emerging therapies not only deepen our ability to manage low-density lipoprotein, but to target other aspects of lipid risk factors. See text for explanation.