Control of residual dyslipidaemic risk (original) (raw)

In 1938, Carl Müller, a Norwegian physician, described a familial condition characterized by hypercholesterolaemia, xanthomata, and a heightened risk of early myocardial infarction.1 This pioneering observation ultimately led to our current understanding that elevation of LDL-cholesterol (LDL-C) is the most important risk factor for the development and progression of arteriosclerotic cardiovascular disease (ASCVD). Three drug classes, statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and inhibitors of cholesterol absorption are effective in lowering LDL-C and have reduced mortality and morbidity in millions of persons worldwide. However, they have not eliminated dyslipidaemia-related residual risk, which remains substantial. Dyslipidaemia occurs in patients with absent or poorly functioning LDL receptors, in those with hypertriglyceridaemia as well as in patients with elevation of any of four proteins synthesized in the liver discussed here.

PCSK9

The first of these proteins raises circulating LDL-C by reducing its receptors at the cell surface. Loss-of-function variations of the gene that encodes PCSK9 lower circulating LDL-C and reduce the risk of ASCVD.2 This observation led to the development of three approved agents, two monoclonal antibodies that target the PCSK9 protein, and a small interfering RNA (siRNA), inclisiran, that targets PCSK9 mRNA, and thereby reduces circulating LDL-C.3 A similar approach, i.e. identifying protective mutations that alter the function of genes responsible for other dyslipidaemias and developing agents that mimic the action of these protective genes, represents promising approaches to reducing residual dyslipidaemia and thereby the risk of ASCVD.

Angiopoietin-like protein 3

This protein is a powerful regulator of lipid metabolism which inhibits lipoprotein lipase (LPL) and endothelial lipase, the enzymes involved in triglyceride as well as LDL-C metabolism, respectively. Angiopoietin-like protein 3 (ANGPTL3) increases the production of very LDL (VLDL) and LDL and decreases their clearance from plasma. ANGPTL3, in conjunction with its ‘sister’ protein ANGPTL8, is therefore atherogenic by increasing circulating triglyceride-rich lipoproteins (TRLs), LDL-C, and remnant cholesterol. Reduced function of ANGPTL3 lowers these atherogenic stimuli and the risk of ASCVD.4

Three therapeutic approaches to reducing ANGPTL3 are currently approved and/or under investigation. Evinacumab is an approved humanized monoclonal antibody to ANGPTL3 which, by inhibiting ANGPTL3, lowers both circulating TRL and LDL-C by about 50%. By acting independently of the LDL receptor, this antibody offers impressive LDL-C reduction in previously difficult to manage patients with homozygous hypercholesterolaemia.5 The second approach involves antisense oligonucleotides (ASOs), which are short (16 to 20 nucleic acid bases) fragments of DNA that complement and inhibit mRNA transcription of the targets. ASOs have been developed to target ANGPTL3 mRNA and reduce TRL. The third approach involves an siRNA that also targets ANGPTL3 mRNA. However, thus far, the LDL-C reductions by the ASO and siRNA approaches have been modest, and the search for optimal mRNA-targeting agents to inhibit this important atherogenic protein continues.

Apolipoprotein C

Apolipoprotein C (APOC3) is a small glycoprotein which raises circulating triglyceride levels by inhibiting both LPL as well as the hepatic clearance of TRL, leading to an increased risk of ASCVD. Loss-of-function mutations of APOC3 are characterized by reduced levels of fasting and post-prandial triglycerides and of VLDL-C. Oleizarsen is an ASO that is targeted to and blocks the production of APOC3 mRNA. Like the loss-of-function mutations, this has also been shown to lower circulating TRL, VLDL-C, and remnant cholesterol in a phase 2 trial conducted in patients with hypertriglyceridaemia and high risk of ASCVD. This agent was well tolerated and appears to be promising.6

Lipoprotein(a)

