Lipoprotein(a) in clinical practice: From genetic risk assessment to therapeutic silencing

Abstract

Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein particle increasingly recognized as an independent and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Its unique structure, composed of a low-density lipoprotein-like particle bound to apolipoprotein(a), confers both atherogenic and proinflammatory properties that distinguish it from other circulating lipoproteins. This review examines the molecular structure of Lp(a), its genetic determinants, and the mechanisms linking elevated Lp(a) levels to atherogenesis and vascular inflammation. We critically discuss the role of apolipoprotein(a) isoform variability, kringle domain polymorphisms, oxidized phospholipid transport, endothelial dysfunction, inflammatory signaling pathways, and thrombogenic pathways in mediating cardiovascular risk. In addition, we review current approaches for laboratory assessment and summarize emerging therapeutic strategies aimed at selectively lowering Lp(a), including antisense oligonucleotides and small interfering RNA-based therapies. Recent advances in molecular therapeutics have demonstrated substantial reductions in circulating Lp(a) concentrations, although definitive evidence regarding cardiovascular outcome benefits is still under investigation. A better understanding of Lp(a) biology and its inflammatory and atherogenic mechanisms may improve risk stratification and support the development of personalized preventive and therapeutic strategies in cardiovascular medicine.

Key Words: Lipoprotein(a); Residual cardiovascular risk; Gene silencing; Small interfering RNA; Antisense oligonucleotides

Core Tip: Lipoprotein(a) [Lp(a)] is increasingly recognized as an important genetically determined cardiovascular risk factor with proatherogenic, proinflammatory, and prothrombotic properties that contribute to atherosclerotic cardiovascular disease and calcific aortic valve disease. This review discusses the molecular structure, genetic determinants, pathogenic mechanisms, and clinical relevance of Lp(a), as well as current challenges in laboratory assessment and emerging targeted therapies. Advances in understanding and treating elevated Lp(a) may improve cardiovascular risk stratification and open new perspectives for personalized preventive cardiology.

INTRODUCTION

Cardiovascular disease remains the leading cause of morbidity and mortality worldwide, and accurate cardiovascular risk stratification is essential for identifying individuals at increased risk and guiding preventive strategies[1-3]. However, a substantial proportion of patients who develop premature coronary artery disease or recurrent cardiovascular events do not present significant abnormalities in conventional risk factors, suggesting that additional determinants contribute to residual cardiovascular risk[4-6]. In this context, lipoprotein(a) [Lp(a)] has progressively emerged as an important, independent, and causal risk factor for atherosclerotic cardiovascular disease and calcific aortic valve disease. Elevated plasma concentrations of Lp(a) have been consistently associated with increased risks of acute myocardial infarction, ischemic stroke, coronary artery disease, and aortic valve calcification, reinforcing its relevance in contemporary cardiovascular medicine[7-10]. Structurally, Lp(a) is a unique lipoprotein particle composed of a low-density lipoprotein (LDL)-like core covalently bound to apolipoprotein(a) [apo(a)], a highly polymorphic glycoprotein that is structurally homologous to plasminogen[11,12]. This distinct molecular configuration combines pro-atherogenic, pro-inflammatory, and pro-thrombotic effects within the vascular milieu[13-15], strongly driven by its genetic architecture. The Lp(a) (LPA) gene, located on chromosome 6q27, exerts sovereign control over this particle, accounting for approximately 70%-90% of the observed variation in plasma Lp(a) concentrations[9,16]. Unlike most traditional lipid biomarkers, Lp(a) levels remain relatively stable throughout life and are minimally influenced by environmental factors, diet, or lifestyle interventions. An important part of this hereditary regulation relies on copy number variation (CNV) within the kringle IV type 2 (KIV-2) repeat domain of the LPA gene[17-19]. This structural variability determines the size of the apo(a) molecule, resulting in a strong inverse correlation, where smaller apo(a) isoforms are more efficiently secreted by the liver, leading to higher plasma levels and more pronounced pathogenic effects[9,10,20]. In addition to apo(a) isoform size polymorphism, multiple single nucleotide polymorphisms (SNPs) influence the circulating levels and cardiovascular risk, highlighting the complex hereditary regulation of this lipoprotein[7]. This strong genetic determinism explains why Lp(a) has become increasingly recognized as a marker of inherited cardiovascular risk and an important component of precision cardiovascular medicine (Table 1)[21]. The atherogenic potential of Lp(a) is mediated through multiple molecular pathways. Lp(a) promotes endothelial dysfunction, facilitates lipid deposition in the arterial wall, enhances monocyte recruitment, and contributes to foam cell formation and plaque progression[15,22,23]. In addition, Lp(a) is the main plasma carrier of oxidized phospholipids (OxPL), which exert potent pro-inflammatory and pro-atherogenic effects by stimulating endothelial cells, macrophages, and vascular smooth muscle cells, thereby amplifying vascular inflammation and atherosclerotic progression[14,15,24]. Its structural homology with plasminogen also contributes to thrombogenicity by interfering with fibrinolysis and favoring clot persistence, further increasing cardiovascular burden[11,12,25]. As scientific evidence has accumulated, major international guidelines have incorporated Lp(a) into cardiovascular risk assessment strategies. Current recommendations from the European Society of Cardiology, European Atherosclerosis Society, National Lipid Association, and American College of Cardiology/American Heart Association advocate measuring Lp(a) at least once in adulthood, particularly in individuals with family history of premature cardiovascular disease, familial hypercholesterolemia (FH), recurrent atherosclerotic events, or intermediate cardiovascular risk[4,6]. Despite growing recognition of its clinical importance, important challenges remain regarding laboratory standardization, interpretation of concentration thresholds, and the implementation of targeted therapies. For decades, Lp(a) was considered a largely non-modifiable cardiovascular risk factor. However, recent advances in antisense oligonucleotide (ASO) and small interfering RNA-based therapies have changed this paradigm, offering the possibility of selective and profound reductions in circulating Lp(a) levels[26]. Therefore, this review aims to examine the molecular structure of Lp(a), its genetic determinants, and the mechanisms linking elevated Lp(a) concentrations to atherogenesis and inflammation, as well as to discuss current laboratory assessment and emerging therapeutic strategies targeting this increasingly relevant cardiovascular risk factor. Furthermore, this review is warranted given the rapid convergence between genomic medicine and targeted therapies. Although the hypervariability of the LPA locus represents the primordial and sovereign determinant of these clinical phenotypes, multiple studies also demonstrate a significant modulating influence from independent lipid-related loci[27-29]. Nonetheless, translating this genetic architecture into routine clinical practice remains a profound challenge for contemporary medicine. This review is critically necessary to scrutinize how distinct SNPs and splicing errors modulate plasma concentrations[30], establishing a direct biological link to clinical risk. Furthermore, as pioneering gene-silencing technologies, such as ASOs and short interfering RNAs, move closer to transforming clinical practice[26], a comprehensive consolidation of this topic becomes indispensable. Consequently, this article aims to review the genomic structure of Lp(a), elucidate its molecular pathogenic pathways, and provide a critical analysis of emerging RNA-targeted therapies, offering a definitive roadmap for precision preventive cardiology.

