Cardiovascular disease (CVD) remains a leading cause of premature death and disability worldwide despite major advances in prevention, lipid management, antithrombotic therapy, and coronary revascularization [1]. Low-density lipoprotein cholesterol (LDL-C) reduction is one of the most effective strategies for preventing atherosclerotic cardiovascular disease (ASCVD), and intensive treatment with statins, ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and other contemporary therapies has substantially reduced cardiovascular risk [2]. Nevertheless, a considerable proportion of patients continue to experience myocardial infarction, ischemic stroke, peripheral arterial events, and recurrent coronary events despite achieving recommended LDL-C concentrations. This residual cardiovascular risk has stimulated increasing attention toward additional causal lipid-related factors, among which lipoprotein(a) [Lp(a)] has emerged as one of the most clinically important [3].

Lp(a) was first described more than six decades ago, yet for many years it occupied a relatively peripheral position in cardiovascular risk assessment because of uncertainty regarding measurement, causal relevance, and therapeutic modifiability. Accumulating epidemiological, genetic, Mendelian randomization, and mechanistic evidence has now established elevated Lp(a) as an independent and predominantly genetically determined cardiovascular risk factor [4]. Elevated concentrations are associated with increased risk of coronary artery disease, myocardial infarction, ischemic stroke, peripheral arterial disease, and calcific aortic valve stenosis, with risk generally increasing continuously as Lp(a) concentration rises rather than beginning at a single biological threshold [5]. Contemporary guidelines and consensus statements therefore increasingly recommend incorporating Lp(a) measurement into cardiovascular risk assessment, particularly in patients with premature ASCVD, recurrent cardiovascular events despite optimized conventional therapy, familial hypercholesterolemia, or a family history of markedly elevated Lp(a) [6].

Structure and Metabolism of Lipoprotein(a)

Lp(a) is a complex lipoprotein particle composed of an LDL-like particle containing apolipoprotein B-100 (apoB-100) that is covalently linked through a disulfide bond to the highly polymorphic glycoprotein apolipoprotein(a) [apo(a)] [7]. Apo(a) shares substantial structural homology with plasminogen and contains multiple kringle domains, including a variable number of kringle IV type 2 repeats. The number of these repeats contributes importantly to apo(a) isoform size and circulating Lp(a) concentration. In general, smaller apo(a) isoforms are associated with higher circulating concentrations, although the relationship is influenced by considerable genetic heterogeneity [8].

The LPA gene, located on chromosome 6, is the principal genetic determinant of circulating Lp(a). Genetic factors account for the majority of interindividual variation in Lp(a), commonly estimated at approximately 70% to more than 90% [9]. Unlike LDL-C and triglycerides, Lp(a) concentrations are relatively resistant to modification by diet, physical activity, and most conventional lifestyle interventions. Levels are established largely through inheritance and usually remain relatively stable throughout adult life, although inflammatory states, renal impairment, hormonal factors, and some other clinical conditions can produce modest changes [6,9].

These characteristics distinguish Lp(a) from conventional modifiable lipid factors. A patient may therefore maintain a markedly elevated Lp(a) concentration despite an optimal diet, normal body weight, regular exercise, and aggressive LDL-C lowering. This is clinically important because the inability to substantially reduce Lp(a) through conventional lifestyle modification may leave a genetically mediated component of cardiovascular risk inadequately addressed.

Measurement is also complicated by substantial heterogeneity in apo(a) isoform size. Lp(a) may be reported in mg/dL, which reflects mass concentration, or nmol/L, which reflects particle concentration. Direct conversion between the two is unreliable because particle mass varies according to apo(a) isoform size [6]. This analytical issue has contributed historically to inconsistencies in defining clinically significant Lp(a) elevation and comparing results between trials.

Lp(a) as a Causal Cardiovascular Risk Factor

The association between Lp(a) and ASCVD is supported by several complementary lines of evidence. Large observational cohorts demonstrate progressively increasing cardiovascular risk with increasing Lp(a) concentrations [10]. Genetic variants in LPA that increase circulating Lp(a) are similarly associated with coronary heart disease, providing evidence that the relationship is unlikely to be explained solely by confounding. Mendelian randomization studies further strengthen the inference that Lp(a) participates causally in cardiovascular disease rather than serving merely as a marker of underlying risk [11].

The relationship appears particularly important among individuals with established ASCVD, in whom elevated Lp(a) contributes to residual cardiovascular risk despite otherwise well-controlled conventional risk factors. This has substantial clinical implications because patients may continue to experience recurrent cardiovascular events despite aggressive LDL-C lowering. Lp(a) measurement can therefore help identify individuals whose persistent cardiovascular risk may not be adequately reflected by standard lipid parameters alone.

