A Position Paper on Lipoprotein(a) From the Lipoprotein(a) Task Force of the Korean Society of Lipid and Atherosclerosis: Current Evidence, Clinical Applications, and Future Directions

Abstract

Lipoprotein(a) [Lp(a)] is a genetically determined risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS), with plasma levels largely unaffected by lifestyle modification or conventional lipid-lowering therapy. Although international guidelines increasingly recognize Lp(a) as a risk-enhancing factor, in many Asian populations thresholds for high Lp(a) and treatment strategies remain undefined. This Korean position paper, developed by the Lp(a) Task Force of the Korean Society of Lipid and Atherosclerosis, presents an evidence-based summary of the pathophysiology, clinical relevance, and therapeutic landscape surrounding Lp(a), with a focus on Korean-specific data. It reviews the genetic architecture of Lp(a), ethnic variability in concentrations, and its mechanistic roles in inflammation, thrombosis, and calcification. Based on large Korean cohorts, a 3-tiered classification is proposed of normal (<30 mg/dL), borderline high (30–49 mg/dL), and high (≥50 mg/dL), harmonizing global thresholds with local data. The document also highlights the limitations of current Lp(a) assays in Korea, and calls for standardized, isoform-insensitive testing. Novel therapeutics, including antisense oligonucleotides, small interfering RNAs, and small molecular inhibitors, have shown promising Lp(a)-lowering effects, with multiple phase 3 trials currently ongoing, or in planning. Given the unmet clinical need, the paper recommends incorporating Lp(a) into cardiovascular risk assessment, and calls for Korean-specific longitudinal studies, national screening strategies, and participation in clinical trials. These efforts will help clarify Lp(a)-associated risk in Korean patients and guide the adoption of future targeted therapies.

INTRODUCTION

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality worldwide, and in Korea.¹,² Despite substantial advances in the identification of CVD risk factors and the widespread use of pharmacological therapies, considerable residual CVD risk persists, even among well-treated individuals. Among the various contributors to this residual risk, lipoprotein(a) [Lp(a)] has been firmly established as a causal factor for atherosclerotic cardiovascular diseases (ASCVDs).³

In 1963, Berg⁴ first identified Lp(a), demonstrating its heritable nature through studies that involved 34 families. In 1974, he further reported that individuals with familial hypercholesterolemia and coronary heart disease were more likely to have elevated Lp(a) levels.⁵ In 1977, a method to quantify plasma Lp(a) concentrations was developed.⁶ By 1981, elevated Lp(a) levels (≥30 mg/dL) were linked to the risk of first myocardial infarction (MI).⁷ In the late 1980s, cloning of the apolipoprotein(a) [apo(a)] gene revealed that the LPA gene, the gene that encodes apo(a), originated from a duplication of the plasminogen gene, providing important insights into the pathophysiology of Lp(a).⁸ Subsequent large-scale epidemiologic and Mendelian randomization (MR) studies have confirmed Lp(a) as a causal factor in MI, ischemic stroke, heart failure (HF), and calcific aortic valve stenosis (CAVS).⁹,¹⁰,¹¹,¹²

Given the established causal role of Lp(a) in CVD, recent guidelines increasingly recommend its measurement as part of individual CVD risk assessment. Additionally, the role of Lp(a) as a risk-enhancing factor has been increasingly emphasized across recent international guidelines.³,¹³,¹⁴,¹⁵ However, despite this growing international consensus, there is currently no clearly defined high Lp(a) threshold or treatment recommendation tailored to the Korean population. Other key challenges also remain; these include assay standardization, the development of generalized guidelines, and the establishment of therapeutic targets. This position paper provides a comprehensive overview of the biology, pathophysiology, clinical evidence, and therapeutic landscape of Lp(a), with particular focus on Korean data. It also outlines current knowledge gaps, and proposes future directions to address Lp(a)-associated ASCVD risk in Korea.

BASIC CONCEPT OF LP(a)

1. Structure of Lp(a)

Lp(a) consists of a low-density lipoprotein (LDL)-like particle that contains apolipoprotein B (ApoB)-100 with a similar lipid composition to LDL.¹⁶ The key distinguishing feature of Lp(a) is the presence of Apo(a), a unique glycoprotein that is covalently linked to ApoB-100 of the LDL-like particle via a disulfide bond between cysteine residues (Fig. 1).¹⁷

Fig. 1. Structural comparison between Lp(a) and LDL. Schematic illustration showing the major structural components of Lp(a) (A) and LDL (B). Lp(a) consists of an LDL-like particle containing ApoB-100 covalently linked via a disulfide bond to Apo(a), which contains multiple KIV repeats, a single KV domain, and an inactive protease domain. OxPL are carried primarily on Apo(a). The LDL particle lacks Apo(a) and OxPL, highlighting the structural and functional distinction between the 2 lipoproteins.

Apo(a), apolipoprotein(a); ApoB, apolipoprotein B; KIV, kringle IV; KV, kringle V; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); OxPL, oxidized phospholipid.

Apo(a) is a large glycoprotein characterized by substantial size heterogeneity across individuals. It is encoded by the LPA gene, which is located on chromosome 6 at 6q26-27, adjacent to the human plasminogen gene.¹⁸ The LPA gene shares high sequence homology with the plasminogen gene, having arisen through gene duplication during primate evolution.⁸ As a result, Apo(a) shares significant sequence homology with plasminogen, which contains 5 domains, named kringles I to V (KI to KV), and a C-terminal serine protease domain. In contrast, Apo(a) contains 2 different types of kringle domains, multiple kringle IV (KIV) repeats and a single kringle V (KV), as well as one inactive protease domain. The KIV domain is subdivided into 10 types (KIV-1 to KIV-10), among which KIV-1 and KIV-3 through KIV-10 are present in a single copy, while KIV-2 exists in variable numbers ranging (2 to over 40) copies. This copy number variation in KIV-2 results in marked size polymorphism of the Apo(a) molecule, which in turn leads to significant heterogeneity among Lp(a) particles. Notably, particle size is inversely correlated to plasma Lp(a) concentrations. The cysteine-cysteine disulfide bond that links Apo(a) to ApoB–100 is located within the KIV-9 domain.¹⁹

Another key structural feature of Lp(a) is its enrichment in oxidized phospholipids (OxPLs). Unlike LDL, Lp(a) carries a substantially higher OxPL burden, with these pro-inflammatory lipids being transported both by the ApoB-100 component of the LDL-like particle, and by being covalently bound to the Apo(a) moiety (Fig. 1).²⁰ Experimental studies have demonstrated that OxPLs can be transferred from LDL to Lp(a) in vitro, supporting the notion that Lp(a) serves as the preferential carrier of OxPLs in plasma.²¹ Within the human KIV-10 domain of Apo(a), a high-affinity lysine-binding site facilitates the binding of OxPLs, thereby mediating the pro-inflammatory properties of Lp(a). The abundant presence of OxPLs on Lp(a) has been shown to significantly contribute to its atherogenic potential.

