Why, how and in whom should we measure levels of lipoprotein(a): A review of the latest evidence and clinical implications

Abstract

Lipoprotein(a) [Lp(a)] is a genetically determined, causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). Despite robust evidence from epidemiological and genetic studies, Lp(a) remains underrecognised in clinical practice due to challenges in measurement, lack of guideline familiarity and limited therapeutic options. In this narrative review, we summarise the pathophysiological mechanisms linking Lp(a) to atherogenesis, thrombosis and inflammation, emphasising its unique structural features and causal role in cardiovascular disease. We discuss assay methodologies and make the case for a single lifetime measurement given the genetic stability of Lp(a). We review guideline‐based indications for testing, highlighting high‐risk populations such as those with premature ASCVD, a family history of cardiovascular disease and individuals of African or South Asian ancestry. We additionally outline clinical strategies to reduce ASCVD risk in individuals with elevated Lp(a), including lifestyle optimisation, statin therapy, PCSK9 inhibitors, and aspirin in select populations. Emerging targeted therapies, including antisense oligonucleotides and siRNA‐based agents, demonstrate up to 90% Lp(a) reduction and are currently being evaluated in large‐scale cardiovascular outcomes trials. As precision medicine advances, Lp(a) represents both a critical risk factor and a promising therapeutic target. Broader implementation of Lp(a) testing, particularly in high‐risk individuals, will help improve ASCVD prevention efforts.

1. INTRODUCTION

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, underscoring the critical need for accurate and individualised risk assessment strategies. ¹ Traditional cardiovascular risk calculators that incorporate risk factors such as age, blood pressure, cholesterol levels, smoking status and diabetes have significantly advanced population‐level risk prediction. ² However, these calculators often fall short in identifying high‐risk individuals who lack traditional risk factors. ³ In this context, cardiovascular biomarkers have emerged as important tools that improve risk stratification and guide personalised therapeutic interventions, while providing deeper insights into pathophysiological mechanisms. ⁴ Biomarkers can not only help identify at‐risk individuals but also enable early disease detection, adverse outcome prognostication and may even serve as therapeutic targets. ⁵ As the paradigm of clinical care shifts towards precision medicine, the role of biomarkers in refining risk prediction and guiding treatment strategies has become increasingly prominent.

Among the vast array of cardiovascular biomarkers, lipoprotein(a) [Lp(a)] stands out as a unique and often underrecognised causal risk factor. ⁶ Structurally, Lp(a) is comprised of an LDL‐like particle that is covalently bound to apolipoprotein(a) [apo(a)], which confers distinct proatherogenic, proinflammatory and antifibrinolytic properties. ⁷ Unlike traditional lipid and lipoprotein parameters, Lp(a) levels are predominantly genetically determined and remain relatively stable throughout the lifespan. ⁸ Approximately one in five individuals globally have elevated Lp(a). Elevated Lp(a) levels in the circulation have been causally linked to atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD), independent of other lipid parameters. ⁹ Despite robust evidence from traditional and genetic epidemiological studies underscoring Lp(a) as a causal cardiovascular risk factor, it remains significantly underrecognised in routine clinical practice. ¹⁰ , ¹¹ This is partly related to challenges in measurement assay standardisation, uncertainty regarding actionable risk thresholds and a lack of widely available, effective therapies specifically targeting Lp(a). This is compounded by a general lack of awareness among clinicians regarding its clinical significance. While Lp(a) may already be considered for measurement among individuals with premature ASCVD, strong family history or recurrent events, the lack of universal Lp(a) testing represents a missed opportunity for ASCVD risk stratification and prevention in the general population. ¹²

The objectives of this narrative review are threefold. First, we discuss underlying pathophysiological mechanisms that make Lp(a) a potent contributor to cardiovascular risk. Second, we discuss the current landscape of Lp(a) measurement, including available assay techniques, standardisation efforts and interpretation of results, with a particular focus on addressing the ongoing challenges in clinical application. Third, we outline recommendations regarding who should undergo Lp(a) testing, incorporating insights from recent clinical practice guidelines. By synthesising the latest data, this review seeks to inform clinicians and provide practical guidance on integrating Lp(a) measurement into routine cardiovascular risk assessment. Lastly, we explore emerging therapeutic strategies targeting Lp(a), underscoring their potential to reshape clinical practice in the future.

1.1. Pathophysiological role

Lp(a) is a structurally unique lipoprotein particle consisting of an LDL‐like core (apolipoprotein‐B‐100) that is attached to apo(a) via a disulfide bond. Though both LDL and Lp(a) contain one apolipoprotein‐B (ApoB) molecule, Lp(a) does not bind to LDL receptors with the same affinity as LDL due to the steric interference of the apo(a) moiety on Lp(a). ¹³ Additionally, apo(a) alters the shape of ApoB, which may in turn decrease binding to the LDL receptor. ¹³ Decreased uptake by the LDL receptor and the presence of oxidised phospholipids on the apo(a) moiety overall contribute to an approximately six‐fold higher atherogenicity for Lp(a) when compared to LDL. ¹⁴ Lp(a) levels are predominantly determined by the LPA gene, and heritability estimates exceed 90%. ¹⁵ Unlike other lipid markers, Lp(a) levels remain relatively stable throughout life and are minimally influenced by lifestyle factors. ⁸

Beyond atherogenesis, the apo(a) moiety and accompanying oxidised phospholipids confer antifibrinolytic and inflammatory properties. ¹⁶ Apo(a) bears structural similarity to plasminogen and may compete with it for binding to fibrin and increase thrombotic risk due to inhibition of plasminogen activation. Additionally, Lp(a) is a predominant carrier of oxidised phospholipids which may directly activate platelets and prothrombotic pathways. Apo(a) and oxidised phospholipids also induce inflammation via recruitment and activation of monocytes within the arterial wall as well as upregulation of interleukin‐1B, interleukin‐6 and tumour necrosis factor‐alpha. ¹³

Lp(a) levels vary significantly across individuals and ancestry groups, with individuals of African descent generally exhibiting the highest levels, followed by South Asian individuals, while levels are lower in East Asian individuals as compared with those of European ancestry. ¹⁷ These population differences are partly attributable to variations in the LPA gene that codes for apo(a). ¹⁷ Apo(a) contains a variable number of kringle IV type 2 (KIV‐2) repeats, which in turn determines the size of the Lp(a) particle. ¹⁶ Smaller apo(a) isoforms have a lower number of KIV‐2 repeats (generally less than 22) and are associated with higher circulating Lp(a) concentration as well as greater cardiovascular risk.