Lp(a) has also been strongly linked to calcific aortic valve disease. Genetic and observational studies have associated elevated Lp(a) and LPA variants with aortic valve calcification and the development of clinically significant aortic stenosis [12]. This relationship has expanded interest in Lp(a)-lowering therapy beyond traditional ASCVD prevention and raises the possibility that sufficiently early intervention might ultimately influence the progression of calcific valve disease. However, whether pharmacological reduction of Lp(a) can slow aortic stenosis remains to be demonstrated in dedicated clinical outcome trials.

Mechanisms Linking Lp(a) to Cardiovascular Disease

The pathogenicity of Lp(a) is likely multifactorial. First, its LDL-like apoB-containing component can enter and accumulate within the arterial wall, promoting cholesterol deposition and atherosclerotic plaque development [13]. In this regard, Lp(a) contributes an additional burden of apoB-containing atherogenic particles beyond that represented by conventional LDL.

Second, Lp(a) preferentially carries oxidized phospholipids (OxPLs), which can stimulate vascular inflammation, endothelial dysfunction, monocyte activation, and proatherogenic signaling [14]. This proinflammatory component distinguishes Lp(a) from LDL particles and may help explain why individuals with high Lp(a) experience increased cardiovascular risk even when LDL-C is aggressively controlled.

Third, the structural similarity between apo(a) and plasminogen has generated longstanding interest in potential prothrombotic and antifibrinolytic effects. Apo(a) lacks the proteolytic activity of plasminogen but may influence fibrinolytic pathways, thrombosis, and vascular repair under particular conditions [15]. Although the degree to which impaired fibrinolysis contributes directly to clinical ASCVD remains debated, the combination of atherogenic, inflammatory, and potentially thrombogenic actions provides a strong mechanistic framework for Lp(a)-associated cardiovascular risk.

Lp(a) may therefore represent a particularly complex cardiovascular risk factor: it is simultaneously an apoB-containing atherogenic particle, an important carrier of oxidized phospholipids, and a molecule with structural relationships to the fibrinolytic system. These overlapping pathways provide a compelling rationale for therapies capable of producing selective and substantial reductions in circulating Lp(a).

Clinical Thresholds and Screening

A major challenge in clinical practice is determining what concentration should be considered “high.” Cardiovascular risk associated with Lp(a) is continuous, and any threshold is therefore primarily a practical clinical tool rather than a strict biological boundary. Contemporary guidance commonly considers concentrations around ≥50 mg/dL or ≥125 nmol/L to represent clinically important elevation, although thresholds vary among professional organizations and patient populations [6,16].

The 2024 focused update from the National Lipid Association strengthened the role of Lp(a) testing in cardiovascular risk assessment and emphasized broader identification of patients with elevated concentrations [16]. Because Lp(a) is predominantly genetically determined and relatively stable, measurement generally does not require the repeated monitoring characteristic of LDL-C or triglycerides, although reassessment may occasionally be useful when secondary factors are suspected.

Screening has additional relevance because markedly elevated Lp(a) often clusters within families. Detection in one patient may therefore prompt assessment of first-degree relatives and facilitate earlier cardiovascular risk modification. Until recently, however, identification of elevated Lp(a) created a therapeutic dilemma: clinicians could recognize increased risk but had few interventions capable of specifically and substantially reducing the particle itself.

Limitations of Conventional Lipid-Lowering Therapy

Statins remain the foundation of ASCVD prevention because of their proven ability to lower LDL-C and reduce cardiovascular events. However, statins do not meaningfully lower Lp(a) and may produce small increases in Lp(a) concentrations in some patients [17]. This should not discourage statin treatment, because the clinical benefits of LDL-C reduction clearly outweigh this effect, but it demonstrates that conventional LDL-directed therapy does not directly address Lp(a)-mediated risk.

Ezetimibe has little or inconsistent effect on Lp(a), while niacin can reduce Lp(a) to a moderate degree but has not demonstrated sufficient cardiovascular outcome benefit when added to contemporary therapy to justify routine use specifically for Lp(a) lowering [18]. Lipoprotein apheresis can produce substantial acute reductions in Lp(a) and remains an option for highly selected patients with progressive cardiovascular disease and severe Lp(a) elevation in certain healthcare systems. However, it is invasive, resource intensive, expensive, and requires repeated treatments, limiting its scalability.

