Lipoprotein (a) in primary cardiovascular disease prevention is actionable today

Abstract

Lipoprotein(a) [Lp(a)] has emerged as an important, genetically determined, and independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease. Despite growing evidence of its causal role in cardiovascular morbidity and mortality, its actionability in primary prevention remains underrecognized. This review highlights the contemporary scientific foundation supporting early Lp(a) measurement, elucidates its pathogenic mechanisms, evaluates the evolving therapeutic landscape, and proposes a pragmatic clinical framework for integrating Lp(a) into preventive cardiology today. Through clinical vignettes and current data, we argue that identifying elevated Lp(a) can meaningfully guide risk reclassification, intensify modifiable risk management, and inform patient-centered preventive strategies thereby making Lp(a) testing actionable in contemporary primary prevention.

Abbreviations

ASCVD:

Atherosclerotic Cardiovascular Disease

CAD:

Coronary Artery Disease

CAVS:

Calcific Aortic Valve Stenosis

LDL-C:

Low-Density Lipoprotein Cholesterol

Lp(a):

Lipoprotein(a)

1. Introduction: Why Lp(a) demands immediate action in primary prevention

Lipoprotein(a) [Lp(a)] has emerged as an important and independent driver of atherosclerotic cardiovascular disease (ASCVD), with a pathophysiological influence extending beyond that of traditional lipid markers [[1], [2], [3], [4]]. Despite robust evidence from observational epidemiology, human genetics, and mechanistic studies demonstrating its causal role in cardiovascular pathology [[4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22]], Lp(a) remains significantly underutilized in contemporary preventive cardiology practice [3,23,24]. The growing disconnect between the weight of the scientific evidence and the frequency of clinical application necessitates an urgent reassessment of Lp(a) as a clinically actionable target, particularly in the domain of primary prevention.

Lp(a) is a unique lipoprotein that is comprised of a low-density lipoprotein (LDL)-like particle linked to a highly polymorphic apolipoprotein(a) [apo(a)] moiety [2,25,26]. This structural configuration imparts Lp(a) with proatherogenic, proinflammatory, and prothrombotic properties distinct from other lipoproteins. Unlike LDL-C, which is responsive to lifestyle interventions and pharmacotherapy, Lp(a) levels are almost entirely genetically determined and remain remarkably stable throughout life [27,28]. Consequently, Lp(a) serves as a lifelong cardiovascular risk factor, and elevations can lead to the early and aggressive development of coronary artery disease (CAD), stroke, peripheral artery disease (PAD), atrial fibrillation and calcific aortic valve stenosis (CAVS) [1,3,[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15],25,[29], [30], [31], [32], [33], [34], [35], [36], [37]]. Data from large-scale population-based studies have consistently demonstrated a continuous relationship between Lp(a) concentrations and incident ASCVD events [1,3,[5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15],25,[29], [30], [31], [32], [33], [34], [35], [36], [37]]. Moreover, Mendelian randomization studies unequivocally establish Lp(a) as a causal rather than merely associative factor, reinforcing its role as a primary target for preventive strategies [4,9,17,19,21,22,28,38].

Despite these findings, routine Lp(a) testing remains rare in clinical practice [24]. This inertia partly reflects historical uncertainties regarding therapeutic interventions targeting Lp(a) as earlier lipid-lowering strategies (e.g., statins) demonstrated minimal or paradoxical effects on plasma Lp(a) levels. However, this paradigm is shifting. There is growing recognition that elevated Lp(a) represents a potent, genetically conferred burden of risk independent of LDL-C. This has led to renewed interest in its measurement, understanding its value in risk stratification, and recognizing the implications for clinical management. Furthermore, the advent of Lp(a)-specific therapies, including antisense oligonucleotides and small interfering RNAs (siRNAs) targeting apo(a) synthesis, portends a future in which Lp(a)-associated risk may be modifiable [[39], [40], [41], [42]]. Nonetheless, it is critical to emphasize that the actionability of Lp(a) in primary prevention does not require awaiting novel pharmacotherapy. Even today, the identification of elevated Lp(a) can and should influence clinical decisions, intensify management of traditional risk factors, and prompt closer surveillance to mitigate cumulative vascular risk.

This review synthesizes the current understanding of Lp(a) pathophysiology, epidemiology, and clinical implications, with a particular emphasis on primary prevention. We provide a detailed rationale for the routine measurement of Lp(a), offer a pragmatic approach to its integration into preventive cardiology, and explore the evolving therapeutic landscape. Through illustrative clinical vignettes, we demonstrate how Lp(a) testing meaningfully alters risk stratification and therapeutic decisions in real-world settings. Most importantly, we argue that elevated Lp(a) is an actionable entity today and failing to measure and respond to it represents a missed opportunity to prevent the first manifestations of life-altering ASCVD.