2. Metabolism of Lp(a): synthesis, metabolism, and clearance

Lp(a) is produced independently of very low density lipoprotein (VLDL) and LDL, and is secreted as a distinct lipoprotein particle.²² Apo(a) is synthesized exclusively in the liver.²³ While the exact site of Lp(a) assembly remains uncertain, kinetic studies have suggested that a substantial fraction of Lp(a) assembly occurs extracellularly, although the exact proportion remains uncertain, as briefly illustrated in Fig. 2.³,²⁴,²⁵,²⁶,²⁷,²⁸

Fig. 2. Production and metabolism of Lp(a). Apo(a) is synthesized in hepatocytes and covalently attached to ApoB-100 on a triglyceride-rich lipoprotein to form Lp(a), which is secreted into the circulation. Lp(a) interacts with multiple hepatic receptors, including LDLR, LRP1, SRB1, ASGPR, and PlgR, and with renal receptors such as VLDL-R, gp330/megalin, and PlgRKT.

Apo(a), apolipoprotein(a); ApoB, apolipoprotein B; ASGPR, asialoglycoprotein receptor; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; Lp(a), lipoprotein(a); LRP1, low-density lipoprotein receptor-related protein-1; PlgR, plasminogen receptor; PlgRKT, plasminogen receptor with a C-terminal lysine; SRB1, scavenger receptor B1; VLDL-R, very low density lipoprotein receptor.

Plasma Lp(a) concentrations are primarily regulated at the level of biosynthesis, rather than catabolism.²⁹ Among the determinants of Lp(a) production, Apo(a) isoform size plays a central role. It is well established that Lp(a) levels are inversely correlated to Apo(a) isoform size, as smaller isoforms are synthesized at significantly higher rates than larger ones. Interestingly, marked inter-individual variability in Lp(a) concentrations persists even among those with identical Apo(a) isoform sizes, primarily reflecting differences in production rates.²⁶,²⁸,³⁰,³¹

Although the mechanism of Lp(a) clearance remains incompletely understood, current evidence suggests that it is primarily eliminated by the liver, with secondary contributions from the kidneys and macrophage-expressed receptors involved in cell signaling (Fig. 2).²⁴,³²,³³ Multiple receptors have been implicated in the clearance of Lp(a), with 5 major receptor classes identified: (1) lipoprotein receptors (LDL receptor, VLDL receptor, and LDL receptor-related protein), (2) Toll-like receptors, (3) scavenger receptors class B type 1, (4) lectins, such as Galectin-1 and asialoglycoprotein receptor 1, and (5) plasminogen receptors, including annexin A2, S100 calcium binding protein A10, and plasminogen receptor with a C-terminal lysine.³⁴ Apo(a), ApoB, and OxPLs carried by the Lp(a) particle have been identified as ligands for these receptors. The role of LDL receptor in Lp(a) catabolism remains controversial; the current genetic data does not strongly support a direct role for the LDL receptor in mediating Lp(a) clearance.³⁵

DETERMINANTS OF LP(a)

1. Genetic: KIV repeat polymorphism

There is substantial variation in measured plasma Lp(a) levels across individuals from different racial and ethnic backgrounds,³⁶ which can largely be attributed to genetic variants within the LPA gene locus.³ Most individuals (>80%) express 2 different Apo(a) isoforms,²⁰ each inherited from one parent, contributing to Lp(a) levels in a codominant manner.²⁰,²² Median Lp(a) levels are 4 to 5 times higher in individuals with small Apo(a) isoforms (<22 KIV-2 repeats), compared to those with only large isoforms (≥22 KIV-2 repeats).³ However, the contribution of Apo(a) isoform size to observed Lp(a) levels varies among different racial and ethnic groups by as much as 80%.³⁷ The inverse correlation between isoform size and Lp(a) concentration appears stronger in individuals of European and Asian ancestry, than in those of African descent.²³

Regarding LPA gene polymorphisms and alternative splicing, complex relationships have been identified among genetic factors affecting Lp(a) levels. The effect of allele size on Lp(a) concentrations is modulated by numerous functional single nucleotide polymorphisms (SNPs) spanning the full spectrum of LPA allele frequencies, as well as interactions between SNPs and short tandem repeats.³⁸ Table 1 summarizes SNPs known to significantly influence phenotypic Lp(a) concentrations.³,³⁸,³⁹,⁴⁰,⁴¹,⁴²,⁴³,⁴⁴

Table 1. The impact of single-nucleotide polymorphisms on Lp(a) levels.

		Effect on Lp(a) levels	Association with race and ethnicity
Variants associated with increased Lp(a)
	rs10455872 (intronic polymorphism)41	• ~30 mg/dL increase in Lp(a)	• Most common in White individuals (14.3%), less common in Hispanic (5.5%) and Black populations (1.8%)
		• Explains ~25% of Lp(a) variance
	rs3798220 (I4339M mutation in the protease like domain)41	• A rare variant associated with small apo(a) isoforms	• Most common in Hispanic individuals (42.4%), less common in White individuals (4.3%), and rare in Black individuals (1.5%)
		• Explains ~8% of Lp(a) variance	• Moderately frequent in South Asian populations (~12%)
		• ~45 mg/dL increase in Lp(a) levels
Variants associated with decreased Lp(a)
	rs14343136838	• Splice site mutation	• 10× more frequent in people of Finnish descent (~5%), compared with non-Finnish Europeans
		• ~9 mg/dL decrease in Lp(a) levels
	rs41272114 (G+1/in kringle IV-8A)39)40	• Loss of function mutation	• Most frequent loss of function mutation in White individuals, accounting for ~25% of all null alleles
		• (5–17) mg/dL decrease in Lp(a) levels	• Frequencies range 0 to 18% between populations: 0.7% in African American individuals and 4.7% in European American individuals; 3% in European populations (PROCARDIS cohort); 18 % in Peruvians
	rs41272110 (T3888P)44	• Early studies suggest Lp(a)-lowering effect	• Identified in European American (14.3%), African American (2.4%), White (26.7%), Black (4.5%), and Hispanic (17.4%) individuals
	4925G>A38)44	• Splice variant	• Common in White European individuals (22%)
		• The second strongest influence on Lp(a) levels after apo(a) isoform size: ~31 mg/dL decrease in Lp(a) levels
	4733G>A43	• The third strongest influence on Lp(a) levels after isoform size: ~14 mg/dL decrease in Lp(a) levels	• Common in White European individuals (35.1%) and Latin American populations (26.3%)
			• Rarer in South Asian (5.2%) and Black (1.5%) individuals, and undetectable in East Asian populations

Lp(a), lipoprotein(a); PROCARDIS, precocious coronary artery disease.