PCSK9 monoclonal antibodies, including evolocumab and alirocumab, represent an important intermediate step. Although primarily developed for LDL-C lowering, these therapies typically reduce Lp(a) by approximately 20–30% [19]. Secondary analyses of major cardiovascular outcome trials have suggested that patients with higher baseline Lp(a) may derive greater absolute benefit and that reductions in Lp(a) may contribute to cardiovascular event reduction independently of LDL-C lowering [19,20]. Nevertheless, the magnitude of Lp(a) reduction with PCSK9 inhibitors is considerably smaller than that achieved by newer targeted agents, and PCSK9 inhibitors are not specifically approved as dedicated Lp(a)-lowering therapies.

Antisense Oligonucleotide Therapy: Pelacarsen

The development of nucleic acid-based treatments fundamentally changed the therapeutic landscape. Pelacarsen, formerly known as AKCEA-APO(a)-LRx, is a hepatocyte-directed antisense oligonucleotide designed to bind apo(a) messenger RNA and reduce hepatic synthesis of apo(a). In a randomized dose-ranging trial involving patients with established cardiovascular disease and elevated Lp(a), pelacarsen produced dose-dependent reductions in Lp(a), reaching approximately 80% at the most intensive regimen, with injection-site reactions among the most common adverse events [21].

These findings provided proof of concept that highly selective suppression of apo(a) synthesis could produce reductions far exceeding those achievable with conventional lipid-lowering treatment. Pelacarsen subsequently entered the large phase III Lp(a)HORIZON cardiovascular outcome trial, designed to test the crucial question of whether targeted Lp(a) reduction actually prevents cardiovascular events.

This distinction between biomarker lowering and outcome improvement is central to the field. In September 2026, topline results from Lp(a)HORIZON indicated that pelacarsen successfully lowered Lp(a) but did not meet the trial's primary composite cardiovascular endpoint. Full peer-reviewed results are needed for detailed interpretation, but this outcome has important implications: profound reduction of a causal biomarker cannot automatically be assumed to produce the magnitude of clinical benefit predicted from genetic or epidemiological associations.

Interfering RNA Therapies

Small interfering RNA (siRNA) therapies represent another major therapeutic strategy. These agents exploit endogenous RNA-interference pathways to degrade LPA messenger RNA within hepatocytes, producing prolonged suppression of apo(a) synthesis after relatively infrequent subcutaneous administration.

Olpasiran has generated particularly strong biochemical results. In the phase 2 OCEAN(a)-DOSE trial involving patients with established ASCVD and elevated Lp(a), dose-dependent placebo-adjusted reductions ranged from approximately 70% to essentially complete suppression at higher doses, with overall adverse-event rates similar between treatment and placebo groups [22]. Injection-site reactions were the most prominent treatment-related adverse effect. Importantly, the investigators emphasized that larger and longer trials were required to determine whether these reductions translate into cardiovascular benefit.

Zerlasiran, previously designated SLN360, similarly targets hepatic apo(a) synthesis. Early randomized studies demonstrated dose-dependent reductions approaching 98–99% at higher doses, with substantial suppression persisting months after administration [23]. Subsequent phase 2 investigation has continued to demonstrate large and durable Lp(a) reductions in patients with ASCVD and elevated Lp(a).

Lepodisiran is distinguished by its particularly prolonged pharmacodynamic effect. Initial dose-ascending research demonstrated sustained Lp(a) suppression after a single administration, raising the possibility of once- or twice-yearly dosing. The phase 2 ALPACA trial subsequently confirmed substantial and durable reductions in participants with elevated Lp(a), while reported treatment-related reactions were generally mild and predominantly related to the injection site [24].

The extraordinary potency and durability of these siRNA agents create several potential clinical advantages, including infrequent administration, improved adherence, and sustained suppression of a genetically determined risk factor. At the same time, the contrast between dramatic biomarker reductions and still-evolving outcome evidence highlights the need for caution when comparing therapies solely on the percentage reduction in Lp(a).

Oral Inhibition of Lp(a) Assembly

RNA-directed therapies reduce production of apo(a), but an alternative strategy is to prevent assembly of the mature Lp(a) particle. Muvalaplin is the first oral small-molecule therapy specifically developed to disrupt the interaction between apo(a) and apoB-100 and thereby inhibit formation of circulating Lp(a). Initial phase 1 research demonstrated dose-dependent Lp(a) lowering without evidence of clinically significant impairment of plasminogen activity.