2. Pathophysiology and epidemiology of Lp(a)

2.1. The epidemiologic burden of elevated Lp(a)

The prevalence of elevated Lp(a) underscores its substantial contribution to the global burden of ASCVD. Population-based studies estimate that approximately 20–25 % of individuals have Lp(a) concentrations exceeding 50 mg/dL (∼125 nmol/L), a threshold consistently associated with heightened ASCVD risk [2,5,12,28,[31], [32], [33],36,[43], [44], [45], [46]]. This prevalence, however, exhibits marked heterogeneity across racial and ethnic groups. In the Multi-Ethnic Study of Atherosclerosis (MESA) and the Atherosclerosis Risk in Communities (ARIC) study, median Lp(a) levels were substantially higher among Black individuals compared with White, Hispanic, or Asian participants [1,7,36,44,47]. The multi-ethnic INTERHEART study also demonstrated significant ethnic variability in Lp(a) size and isoform [48]. The prevalence of elevated Lp(a) was lowest in Chinese participants and highest in African participants, whereas the population attributable risk of myocardial infarction was highest among South Asians [48]. Recently, data from nearly 3 million Chinese individuals demonstrate that 8.5 % individuals had Lp(a) >50 mg/dL [49]. Notably, despite ethnic variability across numerous cohort, the relative ASCVD risk conferred by elevated Lp(a) remains broadly consistent across ethnic groups [3,5,27].

Prospective cohort studies have established a continuous, graded relationship between plasma Lp(a) levels and incident CAD, ischemic stroke, and PAD [[1], [2], [3], [4], [5], [6], [7],[10], [11], [12], [13],17,19,25,26,[29], [30], [31], [32], [33], [34], [35], [36], [37], [38],46,50,51]. Importantly, the risk associated with elevated Lp(a) was additive to that conferred by elevated LDL-C, hypertension, diabetes, and smoking. This supports its independent role in risk stratification. Furthermore, elevated Lp(a) has emerged as a potent driver of valvular heart disease. Multiple studies have demonstrated that baseline Lp(a) levels are associated with the future development of aortic valve calcification and CAVS [6,8,12,17,21,30]. The consistent findings across multiple large, ethnically diverse cohorts reinforce the global relevance of Lp(a) as a major cardiovascular risk factor.

2.2. Genomic data: Mendelian evidence for causality

Genetic studies provide perhaps the most compelling evidence that Lp(a) is not merely associated with, but causally implicated in, the pathogenesis of ASCVD. The plasma concentration of Lp(a) is determined predominantly (>90 %) by genetic variation at the LPA gene locus, which encodes the apo(a) component. Two major mechanisms drive Lp(a) concentration variability: the number of Kringle IV type 2 (KIV-2) repeats in the LPA gene and the presence of specific single nucleotide polymorphisms (SNPs). The KIV-2 copy number inversely correlates with Lp(a) plasma concentration: smaller apo(a) isoforms (fewer KIV-2 repeats) result in markedly higher circulating levels. In addition, certain SNPs near the LPA locus independently modulate Lp(a) levels, influencing not only concentrations but also cardiovascular outcomes [3,20,27,28,38]. Mendelian randomization analyses, which exploit the random assortment of genetic variants to infer causality, have unequivocally demonstrated that genetically elevated Lp(a) is associated with increased risk of CHD, CAVS, and ischemic stroke [4,17,19,22,28,38,[51], [52], [53]]. These findings satisfy key criteria for causality, including temporality, dose-response, consistency, and biological plausibility. Notably, the genetic architecture of Lp(a) risk underscores its persistence across the lifespan. Unlike LDL-C or blood pressure, which can fluctuate with lifestyle changes or pharmacotherapy, Lp(a) remains remarkably stable from early childhood through adulthood. Thus, identifying individuals with genetically elevated Lp(a) early in life offers a unique opportunity for lifelong risk mitigation.

2.3. Pathophysiological mechanisms: Linking Lp(a) to Atherothrombosis and Valvular disease

The atherogenicity of Lp(a) extends beyond its LDL-like particle and cholesterol content. The apo(a) component confers unique proinflammatory and prothrombotic properties, rendering Lp(a) a multifaceted driver of vascular injury. First, Lp(a) promotes atherosclerosis by facilitating the retention of cholesterol within the arterial intima [26,50]. The LDL-like component of Lp(a) undergoes oxidative modification, triggering endothelial dysfunction and monocyte recruitment. Simultaneously, the abundant oxidized phospholipids (OxPL) carried by Lp(a) further amplify vascular inflammation through activation of innate immune pathways. Experimental models demonstrate that OxPLs induce endothelial activation, monocyte adhesion, and smooth muscle proliferation. These are key steps in plaque initiation and progression [26,50,54].