Table 1 Lipoprotein(a) concentration and cardiovascular risk categories.

Cardiovascular risk category	Lp(a) concentration (mg/dL)	Lp(a) concentration (nmol/L)	Ref.
Low risk	< 30 mg/dL	< 75 nmol/L	Grundy et al[21]
Intermediate risk	30-50 mg/dL	75-125 nmol/L
High risk	≥ 50 mg/dL	≥ 125 nmol/L

Lp(a): Lipoprotein(a).

LP(A) STRUCTURE AND ITS RELATIONSHIP WITH ATHEROGENESIS AND INFLAMMATION

The basic structure of the Lp(a) molecule is an LDL cholesterol (LDL-C), that is, a lipid core containing apolipoprotein B-100 (ApoB-100), linked to an apo(a) via a disulfide bridge[31]. This apo(a) contains kringle domains consisting of two structures with three loops (KIV, KV), with the KIV portion having 10 possible types[31,32]. These KIV types have a variable number of repeats, particularly KIV2, resulting in Lp(a) with distinct molecular sizes, with larger isoforms being secreted with greater difficulty by the liver. In other words, there is a relationship between Lp(a) size and serum concentration, such that patients with smaller isoforms have higher concentrations[33]. As several large-scale studies have already documented a gradual increase in the risk of coronary artery disease (CAD) and stroke with rising Lp(a) levels[34-36], the size of the molecule impacts cardiovascular risk, as it influences Lp(a) concentration.

Possibly due to its great structural similarity to LDL-C, Lp(a) can also be internalized into the arterial intima depending on conditions such as blood pressure, arterial wall permeability, molecular size, and serum concentration[37,38]. Factors such as its high affinity for endothelial surface proteins and the possibility of accumulation beyond sites of atherosclerotic lesions indicate that Lp(a) has a greater atherogenic effect than LDL-C[37,39,40]. This internalization mechanism also occurs at the aortic valve leaflets, which may explain why elevated Lp(a) levels are a risk factor for degenerative stenosis of this valve[41].

In addition to its role in atherogenesis, Lp(a) also influences atherothrombosis through certain prothrombotic mechanisms. Among these mechanisms, its homology with plasminogen[11], stands out, due to apo(a), which shares more than 80% of its protein sequence with plasminogen[12]. This similarity allows Lp(a) to occupy plasminogen receptors on platelets, which prevents tissue plasminogen activator from converting plasminogen into plasmin[13,25]. The smaller isoforms of Lp(a) can exert even more profound antifibrinolytic effects due to their higher binding affinity for fibrin, thereby reducing the binding efficacy of those plasmins that have been activated[42]. Furthermore, another relevant mechanism is that, within the endothelium, Lp(a) promotes the production of tissue factor; thus, endothelial injury releases this tissue factor into the blood, triggering the extrinsic coagulation pathway[13].

Lp(a), like other lipoproteins, is susceptible to oxidative modifications and the formation of OxPL. It contains more than 80% of these OxPLs in its particles through bonds to lysine residues in KV fragments of apo(a)[14], which promotes pro-inflammatory and pro-thrombotic activities in the arterial wall[15]. Due to this transport of OxPL, when Lp(a) is present at low concentrations, it acts as an anti-inflammatory agent, as it carries OxPL to phospholipase A2 enzymes for degradation[15]. However, at high concentrations, excess OxPL in apo(a) competes for the binding site on phospholipase A2, which reduces catalytic activity and renders degradation insufficient[24], promoting deposition in the vascular wall and the secretion of cytokines and chemokines[15].

Monocyte chemotactic protein-1 is also transported by Lp(a), and there is evidence suggesting that this association directs monocytes to the vascular wall[22]. The mobilization of monocytes in pro-inflammatory and proteolytic environments within the vascular wall is a fundamental step in cholesterol oxidation and the formation of atheromatous plaques[23]. The number of KIV2 repeats is inversely proportional to this stimulation; that is, the smaller the Lp(a) isoform due to fewer KIV2 repeats, the greater the deleterious effects (Figures 1 and 2)[20].

Figure 1 Schematic representation of the structural organization of lipoprotein(a). LDL: Low-density lipoprotein; ApoB-100: Apolipoprotein B-100; KIV: Kringle IV.

Figure 2 Schematic representation of the pro-atherogenic and pro-thrombotic mechanisms associated with elevated lipoprotein(a), highlighting the role of smaller apolipoprotein(a) isoforms with fewer kringle IV type 2 repeats in promoting atherosclerosis and thrombosis. apo(a): Apolipoprotein(a); KIV-2: Kringle IV type 2; Lp(a): Lipoprotein(a); MCP-1: Monocyte chemotactic protein-1; OxPL: Oxidized phospholipids.

BIOSYNTHESIS AND MOLECULAR MECHANISMS OF LP(A) ASSEMBLY

The biogenesis of Lp(a) is an exclusively hepatic process that occurs via a two-step assembly pathway. Initially, apo(a) binds non-covalently to apoB-100 within the early secretory pathway of hepatocytes, including the endoplasmic reticulum, trans-Golgi, and early endosomes. This intracellular docking is mediated by weak lysine-binding sites in the KIV-7 and KIV-8 domains of apo(a), directly coupling apo(a) secretion to apoB trafficking[43].

Subsequently, the assembly is covalently sealed in the extracellular space via a single disulfide bond between Cys67 (KIV-9) of apo(a) and Cys3734 of apoB-100, a step likely catalyzed by local cell-surface oxidases. Targeted disruption of the initial non-covalent interaction in the KIV-7 and KIV-8 domains, whether pharmacologically or via genetic mutation, completely prevents covalent bond formation, confirming this intracellular recognition phase as the essential checkpoint in Lp(a) formation[44].

GENOMIC STRUCTURE AND EVOLUTIONARY ORIGIN

The LPA gene is located on chromosome 6, specifically on the reverse strand of the 6q27 region, spanning an extension of approximately 132 kb[16,45]. Considered the primary determinant of the Lp(a) hereditary trait, LPA is responsible for explaining between 70% and 90% of the variation observed in the plasma levels of this particle[9,10]. From an evolutionary perspective, this gene presents a close relationship with the plasminogen gene, from which it diverged about 40 million years ago during the primate lineage through complex processes of duplication, deletion, gene conversion, and point mutations[46,47].