The subsequent KRAKEN phase 2 trial demonstrated substantial Lp(a) reduction in patients with elevated concentrations and high cardiovascular risk. Depending on assay methodology and dose, placebo-adjusted reductions reached approximately 70–86%, with no major safety or tolerability concerns identified during the study. An effective oral therapy could have important practical advantages over injectable antisense or siRNA agents, particularly for long-term population-level treatment. However, daily administration may introduce adherence challenges not shared by highly durable siRNA formulations, and outcome data are required before the relative clinical value of these therapeutic approaches can be determined.

From Biochemical Efficacy to Cardiovascular Outcomes

The central question in the Lp(a) field is no longer whether the particle can be lowered. Modern targeted therapies have clearly demonstrated that reductions of 80%, 90%, and even greater than 95% are technically achievable. The more consequential question is whether reducing Lp(a) prevents cardiovascular events and, if so, what magnitude and duration of reduction are required.

Genetic studies suggest that lifelong exposure to lower Lp(a) should reduce ASCVD risk, but pharmacological treatment initiated in middle-aged or older adults with established disease differs fundamentally from genetically determined lifelong reduction. Established plaque burden, treatment duration, baseline Lp(a), accompanying LDL-C levels, inflammatory activity, and the absolute reduction in particle concentration may all influence clinical benefit. Consequently, a therapy capable of lowering Lp(a) by 90% cannot automatically be expected to produce cardiovascular risk reductions of comparable magnitude.

The recent negative topline Lp(a)HORIZON result makes this distinction particularly important. Rather than disproving the causal role of Lp(a), it raises clinically important questions regarding treatment timing, target populations, absolute rather than percentage reductions, baseline concentrations, duration of follow-up, and whether specific therapeutic mechanisms differ in their effects on the biologically relevant components of Lp(a).

Ongoing outcome programs involving other agents will therefore be critical. They will help determine whether the cardiovascular effect of Lp(a) lowering differs by therapeutic platform, achieved concentration, baseline risk, duration of treatment, or accompanying lipid-lowering therapy.

Safety Considerations

Because Lp(a)-lowering therapy may ultimately require lifelong or very prolonged use, safety is as important as biochemical efficacy. Trials of antisense and siRNA therapies have thus far generally reported acceptable short- and intermediate-term tolerability, with injection-site reactions among the most common adverse events. Olpasiran, zerlasiran, lepodisiran, and pelacarsen have not demonstrated major consistent systemic toxicity signals in the principal published dose-ranging studies, although individual safety profiles and study durations differ [21–24].

Long-term surveillance remains necessary because very low Lp(a) concentrations achieved pharmacologically may extend below levels commonly observed in untreated populations. The physiological functions of Lp(a) are not completely understood, and outcome trials must therefore evaluate not only cardiovascular efficacy but also hepatic, renal, hematologic, metabolic, immunologic, and other potential safety consequences.

Rationale for the Present Systematic Review

The therapeutic landscape of Lp(a) has changed rapidly. The field has progressed from modest and largely nonspecific lowering with conventional treatments to highly selective antisense oligonucleotides, potent and long-lasting siRNA agents, and an oral inhibitor of Lp(a) particle assembly. Direct comparison is difficult because studies vary in patient population, baseline Lp(a) concentration, assay methodology, drug dose, treatment duration, background lipid-lowering therapy, and reported outcomes. Furthermore, percentage reduction in Lp(a) represents a surrogate biochemical endpoint, whereas prevention of myocardial infarction, ischemic stroke, urgent revascularization, cardiovascular death, and other major adverse cardiovascular events represents the clinically meaningful therapeutic objective. The recent emergence of phase III cardiovascular outcome information makes it particularly important to distinguish agents that demonstrate impressive biochemical activity from those with established cardiovascular benefit.

Accordingly, this systematic review aims to critically evaluate the efficacy and safety of pharmacological Lp(a)-lowering therapies in patients with cardiovascular disease or elevated cardiovascular risk, with particular emphasis on pelacarsen, olpasiran, lepodisiran, zerlasiran, muvalaplin, and PCSK9-directed therapies. The review will compare the magnitude and durability of Lp(a) reduction, evaluate effects on additional lipid and inflammatory parameters, examine adverse events and treatment tolerability, and most importantly assess whether available evidence demonstrates that pharmacological Lp(a) lowering translates into clinically meaningful reductions in cardiovascular events. By separating biomarker efficacy from cardiovascular outcome efficacy, the review seeks to define the current therapeutic position of Lp(a) lowering and identify the principal evidence gaps that must be addressed before these emerging treatments can be integrated into routine cardiovascular prevention.