The atherogenic potential of Lp(a) stems from three distinct mechanisms (Figure 1). ¹⁸ Like LDL, Lp(a) contributes to cholesterol deposition in the arterial intima. However, Lp(a) potentiates additional risks by carrying proinflammatory oxidised phospholipids (OxPLs) in the plasma. These OxPLs promote endothelial dysfunction, enhance recruitment of inflammatory cells and stimulate smooth muscle cell proliferation, which are key processes in atherogenesis. ¹⁹ Lastly, the apo(a) component shares structural homology with plasminogen but lacks fibrinolytic activity. ²⁰ This resemblance results in interference with fibrinolysis by competing with plasminogen binding sites, thereby promoting thrombosis. ¹⁸ Additionally, Lp(a) itself, via the apo(a) moiety, may have proplatelet effects. ²¹ Beyond ASCVD, Lp(a) also plays a role in CAVD, where it accelerates aortic valve calcification through proinflammatory and osteogenic pathways, ²² highlighting its broader cardiovascular relevance.

FIGURE 1.

Mechanistic pathways linking Lipoprotein(a) [Lp(a)] to atherosclerosis. This figure illustrates the central role of Lp(a) in promoting atherogenesis, inflammation and thrombosis. Elevated Lp(a) levels contribute to atherogenesis through its structural similarity with low‐density lipoprotein (LDL) particles. Oxidised phospholipids carried on Lp(a) promote inflammation that amplifies vascular immune activation and foam cell formation. Thrombosis risk is increased via structural homology between apolipoprotein(a) and plasminogen, inhibiting fibrinolysis and promoting clot formation. Collectively, these mechanisms link elevated Lp(a) to heightened cardiovascular risk. Apo(a), apolipoprotein(a); CE, cholesteryl ester; FC, free cholesterol; OxPL, oxidiseized phospholipids; TG, triglyceride.

1.2. Epidemiological evidence linking Lp(a) to cardiovascular risk

Robust epidemiological, mendelian randomisation and genome wide association studies have established elevated Lp(a) as an independent and causal risk factor for ASCVD and CAVD. Early studies focusing on White European populations first identified the association between Lp(a) and cardiovascular risk. ²³ Subsequent large‐scale, multiethnic cohorts have confirmed these findings across diverse populations, highlighting the global relevance of elevated Lp(a). Investigators from the Atherosclerosis Risk in Communities (ARIC) study evaluated over 13 000 Black and White participants in the United States and demonstrated that elevated Lp(a) levels are associated with an increased risk of coronary heart disease (CHD), stroke and overall CVD events. ²⁴ Subsequently, the Multiethnic Study of Atherosclerosis (MESA) and Dallas Heart Study (DHS) demonstrated that White, Black, Hispanic and Chinese Americans with elevated Lp(a) levels had significantly higher incidence of CHD and CVD events, independent of traditional risk factors. ²⁵ , ²⁶ Subsequently, the case–control INTERHEART study demonstrated that while elevated Lp(a) levels confer cardiovascular risk across multiple ethnic groups, the absolute risk varies due to differences in Lp(a) distribution and the prevalence of other risk factors. ²⁷

In addition to atherosclerotic disease, Lp(a) has emerged as an important risk factor for CAVD. The Copenhagen General Population Study provided compelling evidence linking elevated Lp(a) levels to increased risk of aortic valve stenosis. ²⁸ Notably, Mendelian randomisation analyses from this cohort highlighted a causal role for Lp(a) in CAVD, further solidifying its significance in cardiovascular pathology. Mendelian randomisation studies have provided compelling evidence for a causal relationship between genetically elevated Lp(a) and ASCVD as well as CAVD, independent of other lipid parameters. These findings support the hypothesis that Lp(a) is not merely a biomarker of cardiovascular risk but a causal factor in ASCVD ²⁹ and CAVD ³⁰ pathogenesis.

2. HOW SHOULD Lp(a) BE MEASURED?

Accurate measurement of Lp(a) is essential for integrating this risk factor into routine clinical practice. However, unlike conventional lipid and lipoprotein measurements, Lp(a) quantification presents unique challenges due to the structural complexity of the apo(a) component and the variability in assay techniques. Understanding the strengths and limitations of available assays, the implications of apo(a) isoform size dependency and standardisation needs are critical for interpreting Lp(a) levels. ³¹

2.1. Assay techniques for measuring Lp(a)

Various assay techniques have been developed to measure plasma Lp(a) levels, each with distinct advantages and limitations. Common methods include immunoassays such as enzyme‐linked immunosorbent assays (ELISA), nephelometry, radioimmunoassay and immunoturbidimetry. ³² These techniques rely on antibodies targeting the apo(a) component of Lp(a) and are widely available in clinical laboratories. However, despite their accessibility, these assays are often influenced by the size heterogeneity of apo(a), which undermines accurate quantification. ³³ The primary challenge stems from the variability in the number of KIV‐2 repeats in apo(a). This size heterogeneity affects antibody binding in isoform‐sensitive assays, leading to under‐ or overestimation of Lp(a) levels depending on the predominant isoform present. ³⁴ As a result, individuals with smaller apo(a) isoforms (underestimation of Lp(a); associated with higher ASCVD risk) and larger apo(a) isoforms (overestimation of Lp(a); associated with lower ASCVD risk) may have their Lp(a) levels inaccurately quantified, potentially leading to misclassification of risk. ³³

To address this issue, isoform‐insensitive assays have been developed, though there is no fully isoform‐independent commercial assay. These assays employ antibodies that target apo(a) epitopes not affected by KIV‐2 repeat variations, thus providing more accurate and consistent measurements. The World Health Organization (WHO) and the International Federation of Clinical Chemistry (IFCC) have established a reference material (WHO/IFCC SRM 2B) and recommend the use of isoform‐insensitive assays standardised against this reference. ³⁵ The variability in methodologies underscores the need for widespread adoption of standardised isoform‐insensitive assays and the development of a reference isoform‐insensitive assay.

