Review Article

The Impact of Current and Emerging Therapies on Lipoprotein(a)

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Abstract

Increasing evidence has implicated lipoprotein (a) (Lp(a)) in the causality of cardiovascular disease. While measuring Lp(a) has an established role in cardiovascular risk assessment and triaging patients for more intensive risk factor control, there is considerable interest in the ability of medical therapies to lower Lp(a) levels. While statins have been reported to increase Lp(a) levels, a number of existing lipid-lowering interventions have been reported to modestly lower Lp(a) levels, with evidence that this contributes to the reduction in cardiovascular risk observed with proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors. Lp(a) lowering has also been reported with emerging therapies via direct inhibition of apolipoprotein A (Apo A) synthesis or Lp(a) particle formation and indirectly in response to treatment with cholesteryl ester transfer protein (CETP) inhibitors. This article will review the effects of these therapies and implications for cardiovascular risk.

Keywords

Lipoprotein(a), cardiovascular disease, cardiovascular risk, lipid lowering, prevention,

Received:

Accepted:

Published online:

DOI: https://doi.org/10.15420/ecr.2025.96

Disclosure: SJN has received grant/research support from AstraZeneca, NewAmsterdam Pharma, Amgen, Anthera, Cyclarity, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience; was a consultant for Abcentra, AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, Daiichi Sankyo, Scribe Therapeutics, Silence Therapeutics, CSL Seqirus and Vaxxinity; and holds stock options for NewAmsterdam Pharma. AJN has received research support from AstraZeneca, Amgen, Eli Lilly, Novartis and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Sequiris, Eli Lilly, GSK, Novartis, Novo Nordisk, Sanofi Pasteur and Vaxxinity.

Correspondence: Stephen Nicholls, Monash Victorian Heart Institute, Monash University, 631 Blackburn Rd, Clayton, VIC, 3168, Australia. E: stephen.nicholls@monash.edu

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Lowering levels of LDL cholesterol (LDL-C) with statins as monotherapy and in combination with other lipid-lowering agents reduces cardiovascular risk in large clinical trials.1–4 These findings have transformed our approach to cardiovascular prevention and form a cornerstone of treatment guidelines.5,6 However, a substantial residual risk of cardiovascular events continues to be observed, highlighting the need to target other factors involved in atherosclerotic cardiovascular disease to achieve more effective reductions in risk.7

Lipoprotein(a) and Cardiovascular Risk

Lipoprotein (a) (Lp(a)) is formed in the liver via binding of an apolipoprotein B (Apo B) particle to apolipoprotein A (Apo[a]). Lp(a) levels demonstrate a high degree of genetic influence, with the circulating Lp(a) concentration inversely associated with the length of Apo(a).8–10 The data increasingly suggests that Lp(a) levels rise after menopause.11 The population distribution of Lp(a) levels is highly skewed, with 20% of individuals worldwide projected to have an elevated Lp(a).12 Numerous lines of evidence demonstrate that elevated Lp(a) levels are associated with greater plaque burden, vulnerability and progression on serial imaging and an increased risk of cardiovascular events.13–24

The finding of a causal role for Lp(a) in atherosclerotic disease has been extended beyond the coronary vasculature to include ischaemic stroke, peripheral arterial disease, heart failure and calcific aortic valve stenosis.20–24 The enhanced cardiovascular risk is likely to reflect the impact of the constituent Apo B lipoprotein and the carriage of oxidised phospholipids within the circulation.25–28 Prevention guidelines currently advocate widespread Lp(a) testing, given its role in risk restratification, triaging patients for more intensive risk factor modification and the potential for direct Lp(a) lowering.29

Testing has transitioned from a mass- to molar-based approach to measurement as the heterogeneity of Lp(a) particle size can influence mass measurements.30 There is currently no reliable conversion factor for comparing the older mass measurement with more contemporary molar-based assays.30 With emerging evidence that variation in Lp(a) measurement is likely to be greater than originally thought – possibly up to 25% – there may be implications for future guidance on whether testing should be a one-off or should be performed multiple times.8 Nevertheless, as a result of the large body of accumulating evidence of the cardiovascular effects of Lp(a), there is considerable interest in the development of therapeutic strategies that lower its levels.