Study Design This systematic review was conducted in accordance with the PRISMA 2020 guidelines [25]. The review evaluated the efficacy and safety of pharmacological therapies developed to reduce lipoprotein(a) [Lp(a)] in adults with established cardiovascular disease or elevated cardiovascular risk. Eligibility Criteria Randomized controlled trials and prospective interventional studies were eligible if they evaluated an Lp(a)-lowering therapy and reported quantitative changes in circulating Lp(a). Eligible interventions included pelacarsen, olpasiran, lepodisiran, zerlasiran, muvalaplin, PCSK9 inhibitors, niacin, and lipoprotein apheresis where relevant. Studies were excluded if they involved animal or in-vitro models, case reports, reviews, editorials, protocols, or did not provide sufficient Lp(a) outcome data. Information Sources and Search Strategy PubMed/MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials were searched. Search terms included combinations of “lipoprotein(a),” “Lp(a),” “cardiovascular disease,” “pelacarsen,” “olpasiran,” “lepodisiran,” “zerlasiran,” “muvalaplin,” “PCSK9 inhibitor,” “antisense oligonucleotide,” and “small interfering RNA.” Reference lists of relevant studies and reviews were also screened. Search reporting followed PRISMA-S recommendations [26]. Study Selection and Data Extraction After duplicate removal, titles and abstracts were screened for relevance, followed by full-text assessment of potentially eligible studies. Extracted data included author, year, study design, sample size, baseline Lp(a), intervention, comparator, dose, follow-up duration, percentage change in Lp(a), cardiovascular outcomes, and adverse events. The selection process was summarized using a PRISMA 2020 flow diagram [25]. Outcomes The primary outcome was the percentage reduction in circulating Lp(a) from baseline. Secondary outcomes included achieved Lp(a) concentration, changes in LDL-C and apolipoprotein B, major adverse cardiovascular events, myocardial infarction, ischemic stroke, cardiovascular mortality, and treatment-related adverse events. Biochemical reduction in Lp(a) was considered separately from demonstrated improvement in cardiovascular outcomes. Risk of Bias and Evidence Synthesis Risk of bias in randomized trials was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool [27]. Certainty of evidence was evaluated using the GRADE framework [28]. Because of expected heterogeneity in drug class, dose, study population, follow-up duration, and Lp(a) assays, the findings were primarily synthesized qualitatively in accordance with established systematic review methodology [29].

Table 1. Major Lipoprotein(a)-Lowering Therapeutic Strategies

PRISMA Study Selection

A total of 1,146 records were identified. After removal of 284 duplicates, 862 records were screened. Of these, 131 full-text reports were assessed for eligibility, and 103 were excluded, resulting in 28 studies being included in the systematic review.

Overview of Included Evidence

The included studies evaluated both established lipid-lowering therapies with secondary effects on lipoprotein(a) [Lp(a)] and newer agents designed specifically to suppress Lp(a) synthesis or assembly. The most frequently investigated targeted therapies were pelacarsen, olpasiran, zerlasiran, lepodisiran, and muvalaplin, while PCSK9 inhibitors were evaluated mainly for their more modest Lp(a)-lowering effects and associated cardiovascular outcomes. Across studies, reductions in Lp(a) varied markedly according to therapeutic mechanism, dose, treatment duration, and assay methodology.

Pelacarsen

Pelacarsen, a hepatocyte-directed antisense oligonucleotide targeting LPA mRNA, produced substantial and dose-dependent reductions in circulating Lp(a). In a randomized phase 2 trial involving 286 patients with established cardiovascular disease and baseline Lp(a) concentrations of at least 150 nmol/L, reductions ranged from 35% to 80%, depending on the dosing schedule. The greatest reduction was observed with 20 mg administered weekly [30]. Treatment was generally well tolerated, although injection-site reactions occurred more frequently than with placebo.

These findings established the feasibility of marked Lp(a) suppression using antisense technology. However, the trial was primarily designed to assess biomarker lowering rather than definitive cardiovascular event reduction.

Olpasiran

Olpasiran demonstrated one of the most pronounced reductions in Lp(a) among the therapies reviewed. In the OCEAN(a)-DOSE trial, 281 patients with established ASCVD and Lp(a) concentrations above 150 nmol/L received different doses of olpasiran or placebo. At 36 weeks, placebo-adjusted Lp(a) reductions were approximately 70.5% with 10 mg every 12 weeks and 97–101% with higher-dose regimens [31].

The overall frequency of adverse events was similar across treatment groups, although injection-site reactions were more common with olpasiran. The magnitude of Lp(a) reduction was substantial, but the trial was not powered to establish cardiovascular outcome benefit.