Furthermore, interpreting Lp(a) levels requires an understanding of the units used in reporting. Lp(a) concentrations are reported in either mass units (mg/dL) or molar units (nmol/L). Mass units reflect the total mass of Lp(a) particles, including cholesterol, triglycerides, phospholipids and apo(a), whereas molar units reflect the number of Lp(a) particles. ³⁶ Because cardiovascular risk correlates more closely with Lp(a) particle number rather than mass, nmol/L is considered the preferred unit for clinical reporting. However, a major barrier to harmonisation is the lack of a uniform conversion factor between mg/dL and nmol/L. The molecular weight of Lp(a) varies significantly depending on apo(a) isoform size, preventing a fixed conversion factor. ³⁷ This variability complicates the interpretation of Lp(a) levels when switching between units, particularly when applying guideline‐recommended thresholds derived from studies using different measurement units. ³⁷ Given these discrepancies, adoption of nmol/L as the standard reporting unit, in line with recommendations from international organisations, would enable more precise risk assessment and consistent application of evidence‐based thresholds. ³⁸ However, the prognostic utility of different assays is similar and discrepancies in measurement between mass versus particle‐based measurement are most relevant at the extremes of Lp(a) values. ³⁹

2.2. Frequency of testing: The case for a single lifetime measurement

Unlike other lipid parameters, Lp(a) levels are largely stable throughout an individual's life due to the predominant genetic determination. Heritability estimates exceed 90%, with minimal influence from lifestyle factors, diet or most conventional lipid‐lowering therapies. ⁸ This stability obviates the need for repeated Lp(a) measurements in most clinical scenarios. Intraindividual variability in Lp(a), especially for those with intermediate Lp(a) levels, is an ongoing area of study and will be important in the era of dedicated Lp(a)‐lowering therapies. ⁴⁰ A single, accurately performed Lp(a) measurement can provide lifelong insights into cardiovascular risk. ¹² The cost of an Lp(a) test to an individual or insurance company ranges from $21 to $99; therefore, once‐per‐lifetime Lp(a) testing is relatively inexpensive and likely to be cost‐effective for CVD risk assessment. ⁴¹

Once elevated Lp(a) levels are identified, no routine serial testing is typically required, except in specific circumstances. For instance, in individuals undergoing treatment with emerging Lp(a)‐lowering therapies, repeat measurements will be necessary to assess therapeutic response. Ideally, Lp(a) should be measured in an outpatient setting and not after recent myocardial infarction, as Lp(a) may be paradoxically lower in the peri‐infarction period compared to 6 months after myocardial infarction. ⁴²

3. IN WHOM SHOULD Lp(a) BE MEASURED?

The identification of individuals who would benefit most from Lp(a) testing is essential for optimising cardiovascular risk assessment and implementing effective prevention strategies. While the evidence supporting Lp(a) as an independent risk factor for ASCVD and CAVD continues to grow, testing remains grossly underutilised. Determining appropriate testing strategies involves integrating guideline recommendations, identifying high‐risk groups, addressing population‐specific risks and overcoming practical barriers to implementation.

3.1. Guidelines and recommendations: A shift towards universal testing

Over the past decade, guidelines regarding Lp(a) measurement have evolved significantly, reflecting the growing recognition of its role in cardiovascular risk stratification. It is estimated that nearly 1 in 5 individuals worldwide have an elevated Lp(a) level (≥50 mg/dL or ≥125 nmol/L). ⁴³ In 2018, the American Heart Association (AHA) and American College of Cardiology (ACC) included elevated Lp(a) (≥50 mg/dL or ≥125 nmol/L) as a ‘risk‐enhancing factor’ in the American cholesterol management guidelines. ⁴⁴

The 2019 ESC/EAS guidelines recommended a ‘once‐in‐a‐lifetime’ measurement of Lp(a) for all adults ≥18 years old, specifically to identify individuals with very high Lp(a) levels (>180 mg/dL or >430 nmol/L), which may confer a lifetime risk equivalent to heterozygous familial hypercholesterolaemia. ⁴⁵ The rationale behind this universal testing approach is grounded in the genetic determination of Lp(a) levels, which remain relatively stable over a person's lifetime and are minimally influenced by lifestyle factors. ⁴⁵ Most recently, from 2020 to 2024, various expert consensus statements have further strengthened the case for broader Lp(a) screening. ³⁸ , ⁴⁶

However, universal testing poses challenges, particularly in resource‐limited settings, where prioritisation becomes essential. In such contexts, testing may be reserved for individuals at the highest risk of Lp(a)‐mediated CVD, ensuring that limited healthcare resources are utilised where they can have the greatest impact.

3.2. Identifying high‐risk groups for Lp(a) testing

While universal testing may be ideal, targeted testing remains a pragmatic approach in most clinical settings. The following groups should be prioritised for Lp(a) measurement (Table 1):

1. Individuals with premature ASCVD. Premature ASCVD, defined as cardiovascular events occurring before age 55 years in men and 65 years in women, points to possible underlying genetic contributors, including elevated Lp(a). ⁴⁷ In these individuals, Lp(a) measurement may uncover a risk factor that may not be addressed by standard lipid‐lowering therapies alone.

2. Family history of premature ASCVD or elevated Lp(a). Given the strong heritability of Lp(a) levels, first‐degree relatives of individuals with premature ASCVD or elevated Lp(a) should undergo testing. Cascade screening in such families can identify at‐risk individuals before the onset of clinical disease, allowing for early intervention. ⁴⁸

3. Recurrent ASCVD despite optimal LDL‐lowering therapy. Patients with less than expected response to statins or who continue to experience cardiovascular events despite achieving low‐density lipoprotein‐cholesterol (LDL‐C) targets may have residual risk driven by elevated Lp(a). ⁴⁹ In such cases, Lp(a) measurement can inform the need for more aggressive secondary preventive strategies.

4. Patients with suspected or confirmed familial hypercholesterolaemia (FH). Lp(a) elevation is common among individuals with FH and may contribute to the observed variability in cardiovascular risk within this group. ⁵⁰ Identifying elevated Lp(a) in these patients can help stratify risk and tailor management strategies.