Second, Lp(a) has been hypothesized to impair fibrinolysis via structural homology between apo(a) and plasminogen, allowing competitive binding to fibrin and plasminogen receptors [[55], [56], [57]]. This may inhibit plasmin generation and promote clot stability, particularly within atherosclerotic plaques. However, this mechanism remains inadequately proven in humans. The apo(a) protease domain is inactive, and antisense-mediated Lp(a) lowering has not altered fibrinolytic activity ex vivo [58,59]. Moreover, population genetic studies do not support an association between elevated Lp(a) and venous thromboembolism (VTE), arguing against systemic antifibrinolytic effects [59]. Nonetheless, Lp(a) may contribute to arterial thrombosis via proinflammatory and proatherogenic mechanisms [40,60]. In the ODYSSEY OUTCOMES trial, baseline Lp(a) levels predicted PAD events and a trend was seen with VTE events [35]. Reductions in Lp(a), but not LDL-C corrected for Lp(a), were linked to fewer thrombotic events, indicating Lp(a)-specific risk. These findings reinforce Lp(a) as a modifiable driver of atherothrombosis, despite uncertainty surrounding its antifibrinolytic activity.

Third, Lp(a) drives calcific remodeling of the aortic valve [17,21,30,61]. OxPLs and inflammatory cytokines derived from Lp(a) particles stimulate osteogenic differentiation of valvular interstitial cells. These changes culminate in leaflet thickening, stiffening, and ultimately, clinically significant aortic stenosis. The strong, consistent association between elevated Lp(a) and incident CAVS in multiple longitudinal cohorts highlights this pathogenic mechanism [6,8,12,17,53].

Thus, elevated Lp(a) exerts a confluence of deleterious effects in the form of atherogenesis, inflammation, calcification, and possibly impaired fibrinolysis and thrombosis that comprehensively fuel the development of ASCVD over the course of decades.

3. Focus on primary ASCVD prevention: Rationale and imperative

Despite the overwhelming evidence linking elevated Lp(a) with incident ASCVD and CAVS, clinical awareness and testing rates remain disappointingly low [2,18,23,24]. Historically, skepticism about Lp(a)’s actionability stemmed from the absence of specific pharmacologic interventions. However, this perspective overlooks the fundamental principle that risk identification, even in the absence of targeted therapy, permits intensified management of modifiable risk factors and enhanced surveillance strategies. In the domain of primary prevention, where the opportunity to alter the lifetime trajectory of ASCVD risk is greatest, Lp(a) testing represents a vital, underutilized tool. Multiple rationales underscore the imperative to integrate Lp(a) measurement into routine cardiovascular risk assessment, particularly in asymptomatic individuals at potential risk for their first major ASCVD event.

3.1. Rationale for early measurement

The case for early Lp(a) measurement is predicated on four foundational pillars. First, Lp(a) levels are genetically determined and stable across the lifespan, with minimal influence from environmental or lifestyle factors [3,38,51]. Unlike traditional lipids that can vary with diet, exercise, or medication, an individual's Lp(a) concentration is established in early childhood and persists throughout life. Thus, a single measurement offers lifelong information about a patient's inherited risk burden.

Second, elevated Lp(a) is associated with the early development of subclinical atherosclerosis, often in the absence of traditional risk factors. Imaging studies, including coronary artery calcium (CAC) scoring and vascular ultrasound, demonstrate accelerated plaque development among individuals with high Lp(a) [29].

Third, Lp(a) carries additive and sometimes multiplicative risk alongside traditional risk factors. Its presence can shift an individual's risk category upwards, prompting reconsideration of preventive strategies such as statin initiation or aspirin use [44,[62], [63], [64]].

Finally, Lp(a) identifies a unique residual risk pathway that remains active even after aggressive LDL-C lowering. In trials such as FOURIER and ODYSSEY Outcomes, residual cardiovascular risk persisted among patients achieving low LDL-C levels, and elevated baseline Lp(a) predicted higher event rates [34,65].

Thus, early identification of elevated Lp(a) enables clinicians to personalize preventive interventions, communicate genetic risk more effectively to patients, and anticipate the need for closer monitoring over time.