2. Non-genetic

A range of non-genetic factors have been implicated in the regulation of Lp(a) concentration (Table 2).⁴⁵,⁴⁶,⁴⁷,⁴⁸,⁴⁹,⁵⁰,⁵¹,⁵² Physical activity appears to have no or minimal effect on Lp(a) levels,⁴¹ whereas the influence by dietary modifications were inconsistent.⁵¹,⁵³ Thyroid function can be another modulator: Lp(a) concentrations increase following thyroidectomy or the administration of antithyroid agents in overt hyperthyroidism, and conversely decrease with levothyroxine replacement in overt hypothyroidism.⁵⁰ Hormonal status also plays a role: low testosterone levels in men have been associated with elevated Lp(a),⁴⁹ while menopausal transition is linked to rising Lp(a) levels, but hormone replacement therapy may have a lowering effect.⁴⁷,⁵² In addition, chronic kidney disease is consistently associated with elevated Lp(a) concentrations,⁴⁵ whereas hepatic dysfunction, especially hepatocellular damage, tends to reduce Lp(a) levels.⁴⁸ These observations reflect the potential impact of various non-genetic factors on Lp(a) regulation beyond genetics, although their clinical significance remains incompletely understood.

Table 2. Non-genetic determinants of plasma Lp(a) levels.

		Drugs and comorbidities	Effect on Lp(a) levels
Conditions associated with increased Lp(a)
	Overt hyperthyroidism	• Thyroidectomy	↑ (mean 4.18 mg/dL)50
		• Antithyroid drug
		• Radioactive iodine
	Hypogonadal men	• Low serum testosterone (<15 nmol/L)	↑ (×3 the upper limit of normal)49
		• Human growth hormone	↑48
	Postmenopausal women	• ↓Estrogen	↑ (up to 13% higher than premenopausal women)47
	Saturated fatty acid	• ↓Intake	↑ (R=−0.43, p=0.02)51
	Chronic kidney disease	• Hemodialysis	↑ (×5–10 higher than stage 1 to 2 chronic kidney disease)45
Conditions associated with decreased Lp(a)
	Overt hypothyroidism	• Levothyroxine	↓ (mean −5.6 mg/dL)50
	Postmenopausal women	• Hormone replacement therapy	↓ (−5.8 mg/dL)52
	Liver disease	• Hepatitis, liver cirrhosis	↓48
	Low-carbohydrate diet	• Intake	↓ (mean −14.7%, p<0.001)53

Lp(a), lipoprotein(a).

PATHOPHYSIOLOGY OF LP(a) ON CVD

1. Inflammation

Lp(a) promotes inflammation by inducing OxPL-driven transcriptomic changes in endothelial cells and monocytes, thereby enhancing monocyte chemotaxis, transendothelial migration, and endothelial permeability.⁵⁴ Individuals with elevated Lp(a) levels have greater potential for OxPL-mediated atherogenic activation.⁵⁴,⁵⁵ Lp(a) has also been implicated in various inflammatory conditions, including coronavirus disease 19, chronic kidney disease, and rheumatoid arthritis. Since the LPA promoter contains interleukin-6 (IL-6) response elements, a positive association between Lp(a) and IL-6 levels has been observed.⁵⁶,⁵⁷ Lp(a) may further act as a monocyte chemoattractant and regulate IL-6 expression and endothelial adhesion molecules, promoting early plaque development.⁵⁴,⁵⁵

2. Thrombosis and venous thromboembolism

Lp(a) may contribute to thrombosis via mechanisms that extend beyond the inhibition of fibrinolysis. It promotes coagulation by binding to and inactivating tissue factor pathway inhibitor, and by enhancing tissue factor expression on monocytes.⁵⁸,⁵⁹ Due to its structural homology with plasminogen, Lp(a) competitively inhibits plasminogen binding to fibrin and endothelial surfaces, thereby reducing plasmin-mediated fibrinolysis.⁵⁵ However, clinical studies suggest that antifibrinolytic activity alone does not fully account for the prothrombotic potential of Lp(a).⁵⁵,⁶⁰,⁶¹,⁶²,⁶³ The association between elevated Lp(a) levels and venous thromboembolism remains inconclusive, as most MR and cohort studies have not demonstrated a strong relationship.⁶⁰,⁶¹,⁶²,⁶³

3. Calcification

Elevated Lp(a) levels are strongly associated with CAVS, primarily due to the OxPLs carried by Lp(a). These OxPLs promote the osteogenic differentiation of valvular interstitial cells by upregulating transcription factors such as RUNX2 and BMP2, ultimately leading to aortic valve calcification.⁶⁴,⁶⁵ Autotaxin, an enzyme transported by Lp(a) and secreted by valvular interstitial cells, converts lysophosphatidylcholine into lysophosphatidic acid (LysoPA).⁶⁴ LysoPA activates inflammatory pathways, including nuclear factor-kappa B, further contributing to the calcification process. In addition, Lp(a) promotes cholesterol deposition and fibrin accumulation on the aortic valve, exacerbating lesion progression.⁶⁶

EPIDEMIOLOGY OF LP(a)