5. Individuals of African and South Asian ancestry. Evidence consistently demonstrates that individuals of African descent have the highest median Lp(a) levels, followed by South Asians. Despite this, awareness and testing rates remain disproportionately low in these groups. ¹⁷ Given the increased cardiovascular risk conferred by elevated Lp(a), routine screening should be considered, particularly among those with other risk factors or a family history of ASCVD.

6. Patients with CAVD. Lp(a) has emerged as a causal factor in the development of CAVD, independent of traditional cardiovascular risk factors. In patients presenting with CAVD, especially at a young age or without significant atherosclerotic burden, Lp(a) testing can provide insights into disease aetiology and may inform the intensity of surveillance and management strategies. ⁹

7. Patients with advanced subclinical atherosclerosis or enriched in ASCVD risk factors. Prior observational studies demonstrate individuals with coronary artery calcium ≥300 experience a risk similar to that of individuals with prior myocardial infarction or stroke ⁵¹ ; therefore, identification of individuals with advanced subclinical atherosclerosis with elevated Lp(a) may facilitate earlier prevention efforts. Additionally, there is evidence that Lp(a) may interact with several traditional risk factors, including diabetes ⁵² and hypertension, ⁵³ to enhance ASCVD risk; however, this is an active area of ongoing research.

8. High‐risk individuals <18 years old. Selective Lp(a) testing is recommended for children with clinically suspected or genetically confirmed familial hypercholesterolaemia, ischaemic stroke of undetermined aetiology, first‐degree relatives with a history of premature ASCVD or first‐degree relatives with elevated Lp(a). ³⁸ However, clinicians should acknowledge that Lp(a) levels may not fully stabilise until late teenage years and there is considerable variability in Lp(a) levels among youth, as intraindividual variation may be as high as 70%. ⁵⁴ Thus, repeat Lp(a) testing may be considered among high‐risk individuals <18 years old, especially if initially measured during early childhood.

TABLE 1.

High‐risk groups for lipoprotein(a) [Lp(a)] testing.

High‐risk group	Rationale for Lp(a) testing
Premature atherosclerotic cardiovascular disease (ASCVD)	May indicate genetic contributors; not addressed by standard lipid‐lowering therapy.
Family history of premature ASCVD or elevated Lp(a)	High heritability: cascade screening can identify at‐risk individuals early.
Recurrent ASCVD despite optimal low‐density lipoprotein (LDL)‐lowering therapy	Residual risk despite LDL‐C control; guides secondary preventive strategies.
Familial hypercholesterolaemia (FH)	Lp(a) contributes to risk variability; aids in risk stratification and management.
African and South Asian ancestry	Highest median Lp(a) levels; underrecognised risk factor for ASCVD.
Calcific aortic valve disease (CAVD)	Causal factor in CAVD; may influence surveillance and management intensity.
Advanced subclinical atherosclerosis or high burden of ASCVD risk factors	Individuals with coronary artery calcium score >300 experience risk comparable to prior ASCVD events. Lp(a) may amplify risk in the presence of diabetes, hypertension or other traditional risk factors.
High‐risk individuals <18 years old	Selective testing may be considered in children with FH, ischaemic stroke or a family history of premature ASCVD or elevated Lp(a). Levels may not stabilise until adolescence; repeat testing may be warranted if measured in early childhood.

Note: This table summarises key populations that should be prioritised for Lp(a) measurement in clinical practice.

3.3. Barriers to Lp(a) testing

In many healthcare systems, Lp(a) testing rates remain below 1%, ¹⁰ , ⁵⁵ even among high‐risk individuals who would benefit most from early identification and management of elevated levels. One key barrier hindering the widespread adoption of Lp(a) testing in clinical practice is limited clinician awareness. Despite growing evidence of its role in cardiovascular risk, many clinicians are still unfamiliar with the clinical relevance, leading to underutilisation of testing. This knowledge gap is particularly pronounced in primary care settings, where early risk assessment decisions are typically made.

3.4. Solutions to enhance Lp(a) testing

Addressing these barriers requires a multifaceted approach. Educational campaigns targeting primary care providers, endocrinologists, cardiologists and lipid specialists are essential for raising awareness about Lp(a) and its clinical implications. Incorporating Lp(a)‐related content into continuing medical education (CME) programs can further close knowledge gaps and promote best practices in cardiovascular risk assessment. Additionally, incorporation into standard risk assessments is crucial. Embedding Lp(a) measurement within routine lipid panels, particularly for high‐risk populations, can normalise testing and ensure early detection of elevated levels. To overcome technical challenges, developing cost‐effective testing protocols is also vital. Streamlining laboratory processes and adopting isoform‐insensitive assays, alongside standardising reporting units, would improve measurement consistency and clinical applicability. Lastly, integration into electronic health records (EHRs) can play a pivotal role. Implementing automated prompts for Lp(a) testing based on relevant clinical histories can ensure that testing opportunities are not overlooked during routine care, facilitating earlier identification of at‐risk individuals and enabling targeted prevention strategies.

4. CLINICAL IMPLICATIONS OF MEASURING Lp(a)

4.1. Cardiovascular risk assessment

There is a stepwise higher risk of ASCVD and CAVD across increasing Lp(a) levels ⁸ with about a 40% higher risk of ASCVD per 50 mg/dL increase in Lp(a). ⁵⁶ Similarly, an approximate 82% higher risk for incident aortic valve calcium (AVC) begins as low as 18 mg/dL Lp(a). ⁵⁷ The commonly used threshold for elevated Lp(a) level internationally is ≥50 mg/dL or ≥125 nmol/L (Table 2). In 2024, the U.S. National Lipid Association introduced a gradation of risk across Lp(a), defining individuals with low (<30 mg/dL or <75 nmol/L), intermediate (30–49 mg/dL or 75–124 nmol/L) and high (≥50 mg/dL or ≥125 nmol/L) risk. ³⁸ The European Society of Cardiology and European Atherosclerosis Society define very‐high Lp(a) level at a threshold of ≥180 mg/dL or 430 nmol/L, which corresponds to the 99th percentile and risk similar to that of familial hypercholesterolaemia. ⁴⁵

TABLE 2.