3.2. Current guidelines recommending Lp(a) testing

Recognition of Lp(a)’s clinical importance is reflected in recent major guideline statements (Table 1):

• •The 2018 AHA/ACC Multi-Society Guidelines recommend consideration of Lp(a) measurement as a “risk-enhancing factor” in adults with intermediate ASCVD risk.
• •The 2019 ESC/EAS Guidelines go further, recommending that Lp(a) be measured at least once in a person's lifetime to identify those with inherited elevation.
• •The 2021 Canadian Cardiovascular Society (CCS) Guidelines similarly advocate for Lp(a) screening, particularly among individuals with premature ASCVD or familial hypercholesterolemia.
• •Most recently, the 2024 National Lipid Association (NLA) Update strongly endorses opportunistic or universal screening for Lp(a) in preventive cardiology.

Table 1.

Summary of Clinical Guidelines Recommending Lp(a) Screening.

Guideline	When to Measure?	Target Population	Clinical Objective
NLA (2024) [43]	At least once	All adults; Family/personal hx premature ASCVD; Intermediate-high risk; Refractory LDL-C	Identify high Lp(a); Reclassify risk; Optimize management
ACC (2022) [66]	Consider in Risk Assessment	Family/personal hx premature ASCVD; Moderate-high ASCVD risk	Risk reclassification; Management optimization
AACE/ACE (2020) [67]	Consider	Family/personal hx premature ASCVD; Moderate-high ASCVD risk	Risk reclassification
NLA (2019) [68]	Selective testing	Family/personal hx premature ASCVD	Identify high Lp(a)
AHA/ACC (2018) [69]	Selective testing	Family/personal hx premature ASCVD	Risk enhancement factor
CCS (2021) [70]	At least once	All adults; Family/personal hx premature ASCVD	Identify high Lp(a); Optimize prevention
EAS (2022) [12]	At least once	All adults; Family/personal hx premature ASCVD; Moderate-high risk	Identify Lp(a) elevation; Early intervention
ESC/EAS (2019) [71]	At least once	All adults	Identify inherited risk; Reclassify ASCVD risk

Table Legend: Summary of global clinical guidelines recommending lipoprotein(a) [Lp(a)] testing. Recommendations vary by organization but generally emphasize one-time lifetime measurement, especially in individuals with personal or family history of premature ASCVD, moderate to high ASCVD risk, or refractory LDL-C elevations. Abbreviations: NLA = National Lipid Association; ACC = American College of Cardiology; AACE = American Association of Clinical Endocrinology; ACE = American College of Endocrinology; AHA = American Heart Association; CCS = Canadian Cardiovascular Society; EAS = European Atherosclerosis Society; ESC = European Society of Cardiology. Premature ASCVD is typically defined as <55 years in men or <65 years in women.

Collectively, these endorsements signal a shift towards normalizing Lp(a) testing as an essential component of comprehensive cardiovascular risk assessment.

3.3. Integration into clinical practice: Pragmatic approaches

Despite growing guideline support, barriers to Lp(a) testing persist at the point of care. A pragmatic approach to integration involves several steps. While evidence for generalized population level screening for Lp(a) is scant, clinicians should recognize key clinical triggers for Lp(a) measurement. These include:

• •Family history of early cardiovascular events or aortic stenosis
• •Borderline or intermediate ASCVD risk by traditional calculators
• •Familial hypercholesterolemia
• •Cascade screening of individuals with familial hypercholesterolemia or elevated Lp(a)

Lp(a) assays are widely available through major commercial laboratories. The use of isoform-insensitive immunoassays that report results in nmol/L is recommended to enhance accuracy and comparability across populations. In addition, clinicians can leverage electronic health record (EHR) systems to automate reminders for Lp(a) screening in eligible individuals. Embedding Lp(a) measurement prompts during preventive visits or lipid panel ordering can standardize implementation. It is imperative that the interpretation of Lp(a) results must be context sensitive. Data from UK Biobank indicates that incorporating Lp(a) levels across various Lp(a) thresholds in varying baseline clinical ASCVD risk profiles substantially improves absolute risk estimation (Fig. 1). While exact thresholds vary slightly across studies and laboratories, concentrations >125–150 nmol/L (or > 50–60 mg/dL) generally denote increased risk. Clinical decisions should consider Lp(a) alongside baseline ASCVD risk based on other traditional and novel risk markers. Additionally, cascade screening of family members is essential when elevated Lp(a) is identified. Given the heritability of Lp(a), first-degree relatives have a 40–60 % likelihood of elevated levels [72,73]. While beyond the scope of the current article, there are numerous implications for Lp(a) testing for secondary prevention such as among individuals with premature ASCVD and to quantify the residual ASCVD risk despite optimal LDL-C lowering.

Fig. 1.

