The Dawn of a New Era of Targeted Lipid-Lowering Therapies

Lale Tokgözoğlu; Peter Libby

Disclosures

Eur Heart J. 2022;43(34):3198-3208. 

In This Article

Abstract and Introduction

Abstract

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.

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.

Introduction

Lipids comprise key modifiable risk factors for atherosclerotic vascular disease (ASVD), a chronic immunoinflammatory process in the arterial wall that causes most cardiovascular (CV) events. The accumulation and retention of apolipoprotein B (apoB)-containing lipoproteins, mainly low-density lipoprotein (LDL) in the arterial intima, accompanies early atherogenesis.[1] An inflammatory response ensues that promotes plaque progression and eventually plaque disruption.[2] LDL particles constitute 90% of apoB-containing lipoproteins in fasting humans, and have become the prime treatment target in clinical practice. But other apoB-containing lipoproteins also contribute causally to atherosclerosis[3] (Figure 1). Triglyceride-rich lipoproteins that are <70 nm in diameter such as chylomicron remnants, very low density lipoprotein (VLDL) remnants, and intermediate-density lipoprotein (IDL) can traverse the endothelium, accumulate, and promote atherogenesis. Recent epidemiologic and genetic studies have established that cholesterol-rich remnant particles that accumulate in individuals with hypertriglyceridaemia are atherogenic and contribute to ASVD.[4,5]

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.

In general, LDL-cholesterol (LDL-C) correlates tightly with apoB, but in some circumstances like diabetes, obesity, or very low LDL-C, it may underestimate the risk conferred by other apoB-containing lipoproteins. In these conditions, the simple calculation of non-high-density lipoprotein cholesterol (HDL-C) (total cholesterol – HDL) captures all apoB-containing lipoproteins including remnant cholesterol. The measurement of apoB also yields a more accurate estimation of risk than measurement of LDL concentrations in such individuals. Emerging evidence also suggests that non-HDL-C and apoB reflect residual risk better than LDL in statin-treated patients.[6] Thus, non-HDL-C has become a secondary target in European and other guidelines. Emerging novel therapies can target these non-LDL lipid fractions and promise to provide practitioners with new tools to confront residual risk.

Strong and consistent evidence from monogenic disorders, Mendelian randomization and genome-wide association studies (GWAS), and observational epidemiological, clinical, and interventional investigations have established that LDL satisfies modified Koch's postulates for causing atherosclerosis[7] (Figure 2). Without elevated LDL, atherosclerosis would likely be an orphan disease. LDL is the most extensively studied and targeted lipoprotein and remains justifiably the main lipid focus in clinical practice.

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.

Multiple lines of evidence show that the magnitude and duration of exposure to LDL determine the risk of ASVD and its complications.[8] Thus, more and earlier LDL-C reduction provide greater CV prevention. This observation underscores the urgency of identification and early treatment of high LDL. Based on accumulating clinical trial evidence, guidelines and practice have evolved towards the achievement of more stringent LDL-C goals, especially in higher risk patients.[9] Recent studies that lowered LDL-C with combination therapy have not shown a threshold for clinical benefit and have allayed many safety concerns, thus reinforcing the 'lower is better' concept.[10–12]

Recent successes of the trials with non-statin lipid-lowering agents in decreasing CV events have shown that LDL-C lowering by a variety of mechanisms including increased LDL receptor expression or reduced cholesterol adsorption yields CV benefit.[13] Focus has therefore broadened from 'high-intensity statin therapy' to 'high-intensity lipid-lowering therapy' for LDL-C management. This recognition, along with the considerable remaining CV risk even in statin-treated individuals, has accelerated the quest for therapies that reduce atherogenic apoB-containing lipoproteins. Targeted delivery of nucleic acid-based therapies has progressed substantially, enabling safe and effective modulation of causal atherogenic particles, thus ushering in a new era in lipid management (Graphical Abstract).

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