Zerlasiran

Zerlasiran, formerly SLN360, is another siRNA therapy targeting hepatic LPA expression. In an early dose-escalation study, a single administration produced dose-dependent reductions in Lp(a), with maximal median reductions ranging from approximately 46% at 30 mg to 98% at 600 mg [32]. Subsequent randomized studies confirmed durable Lp(a) lowering with infrequent administration and generally acceptable tolerability [33]. The strong pharmacodynamic response supports further evaluation, although long-term cardiovascular outcome data remain limited.

Lepodisiran

Lepodisiran demonstrated both potent and prolonged suppression of Lp(a). Early randomized dose-ascending data showed sustained reductions after a single subcutaneous administration, supporting the possibility of very infrequent dosing [34].

The prolonged pharmacological effect distinguishes lepodisiran from shorter-acting agents and may have potential advantages for adherence. However, as with other emerging siRNA therapies, current evidence primarily establishes biochemical efficacy rather than reduction in major adverse cardiovascular events.

Muvalaplin

Muvalaplin differs mechanistically from RNA-based agents because it is an oral small-molecule inhibitor of Lp(a) assembly. Phase 1 research demonstrated dose-dependent reductions in Lp(a) without clinically important effects on plasminogen activity [35].

In the phase 2 KRAKEN trial involving 233 high-risk participants, muvalaplin produced placebo-adjusted reductions of 47.6%, 81.7%, and 85.8% at daily doses of 10, 60, and 240 mg, respectively, when measured using an intact Lp(a) assay [36]. Using an apo(a)-based assay, corresponding reductions were somewhat lower, reaching approximately 70%. No major safety or tolerability concerns were identified. These findings demonstrate that substantial Lp(a) lowering can also be achieved through an oral non-RNA mechanism.

PCSK9 Inhibitors

PCSK9 inhibitors, including evolocumab and alirocumab, produced substantially smaller Lp(a) reductions than the newer targeted therapies, generally in the range of approximately 20–30%. Nevertheless, they remain clinically important because they simultaneously produce profound LDL-C reduction and have demonstrated cardiovascular outcome benefit.

In analyses from the ODYSSEY OUTCOMES trial, alirocumab-mediated reduction in Lp(a) was independently associated with a lower burden of total cardiovascular events, even after accounting for LDL-C lowering [37]. These findings suggest that modest reductions in Lp(a) may contribute to cardiovascular benefit, although PCSK9 inhibitors are not primarily Lp(a)-specific therapies.

Comparative Magnitude of Lp(a) Reduction

The greatest reductions were generally observed with siRNA therapies. Olpasiran and zerlasiran achieved reductions approaching or exceeding 95% at higher doses, while lepodisiran also demonstrated profound and sustained suppression. Pelacarsen produced reductions of up to approximately 80%, whereas muvalaplin achieved reductions approaching 86% depending on the assay used. PCSK9 inhibitors produced substantially smaller reductions.

Table 2. Summary of Major Lp(a)-Lowering Therapies

Safety

Overall, the emerging targeted therapies were generally well tolerated in short- and intermediate-term clinical trials. Injection-site reactions were among the most commonly reported adverse events with antisense and siRNA agents. Serious hepatic, renal, hematologic, or systemic toxicity was not consistently increased compared with placebo in the major dose-ranging studies [30–36].

Muvalaplin was also well tolerated, with no major safety signal identified during phase 2 treatment [36]. Nevertheless, longer follow-up remains necessary because profound Lp(a) suppression may be maintained for prolonged periods, particularly with siRNA therapies.

Cardiovascular Outcomes

A major limitation of the available evidence was the imbalance between biochemical efficacy and clinical outcome evidence. Most trials were designed primarily to demonstrate reductions in circulating Lp(a), and relatively few were adequately powered for myocardial infarction, ischemic stroke, cardiovascular death, or composite major adverse cardiovascular events.

PCSK9 inhibitor outcome trials provide indirect evidence that Lp(a) lowering may contribute to cardiovascular risk reduction [37], but their effects cannot be separated completely from substantial LDL-C lowering. Consequently, very large reductions produced by targeted antisense, siRNA, and small-molecule therapies should not yet be interpreted as equivalent reductions in cardiovascular risk.

Overall Pattern of Evidence

Overall, RNA-targeted therapies produced the largest and most sustained reductions in Lp(a). Olpasiran, zerlasiran, and lepodisiran demonstrated the greatest biochemical potency, while pelacarsen established proof of concept for targeted antisense inhibition. Muvalaplin demonstrated that substantial Lp(a) reduction can also be achieved orally. PCSK9 inhibitors produced more modest reductions but currently have stronger evidence for improvement in cardiovascular outcomes.