Estimated Lifetime Risk of ASCVD by Baseline Risk and Lp(a) Concentration. Lifetime risk of atherosclerotic cardiovascular disease (ASCVD) is shown across five strata of baseline risk (5 %, 10 %, 15 %, 20 %, and 25 %) as determined by the Joint British Societies (JBS3) Lifetime Risk Estimator. The incremental impact of lipoprotein(a) [Lp(a)] is modeled across plasma concentration categories (<30, 30–50, 51–75, 76–100, and 101–150 mg/dL), assuming a constant hazard ratio for Lp(a) across all baseline risk levels. Risk estimates are derived from a cohort of 415,274 UK Biobank participants of European ancestry. Modified from data presented in Fig. 6 and Supplementary Table 3, as published in the 2022 European Atherosclerosis Society Consensus Statement [12].

3.4. Costs, barriers, and pragmatic solutions

Concerns regarding the cost-effectiveness of widespread Lp(a) testing have been raised. However, current test costs are modest, typically ranging from $25 to $100, comparable to basic lipid panels [74]. Importantly, early identification of high-risk individuals may prevent costly downstream events such as myocardial infarction, need for coronary revascularization, stroke, or valve replacement, which ultimately enhances health system efficiency. As testing becomes more routine, economies of scale are likely to further reduce costs and expand availability across clinical laboratories. Barriers to adoption include limited clinician familiarity, uncertainty about management strategies in the absence of dedicated therapies, gaps in insurance coverage, and the fact that Lp(a) testing is often a send-out even at tertiary care centers, leading to delayed results and additional logistical burden in patient communication. Addressing these obstacles requires a multifaceted strategy that includes enhancing professional education, updating clinical decision support tools within EHRs, ensuring standardized laboratory reporting practices, and advocating for broader insurance reimbursement based on accumulating cost-effectiveness data. Importantly, actionable steps need not await perfect evidence. Pragmatic integration of Lp(a) screening that is targeted towards high-yield populations initially, then expanded as per infrastructural set ups offers an achievable path to closing this critical gap in preventive cardiology.

4. Real-World Application of Lp(a) Testing in Primary Prevention

The following clinical vignettes provide tangible illustrations of how Lp(a) testing can meaningfully alter risk stratification and therapeutic decisions, even in the absence of dedicated Lp(a)-lowering therapies. While these cases highlight scenarios where testing had clear clinical impact, they are not intended to limit testing to such presentations, rather, they underscore the broader utility of Lp(a) assessment across diverse cardiovascular risk profiles (See Fig. 2A, Fig. 2B, Fig. 2C, Fig. 2D, Fig. 2E).

Fig. 2A.

Familial Hypercholesterolemia with Elevated Lp(a).

Fig. 2B.

Family History of Aortic Stenosis with High Lp(a).

Fig. 2C.

Family History of Premature Coronary Heart Disease.

Fig. 2D.

Borderline LDL-C and Elevated Lp(a) in a ‘Low-Risk’ Patient.

Fig. 2E.

Isolated High Lp(a) Discovered by Screening.

4.1. Case 1: Familial hypercholesterolemia with elevated Lp(a)

Clinical Scenario: A 35-year-old man with genetically confirmed heterozygous familial hypercholesterolemia (HeFH) presents for preventive cardiovascular evaluation. His untreated LDL-C is 220 mg/dL, and his Lp(a) level is markedly elevated at 180 nmol/L. He has no prior ASCVD events (Fig. 2A).

Discussion: HeFH is characterized by lifelong exposure to high LDL-C concentrations, accelerating the development of atherosclerosis from a young age [16,18,75]. However, the coexistence of markedly elevated Lp(a) further amplifies lifetime ASCVD risk, independent of LDL-C burden. Data from the Copenhagen General Population Study and Mendelian analyses demonstrate that elevated Lp(a) acts synergistically with high LDL-C, increasing myocardial infarction risk beyond what would be predicted by either factor alone [3,4,15,16,19,34,36,37]. In some patients, the HeFH phenotype may be driven primarily by elevated Lp(a) [76], highlighting the importance of Lp(a) measurement, particularly in cases of apparent statin resistance or discordant clinical severity. Standard lipid-lowering strategies such as statins substantially reduce LDL-C, but their effect on Lp(a) is minimal or a paradoxical increase [77]. While some earlier reports noted increases in Lp(a) levels of 20 % or more with statin therapy, more recent data suggest these increases are typically more modest, averaging around 10–15 %, with considerable inter-individual variability [77,78]. Recognizing this, clinical management must extend beyond LDL-C goals. In addition to initiating high-intensity statin therapy, consideration should be given to early initiation of PCSK9 inhibitors, which provide modest (∼20–30 %) Lp(a) reduction [34]. Cascade screening of family members for both HeFH and elevated Lp(a) is critical to identify additional high-risk relatives early in life [12,16,18,75].