1. Distribution of Lp(a) levels in various populations: ethnic differences

The distribution of Lp(a) levels varies significantly across populations due to genetic, environmental, and methodological factors, as illustrated in Tables 1 and 2. Multiple studies have investigated the variability in Lp(a) concentrations and their implications for CVD risk. In the UK Biobank study, which included 6,857 participants from diverse ethnic backgrounds, median Lp(a) concentrations in Chinese, Europeans, South Asians, Arabs, and Africans were 9.8, 11.5, 12.9, 18.1, and 27.1 mg/dL, respectively.³⁶,⁶⁷ In the Multi-Ethnic Study of Atherosclerosis, which evaluated 6,814 participants primarily for primary prevention, Black participants exhibited the highest median Lp(a) levels at 35 mg/dL, followed by Whites, Hispanics, and Chinese Americans at 12, 8, and 6 mg/dL, respectively.⁶⁸ The effect of potentially modifiable risk factors associated with MI in 52 countries (INTERHEART) study reported Lp(a) concentrations in nmol/L. Among the Chinese subset, the median level was 16 nmol/L (6.4 mg/dL), compared to 31, 19, and 75 nmol/L or 12.4, 7.6, and 30 mg/dL in South Asians, Whites, and Black individuals, respectively.⁶⁵ These findings consistently highlight marked ethnic differences in Lp(a) concentrations, with Black individuals exhibiting the highest levels across cohorts.⁶⁹,⁷⁰ Korean data also demonstrate variability in Lp(a) levels across different cohorts, with most studies conducted in primary prevention setting.⁷¹,⁷²,⁷³,⁷⁴,⁷⁵,⁷⁶,⁷⁷,⁷⁸ The Kangbuk Samsung Health Study assessed Lp(a) levels in a large cohort of individuals undergoing routine health check-ups,⁷¹ with a subset also evaluated for coronary artery calcium scoring.⁷² Median Lp(a) concentration was 18.5 mg/dL, measured using the Roche Diagnostics Modular P Analyzer and Cobas 8000 c702 system.⁷¹ Choi et al.⁷³ also analyzed data from 14,158 adults who underwent Lp(a) testing across 82 hospitals and clinics nationwide. The study reported a median Lp(a) level of 19.6 nmol/L, with 15.3 and 7.9% of individuals exceeding 75 and 120 nmol/L, respectively, thereby providing a reference distribution for the Korean population. In secondary prevention settings, 2 Korean studies have reported median Lp(a) levels. In a cohort of patients with acute MI, the median Lp(a) level was 17 mg/dL, with a median age of 62 years.⁷⁹ In a post-percutaneous coronary intervention (PCI) cohort, the median Lp(a) level was 18.6 mg/dL (interquartile range: 9.2 to 35.5 mg/dL), among patients aged 65 years.⁸⁰

Despite ethnic differences in median Lp(a) concentrations, the association between Lp(a) levels and ASCVD risk appears to be consistent across populations. This consistency is further supported by findings from a large Korean study.⁷¹ However, current evidence remains insufficient to determine whether absolute or ethnicity-specific Lp(a) cut-off values are more appropriate for risk assessment in the Korean population.

2. Lp(a) as a CV risk

Interpretation of Lp(a) levels in the context of overall CVD

Unlike other lipoproteins, Lp(a) levels are primarily influenced by genetic factors, rather than lifestyle. MR studies conducted across multiple ethnic groups have demonstrated a strong association between Lp(a) concentration and CVD risk.¹¹,⁸¹,⁸²,⁸³,⁸⁴ Individuals from various ethnicities who carry polymorphisms associated with smaller Apo(a) isoforms but higher Lp(a) levels exhibit an increased risk of CVD.⁸¹ As discussed in section ‘Genetic: KIV repeat polymorphism’ and shown in Table 1, specific SNPs, such as rs3798220 and rs10455872, are linked to a lower number of KIV-2 repeats. This leads to smaller Apo(a) isoforms, and consequently, higher Lp(a) concentrations.⁹ These variants are also strongly associated with increased odds ratios for coronary artery disease (CAD). Notably, individuals carrying both SNPs have more than a 4-fold increase in CAD risk, exceeding that of most traditional CAD risk factors.⁹

Several large-scale epidemiologic studies have consistently confirmed that elevated Lp(a) is an independent risk factor for ASCVD. The Emerging Risk Factors Collaboration¹⁰ and the Copenhagen reported a dose-dependent increase in MI risk with rising Lp(a) levels.⁸⁵ Furthermore, a recent Chinese study involving 2.9 million adults reinforced the association between Lp(a) levels and subclinical atherosclerosis across multiple vascular territories.⁷⁰

Genetic associations with CAVS and HF

Lp(a) has been identified as a major contributor to CAVS and HF, with MR studies supporting its causal role.⁸⁴,⁸⁶,⁸⁷,⁸⁸,⁸⁹,⁹⁰ A case-control study revealed that patients with CAVS exhibited elevated levels of Lp(a), OxPL-ApoB, and autotaxin, suggesting that Lp(a) functions as a carrier of OxPL and autotaxin to valvular tissues, exacerbating inflammation and calcification.⁹¹ Moreover, in individuals with mild-to-moderate aortic stenosis, higher levels of OxPL-ApoB, OxPL-Apo(a), and Lp(a) were associated with more rapid disease progression, and a greater likelihood of requiring aortic valve replacement.⁵⁹

Lp(a) has also been linked to an increased risk of HF by MR studies. However, it remains open to debate whether this phenomenon is confounded by CAD. In addition, mechanisms such as direct structural damage to the heart valves and myocardium may also contribute,⁹² although further research is needed.

Lp(a) as a risk-enhancing factor in primary prevention

In the context of primary prevention, elevated Lp(a) has been associated with a range of ASCVD outcomes, along with increased risks of CAVS, CV mortality, and all-cause mortality. Across major international guidelines, Lp(a) ≥50 mg/dL (≥100–125 nmol/L) is recognized as a risk-enhancing factor in primary prevention.⁹³ Elevated Lp(a) warrants intensified management of traditional risk factors and consideration of more aggressive low-density lipoprotein cholesterol (LDL-C)-lowering strategies, even among individuals with otherwise optimal lipid profiles. Furthermore, Lp(a) ≥180 mg/dL (≥430 nmol/L) confers a lifetime ASCVD risk comparable to that of untreated heterozygous familial hypercholesterolemia.

Multiple Korean observational studies have reinforced the role of Lp(a) as a risk-enhancing factor for ASCVD, consistent with international evidence (Fig. 3A, Table 3). In a large-scale general health check-up cohort (n=275,430), elevated Lp(a) was significantly associated with increased CVD, MI, and all-cause mortality, underscoring its prognostic value in the general population.⁷¹ Among 662 individuals with type 2 diabetes mellitus and no history of CVD, higher Lp(a) levels were linked to carotid atherosclerosis, defined as carotid intima-media thickness ≥1.0 mm or the presence of carotid plaque, indicating a potential role in early vascular disease progression.⁷⁷ In a coronary computed tomography angiography study of 7,201 asymptomatic individuals, high Lp(a) levels were associated with subclinical coronary atherosclerosis, including both calcified and non-calcified plaques, suggesting its involvement in early plaque development prior to the onset of clinical events.⁷⁴ A recent study further extended these findings by evaluating 2,750 adults without known ASCVD, specifically assessing CAC progression. The study demonstrated that higher Lp(a) tertiles were significantly associated with greater CAC progression.⁷⁵ In addition, a large echocardiography-based cohort of 44,742 Korean adults revealed that individuals with very high Lp(a) concentrations (>100 mg/dL) had an approximately 2-fold higher risk of developing severe degenerative aortic stenosis and requiring aortic valve replacement, independent of traditional risk factors.⁹⁴

Fig. 3. Summary of Korean data and proposed cardiovascular risk classification according to Lp(a) levels. (A) Conceptual summary of findings from Korean cohorts demonstrating that individuals with elevated Lp(a) levels exhibit a higher risk of CVD and CV mortality. (B) Proposed Lp(a)-based cardiovascular risk classification for the Korean population: normal (<30 mg/dL), borderline high (30–49 mg/dL), and high (≥50 mg/dL). These thresholds align with major international guidelines while reflecting population-specific distributions observed in Korean studies.