While plasminogen consists of an amino-terminal tail, five unique kringle domains (KI to KV), and a functional protease domain, the evolution of the LPA gene resulted in the loss of the terminal tail and the KI, KII, and KIII domains[48]. One of the most striking alterations was the massive expansion of the KIV domain, which in LPA differentiated into 10 distinct types (KIV-1 to KIV-10)[14,17]. The most unique feature of the LPA gene is the hypervariability of the KIV-2 domain. This segment exhibits CNV, which can repeat from one to more than 40 times on a single allele. This variation is the basis for the size polymorphism of the apo(a) molecule, resulting in an estimate of more than 1600 possible genotypes in the population[27-29]. Additionally, although the protease domain is crucial for fibrinolytic activity in plasminogen, in apo(a), this domain is enzymatically inactive[18].

SECRETORY DYNAMICS AND CLINICAL IMPLICATIONS

A robust inverse correlation is observed between the number of KIV-2 repeats and the plasma concentration of Lp(a). This phenomenon is explained by the intracellular kinetics within hepatocytes. Larger apo(a) isoforms undergo greater retention in the endoplasmic reticulum and more intense pre-secretory degradation. Consequently, shorter isoforms are secreted more efficiently, leading to higher circulating levels[19,49,50]. Epidemiological studies and meta-analyses reinforce that the presence of short apo(a) isoforms is associated with a significantly elevated risk of cardiovascular diseases. Individuals carrying these isoforms present an approximately twofold higher risk for developing CAD and stroke compared to those with long isoforms[51]. However, although KIV-2 CNV is a determining factor, it explains only a fraction of the plasma variation (between 19% and 77%, depending on the cohort analyzed). Additional genetic factors influence the final expression[52-55], as individuals with the same number of KIV-2 repeats can exhibit Lp(a) concentrations with up to 200-fold disparities between them[55,56].

MOLECULAR DETERMINANTS OF LP(A) ELEVATION: BEYOND LPA GENE SIZE POLYMORPHISM

The genetic architecture of Lp(a) is decisively modulated by SNPs, which act as regulators of circulating levels and associated cardiovascular risk. Among the identified variants, the SNPs rs3798220 and rs10455872 stand out as the most prevalent, collectively explaining up to 38% of Lp(a) plasma variability[7].

The rs3798220 variant is characterized by a non-synonymous (missense) substitution that promotes the exchange of isoleucine for methionine in the molecule’s protease domain. Biochemically, this alteration may increase the affinity of Lp(a) for OxPL or delay fibrinolysis by increasing clot lysis time. In European populations, heterozygous carriers demonstrate a 57% higher risk for developing coronary disease and Lp(a) levels up to eight times higher[57,58]. However, such associations are not consistently observed in non-European groups[59]. Conversely, rs10455872 is an intronic SNP (A>G) located in the KIV-7 domain. With a prevalence of approximately 7% in Europeans[30], this variant increases the risk of CAD by 42%[60]. Liver tissue analyses indicate that carriers have increased messenger RNA (mRNA) levels of the LPA gene, accelerating the molecule’s biosynthesis, although the transcriptional effect may be linked to adjacent mutations in linkage disequilibrium[61].

Despite the relevance of these markers, their predictive utility presents geographic and genotypic limitations. Approximately 47% of Europeans who possess short apo(a) isoforms (high risk) do not carry rs10455872 or rs3798220. Additionally, 11% of carriers of these SNPs paradoxically encode long isoforms associated with lower risk, which may compromise the accuracy of risk stratification based exclusively on these polymorphisms[62]. On the other hand, the AC haplotype (rs10455872/rs3798220 association) correlates with a markedly inflammatory vascular phenotype. Patients carrying this genetic arrangement exhibit elevated concentrations of tumor necrosis factor α, a potent pro-inflammatory mediator, and plasminogen activator inhibitor-1, a protein that impairs thrombus dissolution, thereby exacerbating the cardiovascular burden[33].

Other variants also exert significant biological impacts. The rs186696265 SNP, with an estimated frequency of approximately 1.1% in the European population, this variant exhibits the most potent individual biological effect identified to date on Lp(a) levels. Strategically located near enhancer regions, rs186696265 acts as an influential regulator; the presence of a single copy of this SNP is associated with an increase of 48 mg/dL in Lp(a) concentration in isoform-adjusted models, conferring a significant impact on CAD risk[63]. Similarly, rs140570886 is an intronic variant (T>C) situated in the KIV-6 domain region, identified in about 1.6% of the population of European ancestry. This polymorphism exhibits a strong association with the short isoform phenotype and elevated Lp(a) concentrations, which translates into an increased risk for both CAD and calcific aortic valve stenosis[64,65]. Even after statistical adjustments for adjacent variants, rs140570886 promotes a residual increase of approximately 23 mg/dL in plasma lipoprotein levels[66]. Finally, the rs1800769 variant is characterized by a guanine-to-adenine (G>A) substitution in the 5’ region of the LPA gene. This promoter variant is linked to higher transcriptive activity in vitro and elevated circulating levels of Lp(a) in vivo. Its epidemiological distribution reveals distinct patterns: In African American populations, rs1800769 is predominantly associated with intermediate sizes of KIV-2 CNV, whereas in Euro-Americans, its frequency is higher in long alleles. Independent of ancestry, a consistent increase in Lp(a) levels adjusted for CNV size is observed for the variant allele[67,68].

MECHANISMS OF LP(A) REDUCTION: SPLICING VARIANTS AND ALLELIC INTERACTIONS

Mutations located within the repeat region of the KIV-2 domain are central determinants of the low Lp(a) concentration phenotype. Among them, the 4925G>A variant (present in approximately 13% of the European population) induces a splicing error by promoting the inappropriate retention of 87 intronic nucleotides during transcription. This event results in a premature stop signal (early stop codon), reducing plasma concentrations by approximately 31.3 mg/dL. Its occurrence is predominantly observed in isoforms containing between 19 and 25 KIV-2 repeats, with a higher prevalence in those with 23 and 24 units. Another relevant mutation in this domain is 4733G>A, identified in 22% of European chromosomes. This variant is characterized by a substitution that leads to the loss of a cysteine residue fundamental for the conformational stabilization of the protein, resulting in an average reduction of 13.6 mg/dL in Lp(a) levels[69,70].

The rs41272110 variant (LPA Thr3888Pro) clearly exemplifies how haplotype architecture determines clinical risk through a functional duality. In isolation, this missense mutation acts as a potent biological accelerator, elevating plasma Lp(a) concentrations and the risk of CAD. However, in approximately 85% of cases, it is co-inherited with the 4925G>A splicing variant, which inhibits protein synthesis and drastically reduces Lp(a) levels. This protective effect disappears in the remaining 15% of carriers (approximately 4% of the general population) who harbor the rs41272110 variant in isolation; in these individuals, an increase of up to 29 mg/dL in Lp(a) and a significant elevation in CAD risk are observed[71].