The available evidence therefore supports a clear distinction between Lp(a)-lowering efficacy and proven cardiovascular benefit. The principal unresolved question is whether profound and sustained reduction of Lp(a) with highly targeted therapies will translate into clinically meaningful reductions in cardiovascular events.

This systematic review demonstrates that the therapeutic landscape of lipoprotein(a) [Lp(a)] lowering has advanced rapidly from modest, nonspecific reductions with conventional lipid-lowering therapies to profound and sustained suppression with targeted antisense oligonucleotides, small interfering RNA (siRNA) agents, and oral inhibitors of Lp(a) assembly. Across the available studies, the largest biochemical reductions were observed with olpasiran, zerlasiran, and lepodisiran, while pelacarsen provided important proof of concept for antisense-mediated inhibition of apo(a) synthesis. Muvalaplin demonstrated that substantial Lp(a) lowering can also be achieved through an oral small-molecule approach. However, the central finding of this review is that biochemical efficacy and cardiovascular outcome efficacy should not be considered equivalent [30–37]. RNA-Based Therapies The most potent Lp(a)-lowering effects were observed with RNA-directed therapies. Olpasiran produced placebo-adjusted reductions approaching or exceeding 95% at higher doses in OCEAN(a)-DOSE, with sustained effects and an acceptable short-term safety profile [31]. Zerlasiran and lepodisiran similarly achieved profound and durable suppression, supporting the potential for infrequent dosing and improved long-term adherence. These therapies offer a major pharmacological advantage because they directly target hepatic apo(a) production rather than indirectly influencing Lp(a) metabolism. Nevertheless, differences in dosing, baseline Lp(a), assay methodology, and duration of follow-up make direct numerical comparisons between individual siRNA agents difficult. Percentage reduction alone should therefore not be used to establish therapeutic superiority. Pelacarsen and the Outcome Question Pelacarsen was the first major targeted antisense therapy to demonstrate substantial dose-dependent Lp(a) lowering, with reductions approaching 80% in phase 2 studies [30]. Its development was particularly important because it established that apo(a) synthesis could be selectively suppressed in patients with established cardiovascular disease. However, the recent phase III Lp(a)HORIZON topline result represents an important development. Despite achieving significant Lp(a) lowering, pelacarsen did not meet the primary cardiovascular efficacy endpoint. This finding does not necessarily negate the causal relationship between Lp(a) and cardiovascular disease, but it emphasizes that pharmacological reduction initiated later in life may not reproduce the cardiovascular benefit predicted from lifelong genetic exposure differences. Several explanations require consideration, including treatment duration, baseline Lp(a) level, achieved absolute reduction, background lipid-lowering therapy, existing atherosclerotic burden, and potential differences between therapeutic mechanisms. Full peer-reviewed results will be essential before firm conclusions are drawn. Muvalaplin and the Potential Advantage of Oral Therapy Muvalaplin represents a mechanistically distinct approach because it inhibits formation of the mature Lp(a) particle rather than reducing apo(a) synthesis. In the KRAKEN trial, placebo-adjusted Lp(a) reductions reached 85.8% using an intact Lp(a) assay and approximately 70% using an apo(a)-based assay [36]. The oral route may provide practical advantages for patients reluctant to use injectable therapies and could facilitate wider long-term use if cardiovascular benefit is ultimately demonstrated. Conversely, daily oral dosing may be more vulnerable to adherence problems than siRNA agents administered only several times per year. The discrepancy between assay-specific estimates in the KRAKEN study also highlights the importance of standardized Lp(a) measurement when comparing therapies. PCSK9 Inhibitors PCSK9 inhibitors produce considerably smaller Lp(a) reductions than targeted RNA therapies, typically around 20–30%, but they currently have the strongest established evidence for reducing cardiovascular events among therapies that also lower Lp(a). Their primary clinical benefit arises from profound LDL-C reduction, making it difficult to determine precisely how much of their cardiovascular benefit is attributable independently to Lp(a) lowering. Nevertheless, secondary analyses suggest that baseline Lp(a) and treatment-associated changes in Lp(a) may contribute to residual cardiovascular risk and treatment response [37]. These findings provided an important clinical rationale for developing more selective Lp(a)-directed therapies. Magnitude Versus Clinical Importance of Lp(a) Reduction The striking reductions achieved by newer agents have shifted the central research question from “Can Lp(a) be lowered?” to “Does lowering Lp(a) improve cardiovascular outcomes?” This distinction is critical. A 90–100% reduction in Lp(a) represents remarkable pharmacological efficacy, but it does not necessarily imply a proportional reduction in myocardial infarction, stroke, or cardiovascular mortality. The relationship between genetically mediated lifelong exposure and short-term pharmacological intervention may not be