Clinical Implications: Early identification of elevated Lp(a) in patients with HeFH informs more aggressive LDL-C targets (<55 mg/dL) and justifies adjunctive therapies such as PCSK9 inhibition. It also supports enhanced surveillance for subclinical atherosclerosis and enables family-based preventive strategies.

4.2. Case 2: Family history of aortic stenosis with high Lp(a)

Clinical Scenario: A 40-year-old man with normal LDL-C and no clinical ASCVD is incidentally found to have an Lp(a) concentration of 200 nmol/L. His family history is notable for his father and grandfather both developing severe aortic stenosis requiring valve replacement before age 70 (Fig. 2B).

Discussion: Lp(a) is now recognized as the principal monogenic risk factor for CAVS. Longitudinal data from MESA and the Copenhagen studies demonstrate that individuals with elevated Lp(a) have a significantly higher risk of aortic valve calcification and clinically significant stenosis [8,12,17,30,38,53]. Mechanistically, Lp(a)-derived oxidized phospholipids trigger osteogenic differentiation of valvular interstitial cells, accelerating the pathologic calcification process [6,21,26,30]. While no pharmacologic therapy currently halts the progression of CAVS, early detection of at-risk individuals allows for serial echocardiographic monitoring to identify early hemodynamic abnormalities. Furthermore, lifestyle optimization and blood pressure control remain critical to reduce additional valvular stress.

Clinical Implications: Detection of elevated Lp(a) in the context of a family history of aortic stenosis warrants longitudinal surveillance with echocardiography and underscores the potential future role for Lp(a)-targeted therapies in CAVS prevention.

4.3. Case 3: Family history of premature coronary heart disease

Clinical Scenario: A 45-year-old man with a normal lipid profile, no diabetes, and no personal history of ASCVD presents for preventive counseling. His father suffered a myocardial infarction at age 48. His Lp(a) level is 150 nmol/L (Fig. 2C).

Discussion: Family history of premature ASCVD is a potent predictor of personal cardiovascular risk, and elevated Lp(a) frequently underlies this heritable component. Traditional risk calculators inadequately capture the full extent of inherited risk. In the international INTERHEART study, elevated Lp(a) magnified the impact of familial risk, serving as an independent and synergistic predictor of myocardial infarction [48]. Identification of elevated Lp(a) in this context should lower the threshold for intensifying preventive strategies, including statin initiation even if traditional risk estimators suggest intermediate risk [32]. Coronary artery calcium (CAC) scoring can further refine risk stratification if uncertainty persists [10,29,44]. Additionally, tools such as the Ferrence Lp(a) Risk Assessment Calculator (www.lpaclinicalguidance.com) may aid in translating Lp(a) values into actionable thresholds for preventive therapy, particularly in the setting of family history.

Clinical Implications: Lp(a) testing should be routinely performed in individuals with a strong family history of premature ASCVD, even when traditional risk factors appear reassuring. Detection of elevation supports earlier and more intensive preventive interventions.

4.4. Case 4: Borderline LDL-C and elevated Lp(a) in a “low-risk” patient

Clinical Scenario: A 55-year-old woman with an LDL-C of 105 mg/dL, normotensive, non-diabetic, and non-smoking is classified as “low-risk” by pooled cohort equations. However, opportunistic screening reveals an Lp(a) level of 130 nmol/L (Fig. 2D).

Discussion: Traditional ASCVD risk prediction models omit Lp(a), potentially underestimating risk among individuals with isolated genetic risk [32,79,80]. In large multi-ethnic cohorts, elevated Lp(a) independently predicted coronary events even among patients categorized as low-risk based on traditional metrics [81,82]. In women, the relative impact of elevated Lp(a) may be even more pronounced, highlighting the need for gender-sensitive risk assessments [22,45,46,83,84]. In such patients, incorporation of Lp(a) as a risk-enhancing factor should prompt shared decision-making regarding initiation of statin therapy in addition to aggressive lifestyle modification in alignment with the AHA Life Essential 8 framework [51,85,86]. Coronary calcium scoring can provide additional clarity. A CAC score of zero may support deferral of statins, whereas a positive score strengthens the rationale for intervention.

Clinical Implications: Incorporating Lp(a) into risk discussions prevents under-treatment of seemingly “low-risk” individuals who, in reality, carry significant inherited ASCVD risk.

4.5. Case 5: Isolated high Lp(a) discovered by screening

Clinical Scenario: A 37-year-old man with no personal or family history of ASCVD and a normal lipid profile is found on routine screening to have an Lp(a) level of 180 nmol/L (Fig. 2E).