Existing Approaches to Lowering Lipoprotein (a)

Several therapeutic interventions that are currently employed in the prevention clinic have been demonstrated to have effects on Lp(a) levels. While statins have consistently been shown to lower LDL-C levels and cardiovascular risk, they appear to increase Lp(a) levels by approximately 10%. The mechanism that underlies this effect remains uncertain, although the ability of statins to reduce cardiovascular risk is similar in those with lower and higher Lp(a) levels.31 For decades, niacin has been the most effective Lp(a) lowering agent, reducing levels by up to 30%, although it is poorly tolerated by patients and contemporary clinical trials have failed to demonstrate a reduction in cardiovascular risk when used in combination with statins.32

Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors have also been reported to reduce Lp(a) levels by up to 30%, with recent evidence that this has an independent association with the ability of these agents to reduce the rate of cardiovascular events in patients with either stable atherosclerotic disease or a recent acute coronary syndrome.33,34 While Lp(a) lowering with PCSK9 inhibitors has not been shown to be associated with these agents’ ability to promote coronary plaque regression, the effect of these agents on plaque burden and vulnerability is greater in patients with higher baseline Lp(a) levels.35 This further supports the potential modifiability of risk in the setting of high Lp(a) levels. Lp(a) lowering (up to 40%) has also been reported in response to the use of mipomersen, lomitapide (up to 17%) and apheresis (an average of 35%), although each of these agents is expensive and difficult to access and not widely used, with apheresis requiring frequent administration.32 More recent reports have also demonstrated modest reductions in Lp(a) with bariatric surgery, and nutraceuticals such as flaxseed and pioglitazone, although the clinical impact of these changes remains unknown.36–38

On the basis of current evidence, the presence of an elevated Lp(a) indicates that a patient should undergo an intensification in treatment for other cardiovascular risk factors, such as lowering LDL-C levels and blood pressure.39,40 Given sequence homology between Apo(a) and plasminogen, there has been a long-held view that Lp(a) may play a role in enhancing thrombogenicity, raising the question of whether aspirin has any role in patient management. Recent analyses from clinical trials and observational studies have suggested that cardiovascular risk is reduced in the setting of concomitant use of aspirin in individuals with very high Lp(a) levels.41,42 These findings suggest that aspirin may be a useful therapeutic adjunct in asymptomatic individuals with very high Lp(a) levels, although this has not been directly evaluated in a prospective cardiovascular outcomes trial. In recent years, attention has focused on the potential for novel therapeutic interventions that produce robust and more specific reductions in Lp(a) to lower cardiovascular risk and be useful in the prevention clinic.

Emerging Approaches to Reduce Apoprotein A Synthesis

RNA-targeted therapeutics have the potential to reduce hepatic Apo(a) synthesis and subsequent production of Lp(a) particles. Pelacarsen is an antisense oligonucleotide, administered via monthly subcutaneous injections, with evidence of Lp(a) lowering by up to 80%.43,44 This agent is under evaluation in a large cardiovascular outcomes trial of patients with established atherosclerotic cardiovascular disease and Lp(a) levels greater than 70 mg/dl.45 This is the agent at the most advanced stage of clinical development and the findings of the cardiovascular outcomes are due to report in 2026. It will be critical as it has the potential to be the first validation of the concept of substantial and specific lowering of Lp(a) not only being able to determine whether substantially lowering Lp(a) levels translates to cardiovascular benefit, but also to establish whether there is a relationship between the degree of Lp(a) lowering and benefit and whether a threshold effect exists, suggesting a minimum degree of Lp(a) reduction is required to result in a reduction in cardiovascular event rates.

Three short interfering RNA inhibitors (siRNAs) have been developed that also reduce hepatic synthesis of Apo(a).46–50 Zerlasiran, administered monthly by subcutaneous injection, lowers Lp(a) levels by more than 90% and has not currently progressed to evaluation in a large cardiovascular outcomes trial (NCT05537571).46 Olpasiran, administered every 3 months, lowers Lp(a) levels by more than 95% with good durability of effect.47,48 This agent is currently being evaluated in an outcomes trial of patients with established cardiovascular disease and Lp(a) ≥200 nmol/l, which is fully recruited (NCT05581303). A new trial has been initiated, which will evaluate the impact of olpasiran on cardiovascular outcomes in patients at high cardiovascular risk, yet to experience an event, with a Lp(a) ≥200 nmol/l.51 Lepodisiran, administered every 6 months lowers Lp(a) levels by more than 95%.49,50 The ongoing cardiovascular outcomes trial is evaluating the impact of lepodisiran in a mixture of patients with either clinically manifest atherosclerotic cardiovascular disease or those at high cardiovascular risk with a Lp(a) level at a lower entry point (≥175 nmol/l) (NCT06292013).