Lipoprotein(a) [Lp(a)], described by Kare Berg in 1963, is a glycoprotein that consists of a lipid particle linked to an apo-B100-containing lipoprotein molecule and an apo(a) molecule; the latter occurs in more than 40 isoforms.7,8 Postulated contributors to Lp(a)’s proatherogenic properties include its binding to proteoglycans and fibronectin on endothelial cells as well as to the proinflammatory action of the oxidized phospholipid to which it is frequently attached. In addition, Lp(a) also inhibits the conversion of plasminogen to plasmin, that is hypothesized to contribute to its prothrombotic action. At least two single nucleotide polymorphisms in the LPA gene that are associated with elevated Lp(a) concentrations and the risk of ASCVD have been identified.7

The concentration-distribution curve of Lp(a) is skewed leftward, i.e. to low levels. Approximately one-third of the adult population has concentrations >30 mg/dL, one of the proposed risk thresholds. Persons with marked elevations of Lp(a) >90 mg/dL, observed in 5% of the population, exhibit a tripling of the incidence of myocardial infarction when compared to those with concentrations <30 mg/dL. The causality of Lp(a) for ASCVD has been observed in multiple cohorts, in genome-wide association studies and by Mendelian randomization. Elevated concentrations of this protein, which are frequently familial, are also risk factors for calcific aortic stenosis, ischaemic stroke, and peripheral artery disease.

Until recently, reduction of elevated concentrations of Lp(a) has been challenging. Despite containing ApoB, Lp(a) is not cleared by the LDL receptor, and thus Lp(a) levels are not decreased by statins. Although PCSK9 inhibitors lower Lp(a) by about 25-30%,7 much greater reductions are thought to be required to provide clinical benefit. While lipid apheresis can reduce Lp(a) by about 65% per session, this mode of therapy requires weekly or biweekly application and is rarely used for Lp(a) lowering. However, the future of Lp(a)-lowering therapy has brightened. In a dose ranging phase 2 trial of patients with elevated Lp(a), pelacarsen, a well-tolerated ASO, enters hepatocytes where it forms a complex with apo(a) mRNA and reduces its concentration by up to 80%.9 A phase 3 trial, Lp(a) HORIZON, in ASCVD patients with elevated Lp(a) is ongoing.

Two siRNAs that target Lp(a) are currently being studied. The results of TIMI 67 which tested olpasiran in a phase 2 trial8 were recently announced. Olpasiran reduced Lp(a) by 90%; complete results are pending. Nissen et al.10 have reported a dose-escalation phase 1 trial with a second siRNA that showed an Lp(a) reduction exceeding 95%.

The future

Several of the current and soon-to-be-available agents that combat residual dyslipidaemias will require long-term adherence, a challenge for patients and providers, especially the former who usually remain asymptomatic until a clinical manifestation of ASCVD appears. Attention is currently directed to inhibition of the genes responsible for the dyslipidaemia. Musunuru et al.11 have developed a single-nucleotide loss-of-function mutation of the gene encoding PCSK9. They employed clustered regularly interspersed short palindromic repeats (CRISPR) base editing delivered by lipid nanoparticles and achieved reductions of circulating PCSK9 and LDL-C by 90% and 60%, respectively, in macaque monkeys. These findings persisted at 8 months in a continuing study. Editing of the gene encoding ANGPTL3 using CRISPR technology in a mouse model of familial hypercholesterolaemia reduced circulating LDL-C and triglycerides by one half.12 CRISPR mediated knockouts of APOC3 have been shown to reduce circulating triglycerides and to inhibit atherogenesis in rabbits.13 The ultimate goal of these gene alterations is to abolish the dyslipidaemia with a single treatment, i.e. ‘one and done.’14 It will, of course, be critical to establish the safety and specificity of these techniques in humans.

ASCVD remains the most common cause of death in industrialized nations and dyslipidaemia remains the most common cause of ASCVD. Despite the substantial progress made possible by vigorous reduction of LDL-C,15 the residual dyslipidaemic risk remains substantial. However, I believe that we are now on the threshold of controlling this risk as well, thereby winning another important battle in the war on ASCVD.

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Author notes

Conflict of interest: Research grant support through Brigham and Women’s Hospital from: AstraZeneca, Daiichi-Sankyo, Merck, and Novartis; consulting for: Amgen, Boehringer-Ingelheim/Lilly, Bristol Myers Squibb (MyoKardia), Cardurion, and Verve.