Other polymorphisms also act as markers or direct modulators of Lp(a) reduction. The rs41267809 variant is an A>G missense mutation located in exon 39 of the LPA gene, resulting in the substitution of the amino acid leucine by a proline, with a frequency of approximately 2.1% in populations of European ancestry[30]. Meanwhile, the rs41267807 missense mutation (T>C), present in about 1.5%-1.7% of Europeans, translates into a reduction of approximately 5 mg/dL in total plasma levels[66,72]. Additionally, the rs75692336 and rs6938647 SNPs function as important genetic signals: The former is strongly linked to reduced Lp(a) concentrations due to its high correlation (82%) with the 4925G>A splicing variant, whereas the latter is used clinically as a genetic marker (tag SNP) for the 4733G>A splicing mutation, presenting a 68% correlation between them[63,73]. Finally, the rs1853021 variant involves a thymine-to-cytosine (T>C) substitution in the 5’ region of the LPA gene[74,75]. This alteration introduces an alternative initiation codon that compromises mRNA reading fidelity, disrupting the cellular machinery and reducing translation efficiency by 60% in laboratory assays[72]. The clinical benefit of this mutation is highly visible in populations of African descent, resulting in Lp(a) levels about 50%-60% lower than expected (a drop of approximately 10 mg/dL). Conversely, in populations of European origin, this reducing effect is almost completely masked, as the mutation is tightly linked (in linkage disequilibrium) to moderately long isoforms[76].

IMPACT OF LPA-INDEPENDENT GENETIC LOCI ON LP(A) LEVELS

Although the LPA gene is the primary determinant of Lp(a) concentrations, mutations in genes involved in systemic lipid metabolism exert a significant modulating influence.

Influence of the LDL receptor and ApoB-100

FH, characterized mainly by mutations that compromise the functionality of the LDL-C receptors gene, results in a reduction in plasma cholesterol clearance. Patients with FH exhibit Lp(a) levels two to three times higher when compared to normolipemic individuals with the same apo(a) isoform[77,78]. A similar phenomenon is observed in Familial Defective ApoB-100, where specific mutations (such as the R3500Q substitution) impair the affinity of apoB for the LDL receptor. Studies with siblings sharing identical isoforms have demonstrated that the co-inheritance of the Familial Defective ApoB-100 mutation consistently elevates circulating Lp(a) concentrations[79].

Metabolic defects and reduction of Lp(a) levels

Certain genetic conditions promote a severe reduction in Lp(a). Familial lipoprotein lipase deficiency, or type I hyperlipoproteinemia, compromises the catabolism of triglyceride-rich lipoproteins and is associated with drastically low plasma levels of Lp(a). In these individuals, an overrepresentation of the “null” phenotype is observed, suggesting that lipoprotein lipase dysfunction interferes with the particle’s accumulation pathways[80]. Even more markedly, abetalipoproteinemia, a severe recessive pathology that prevents the assembly of apoB-containing lipoproteins, results in an up to fivefold reduction in plasma apo(a) concentration. Although total secretion is negligible, patients with abetalipoproteinemia produce anomalous, hypolipidic complexes between apo(a) and residual traces of apoB-100, highlighting that the integrity of hepatic assembly mediated by accessory proteins is essential for the final stability of Lp(a)[81].

Polymorphisms of other modulating genes

In addition to the direct impact of lipid metabolism pathologies, variability in Lp(a) levels is refined by polymorphisms in independent loci involved in lipoprotein regulation and the inflammatory response. One of the best-documented modulators is the APOE gene, specifically the E2 allele (marked by SNPs rs7412 and rs1065853), which exhibits a strong association with reduced Lp(a) concentrations. It is estimated that each copy of this allele promotes a reduction of approximately 3.34 mg/dL in circulating Lp(a). The proposed mechanism suggests that, due to the lower affinity of the apoE2 protein for hepatic receptors, there is less competition for these binding sites, leaving more receptors available for the efficient clearance of Lp(a) from the circulation[82,83]. Other genetic variants also exert significant, albeit more modest, influences. Polymorphisms located upstream of the cholesteryl ester transfer protein gene, such as rs247617, have been consistently associated with decreasing levels of Lp(a). Additionally, the APOH locus, responsible for encoding beta-2-glycoprotein I – a protein that binds to Lp(a) through OxPL – plays a role in particle stability. The rs8178824 variant in this gene is linked to discrete increments in plasma concentrations, highlighting that the genetic architecture of Lp(a) is a complex polygenic trait, where multiple signals contribute to the final phenotype observed in the patient[82].

INTERETHNIC VARIABILITY AND GENETIC DETERMINANTS OF LP(A)

Human plasma concentrations of Lp(a) exhibit an extraordinary range, with values varying from levels below 0.1 mg/dL to levels exceeding 200 mg/dL. This vast distribution is strongly influenced by ethnic factors, which shape the architecture of the alleles at the LPA locus. It is observed that the allele size configuration differs markedly between groups: While Asian populations demonstrate a predominant tendency toward carrying longer alleles, characterized by a greater number of KIV-2 domain repeats, African and European populations exhibit more similar distribution profiles, with comparatively shorter alleles[72].

Although the inverse correlation between the number of KIV-2 copies and Lp(a) levels is a well-established biological phenomenon, the strength of this association is non-linear and fluctuates significantly according to ancestry. In individuals of European descent, CNV can explain between 61% and 69% of the plasma variance; however, this predictive capacity drops drastically in African populations, accounting for only 19%-44% of the observed variability. This discrepancy suggests that other regulatory factors may play a more prominent role in certain ethnic groups[10,53,84-86]. In the context of clinical implications, the association between the presence of short isoforms, elevated Lp(a) concentrations, and CAD risk is considered robust in Europeans and white North Americans, reaching even higher correlation levels in East Asians, such as Chinese and Japanese[51]. In contrast, this relationship is significantly weaker among Asian Indians[54]. The analysis in African Americans is particularly complex due to the high degree of genetic admixture and the influence of European and Asian gene pools[87]. While some evidence points to a link between short isoforms and Lp(a) elevation restricted to the male sex[77], other studies failed to establish a clear association with CAD incidence in this group[78]. Studies in African populations in Africa regarding the role of LPA in CAD are still scarce.

HERITABILITY OF LP(A) LEVELS

The determination of plasma Lp(a) levels is characterized by exceptional genetic control, presenting a codominant expression pattern for the LPA gene alleles[79]. Unlike other lipoproteins, whose variability depends on the complex interaction of hundreds of genetic loci[88,89], the heritability of Lp(a) is extraordinarily high, exceeding 90% in populations of European and African ancestry[90,91]. It is estimated that between 40% and 70% of this variance is directly attributed to the size polymorphism of apo(a) isoforms[48,92], while SNPs and other functional variants shape the remaining percentage[73].

The sovereignty of the genetic determinant over environmental factors is evidenced by comparative studies in twins, which reveal a 94% correlation in Lp(a) levels between monozygotic twins, in contrast to only 32% in dizygotic twins[93]. This genetic stability is also observed in family lineage analyses: Siblings who share the same LPA gene alleles present almost identical plasma concentrations (r = 0.91-0.95), whereas siblings with no shared alleles exhibit completely distinct levels[9]. Even in geographically isolated populations with low admixture, such as rural communities in Gabon known for high Lp(a) medians, the heritability of the trait remains in the range of 76%-80%. Such data ratify that the LPA gene exerts a predominant and sovereign influence, independent of geographical, cultural, or environmental contexts[10]. Furthermore, individual Lp(a) concentrations tend to remain relatively constant throughout life, although recent investigations suggest a temporal variability that may have been historically underestimated by classical literature[94].