CV, cardiovascular; CVD, cardiovascular disease; Lp(a), lipoprotein(a).

Table 3. Lp(a) levels related to CV outcomes in primary and secondary prevention of Korean patients.

	Cohort type/author	Sample size	Study population	Results
Primary prevention	Observational/Kim et al.71	275,430	General health check-up cohort	High Lp(a) was related to CV mortality and all-cause death
	Observational/Kim et al.72	44,354	General health check-up cohort undergoing CAC measurements	High Lp(a) levels and CAC are independently associated with ASCVD
	Observational/Jun et al.77	662	T2DM patients without prior CV disease	Lp(a) associated with carotid atherosclerosis (CIMT ≥1.0 mm or carotid plaque)
	Observational/Lee et al.74	7,201	Asymptomatic individuals undergoing CCTA	High Lp(a) associated with subclinical coronary atherosclerosis (calcified and non-calcified plaques)
	Observational/Lee et al.75	2,750	General health check-up population	Higher Lp(a) levels were associated with coronary artery calcification progression
	Observational/Kim et al.94	44,742	Korean adults undergoing echocardiography and Lp(a) testing	High Lp(a) (>100 mg/dL) independently associated with increased risk of severe degenerative aortic stenosis and need for AVR
Secondary prevention	Observational/Park et al.79	1,908	AMI cohort with stratified Lp(a) levels	No independent association between baseline Lp(a) and major adverse CV events
	Observational/Yoon et al.80	12,064	Post-PCI cohort	High Lp(a) associated with increased recurrent ischemic CV events

AMI, acute myocardial infarction; ASCVD, atherosclerotic cardiovascular disease; AVR, aortic valve replacement; CAC, coronary artery calcium; CIMT, carotid intima-media thickness; CV, cardiovascular; CCTA, coronary computed tomographic angiography; Lp(a), lipoprotein (a); PCI, percutaneous coronary intervention; T2DM, type 2 diabetes mellitus.

Taken together, these findings from Korean cohorts highlight the relevance of Lp(a) as a risk-enhancing factor in primary prevention, with consistent associations observed across mortality outcomes and subclinical atherosclerosis, even in asymptomatic populations.

Prognostic significance of Lp(a) in secondary prevention

In secondary prevention, elevated Lp(a) has been associated with an increased risk of major adverse cardiovascular events (MACE), including recurrent MI, stroke, and CV death.³,¹⁴ Meta-analyses have shown that patients with Lp(a) levels above the 80th percentile have a 40% higher risk of recurrent events, particularly among statin-treated individuals with CAD.⁹⁵ The impact of Lp(a) may be influenced by LDL-C levels. Some studies report a stronger association between Lp(a) and CV outcomes in patients with LDL-C ≥130 mg/dL, while others have observed residual risk even at LDL-C <70 mg/dL.⁹⁶ In post-PCI cohorts, elevated Lp(a) has also been linked to increased ischemic events, including restenosis and stent thrombosis, emphasizing its contribution to residual CV risk.⁸⁰ Despite these associations, current lipid-lowering strategies, including statins and PCSK9 inhibitors, do not adequately address Lp(a)-associated risk, reinforcing the need for targeted Lp(a)-lowering therapies.⁹⁷ Recent analyses from the FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) and SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53) trials have further confirmed that Lp(a) is an independent predictor for MACE, MI, and peripheral artery disease in secondary prevention, irrespective of baseline inflammation status.⁹⁸ Section ‘Novel drugs targeting Lp(a): ASO, siRNA, and oral small molecule inhibitor’ discusses ongoing phase 3 trials of Lp(a)-lowering therapies in the secondary prevention settings.

In Korean secondary prevention cohorts, the prognostic significance of Lp(a) has been variable (Table 3). In an acute MI cohort of 1,908 patients, baseline Lp(a) levels were not independently associated with MACE at 3 years, suggesting a more complex role in post-MI risk stratification.⁷⁹ Meanwhile, in a larger cohort of 12,064 post-PCI patients, elevated Lp(a) was significantly linked to increased recurrent ischemic CV events, including MI, stroke, and CV death, reinforcing its clinical relevance in long-term risk assessment following revascularization.⁸⁰

3. Defining high Lp(a) thresholds in Koreans

There is no universally accepted consensus on the threshold for elevated Lp(a), although many lipid societies and national guidelines commonly adopt >50 mg/dL (>100 to 125 nmol/L depending on converting method) as a clinically meaningful cut-off.¹⁴,⁹⁹,¹⁰⁰,¹⁰¹,¹⁰²,¹⁰³,¹⁰⁴,¹⁰⁵ The European Atherosclerosis Society expert consensus recommends >50 mg/dL, based on large-scale epidemiological and MR studies.³ Similarly, the 2022 National Lipid Association (NLA) statement defines >50 mg/dL as a risk-enhancing level for CVD, particularly in the context of global CV risk stratification.¹⁴ Consensus documents and position statements from several non-Asian countries adopt similar thresholds.¹⁰⁰,¹⁰¹,¹⁰²,¹⁰³,¹⁰⁴,¹⁰⁵

In Asia, a unified threshold for high Lp(a) has not been established. Although Chinese academic societies have defined high Lp(a) as >30 mg/dL (>62 or 75 nmol/L depending on converting method),⁹⁹,¹⁰⁶ the most recent large population-based cohort study in China demonstrated more pronounced CV risk at levels exceeding 50 mg/dL.⁷⁰ In Japan, the Japan Atherosclerosis Society guidelines do not specify a clinical cut-off for elevated Lp(a)¹⁰⁷; however, a recent Japanese cohort study of 2,170 patients found that both (>30 and >50) mg/dL were predictive of CV events. As mentioned previously, a large Korean cohort demonstrated elevated risk of mortality due to CV disease and MI in individuals with Lp(a) levels ≥50 mg/dL.⁷¹ In addition, a post-MI cohort study showed a trend toward increased event rates was observed in individuals with Lp(a) levels of 30–49 and ≥50 mg/dL, compared to those with <30 mg/dL.⁷⁵ Another post-PCI cohort demonstrated that high Lp(a) levels (≥30 mg/dL) were significantly associated with increased CV event risks, compared to low Lp(a) levels (<30 mg/dL).⁷⁶ Considering the results of both primary and secondary prevention studies, the Korean task force has proposed the following practical 3-tiered classification (Fig. 3B):