The final approach to reducing hepatic Apo(a) synthesis involves the application of targeted gene editing or epigenetic therapies.52 With increasing evidence for the role of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas gene editing as a potential therapeutic treatment for dyslipidaemia there is interest in its use to reduce Apo(a) synthesis. Early human studies are in progress that are evaluating the impact of a single application of gene editing of the LPA gene.53 The ability for this approach to effect a permanent change in the LPA gene and lead to substantial and durable reductions in Lp(a) levels may provide a once-in-a-lifetime therapy for patients with high Lp(a) levels. The impact of this approach on Lp(a) levels, in addition to short- and long-term safety and tolerability, and the cost implications of its use are unknown. Epigenetic interventions are also emerging, which have the potential to promote alternative changes in gene expression without the need for permanent genetic disruption. This approach has not yet progressed to clinical evaluation.

Emerging Approaches to Reduce Lp(a) Particle Formation

Considerable effort has been undertaken to develop small molecule inhibitors of Lp(a) that can be administered orally. Muvalaplin is the first oral agent to proceed to clinical development on the basis that it inhibits non-covalent binding of Apo(a) to Apo B-containing particles in the liver.54 This approach has the potential to reduce circulating Lp(a) levels by disrupting its formation. A phase 1 study of muvalaplin in healthy volunteers has demonstrated good tolerability and dose-dependent reduction in Lp(a) levels by up to 65%.55 It is apparent that Apo(a) is present within the circulation in three forms with muvalaplin treatment: Apo(a) bound to Apo B (intact Lp(a) particles); small amounts of free Apo(a); and Apo(a) that is bound to muvalaplin.56 This has implications for how conventional Lp(a) assays are used in this setting, given that they detect and measure Apo(a). With ongoing evaluation, Apo(a) bound to muvalaplin is considered to be non-functional; as a result, it is possible that traditional Apo(a) assays may overestimate Lp(a) levels in the setting of treatment with disruptor therapies such as muvalaplin. This observation led to the development of a novel Lp(a) assay, which requires detection of Apo(a) and Apo B, restricting its focus of measurement to intact Lp(a) particles (intact Lp(a) assay). Early validation of this assay confirmed differences in the degree of Lp(a) lowering detected with the two assays with it being greater with the intact Lp(a) assay with muvalaplin.56

In contrast, samples from people being treated with lepodisiran, an RNA-targeted agent that reduces Apo(a) synthesis, produce a similar degree of Lp(a) lowering with both traditional and intact assays.56 A phase 2 study of muvalaplin in patients with a high cardiovascular risk with elevated Lp(a) levels demonstrated reductions in Lp(a) by up to 86% with the intact assay and by up to 70% with the traditional assay.57 In parallel, reductions of up to 70% in circulating oxidised phospholipid levels were observed with muvalaplin, reaffirming the association between circulating Lp(a) and these mediators of oxidative and inflammatory pathways implicated in cardiovascular disease.57 A large cardiovascular outcomes trial evaluating the impact of muvalaplin on patients with either established atherosclerotic cardiovascular disease or those at high risk of a clinical event, with Lp(a) ≥175 nmol/l has recently commenced recruitment (NCT07157774). This could lead to the introduction of an effective oral therapy for the treatment of patients with high Lp(a) levels.

Effect of Cholesteryl Ester Transfer Protein Inhibitors on Lp(a)