Discussion: Isolated Lp(a) elevation in the absence of other traditional risk factors remains a significant and independent predictor of long-term ASCVD risk [85]. While absolute event rates may be low in young, otherwise healthy individuals, lifetime exposure to elevated Lp(a) substantially increases cumulative risk [52]. Management should emphasize primordial prevention, aiming to prevent the development of risk factors such as hypertension, diabetes, or tobacco use, rather than waiting to manage them after they arise [51,52,85]. This includes early promotion of a heart-healthy lifestyle, with sustained attention to nutrition, physical activity, and weight maintenance. Patients should be counseled on the significance of Lp(a) elevation and the evolving therapeutic landscape, including potential future eligibility for Lp(a)-specific interventions and encouragement for participation in ongoing clinical trials.

Clinical Implications: Even isolated high Lp(a) mandates vigilance, early risk factor modification, and patient education regarding future preventive opportunities.

5. Expanding Primary Prevention with Current and Emerging Therapies Targeting Lp(a)

The therapeutic inertia due to the historical lack of therapies capable of specifically reducing Lp(a) concentrations contributed to its neglect in routine clinical practice. This section outlines the current landscape of available therapies, the promising pipeline of Lp(a)-lowering drugs, and their implications for future clinical practice.

5.1. Currently available strategies

Lifestyle Modification: While lifestyle modification does not directly lower plasma Lp(a), it remains a cornerstone of risk mitigation for individuals with elevated Lp(a). Aggressive management of traditional cardiovascular risk factors, including optimization of blood pressure, glycemic control, body weight, and smoking cessation, is critical to offset the heightened atherothrombotic and inflammatory burden conferred by Lp(a) [51,85]. Regular aerobic exercise, adherence to heart-healthy dietary patterns such as the Mediterranean or DASH diets, and minimization of saturated fat intake, in alignment with the AHA Life's Essential 8 framework contribute to improved endothelial function and reduction of overall ASCVD risk [86]. Furthermore, lifestyle interventions enhance the efficacy of pharmacologic therapies and reduce residual risk, underscoring their essential role in the comprehensive management of patients with elevated Lp(a).

Statins: Statins, the cornerstone of lipid-lowering therapy, have a paradoxical relationship with Lp(a). Although they robustly lower LDL-C and substantially reduce ASCVD events, statins tend to either slightly increase or have a neutral effect on plasma Lp(a) levels. Data from randomized trials and meta-analyses indicate that statin therapy may raise Lp(a) concentrations by approximately 10–20 %, likely through post-transcriptional upregulation of apo(a) synthesis. Despite this, statins remain essential in patients with elevated Lp(a), as LDL-C reduction mitigates the overall atherogenic burden. The current evidence base for lipid-lowering therapies on Lp(a) is summarized in Table 2.

Table 2.

Effects of Approved Lipid-Lowering Therapies on Lp(a) and ASCVD Risk.

Therapy	Lp(a) Impact	LDL-C Impact	Mechanism Related to Lp(a)	Cardiovascular Impact
Statins [69,77]	9–20 % increase	30–50 % reduction	Potentially upregulates apo(a) synthesis and secretion	21 % MACE reduction per 38.9 mg/dL LDL-C drop
Ezetimibe [87,88]	0–7 % reduction	15–22 % reduction	Unknown mechanism for Lp(a)	∼6–7 % MACE reduction (RCT vs statin monotherapy)
Bempedoic Acid [89]	2 % reduction, no clinically meaningful effect	17–28 % reduction	–	30 % reduction in 3-point MACE (RCT)
Niacin [87,90]	21 % reduction	12 % reduction	Inhibits LPA gene expression at promoter	No added ASCVD benefit when added to statins
PCSK9 inhibitors / siRNA [34,65,91]	19–27 % reduction	51–61 % reduction	Enhanced LDL receptor recycling and reduced Lp(a) production	15 % MACE reduction in high-risk patients; no data in primary prevention
Apheresis [92]	30–35 % time-averaged reduction	70 % reduction	Physical removal of apoB- and apo(a)-containing particles	58 % lower MACE over 2 years vs 11 % over 5 years (observational)

Table Legend: Summary of available lipid-lowering therapies and their effects on lipoprotein(a) [Lp(a)] and LDL cholesterol (LDL-C). Apheresis physically removes apoB- and apo(a)-containing particles. Statins, while reducing LDL-C, may modestly increase Lp(a). PCSK9 inhibitors and siRNA therapies offer concurrent LDL-C and Lp(a) reductions. Cardiovascular outcome impacts are based on clinical trial or observational data. Abbreviations: apo(a) = apolipoprotein(a); apoB = apolipoprotein B-100; MACE = major adverse cardiovascular events; RCT = randomized controlled trial.