• • Normal: <30 mg/dL

• • Borderline high: 30–49 mg/dL

• • High: ≥50 mg/dL

LP(a) TESTS

1. Introduction of Lp(a) measurement: isoform sensitive vs. insensitive

Measuring Lp(a) is inherently challenging due to the distinctive structure of Apo(a). A key feature of Apo(a) is the presence of a variable number of repeated KIV-2 repeats.¹⁰⁸,¹⁰⁹ These repeats produce Apo(a) isoforms of differing sizes, complicating accurate quantification. Ideally, clinical assays should target a unique, non-repetitive epitope on Apo(a) to eliminate the variability introduced by KIV-2 copy number. Assays designed in this way, termed isoform-insensitive assays, quantify each Lp(a) particle once, and report concentrations in nmol/L. However in practice, developing antibodies specific to non-repetitive epitopes is difficult, due to the high sequence homology (approximately 75–94%) among Apo(a) kringle domains.⁵ Consequently, most commercially available assays use polyclonal antibodies that bind to multiple epitopes, including the repeated KIV-2 domains, making them isoform-sensitive.³ Isoform-sensitive assays tend to underestimate Lp(a) concentrations in individuals with small Apo(a) isoforms, who typically have higher Lp(a) levels and greater ASCVD risk, while overestimating levels in those with large isoforms.¹⁰⁹ To reduce isoform-related measurement bias, some assays incorporate 5 or more independent calibrators that include a representative distribution of Apo(a) isoform sizes.¹⁴,¹¹⁰

Despite these advances, the use of isoform-insensitive assays or isoform-sensitive assays with 5-point calibrators does not ensure full standardization or harmonization. True standardization requires calibration against certified reference materials traceable to the WHO/WHO/IFCC SRM-2B. This material assigns values in nmol/L based on a one-to-one antibody-apo(a) interaction and provides a common reference point for assay comparability. Although some assays are traceable to WHO/IFCC SRM-2B, many—particularly those reporting results in mg/dL—are not. Adding to the challenge, the current SRM-2B material is nearly depleted. The IFCC is developing new reference materials and reference measurement procedures to facilitate global standardization of Lp(a) testing.

2. Recommended Lp(a) measurement

The variability in Lp(a) isoform sizes highlights the importance of reporting results in particle concentration units (nmol/L), rather than mass units (mg/dL), as the latter are influenced by isoform size. Both the IFCC and the NLA advocate standardized Lp(a) measurements in nmol/L.¹⁰⁹ These assays should ideally employ multi-point calibration, such as a 5-point calibrator, and be traceable to the WHO/IFCC SRM-2B reference material.¹⁴ The growing availability of Lp(a)-lowering therapies further underscores the need for accurate and standardized measurement. Reliable quantification is essential, not just to identify patients who may benefit from treatment, but also to monitor therapeutic efficacy.¹⁰⁹ Therefore, there is an urgent need to develop and implement isoform-insensitive assays that report results in nmol/L. While conversion factors ranging from 2 to 2.5 (mg/dL to nmol/L) are sometimes being used in clinical practice, these represent only rough estimates, and are unreliable, due to isoform-dependent variability.³

In Korea, substantial progress is still needed to achieve assay harmonization for Lp(a) measurement. Currently, most laboratories report Lp(a) concentrations in mass units (mg/dL), rather than particle concentrations (nmol/L) (Table 4). These mass-based results are often not traceable to the WHO/IFCC SRM-2B reference standard. For laboratories using calibrators expressed in nmol/L, it is essential that results are reported in molar units, without conversion to mass units. As emphasized earlier, arbitrary conversion between mass and molar units are unacceptable and may lead to clinically misleading interpretations.

Table 4. Methods for lipoprotein(a) measurement in clinical laboratories participating in the external quality assurance program provided by the Korean Association of External Quality Assessment Service.

Method	Number of laboratories
Roche	24 nmol/L
Roche	23 mg/dL*
Roche	2 (both nmol/L and mg/dL)
Sekisui	21 mg/dL
Siemens Atellica	6 mg/dL
Siemens BN™ II System	1 mg/dL
Nittobo	6 mg/dL
Denka Seiken	3 mg/dL
Randox	2 mg/dL
Genematrix	1 mg/dL
Total	89

Data kindly provided by the Korean Association of External Quality Assessment Service (2024).

^*Results reported by labs in mg/dL using conversion factor [mg/dL=(nmol/L+3.83)×0.4587].

Although Lp(a) concentrations are largely genetically determined and remain relatively stable over time, emerging evidence indicates measurable intra-individual variability, particularly among individuals with borderline Lp(a) levels, elevated LDL-C, or those receiving statin therapy.¹¹¹,¹¹² Accordingly, we recommend that Lp(a) should be measured at least once in adulthood, while repeat testing may be considered in selected patients when initial values are borderline or when clinical circumstances that could influence Lp(a) levels change.

CURRENT AND EMERGING TREATMENT STRATEGIES

1. Therapeutic lifestyle change for Lp(a) concentration

Therapeutic lifestyle change is a well-established approach to reduce CV risk in both primary and secondary prevention. However, dietary interventions have shown minimal effect on lowering Lp(a) concentrations. Several randomized trials have demonstrated unexpected findings, such as higher Lp(a) levels with a low-fat, high-vegetable diet, compared to a low-fat, low-vegetable diet.¹¹³,¹¹⁴ Similarly, the Dietary Approaches to Stop Hypertension diet with higher unsaturated fat intake resulted in greater Lp(a) levels than high-protein or carbohydrate-based diets.¹¹⁵ While unsaturated fats generally improve other lipid profiles like LDL-C, their effect on Lp(a) remains unclear. A comprehensive diet score incorporating fish and whole grain intake showed only modest impacts on Lp(a) levels, despite improving overall CVD outcomes.¹¹⁶

The association between physical activity and Lp(a) levels also remains inconclusive.⁴¹ Some studies suggest an inverse correlation,¹¹⁷ while others report no significant association with exercise capacity, age, sex, or body composition.¹¹⁸ Collectively, these findings suggest that diet and exercise have little to no meaningful impact on Lp(a) levels, reinforcing the predominant role of genetic regulation. Therefore, the development of novel Lp(a)-targeted therapies is essential.