LP(A) SCREENING

While traditional cardiovascular risk scores evaluate standard metabolic and lifestyle factors to estimate event probabilities[1-3], the integration of Lp(a) screening into clinical practice refines risk stratification, particularly for individuals with unexplained premature CAD or a strong family history of cardiovascular events not accounted for by traditional models[4-6].

Since plasma concentrations are predominantly genetically determined, remaining stable throughout life and being minimally influenced by lifestyle factors, the European Society of Cardiology and European Atherosclerosis Society guidelines currently recommend measuring Lp(a) at least once during adulthood, especially in individuals with a family history of premature cardiovascular disease, FH, intermediate cardiovascular risk, or recurrent atherosclerotic events[6-8,95].

The most recent guidelines recommend that Lp(a) levels be analyzed through plasma measurements, expressed in mg/dL or nmol/L. However, due to the structural heterogeneity of apo(a), which is related to variations in the number of KIV-2 repeats, challenges persist in laboratory standardization and conversion between different measurement units[4-6].

The inclusion of Lp(a) in cardiovascular screening strategies has significantly altered the clinical management of patients previously classified as low or intermediate risk by traditional models. The identification of elevated Lp(a) levels now warrants increased cardiovascular surveillance, intensified lipid control, and earlier initiation of aggressive lipid-lowering therapies, especially in individuals with a family history suggestive of a genetic predisposition to atherosclerosis[5]. Therefore, Lp(a) is likely to become even more important in precision cardiovascular medicine, particularly given the development of specific therapies based on gene silencing, such as small interfering RNAs (siRNAs) and ASOs.

According to the American College of Cardiology and American Heart Association Clinical Practice Guidelines for cholesterol management, within the clinical stratification framework, individuals are categorized into three main risk tiers based on their [Lp(a)] concentration levels: (1) The low-risk group, defined by values < 30 mg/dL (< 75 nmol/L); (2) The intermediate-risk group, which comprises the 30-50 mg/dL (75-125 nmol/L) range; and (3) The high-risk group, characterized by levels ≥ 50 mg/dL (≥ 125 nmol/L) (Table 1)[21].

The intermediate Lp(a) range functions as a contextual re-evaluation zone in which Lp(a) serves as a risk modifier, requiring a joint interpretation alongside the patient’s global cardiovascular risk. In these cases, it is recommended to analyze individual patient characteristics (age, sex, lipid profile, and blood pressure) in addition to Lp(a) to predict the absolute benefit derived from controlling other risk factors[5].

Elevated Lp(a) serves as an important cardiovascular risk modifier that directly impacts clinical decision-making. In primary prevention, Lp(a) levels above 50 mg/dL (or 125 nmol/L) lower the threshold for initiating statin therapy, and its measurement is recommended to support therapeutic management in patients with borderline or intermediate 10-year cardiovascular risk. Given the current absence of approved therapies specifically targeted at lowering this marker, guidelines emphasize that the management of patients with elevated Lp(a) should focus on rigorous and comprehensive control of all other modifiable risk factors. This includes strict adherence to therapeutic targets for blood pressure and blood glucose, along with intensive lifestyle interventions, which constitute the cornerstone of cardiovascular prevention[96].

Regarding lipids, although the presence of elevated Lp(a) warrants aggressive LDL-C control, routine adjustment of LDL-C for the cholesterol content within Lp(a) is not recommended when establishing treatment goals. Because the proportion of cholesterol within Lp(a) particles varies widely from 6% to 60%, such correction should be reserved for specific clinical scenarios, such as suspected FH (to avoid unnecessary genetic testing) or when evaluating patients with suspected low responsiveness to statins[97].

Finally, PCSK9 inhibitors reduce Lp(a) concentrations by approximately 15% to 36%, with patients exhibiting elevated Lp(a) deriving the greatest absolute clinical benefit from this therapy. Although these medications are not recommended for the sole purpose of lowering Lp(a), measuring this biomarker is considered a reasonable strategy to inform decisions regarding the initiation of PCSK9 inhibitors in high-risk patients[98].

LP(A)-TARGETED GENE THERAPIES

The siRNA, consists of short double-stranded RNA molecules, generally comprising between 20 nucleotides and 30 nucleotides, designed to act through the silencing of specific genes[99,100]. These molecules recognize mRNA and promote its degradation, thereby preventing the synthesis of specific proteins[101,102].

One of the major advantages of siRNA therapy is its high molecular specificity, allowing the inhibition of proteins previously considered “undruggable” by conventional therapeutic approaches[103,104]. Furthermore, its pharmacological effect is notably prolonged, making it relatively simple to maintain therapeutic activity even with widely spaced dosing intervals[105].

In recent years, siRNA-based therapies have transitioned from experimental strategies into clinical practice. Medications such as Inclisiran, Patisiran, and Givosiran have already received Food and Drug Administration (FDA) approval, demonstrating the therapeutic potential of this technology across multiple metabolic and genetic diseases[106,107].

Inclisiran

Inclisiran is the first siRNA approved by the FDA for the treatment of dyslipidemia, due to its high efficacy in reducing LDL-C by inhibiting the translation of the PCSK9 gene. As a result, there is a decrease in PCSK9 expression in hepatocytes, thereby increasing the availability of receptors for circulating LDL-C[108,109]. Despite its strong association with reductions in LDL-C levels, some studies in this trial series, such as ORION-1[110] and ORION-9[111-113], report apparent modest reductions in Lp(a), but it remains uncertain whether this reduction is significant or not. Therefore, future clinical trials with a greater focus on evaluating this association between inclisiran and Lp(a) and the reduction in cardiovascular risk may be more conclusive[109].

Regarding its mechanism of action. Inclisiran is an siRNA conjugated to triantennary N-acetyl-galactosamine (GalNAc) that binds to the asialoglycoprotein receptor on the hepatocyte membrane. Upon clathrin-mediated endocytosis, it interferes with PCSK9 expression by incorporating into the RISC complex and binding to the mRNA encoding the PCSK9 protein, thereby disrupting this gene expression process[114,115]. This protein reduces the expression of LDL-C receptors on the surface of hepatocytes; therefore, inclisiran blocks this regulation and indirectly reduces LDL-C levels by increasing the uptake of this molecule by the liver[114,116]. The result is a marked decrease in LDL-C levels, with these effects persisting over an extended period.