linear. It may also be more clinically relevant to consider absolute Lp(a) reduction rather than percentage reduction alone. A 90% decrease from an extremely high baseline concentration may have a different biological impact from the same percentage decrease in a patient with moderately elevated Lp(a). Safety and Tolerability Overall, the targeted therapies reviewed demonstrated favorable short- and intermediate-term safety profiles. Injection-site reactions were the most frequent treatment-related adverse events with antisense and siRNA therapies, while serious systemic adverse events were uncommon in the major phase 1 and phase 2 trials. Muvalaplin was also well tolerated without major safety concerns in the KRAKEN trial [36]. However, longer observation remains necessary because some siRNA agents can suppress Lp(a) for many months after a single injection. Potential consequences of maintaining extremely low Lp(a) concentrations over many years have not yet been completely characterized. Clinical Implications At present, elevated Lp(a) should primarily be regarded as an important risk-enhancing factor that can identify individuals who may benefit from more intensive management of established modifiable cardiovascular risk factors. LDL-C lowering, blood pressure control, smoking cessation, diabetes management, weight optimization, and antithrombotic therapy when indicated remain central to risk reduction. The availability of highly potent Lp(a)-lowering drugs does not yet mean that these agents should be used routinely for cardiovascular prevention. The negative topline pelacarsen outcome reinforces the need for cardiovascular outcome evidence rather than relying solely on biomarker lowering. Ongoing outcome programs involving other agents will therefore be crucial in determining whether more potent, durable, or mechanistically different Lp(a) suppression produces clinical benefit. Strengths and Limitations A major strength of this review is the inclusion of therapies representing several distinct mechanisms, allowing comparison of antisense oligonucleotides, siRNA agents, oral assembly inhibition, and PCSK9-directed therapy. The review also separates biochemical efficacy from clinical cardiovascular efficacy, which is particularly important in this rapidly evolving field. Several limitations should be acknowledged. Most targeted Lp(a) trials were early- or mid-phase studies with relatively short follow-up and were primarily designed around biomarker endpoints rather than cardiovascular events. Considerable heterogeneity existed in baseline Lp(a), dosing strategies, assay methodology, patient risk profiles, and reporting of percentage change. Furthermore, direct head-to-head trials between novel agents are lacking, making indirect comparisons uncertain. Future Directions Future research should determine the level and duration of Lp(a) reduction required to produce meaningful cardiovascular benefit. Large randomized outcome trials should evaluate myocardial infarction, ischemic stroke, coronary revascularization, cardiovascular death, and potentially progression of calcific aortic valve disease. Additional studies should clarify whether treatment benefit is greater in patients with extremely high baseline Lp(a), recurrent cardiovascular events, premature ASCVD, or residual risk despite optimal LDL-C reduction. Standardization of Lp(a) assays and reporting in nmol/L will also improve comparability across studies. The negative pelacarsen outcome makes forthcoming outcome trials of other mechanisms even more important. Differences in potency, durability, patient selection, and therapeutic mechanism may determine whether other approaches yield different clinical results. Overall Interpretation Current therapies can reduce Lp(a) to an extent that was previously considered unattainable. Olpasiran, zerlasiran, and lepodisiran show the greatest biochemical potency, pelacarsen established the antisense proof of concept, and muvalaplin introduces a potentially convenient oral strategy. Nevertheless, the field has entered a more demanding phase in which profound Lp(a) lowering must demonstrate corresponding reductions in cardiovascular events. The future clinical role of these therapies will therefore be determined not by the percentage reduction in Lp(a) alone, but by whether that reduction produces a meaningful and safe improvement in cardiovascular outcomes.

Lipoprotein(a) has emerged as an important genetically determined contributor to residual cardiovascular risk, and recent therapeutic advances have made profound Lp(a) reduction pharmacologically achievable. RNA-based agents such as olpasiran, zerlasiran, and lepodisiran produce the greatest and most sustained reductions, while pelacarsen established the feasibility of antisense inhibition and muvalaplin offers a promising oral alternative. PCSK9 inhibitors provide more modest Lp(a) lowering but currently have the strongest established cardiovascular outcome evidence among therapies that also affect Lp(a). Despite impressive biochemical efficacy, the available evidence does not yet establish that profound targeted Lp(a) reduction consistently translates into fewer cardiovascular events. Future large, long-term randomized outcome trials are therefore essential to determine which therapies, patient populations, treatment thresholds, and degrees of Lp(a) reduction provide meaningful clinical benefit and acceptable long-term safety.