While the primary focus in studies on Lp(a) lowering has been the ability to achieve robust and selective reductions in circulating levels, there remains interest in the potential impact of other lipid-modifying agents to reduce Lp(a) levels in addition to other effects. Cholesteryl ester transfer protein (CETP) plays a role in the regulation of lipid metabolism, primarily via its facilitation of the transfer of esterified cholesterol from high-density lipoproteins to very low-density lipoproteins and LDL in exchange for triglycerides.58 The development of CETP inhibitors has prompted considerable interest for more than two decades, although early experiences have been disappointing. Initially developed on the basis of their ability to substantially raise high-density lipoprotein (HDL) cholesterol levels, a number of studies were terminated due to findings of off-target toxicity with torcetrapib and clinical futility with dalcetrapib and evacetrapib. 59­­–61 A larger and longer cardiovascular outcomes trial of the potent CETP inhibitor anacetrapib demonstrated a modest, albeit significant, reduction in cardiovascular events.62 Subsequent analyses demonstrated that this cardiovascular benefit was associated with reductions in levels of non-HDL cholesterol and was not related to increases in HDL cholesterol.62 With evidence of prolonged adipose tissue accumulation, anacetrapib did not progress to regulatory approval.63 Additional investigations of genomic studies demonstrated that CETP is associated with atherosclerotic cardiovascular disease, with the degree of protection associated with low CETP directly related to lower levels of both Apo B and LDL cholesterol.64,65

The findings of the genomic studies and post hoc analyses of the impact of anacetrapib are important in that they suggest the potential for CETP inhibition to be protective via reductions in circulating atherogenic lipoproteins. This has led to the development of obicetrapib, a highly selective CETP inhibitor, which has been demonstrated to reduce LDL cholesterol levels by 35–50% in early studies when administered as monotherapy or in combination with ezetimibe.66–71 The effect of obicetrapib on cardiovascular outcomes is being evaluated in patients with high cardiovascular risk and suboptimal control of LDL cholesterol levels in an ongoing trial (NCT05202509). An additional observation from these studies, in addition to the findings for earlier CETP inhibitors, has been reductions in Lp(a) levels by more than 30%.66–71 The relative impact of CETP inhibitors on hepatic Apo(a) synthesis and removal of Lp(a) from the circulation via an increase in LDL receptor expression and other mechanisms continues to undergo evaluation. The potential impact of this effect on cardiovascular outcomes remains uncertain, although it is at least comparable with the reduction in Lp(a) levels in response to treatment with PCSK9 inhibitors.

The Potential Treatment Toolbox for Elevated Lp(a) Levels

The proliferation in scientific evidence implicating Lp(a) in the causality of a range of forms of cardiovascular disease has been complemented by the development of several therapies, which differ in their mechanism of action, mode and frequency of administration and degree of ability to lower Lp(a) levels. This has the potential to transform treatment of people with high Lp(a) levels, although it remains unclear which therapy would be most ideal for specific clinical settings. While guidelines suggest that cardiovascular risk is particularly high in those with Lp(a) levels greater than 125 nmol/l, the ongoing trials for cardiovascular outcomes are being performed in patients with entry Lp(a) levels that are much higher. If they prove to be successful, it is likely that these entry Lp(a) levels will inform who is most likely to qualify for their use. That has the potential to leave many people with high Lp(a) levels (greater than 125 nmol/l), but not high enough to qualify for treatment with an RNA-targeted agent or muvalaplin, to remain exposed to this high residual risk. This may provide the opportunity for the use of other agents, such as PCSK9 inhibitors or CETP inhibitors, although the use of these agents is likely to be restricted to only those people who have elevated LDL cholesterol levels. As a result, it remains uncertain what will be the most effective approach to treating the individual who has an isolated elevation of Lp(a). For those individuals, the focus will remain on intensification of treatment of traditional risk factors and potential use of aspirin. It is hoped that subsequent studies may focus on those with lower Lp(a) levels and additional agents may proceed to clinical development to provide alternative treatment options for these individuals. As was observed in the development of statins, the findings of benefit in early trials with the patients at highest risk led to subsequent evaluation in those at lower risk with lower baseline levels. The same paradigm, although contingent on the ability of current trials to demonstrate benefit, may similarly apply for the management of people with high Lp(a) levels.

Conclusion

The accumulating body of evidence has established the important role that Lp(a) plays in cardiovascular disease and the residual clinical risk observed in many patients. This has led to the development of a number of therapeutic approaches that lower Lp(a) selectively or in combination with effects on other lipid and lipoprotein parameters. Current clinical trials are essential for validating the Lp(a) hypothesis – whether selective Lp(a) lowering leads to a reduction in cardiovascular events – and then to subsequently determine the degree of Lp(a) lowering that is required to demonstrate this benefit. If these trials prove to be successful, the clinical landscape for treatment of people with high Lp(a) levels has the potential to be transformed dramatically and quickly.

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