The siRNAs, such as inclisiran, are administered intravenously or subcutaneously[113], and their oral use is not feasible, since the harsh environment of the gastrointestinal tract and the negative charge of siRNAs lead to rapid degradation and low absorption[117]. The siRNAs enter the circulation rapidly[118], and upon reaching the liver, access to this organ is facilitated by fenestrated capillaries, ensuring a satisfactory concentration[119]. Because of this phenomenon, the liver is likely one of the target organs for successful siRNA therapies. There are several chemical and molecular techniques designed to prevent siRNAs from being rapidly cleared from the blood and excreted by the kidneys[120,121]. Inclisiran features a set of chemical and structural modifications associated with a GalNAc targeting system, since unmodified or uncoated siRNAs have a half-life of only 5-10 minutes[122], due to factors such as low molecular weight and small size that facilitate filtration[123], rapid degradation by exonucleases and endonucleases[124] and degradation by macrophages[125].

Regarding Lp(a), the phase 2 ORION-1 trial included 501 participants with baseline Lp(a) levels ranging from 25.3 nmol/L to 47 nmol/L, of whom 79% had atherosclerotic disease and 73% were already taking statins. The median reduction observed at 150 days was -15% to -25% depending on the dose, and at 180 days, -14% to -26%[126]. However, the reductions were not statistically significant due to high individual variability. The open-label extension of ORION-1, called ORION-3, documented a 6.3% reduction in the monotherapy arm with inclisiran and a 14.3% reduction in the crossover arm at day 1440[127].

In the ORION-9 study, which included 482 patients with heterozygous FH on statin therapy with baseline Lp(a) in the interquartile range of 57 (22-180) nmol/L in the inclisiran group and 54 (20-185) nmol/L in the placebo group, a reduction of -13.5% was observed in the inclisiran group and an increase of 3.7% in the placebo group on day 540[113].

In the ORION-10 study, involving 1561 participants with atherosclerotic cardiovascular disease, baseline Lp(a) in the interquartile range was 57 (18-181) nmol/L in the inclisiran group and 56 (20-189) nmol/L in the placebo group. Analysis repeated on day 540 identified a 21.9% reduction in the inclisiran group, while the placebo group increased by 3.7%[111,113].

ORION-11, which included 1,617 patients with atherosclerotic cardiovascular disease or equivalent, had a baseline interquartile range of Lp(a) of 42 (18-178) and 35 (18-181) in the placebo group, a 18.6% decrease was observed in the inclisiran group at day 540, while values in the placebo group remained unchanged[111]. Meanwhile, in a prespecified analysis of the ORION-11 study, which included 203 individuals at risk of cardiovascular events and with high LDL-C levels even while taking the maximum dose of a statin, a time-adjusted absolute change (mean, 95%CI) of -12.5 (-17.1 to -8.0) nmol/L for the inclisiran group and +5.5 (1.2, 9.9) nmol/L for the placebo group, whose baseline median and interquartile range were 40 (17, 148) and 27 (14, 138) nmol/L for the inclisiran group (n = 98) and the placebo group (n = 105), respectively[128].

Due to high variability and statistical limitations, many of these results did not reach significance (P not reported) except in this prespecified subgroup analysis of ORION-11, with a placebo-adjusted reduction of 28.5% (P < 0.0001), driven by the elevation of Lp(a) in the placebo group[128]. Therefore, despite the trend toward modest but consistent reductions in Lp(a) levels demonstrated by these studies, larger clinical trials are needed to conclusively define the reduction associated with inclisiran use, as well as its clinical impact.

Regarding adverse effects, inclisiran has been shown to be a safe and well-tolerated drug in diverse populations, including when used concomitantly with statins[129]. In a safety and tolerability study, no association was reported between inclisiran use and increased statin levels, increased insulin resistance, significant drug interactions, the need for dose adjustment in patients with renal impairment, liver injury, or the need for dose adjustment in the elderly[129]. Regarding pregnant women, there are not yet sufficient studies to guarantee the safety of inclisiran in this population. The most relevant adverse effects are local reactions at the injection site, such as pruritus, erythema, pain, edema, and local induration[111,113,127] but these effects were mild and transient, which did not interfere with continued treatment[130].

Olpasiran

Olpasiran acts through an siRNA mechanism; when it binds to Lp(a) mRNA, it recruits the RNA-induced silencing complex, which degrades the mRNA before its translation, specifically blocking the hepatic production of apo(a), the unique structural component of Lp(a)[131,132].

This benefit is observed even in patients with very high Lp(a) levels. In the phase 2 OCEAN(a)-DOSE multicenter, randomized, placebo-controlled trial, which included 281 patients with Lp(a) levels greater than 150 nmol/L, olpasiran was shown to reduce Lp(a) levels by more than 95%, a substantially greater reduction compared to other available therapeutic alternatives[133,134]. In addition to the marked reduction in serum Lp(a) levels, olpasiran may also indirectly interfere with inflammatory mechanisms involved in atherogenesis. Lp(a) acts as the main plasma carrier of OxPL, molecules with significant pro-inflammatory and pro-atherogenic activity[135,136].

These OxPL are primarily carried by apo(a) and participate in the activation of endothelial cells, macrophages, and vascular smooth muscle cells, promoting vascular inflammation, progression of atherosclerotic plaques, and aortic valve calcification[135,137]. Therefore, by reducing hepatic production of Lp(a) by more than 95%, olpasiran may also decrease the circulating burden of Lp(a)-associated OxPL, acting not only on a laboratory biomarker but also on mechanisms directly involved in the pathophysiology of atherosclerotic cardiovascular disease[105,138].

Regarding safety, clinical studies have demonstrated that olpasiran has a favorable tolerability profile. The main adverse effects observed were mild injection-site reactions following subcutaneous administration, as well as transient flu-like symptoms. In both phase 1 and phase 2 trials, no serious adverse events directly related to the drug were identified[139,140].

Although these findings represent a profound biochemical success, it is critical to note that definitive clinical proof regarding the reduction of major adverse cardiovascular events (MACEs) is still pending. Currently, it has not yet been established whether this robust molecular response translates into real clinical protection. Consequently, the large-scale cardiovascular outcome trial OCEAN(a)-outcomes is currently underway to validate the clinical efficacy and long-term benefit of olpasiran in preventing cardiovascular events[133,141].

Zerlasiran

Zerlasiran is a siRNA molecule designed to promote post-transcriptional silencing of the LPA gene in the liver. Its mechanism of action is based on binding to the mRNA responsible for the synthesis of apo(a), thereby inducing intracellular degradation and consequently reducing hepatic production of Lp(a)[142,143]. The substance is based on conjugation with N-acetylgalactosamine (GalNAc), which allows it to bind to asialoglycoprotein receptor (ASGPR) receptors, which are expressed almost exclusively in hepatocytes. This strategy promotes high hepatic selectivity, greater pharmacological potency, and lower systemic exposure[144].