Major societal guideline lipoprotein(a) [Lp(a)] thresholds.

Society	Lipoprotein(a) threshold
AHA/ACC	Lp(a) ≥50 mg/dL or ≥125 nmol/L
NLA	Low: Lp(a) <30 mg/dL or 75 nmol/L Intermediate: Lp(a) 30–49 mg/dL or 75–124 nmol/L High: Lp(a) ≥50 mg/dL or ≥125 nmol/L
ESC/EAS	Lp(a) ≥50 mg/dL or ≥125 nmol/L Very‐high: ≥180 mg/dL or 430 nmol/L
Heart UK	Minor CVD risk: ≥32–90 nmol/L or ≥18–40 mg/dL Moderate CVD risk: ≥90–200 nmol/L or ≥40–90 mg/dL High CVD risk: ≥200–400 nmol/L or ≥90–180 mg/dL Very‐High CVD risk: ≥400 nmol/L or ≥180 mg/dL
Canada	Lp(a) ≥50 mg/dL or 100 nmol/L
Australia	Lp(a) ≥100 nmol/L

Note: Lp(a) thresholds recommended by major societal guidelines, including those from the AHA/ACC, NLA, ESC/EAS and national guidelines from Canada and Australia. These thresholds help clinicians interpret Lp(a) levels and guide risk stratification and management decisions.

Abbreviation: CVD, cardiovascular disease.

Risk assessment and management of individuals with elevated Lp(a) are actionable. Individuals with elevated Lp(a) may benefit from additional risk assessment, including a detailed family history and selective use of subclinical atherosclerosis imaging. Family history of CHD in a first‐degree relative (17%) and elevated Lp(a) (25%) are independently associated with an increased risk of incident ASCVD over 20‐year follow‐up, and those with a concurrent family history of CHD and elevated Lp(a) experience the highest risk (43%). ⁵⁸ Therefore, risk attributable to family history of CHD and elevated Lp(a) appears to be additive, and clinicians should strive to assess such risk, especially among those with elevated Lp(a). These efforts may also facilitate cascade screening. In addition to family history, measurement of subclinical atherosclerosis burden may be helpful to guide risk assessment among individuals with elevated Lp(a) who do not have clinical ASCVD (Figure 2). Among individuals without prior myocardial infarction or stroke, measurement of coronary artery calcium (CAC) provides further granularity to understanding risk for those with elevated Lp(a), as CAC and Lp(a) are independently associated with ASCVD. Compared to persons without elevated Lp(a) and absence of CAC, Lp(a) ≥50 mg/dL is associated with a 29% higher risk of ASCVD, whereas CAC 1‐99 Agatston Units (AU) and ≥100 AU are associated with a 68% and 2.7‐fold higher ASCVD risk, respectively. ⁵⁹ When assessed concurrently, there is a 4.7‐fold higher risk of ASCVD for individuals with Lp(a) ≥50 mg/dL and CAC ≥100. While there is an observed 31% higher ASCVD risk for those with Lp(a) ≥50 mg/dL and CAC = 0, this risk is not significant after adjusting for traditional risk factors and is considerably lower when compared to those with higher CAC burden. However, given the older average age of individuals and inclusion criteria based upon the absence of clinical ASCVD for these population‐based studies, it is possible that individuals with elevated Lp(a) and premature ASCVD events were excluded from this analysis. Thus, measurement of CAC may help personalise risk assessment for individuals with elevated Lp(a) and guide discussions involving lifestyle management as well as the initiation of preventive pharmacotherapies, including statin and aspirin. Further research is needed to understand risk assessment and personalise shared decision‐making involving therapies for individuals with elevated Lp(a) and absence of CAC.

FIGURE 2.

Association of Lipoprotein(a) [Lp(a)] and coronary artery calcium (CAC) score with atherosclerotic cardiovascular disease (ASCVD) risk. This figure illustrates the combined impact of elevated Lp(a) levels and CAC score on the risk of ASCVD. These findings suggest that Lp(a) and CAC score provide additive information for prognosticating cardiovascular risk among asymptomatic individuals.

4.2. Patient communication

Effective communication of elevated Lp(a) results is crucial for patient engagement and long‐term risk management. Clinicians should begin by emphasising the genetic nature of Lp(a), explaining that levels are predominantly inherited and remain stable throughout life. This understanding helps patients recognise that elevated Lp(a) is not a result of lifestyle choices, reducing potential feelings of blame or guilt. Framing Lp(a) as a lifelong risk factor allows for tailored discussions on long‐term cardiovascular risk, reinforcing the importance of proactive management despite the absence of clinically available Lp(a)‐specific therapies. Patients may express concern over limited treatment options specifically targeting Lp(a). Clinicians should acknowledge this reality while emphasising that actionable strategies exist. Optimising traditional risk factors, such as blood pressure, LDL cholesterol and glycemic control, can substantially reduce overall cardiovascular risk. Additionally, lifestyle modifications, including adherence to a heart‐healthy diet, regular physical activity, smoking cessation and maintaining a healthy weight, remain cornerstones of risk reduction. For select high‐risk individuals, discussing aspirin use, statin therapy and the potential role of PCSK9 inhibitors may be appropriate, as discussed below. Importantly, clinicians should reassure patients that emerging Lp(a)‐targeted therapies are on the horizon, providing hope for future tailored treatments.

4.3. Reduction of ASCVD risk not attributable to Lp(a)

Though elevated Lp(a) is an inherited ASCVD risk factor, initial discussions should involve assessment of lifestyle and traditional risk factor control (Table 3). There have been studies in two independent cohorts (EPIC‐Norfolk ⁶⁰ and Multiethnic Study of Atherosclerosis ⁶¹ ) evaluating the role of ideal cardiovascular health across Lp(a) levels. As a part of efforts to promote and measure ideal cardiovascular health, the Life's Simple 7 score was introduced by the American Heart Association in 2010 and includes a summed score of 0 (poor), 1 (average) or 2 (ideal) across seven metrics: body mass index, cholesterol, systolic blood pressure, glycated haemoglobin, smoking status, physical activity and diet. ⁶² Individuals with intermediate and elevated Lp(a) who achieve higher Life's Simple 7 scores have a lower risk of ASCVD, independent of statin and aspirin therapy. ⁶¹ The magnitude of relative risk reduction in ASCVD among individuals with elevated Lp(a) who achieve ideal Life's Simple 7 scores (≥10) among appears to be an approximate 65% relative risk reduction when compared to those with poor Life's Simple 7 scores (<4). ⁶⁰ Overall, these results demonstrate that individuals with elevated Lp(a) benefit from traditional risk factor control, optimal physical activity and adherence to a diet rich in fruits and vegetables with regular fish and fibre intake that limits sodium and added sugars.