2. Evaluation of pre-existing lipid-lowering therapeutics for CV benefit in high Lp(a) concentration

A meta-analysis on statin therapy showed that while statins effectively reduce conventional CV risk factors, they do not lower Lp(a) levels.⁹⁵,¹¹⁹ Notably, patients with Lp(a) ≥50 mg/dL at baseline and follow-up experienced worse CV outcomes, suggesting that elevated Lp(a) contributes to residual CV risk despite statin use.

Several Lp(a)-lowering therapies have been explored for their potential CV benefits. Lipoprotein apheresis, primarily used in patients with Lp(a) >95th percentile, was associated with substantial reductions in MI (97%) and composite CV events (86%).¹²⁰ A subsequent multicenter observational study in 170 high-risk patients (mean LDL-C: 99.0 mg/dL, mean Lp(a): 104.9 mg/dL) reported similar reduction in CV events (−78%), MI (−85.7%), and revascularization (−68.2%).¹²¹ While these findings suggest benefit, the evidence is limited by small sample sizes, retrospective nature, and lack of replication. Extended-release niacin, when combined with statins in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial, achieved a 19% reduction in Lp(a), but failed to reduce CV events, likely due to inadequate statistical power.¹²² Cholesteryl ester transfer protein inhibitors also demonstrated a 20 to 40% reduction in Lp(a). However, 3 agents (torcetrapib, evacetrapib, dalcetrapib) were discontinued, due to toxicity or lack of efficacy.¹²³,¹²⁴,¹²⁵ Anacetrapib and TA-8995 showed Lp(a) lowering effects, but no clear CV benefit was demonstrated.¹²⁶,¹²⁷ PCSK9 monoclonal antibodies have consistently lowered Lp(a), as shown in the FOURIER trial, where evolocumab reduced Lp(a) by 26.9%, regardless of baseline LDL levels. Importantly, patients with Lp(a) >37 nmol/L experienced greater absolute risk reduction (1.41%), and a lower number needed to treat (=71).³³ Inclisiran, a small interfering RNA (siRNA) therapy targeting PCSK9, demonstrated durable LDL-C lowering, but only modest Lp(a) reduction of 18.6 to 25.6% in ORION (Organized Research on Inclisiran for Ongoing Lowering of LDL-C)-10 and ORION-11.¹²⁸ However, in ORION-18,which specifically enrolled Asian patients, inclisiran reduced Lp(a) by 41%, suggesting a potentially enhanced response in this population.¹²⁹ Mipomersen, an ASO targeting ApoB, reduced Lp(a) by 26.4% in patients with familial hypercholesterolemia, though its impact on CV outcomes remains unproven.¹³⁰ These findings underscore the limited efficacy of existing therapies in addressing elevated Lp(a)-associated risk. They highlight the need for novel, potent Lp(a)-targeted agents to effectively reduce CV events in high-risk populations.

3. A need for novel agents with extensive Lp(a)-lowering effect

For clinically significant CV benefits, greater Lp(a) reductions may be required. MR studies suggest that an 80–90% reduction in Lp(a) among individuals with baseline levels (>90–100) mg/dL (225−250 nmol/L) could lead to a 15–20% decrease in CV events.⁸³ The equivalence between LDL-C and Lp(a) lowering remains open to debate. Earlier estimates proposed that reducing Lp(a) by 101.5 mg/dL (253.8 nmol/L) yields a similar benefit to lowering LDL-C by 38.7 mg/dL; however, more recent data suggest that a reduction of 65.7 mg/dL may be sufficient to achieve comparable risk reduction.⁸² Furthermore, secondary prevention studies indicate that Lp(a) reductions of 50 to 99 mg/dL are associated with 20 to 40% reduction in CVD risk, respectively.¹³¹ These findings collectively highlight the need for novel therapeutics that are able to reduce Lp(a) by 60–100 mg/dL, with efficacy validated through large-scale randomized trials to establish their CV benefit.

4. Novel drugs targeting Lp(a): ASO, siRNA, and oral small molecule inhibitor

Pelacarsen, an N-acetylgalactosamine-conjugated ASO, has been shown to reduce Lp(a) levels by up to 92%.¹³² Comparable reductions have been observed with RNA-based siRNA agents, such as olpasiran,¹³³ zerlasiran,¹³⁴,¹³⁵ and lepodisiran.¹³⁶ In addition, muvalaplin, an oral-molecule Lp(a) assembly inhibitor, blocks the interaction between apo(a) and ApoB-100, thereby preventing Lp(a) formation.¹³⁷

Phase II studies of all 5 agents demonstrate consistent and robust Lp(a) reductions, with each showing a reduction of over 80%, highlighting their potential as highly effective Lp(a)-lowering therapies.¹³²,¹³³,¹³⁵,¹³⁸,¹³⁹

Three phase 3 clinical trials investigating ASO or siRNAs are currently underway (Table 5). The Lp(a) HORIZON (Phase 3 Trial of Pelacarsen) trial is investigating pelacarsen in 8,323 patients with ASCVD and Lp(a) ≥70 mg/dL (≥175 nmol/L) (NCT04023552).¹³²,¹⁴⁰ The OCEAN(a) (Olpasiran Cardiovascular Outcomes Study) outcomes trial is evaluating olpasiran in approximately 7,000 patients with ASCVD and Lp(a) ≥200 nmol/L (NCT05581303), while the ACCLAIM-Lp(a) (Lipoprotein(a) Lowering Outcomes Trial of Lepodisiran) (NCT06292013) trial is assessing lepodisiran in 12,500 individuals with Lp(a) ≥175 nmol/L, and either established ASCVD or high-risk individuals (NCT06292013).

Table 5. Summary of ongoing major trials to lower Lp(a).

Drug	Trial name (NCT ID)	Phase	Inclusion criteria	Number	Dose	Dose interval	Primary endpoint	Time frame/estimated completion
Pelacarsen	Lp(a) HORIZON (NCT04023552)	Phase 3	Secondary prevention, Lp(a) ≥70 mg/dL	8,325	80 mg	Every 4 weeks	MACE (CV death, nonfatal MI, nonfatal stroke, and urgent coronary revascularization)	4 years/February, 2026
Olpasiran	OCEAN(a) outcomes trial (NCT05581303)	Phase 3	Secondary prevention, Lp(a) ≥200 nmol/L	7,297	142 mg	Every 12 weeks	CHD death, MI, urgent coronary revascularization	4 years/December, 2026
Lepodisiran	ACCLAIM-Lp(a) (NCT06292013)	Phase 3	Secondary prevention, Lp(a) ≥175 nmol/L	12,500	400 mg	• Initial 3 injections: every 6 months	MACE (CV death, nonfatal MI, nonfatal stroke, and urgent coronary revascularization)	4.5 years/March, 2029
			Primary prevention, Lp(a) ≥175 nmol/L			• Following injections: every 12 months
Zerlasiran130	ALPACAR-360 (NCT05537571)	Phase 2	Stable ASCVD, Lp(a) ≥125 nmol/L	178	300 or 450 mg	Every 16 or 24 weeks	Time-averaged % change in Lp(a) over 36 weeks	1.2 years (60 weeks)/published
Muvalaplin133 (oral)	KRAKEN (NCT05563246)	Phase 2	High-risk (ASCVD, DM, or FH), Lp(a) ≥175 nmol/L	233	10, 60, or 240 mg	Daily (for 12 weeks)	Placebo-adjusted % change in Lp(a) at week 12	12 weeks/published