The key initial clinical data come from the APOLLO study, a phase 1 clinical trial that included 32 participants with elevated Lp(a) levels (≥ 150 nmol/L) and no clinically manifest cardiovascular disease. Participants received either placebo or a single subcutaneous dose of SLN360 at different concentrations (30 mg, 100 mg, 300 mg, and 600 mg). The results showed a significant, dose-dependent reduction in plasma Lp(a) levels[142]. In this regard, the results showed a significant reduction in plasma Lp(a) levels, particularly with the higher doses tested – 300 mg and 600 mg – which produced median maximum reductions of approximately 96% and 98%, respectively, persisting for at least 150 days after a single administration[142].

Another important finding of the study was the initial safety and tolerability profile. Only one participant experienced serious adverse events, which the investigators deemed unrelated to the medication. The most common adverse events were mild, primarily transient local reactions at the injection site. The evaluation of SLN360 in initial clinical trials highlighted the safety and profound capacity of GalNAc-conjugated siRNA technologies to disrupt hepatic LPA mRNA translation, achieving extensive clearance of circulating risk factors. However, as observed with competing RNA-targeted strategies, these data do not yet support an absolute claim of clinical benefit. LOWERING Lp(a) is a highly persuasive biochemical endpoint, but major clinical data regarding cardiovascular outcomes are still pending. Definitively proving a therapeutic reduction in MACEs depends entirely on late-stage phase 3 outcome trials that are currently ongoing or in development, which will ultimately decide the clinical future of this asset in managing cardiovascular risk[142].

Lepodisiran

Lepodisiran, formerly known as LY3819469, is a non-canonical, tetraloop siRNA molecule, a Dicer substrate (i.e., a sequence of base pairs processed by the Dicer enzyme into a shorter functional siRNA), whose purpose is to reduce hepatic synthesis of apo(a) through post-transcriptional silencing of the LPA gene. It promotes the degradation of the mRNA responsible for apo(a) synthesis in hepatocytes, which enables a considerable reduction in plasma Lp(a) formation[145,146]. Like other recent therapies based on RNA interference, lepodisiran also acts in conjunction with GalNAc, which allows for selective targeting of hepatocytes through binding to the ASGPR. This mechanism implies improved pharmacological specificity. Reduced systemic exposure promotes a safer therapeutic profile and allows for subcutaneous administration at longer intervals[5,145,146].

Early phase 1 clinical trials involving lepodisiran, such as those by Nissen et al[145] and Nissen et al[146], demonstrated significant reductions in Lp(a), typically exceeding 90% after a single subcutaneous administration, depending on the dosage. In addition, one of the most notable findings is the prolonged duration of the drug’s effect, with satisfactory suppression of Lp(a) for several months. Some participants maintained detectable reduced levels for periods of nearly a year, suggesting potential for therapeutic regimens with low administration frequency[145].

Furthermore, the adverse events described in early-phase studies were predominantly mild, including primarily local application reactions and transient nonspecific symptoms. However, given that lepodisiran is still in clinical development, further evaluations are needed regarding long-term safety, immunogenicity, and impact on major cardiovascular outcomes[146].

However, despite promising laboratory results, it remains to be demonstrated whether the marked and sustained reduction in Lp(a) induced by lepodisiran actually translates into a reduction in major cardiovascular risks. Therefore, advanced-phase clinical trials will be essential to determine the actual impact of this therapy on cardiovascular morbidity and mortality.

ASOs

ASOs are short, synthetic, single-stranded molecules, typically spanning 16 to 20 nucleotides, designed to induce targeted gene silencing[147]. These molecules recognize the target mRNA and promote its degradation, which is frequently mediated by the activation of the ribonuclease H1 enzyme, thereby preventing the synthesis of specific proteins. A major advantage of ASO-based therapy is its high molecular specificity guided by Watson-Crick base pairing, enabling the inhibition of genetic targets often deemed undruggable by conventional therapeutic approaches[148]. Furthermore, owing to modern chemical modifications and conjugation strategies, their pharmacological effect is remarkably prolonged, rendering the maintenance of therapeutic activity relatively straightforward even with widely spaced dosing intervals[149].

In recent years, ASO-based therapies have transitioned from experimental strategies to clinical practice. Drugs such as olezarsen and mipomersen have already granted regulatory approval from agencies such as the FDA, demonstrating the therapeutic potential of this technology across multiple metabolic, neurological, and genetic disorders[150,151]. For the reduction of Lp(a), pelacarsen stands as the representative agent of this class.

Pelacarsen

Pelacarsen [formerly designated as TQJ230, IONIS-Apo(a)-LRx, and AKCEA-APO(a)-LRx] is an innovative and structurally optimized ASO synthesized to targetedly disrupt Lp(a) biosynthesis at the transcriptional level within hepatocytes[152,153].

The structure of pelacarsen is conjugated to a triantennary GalNAc molecule, which acts as a high-affinity ligand for ASGPR expressed almost exclusively on the hepatocyte membrane. This modification promotes rapid and selective endocytosis of the drug by the liver, enhancing its clinical potency by 15-fold to 30-fold compared with unconjugated ASOs[152,154-156].

In the hepatocyte nucleus, pelacarsen binds complementary and specifically to the mRNA sequence encoding apo(a). The formation of this DNA/RNA heteroduplex activates the endogenous endonuclease ribonuclease H1, which irreversibly cleaves and degrades the target mRNA. Without this mature template, ribosomal translation of apo(a) is disrupted, preventing its linkage with ApoB-100 and ceasing the assembly and secretion of pathogenic Lp(a) particles[153,154].

The clinical impact of this molecule is currently being evaluated in the Lp(a) HORIZON trial, a global, multicenter, double-blind, placebo-controlled phase 3 trial that enrolled 8323 patients with established cardiovascular disease, baseline Lp(a) ≥ 70 mg/dL, and optimized standard lipid-lowering therapy (statins, ezetimibe, and/or PCSK9 inhibitors). These patients were enrolled by July 2022 across 42 countries. The study evaluates the monthly subcutaneous administration of 80 mg of pelacarsen – a dose projected to achieve an 80% reduction in Lp(a) – and analyzes a very high-risk subpopulation with levels ≥ 90 mg/dL, based on Mendelian randomization data indicating that robust absolute reductions are required for a visible clinical benefit. The primary endpoint measures the time to the first occurrence of a 4-point MACE, which comprises cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or urgent revascularization. The investigators will compare the time to the first occurrence of any of these four events between the treatment group and the placebo group. As an event-driven study, the trial will conclude after the confirmation of 993 cumulative events, with termination anticipated by the end of 2026. No clinically relevant side effects were reported[157]. If the results are positive, pelacarsen will become the first drug in history approved specifically to lower Lp(a) and prevent cardiovascular events[147].