TABLE 3.

Lipid‐lowering therapies and lipoprotein(a) [Lp(a)]‐associated risk.

Therapy	Mean change on Lp(a) levels	Reduction in ASCVD risk in Lp(a)
Non‐Lp(a)‐associated risk a
Ideal cardiovascular health	Minimal effect	Ideal versus poor cardiovascular health associated with ~65% lower relative risk of ASCVD events among those with Lp(a) ≥50 mg/dL 61 Primary prevention
Statins	+9 to 19% may depend on apo(a) phenotype	Post hoc analysis from the JUPITER trial, rosuvastatin 20 mg 63 Primary prevention Median Lp(a) 23 nmol/L Lp(a) ≥ median: 28% ASCVD relative risk reduction Lp(a) < median: 54% ASCVD relative risk reduction No evidence of interaction across Lp(a) and rosuvastatin therapy
Ezetimibe	Minimal effect	No data available
Bempedoic acid	Minimal effect
Omega‐3 fatty acids	Minimal effect
Evinacumab	Minimal effect
Lp(a) associated risk b
PCSK9 mAb (evolocumab, alirocumab)	–20% to 25%	Post hoc analyses from FOURIER 66 and ODYSSEY trials 67 , 68 Secondary prevention FOURIER: median Lp(a) 37 nmol/L 3‐year number needed to treat (NNT3) to prevent one recurrent event: 2.5‐fold lower for individuals with Lp(a) ≥ median vs. < median (NNT3: 40 vs. 105) ODYSSEY: Lp(a) Q1 of <7 mg/dL, Q4 of ≥60 mg/dL NNT3 to prevent one recurrent event: ~5‐fold lower when comparing Q4 versus Q1 Lp(a) (49 vs. 238)
PCSK9 siRNA (inclisiran)	–20% to 25%	No data available
Lomitapide	–13%
Niacin	–20% to 30%	Not associated with ASCVD risk reduction in modern trials. Not recommended due to lack of outcome benefit and adverse effects
Aspirin	Targets prothrombotic pathway	~Regular aspirin use associated with ~50% lower risk of CHD 76 and ASCVD mortality 77 for individuals with Lp(a) ≥50 mg/dL
Targeted Lp(a) therapies
Apheresis	–72% acutely –21% to 31% time‐averaged	FDA approved for four groups: A) clinically diagnosed HoFH with LDL‐C >500 mg/dL, B) clinically diagnosed HeFH with >300 mg/dL, C) clinically diagnosed HeFH with LDL‐C >70 mg/dL and either documented CHD or documented PAD, and D) clinically diagnosed HeFH with Lp(a) >60 mg/dL (or 130 nmol/L) with either CHD or PAD. 79
Pelacarsen	–80%	Lp(a) HORIZON trial ongoing (NCT04023552)
Olpasiran	–71% to 100%	OCEAN(a) Outcomes trial ongoing (NCT05581303)
Lepodisiran	–94%	ACCLAIM‐Lp(a) trial ongoing (NCT06292013)
Zerlasiran	–81% to 86%	ALPACAR‐360 trial ongoing (NCT04606602)
Muvalaplin	Up to –86%	KRAKEN trial ongoing (NCT05563246)

Note: This table summarises the effects of various lipid‐lowering therapies on Lp(a) levels and their impact on ASCVD risk. Therapies are categorised based on whether they primarily influence Lp(a)‐associated risk or non‐Lp(a)‐associated risk. While some therapies, such as PCSK9 inhibitors, significantly lower Lp(a), targeted Lp(a)‐lowering therapies like pelacarsen, olpasiran and lepodisiran demonstrate the greatest reductions and are currently undergoing clinical trials to assess their impact on cardiovascular outcomes.

Abbreviations: ASCVD, atherosclerotic cardiovascular disease; CHD, coronary heart disease; FDA, Food and Drug Administration; HeFH, heterozygous familial hypercholesterolemia; HoFH, homozygous familial hypercholesterolemia; LDL, low‐density lipoprotein.

^a Defined across BMI, healthy diet, physical activity, blood pressure, smoking status, total cholesterol, diabetes.

^b Lipid‐lowering therapies with evidence for ≥10% Lp(a)‐lowering grouped within Lp(a)‐associated risk.

[Correction added on 3 July 2025, after first online publication: Under targeted Lp(a) therapies, the indications for apheresis have been updated, and the abbreviations for FDA, HeFH and HoFH have been added.]

In addition to global risk factor control and a healthy lifestyle, there is evidence for the role of statin therapy in reducing risk among individuals with elevated Lp(a). Introduced in the 2018 ACC/AHA Cholesterol Guidelines, ⁴⁴ elevated Lp(a) ≥50 mg/dL or ≥125 nmol/L is defined as a risk‐enhancer that favours initiation of statin therapy. Post hoc analyses from the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) provide the strongest evidence to support these recommendations. Among nearly 8000 JUPITER participants, on‐statin Lp(a) was independently associated with a 25% higher risk of the composite outcome in JUPITER, defined as incident myocardial infarction, stroke, hospitalisation for unstable angina, arterial revascularisation or cardiovascular death. ⁶³ Furthermore, rosuvastatin reduced the risk for the primary composite outcome in JUPITER for individuals with Lp(a) <median (53% relative risk reduction) versus ≥median (38% relative risk reduction) with no significant interaction according to Lp(a). Such analyses were performed among White participants in JUPITER who had a median Lp(a) of 23 nmol/L. While Lp(a) values may modestly rise with statin therapy, post hoc analyses from JUPITER demonstrate that statin therapy is associated with a lower risk of incident ASCVD across the spectrum of Lp(a) values. ⁶³ However, individuals on statin therapy with elevated Lp(a) experience residual risk across the spectrum of achieved low‐density lipoprotein‐cholesterol, and LDL‐C lowering does not fully offset Lp(a)‐mediated risk. ⁶⁴