ACCLAIM-Lp(a), A Study to Investigate the Effect of Lepodisiran on the Reduction of Major Adverse Cardiovascular Events in Adults With Elevated Lipoprotein(a); ALPACAR-360, Assessment of Lipoprotein(a) lowering in Cardiovascular Disease with SLN360; ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; CV, cardiovascular; DM, diabetes mellitus; FH, familial hypercholesterolemia; HORIZON, Phase 3 Trial of Pelacarsen; KRAKEN, Trial of Muvalaplin in High-Risk Patients; Lp(a), lipoprotein(a); MACE, major adverse cardiovascular events; MI, myocardial infarction; OCEAN(a), Olpasiran Trials of Cardiovascular Events And LipoproteiN(a) Reduction.

RESEARCH GAPS AND FUTURE DIRECTIONS

1. The need for Korean-specific longitudinal studies on Lp(a)

The clinical importance of Lp(a) as a genetically determined and independent risk factor for ASCVD and CAVS has gained substantial global recognition. However, significant research gaps remain, particularly concerning Korean populations. These gaps underscore the need for region-specific studies to better understand how genetic, environmental, and metabolic factors interact to influence Lp(a)-related CV risk. Globally, no universally accepted threshold for defining high Lp(a) levels has been established, and this uncertainty extends to Korea. Determining the Lp(a) threshold associated with increased CV risk is therefore a crucial area of investigation. Conducting well-designed, representative longitudinal studies in Korean cohorts will be essential to define appropriate thresholds and guide future risk assessment and management strategies that are tailored to the Korean population.

2. Exploration of genetic and environmental factors unique to Korea

While Lp(a) concentrations are primarily influenced by genetic factors, the role of other modifying factors, such as comorbidities and environmental exposures, remains incompletely understood in Korean populations. Genome-wide association studies specific to Koreans are needed to identify population-specific genetic determinants, such as unique SNPs, or variations in KIV-2 repeats. Emerging therapies targeting Lp(a), such as ASOs and siRNAs, show great promise to reduce residual CV risk. However, their efficacy and safety remain largely untested in East Asians, including Koreans. To address this gap, Korean participation in global trials and dedicated local studies is essential. Pharmacogenomic research is also needed to identify population-specific differences in treatment response.

The interplay between Lp(a) and common metabolic disorders in Korea, such as diabetes or fatty liver disease, warrants further study. Environmental factors, like diet, pollution, and traditional Korean medical practices, should also be examined for their potential influence on Lp(a) levels.

3. Development of cost-effective and standardized testing methods

Accurate measurement of Lp(a) is globally challenged by isoform size heterogeneity and assay variability, with Korea being no exception. Most laboratories still rely on isoform-sensitive assays, leading to inconsistent and potentially misleading values. There is a critical need to develop cost-effective, isoform-insensitive assays that are calibrated to global reference standards, such as the WHO/IFCC SRM-2B. Standardizing the reporting of Lp(a) in nmol/L, rather than mg/dL, is essential to harmonize data and enable meaningful clinical interpretation. In the near future, integrating Lp(a) testing into routine CV risk assessments within Korean healthcare systems is key to more accurately identifying high-risk individuals, and facilitating timely intervention.

4. Cascade screening program in Korea

Major CV prevention guidelines recommend measuring Lp(a) either once in a lifetime for individuals with potential CV risk, or selectively in those at the highest CV risk.³,¹⁰⁵,¹⁰⁹,¹⁴¹ These conditions include family hypercholesterolemia, CAVS, moderate to high CV risk, and insufficient LDL-C reduction despite aggressive lipid-lowering therapy. Given the hereditary nature of Lp(a) concentrations, family-based screening can be a proactive measure for the early detection of individuals at risk. Implementing cascade screening programs that target families with a history of high Lp(a) or premature ASCVD is an important step.³,¹⁰⁹ Establishing national databases for Lp(a) levels would facilitate better tracking and identification of familial clusters. These efforts would also help assess the cost-effectiveness and feasibility of family-based interventions within the Korean healthcare system.

5. Integrating Lp(a) into risk prediction and mechanistic research

Conventional CV risk calculators do not adequately incorporate Lp(a), potentially underestimating risk in individuals with elevated levels. Developing and validating risk prediction models that include Lp(a) as a weighted variable, especially in the Korean population, is essential to improve risk stratification.

Further mechanistic studies are needed to elucidate how Lp(a) contributes to atherosclerosis and thrombosis. This includes investigating OxPL, inflammation, and the interactions of Lp(a) with other lipoproteins, such as LDL and ApoB. Advanced imaging techniques and biomarker research may aid in identifying early signs of Lp(a)-mediated vascular injury and guide the development of targeted intervention.

6. Recommendations on Lp(a) in the Korean population

Since the publication of the 2022 Korean dyslipidemia guidelines,¹⁴² scientific evidence regarding Lp(a) has been increasingly accumulating in Korea. In line with international guidelines and consensus statements, and considering the Korean context, key recommendations were developed and are summarized in the Recommendation box.

7. Recommendation box. Proposed recommendations for Lp(a) screening and risk thresholds in Korea

SUMMARY

Lp(a) is a genetically determined, independent risk factor for ASCVD and CAVS, with consistent associations across diverse populations. Despite growing global consensus on its clinical importance, Lp(a) measurement and management remain underutilized in Korean practice. This position paper consolidates current evidence on Lp(a) biology, distribution, assay methodology, thresholds, and therapeutic strategies, with a focus on Korean data. It proposes a practical 3-tiered classification, underscores the need for isoform-insensitive assays calibrated to WHO/IFCC standards, and reviews novel therapies, such as ASOs, siRNAs, and small-molecule inhibitors. Emphasis is placed on the importance of integrating Lp(a) assessment in routine practice. A call to action is extended to healthcare providers, policymakers, and researchers to prioritize national strategies for screening, research, and equitable access to future Lp(a)-targeted therapies.