Furthermore, this molecule was evaluated in the phase 3 Lp(a) FRONTIERS APHERESIS clinical trial, a multicenter, double-blind, placebo-controlled study conducted in Germany that enrolled 51 adults at extreme cardiovascular risk (presenting with atherosclerotic disease, baseline Lp(a) ≥ 60 mg/dL, and requiring chronic therapeutic apheresis). The protocol tested the subcutaneous administration of 80 mg of pelacarsen or placebo every 4 weeks for 52 weeks, conditioning the apheresis sessions on the persistence of Lp(a) levels above 60 mg/dL. Efficacy outcomes demonstrated that pelacarsen reduced the likelihood of requiring apheresis by 99.4% compared with the placebo group. In the intervention arm, 73.1% of patients remained free from the procedure for at least 24 consecutive weeks, and 69.2% completely discontinued apheresis sessions between weeks 12 and 52. Laboratory assessments revealed that the treatment achieved a placebo-adjusted mean reduction in Lp(a) of up to -77% (in nmol/L) at week 52. The safety profile was favorable, with no drug-related discontinuations or serious adverse events. Direct adverse effects occurred in 69.2% of patients (vs 12% in the placebo group) and were limited to mild or moderate local injection-site reactions, such as erythema (38.5%), pruritus (15.4%), and bruising (11.5%). Despite the profound molecular efficacy of pelacarsen in achieving robust, dose-dependent reductions in circulating Lp(a) concentrations, it is essential to emphasize that its clinical utility in mitigating cardiovascular events remains to be definitively proven. Lowering plasma Lp(a) levels serves currently as a surrogate biochemical success. To validate the clinical translation of this molecular response, the definitive Phase 3 cardiovascular outcome trial, Lp(a) HORIZON, is currently underway. This trial, evaluating more than 7600 patients with established cardiovascular disease, will establish whether the targeted therapeutic silencing of apo(a) translates into a significant reduction in MACE (Table 2 and Figure 3)[110,111,113,126,130-134,137,141-147,152-159].

Figure 3 Schematic representation of the mechanisms of action of GalNAc-conjugated therapies targeting lipoprotein(a) gene expression, reducing apolipoprotein(a) synthesis and circulating lipoprotein(a) levels through messenger RNA degradation. A: N-acetylgalactosamine-asialoglycoprotein receptor-mediated hepatocyte uptake; B: RNase H-mediated apolipoprotein(a) [apo(a)] mRNA degradation by pelacarsen; C: RNA-induced silencing complex-mediated apo(a) mRNA degradation by siRNAs; D: Translation of apo(a) mRNA into apo(a) protein. GalNAc: N-acetylgalactosamine; ASGPR: Asialoglycoprotein receptor; RISC: RNA-induced silencing complex; RNase H: Ribonuclease H; apo(a): Apolipoprotein(a).

Table 2 Estimated lipoprotein(a) reduction, development stage, and safety of small interfering RNA and antisense oligonucleotide therapies.

Therapy	Estimated Lp(a) reduction	Development stage	Safety	Ref.
Inclisiran (siRNA)	-13.5% to -26% (modest and variable reduction)	Approved for LDL-C; Lp(a) effect evaluated in ORION studies	Well tolerated; main adverse events: Mild injection-site reactions	Ray et al[110], Ray et al[111], Raal et al[113], Ray et al[126], Wright et al[130]
Olpasiran (siRNA)	> 95%	Phase 3 ongoing	Favorable profile; mild local reactions and transient flu-like symptoms	Rosenson et al[131], Nurmohamed et al[132], O'Donoghue et al[133], Tweneboah et al[134], Lampsas et al[137], Fazoli et al[141]
Zerlasiran/SLN360 (siRNA)	96%-98%	Phase 1	Good initial tolerability; mild injection-site reactions	Nissen et al[142], Rider et al[143], Nair et al[144]
Lepodisiran (siRNA)	> 90% (prolonged effect, up to 1 year)	Phase 1/2	Predominantly mild and transient adverse events	Nissen et al[145], Nissen et al[146], Tsimikas[159]
Pelacarsen (ASO)	-77% to -80%	Phase 3 ongoing	Favorable profile; mainly mild/moderate injection-site reactions	Bhatia et al[147], Hardy et al[152], Tsimikas et al[153], Yu et al[154], Viney et al[155], Susan-Resiga et al[156], Cho et al[157], Parhofer et al[158]

Lp(a): Lipoprotein(a); siRNA: Small interfering RNA; ASO: Antisense oligonucleotide; LDL-C: Low-density lipoprotein cholesterol.

Considerations on translating Lp(a) lowering into clinical outcome reductions

Several biological and methodological factors may explain why a substantial pharmacological reduction in circulating Lp(a) levels might not translate proportionally into a reduction in MACE. First, Mendelian randomization analyses indicate that, although causal, the relationship between Lp(a) concentration and CAD risk is relatively weak on a per-unit basis: It is estimated that an absolute reduction of approximately 65-100 mg/dL (130-200 nmol/L) is required to achieve a clinical benefit comparable to that produced by a 38.67 mg/dL (1 mmol/L) reduction in LDL-C[160,161].

Therapeutics that lower Lp(a) by only 20%-30%, such as inclisiran, are unlikely to reach this high absolute threshold in the majority of patients, providing a plausible explanation for the absence of a distinct cardiovascular outcome signal in previous analyses. Even potent agents capable of reducing Lp(a) by 80%-98% may fail to surpass this required absolute threshold in individuals with only moderately elevated baseline levels. This critical limitation underscores why outcome trials such as Lp(a) HORIZON and OCEAN(a)-outcomes intentionally enriched their study cohorts with patients presenting with extremely high baseline Lp(a) concentrations.

Furthermore, a significant portion of the atherogenic and proinflammatory burden of Lp(a) is mediated by OxPL incorporated into atherosclerotic plaques and valvular tissue. While lowering circulating Lp(a) successfully clears circulating OxPL and dampens active inflammatory signaling, whether it can truly regress established calcifications and structural scarring within the cardiovascular system remains the crucial answer that medicine eagerly expects to uncover in the near future.

CONCLUSION

In conclusion, the clinical and molecular understanding of Lp(a) has reached a transformative turning point. Decades of research have confirmed that Lp(a) is an independent, genetically determined causal risk factor for atherosclerotic cardiovascular disease, remaining completely resistant to conventional lipid lowering strategies. By shifting the focus toward the underlying genetic architecture of the LPA locus, the scientific community has unlocked a new era in preventive cardiology. Emerging gene silencing technologies, specifically ASOs and siRNAs, have demonstrated an outstanding capacity in laboratory trials to downregulate hepatic apo(a) production, clearing circulating risk factors by up to 95%. While these findings are currently bound to surrogate laboratory metrics, this targeted molecular approach holds an enormous potential to drastically mitigate the global burden of cardiovascular mortality. However, a definitive paradigm shift in secondary prevention relies completely on translating these laboratory achievements into tangible clinical data. The medical community eagerly awaits the results of ongoing late stage phase 3 trials, such as Lp(a) HORIZON and OCEAN(a) Outcomes studies, which are mandatory to prove a real world reduction in MACE. Ultimately, validating these gene silencing platforms could redefine the international guidelines and successfully transition therapeutic silencing from a successful biochemical intervention into a cornerstone strategy to reduce cardiovascular deaths worldwide.