4.4. Reduction of ASCVD risk attributable to Lp(a)

Observational evidence has suggested a role for proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) contributing to a lower ASCVD risk attributable to Lp(a) (Table 3). Meta‐analyses indicate that PCSK9 monoclonal antibodies are associated with an approximate 20%–25% reduction in Lp(a) levels. ⁶⁵ With respect to outcomes, evidence for a potential role of PCSK9i in lowering ASCVD risk arises from post hoc analyses of the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab (ODYSSEY Outcomes) Trials. Among individuals with stable CHD in the FOURIER trial, the median Lp(a) levels were 37 nmol/L. In the evolocumab treatment arm, risk reduction in CHD, myocardial infarction or urgent revascularisation was 2.6‐fold higher among individuals with Lp(a) ≥median (relative risk reduction: 23%, absolute risk reduction: 2.5%) compared to those with Lp(a) <median (relative risk reduction: 9%, absolute risk reduction: 0.95%). ⁶⁶ Such differences corresponded to considerably lower number needed to treat over 3 years with evolocumab for those with Lp(a) ≥median (40 patients) versus <median (105 patients). ⁶⁶

Similar results were observed in post hoc analyses of the ODYSSEY Outcomes trial, which studied individuals with acute coronary syndrome. Individuals in the highest quartile of Lp(a) (>60 mg/dL in ODYSSEY Outcomes) had an absolute risk reduction with alirocumab of 2.1%, which was 5.3‐fold higher compared to the absolute risk reduction of 0.4% observed for those with Lp(a) in the 1st quartile (<6.7 mg/dL). ⁶⁷ These results corresponded to a 3‐year number needed to treat to prevent one major adverse cardiovascular event with alirocumab of 49 versus 238 for the 4th and 1st quartiles of Lp(a), respectively. Among ODYSSEY participants with LDL near 70 mg/dL, post hoc analyses have demonstrated that alirocumab provides additional risk reduction for individuals with Lp(a) ≥median but not <median (~14 mg/dL). ⁶⁸ There are no post hoc outcome data involving Lp(a) and inclisiran, a small interfering RNA (siRNA)‐based therapy; inclisiran is associated with a 20%–25% reduction in Lp(a)—similar to PCSK9 monoclonal antibodies. ⁶⁹ Niacin has been shown to reduce Lp(a) levels by approximately 20%–30%. ⁷⁰ However, clinical trials of niacin, including AIM‐HIGH and HPS2‐THRIVE, did not demonstrate ASCVD event reduction in contemporary settings and were not enriched for individuals with elevated Lp(a). ⁷¹ , ⁷² Due to the lack of benefit and adverse effects, niacin is not currently recommended for ASCVD prevention.

Beyond lipid‐lowering therapy, there is observational evidence to support the utilisation of low‐dose aspirin for individuals with elevated Lp(a) who do not have clinical ASCVD. ⁷³ Post hoc analyses of the Women's Health Study ⁷⁴ and ASPREE trial identified between a 54% and a 76% relative risk reduction with aspirin therapy for individuals with a high‐risk LPA variant (rs3798220), ⁷⁵ and other observational studies have observed similar findings with measured Lp(a) values. Among nearly 2200 individuals in the MultiEthnic Study of Atherosclerosis, individuals with Lp(a) >50 mg/dL reporting aspirin use of at least three times weekly had a 46% lower risk of incident CHD over a median follow‐up of 15.7 years in a propensity‐matched analysis, independent of traditional risk factors. ⁷⁶ In a separate analysis among nearly 3000 individuals without clinical ASCVD in the Third National Health and Nutrition Examination Survey, regular aspirin use was associated with a 52% lower risk of ASCVD mortality for those with Lp(a) ≥50 mg/dL. ⁷⁷ Mechanistically, aspirin may help lower Lp(a)‐associated risk by limiting the thrombotic activity attributable to apo(a). ²¹

Beyond statins, PCSK9 monoclonal antibodies and aspirin, there are no observational data involving outcomes for other lipid‐lowering therapies across Lp(a) levels. While niacin is associated with a reduction in Lp(a), trials involving niacin were not enriched for those with elevated Lp(a) and niacin did not lead to a significant reduction in ASCVD events. ⁷⁸ Among therapies approved for individuals with homozygous familial hypercholesterolaemia, findings from small studies indicate that lomitapide and evinacumab may be associated with a 13% and 6% reduction in Lp(a), respectively.

4.5. Targeted Lp(a)‐lowering therapeutics

The only Food and Drug Administration approved therapy for Lp(a) lowering is apheresis for individuals with clinical ASCVD or heterozygous familial hypercholesterolaemia with Lp(a) ≥60 mg/dL and LDL‐C ≥100 mg/dL on maximally tolerated lipid‐lowering therapy. ⁷⁹ While there is currently no approved Lp(a)‐lowering pharmacotherapy, there are three notable ongoing Phase 3 ASCVD outcome trials involving Lp(a)‐lowering therapy (Table 3). The Lp(a) HORIZON and OCEAN(a)‐Outcomes trials exclusively enrolled individuals with prevalent ASCVD, whereas the ACCLAIM trial includes those with and without clinical ASCVD. Antisense oligonucleotide (ASO), pelacarsen, is being evaluated in the Lp(a)HORIZON trial, and siRNA agents are being assessed in the OCEAN(a) (olpasiran) and ACCLAIM Trials (lepodisiran).

Pelacarsen is an ASO that targets the apo(a) messenger RNA and leads to its destruction via ribonuclease H. Phase 2 clinical trial evidence demonstrates a dose‐dependent and up to 80% reduction in Lp(a) with pelacarsen among individuals with Lp(a) >60 mg/dL and a history of ASCVD, where more than 4 in 5 were taking a statin, one‐half were on ezetimibe, and 1 in 5 were on PCSK9 monoclonal antibody therapy. ⁸⁰ Pelacarsen is administered via subcutaneous injection and is currently being studied as a monthly 80 mg dose in the Lp(a) HORIZON trial.

Olpasiran is an siRNA therapy that also targets apo(a) messenger RNA and leads to its destruction via RNA‐induced silencing complex. In the OCEAN(a)‐Dose Phase 2 clinical trial, olpasiran led to a mean 70% to 100% reduction in Lp(a) among persons with Lp(a) >150 nmol/L and a history of ASCVD. ⁸¹ Olpasiran is also dosed subcutaneously and is currently being studied as an injection every 3 months in the OCEAN(a)‐Outcomes trial. Similar to olpasiran, lepodisiran is a siRNA therapy that led to a maximal median reduction in Lp(a) level of >90% over 1 year with a single dose. ⁸² The ACCLAIM trial is currently enrolling participants with Lp(a) >175 nmol/L with existing ASCVD, FH or a combination of risk factors. An additional siRNA that targets apo(a) and is currently being investigated is zerlasiran. ⁸³ Beyond subcutaneous therapy, muvalaplin is an oral Lp(a)‐lowering agent that prevents the assembly of Lp(a) in the liver and is associated with a maximum 86% reduction in Lp(a) in Phase 2 clinical trial data. ⁸⁴

Beyond Lp(a)‐lowering, siRNA therapies targeting Lp(a) have been shown to lower levels of oxidised phospholipids on ApoB. ⁸⁰ While targeted Lp(a)‐lowering therapies have minimal effect on inflammatory biomarkers, evidence from phase 2 trials demonstrates a dose‐dependent reduction with interleukin‐6 inhibition and Lp(a) lowering. ⁸⁵ These results further support the role that inflammation may modulate levels of Lp(a), as there is an interleukin‐6 response element within the promoter region of the LPA gene. ⁸⁶

4.6. Future directions

Despite significant advances in understanding Lp(a) and its role in CVD, several knowledge gaps remain that warrant future research. One key priority is understanding the role of Lp(a) across diverse populations. While elevated Lp(a) levels are known to vary significantly by ethnicity, limited data exist on how these differences translate into cardiovascular risk across global populations. Large‐scale, multiethnic cohort studies are needed to establish population‐specific risk thresholds and inform tailored clinical guidelines. Additionally, as Lp(a)‐lowering therapies progress through late‐phase clinical trials, critical questions remain regarding long‐term efficacy and safety. While early data show promising reductions in Lp(a) levels, it is essential to determine whether these reductions translate into sustained decreases in cardiovascular events and mortality. Another emerging area of interest is the role of Lp(a) in noncardiovascular diseases, including type 2 diabetes, ⁸⁷ chronic kidney disease ⁸⁸ and advanced steatotic liver disease, ⁸⁹ where preliminary associations have been observed but causality remains unclear. Additionally, assessment of Lp(a) variability will be of value. While most individuals have relatively stable Lp(a) upon reaching adulthood, chronic kidney disease, hepatic disease, perimenopause and inflammation all may be key sources of variability in Lp(a) and potential indications for repeat testing especially among those with intermediate Lp(a) levels. Data gaps also exist regarding the impact of universal Lp(a) testing on clinical outcomes and healthcare costs. Addressing these gaps will be essential for integrating Lp(a)‐targeted strategies into precision cardiovascular care, ultimately improving outcomes for at‐risk populations.

5. CONCLUSIONS

Lp(a) has emerged as a critical yet underrecognised cardiovascular risk factor, with robust evidence demonstrating a causal link between elevated levels and cardiovascular disease. Unlike traditional lipid markers, Lp(a) levels are predominantly genetically determined, relatively stable throughout life and minimally influenced by lifestyle factors. These unique characteristics make Lp(a) an important risk factor for lifelong cardiovascular risk stratification. Importantly, elevated Lp(a) identifies a subset of high‐risk individuals who may remain undetected using conventional risk assessment tools. Effective management in such cases includes optimising traditional risk factors, evaluating for subclinical atherosclerosis, considering statin therapy and, in some instances, exploring the use of PCSK9 inhibitors and aspirin. Given these insights, there is a strong case for routine Lp(a) testing, particularly among high‐risk groups such as individuals with premature ASCVD, a family history of cardiovascular disease, recurrent cardiovascular events despite optimal therapy and populations with inherently higher Lp(a) levels, including those of African and South Asian ancestry. Routine testing would enable earlier identification of at‐risk individuals and inform personalised preventive strategies.

Looking ahead, further research is essential to close existing knowledge gaps. Large‐scale trials such as Lp(a) HORIZON (pelacarsen), OCEAN(a)‐Outcomes (olpasiran) and ACCLAIM (lepodisiran) are poised to provide critical data on whether lowering Lp(a) levels translates into meaningful reductions in cardiovascular events. As these and other studies progress, they will play a pivotal role in shaping future guidelines, advancing Lp(a)‐targeted therapies, and ultimately, transforming cardiovascular risk management.

CONFLICT OF INTEREST STATEMENT

ACR is supported by the National Heart, Lung, and Blood Institute Grants F32HL172499 and L30HL175751. MDS has received grant/research support (through his institution) from Amgen, Arrowhead, Boehringer Ingelheim, 89Bio, Esperion, Novartis, Ionis, Merck, New Amsterdam, Lilly, and Cleerly. He has participated in Scientific Advisory Boards with Amgen, Arrowhead, Ionis, Novartis, New Amsterdam, and Merck. He has served as a consultant for Ionis, Novartis, Regeneron, Aidoc, Shanghai Pharma Biotherapeutics, Kaneka, Novo Nordisk, Arrowhead, and Tourmaline. HSB is supported by National Institutes of Health, Grant 1K08HL166962. He has served as a consultant / advisor for Kaneka, Novartis, Arrowhead and Abbott. AM reports institutional research grants from Novartis and Amgen.

PEER REVIEW

The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer‐review/10.1111/dom.16469.

Razavi AC, Bhatia HS, Blumenthal RS, Shapiro MD, Mehta A. Why, how and in whom should we measure levels of lipoprotein(a): A review of the latest evidence and clinical implications. Diabetes Obes Metab. 2025;27(Suppl. 8):34‐46. doi: 10.1111/dom.16469

DATA AVAILABILITY STATEMENT

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.