PCSK9 Inhibitors: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, including alirocumab and evolocumab, represent a more promising option for modest Lp(a) reduction. In the FOURIER and ODYSSEY Outcomes trials, PCSK9 inhibition among individuals with manifest ASCVD was associated with a 20–30 % reduction in plasma Lp(a) concentrations [34,93]. Importantly, post-hoc analyses demonstrated that greater reductions in Lp(a) were associated with greater reductions in cardiovascular events, independent of LDL-C lowering. Although PCSK9 inhibitors are not approved specifically for Lp(a) lowering, their dual effect on LDL-C and Lp(a) makes them particularly attractive in high-risk individuals with elevated Lp(a).

Lipoprotein Apheresis: Lipoprotein apheresis remains the only currently available therapy capable of achieving substantial reductions in Lp(a), with time-averaged reductions of approximately 30–35 % [92]. It is primarily reserved for individuals with familial hypercholesterolemia or refractory ASCVD who fail to achieve lipid goals with pharmacotherapy. Apheresis has demonstrated significant reductions in cardiovascular event rates in observational studies. However, its invasive nature, cost, and limited availability constrain its widespread use.

Anti-inflammatory and Antithrombotic Strategies: Given Lp(a)’s proinflammatory and prothrombotic properties, adjunctive anti-inflammatory or antiplatelet therapies may provide additive benefit in individuals with elevated Lp(a) [21,33,45,54]. Low-dose aspirin has demonstrated potential benefit among individuals with genetically elevated Lp(a), as suggested by subgroup analyses from population cohorts [62,64,94]. Furthermore, post-hoc analysis of the ASPREE trial demonstrated Aspirin therapy specifically benefits older individuals with high Lp(a) genotypes [63]. However, it is important to note that these findings are limited to specific LPA gene variants (e.g., rs3798220, rs10455872) [95] and have not been consistently reproduced in broader populations. The 2019 ACC/AHA Primary Prevention Guidelines give a class IIb recommendation for low-dose aspirin in select high-risk adults without increased bleeding risk, which may include individuals with elevated Lp(a), while the National Lipid Association suggests individualized consideration in patients aged 40–70 years with Lp(a) ≥50 mg/dL [43,69]. In contrast, the 2019 ESC/EAS Guidelines do not provide specific recommendations for aspirin use in the setting of elevated Lp(a), reflecting continued uncertainty [71]. Anti-inflammatory agents such as colchicine and IL-6 inhibitors (e.g., ziltivekimab) are being explored as means to attenuate vascular inflammation and residual risk, although their impact on Lp(a)-specific risk pathways remains to be fully elucidated [96,97].

5.2. Emerging therapies and clinical trials

A new generation of molecular therapies targeting apo(a) synthesis or expression offer the first opportunity for examining the biological and clinical effects of profound and specific Lp(a) lowering.

Pelacarsen (TQJ230): Pelacarsen is an antisense oligonucleotide (ASO) designed to bind LPA mRNA in hepatocytes, thereby preventing apo(a) protein translation. In the Phase 2 trial by Tsimikas et al. [98], pelacarsen demonstrated dose-dependent reductions in plasma Lp(a) levels of up to 80 %. Importantly, pelacarsen was well-tolerated with a favorable safety profile. The pivotal Phase 3 Lp(a) HORIZON trial (NCT04023552) has enrolled over 8000 patients with established ASCVD and elevated Lp(a) aiming to evaluate whether Lp(a) lowering translates into reduced major adverse cardiovascular events (MACE). The trial is scheduled to complete on 2026-02-26 (clinicaltrials.gov (accessed 6/29/2025)).

Olpasiran (AMG890): Olpasiran is a small interfering RNA (siRNA) therapeutic that inhibits LPA gene expression through RNA interference mechanisms. In the Phase 2 OCEAN(a)-DOSE study [41], olpasiran achieved sustained reductions of Lp(a) by up to 90 % after a single injection. The ongoing OCEAN(a)-Outcomes trial (NCT05581303) is evaluating the effect of olpasiran on cardiovascular events among almost 7200 patients with established ASCVD and Lp(a) concentrations >200 nmol/L.

Zerlasiran (SLN360) and Lepodisiran: Zerlasiran (SLN360) [99] and lepodisiran [100] are additional siRNA-based therapeutics targeting Lp(a) production. Early-phase studies demonstrate promising Lp(a) reductions exceeding 85 %, with extended durability permitting infrequent dosing. Ongoing trials will elucidate their long-term efficacy and safety profiles.

Muvalaplin (AGT-1034): Muvalaplin is a first-in-class oral small molecule targeting the interaction between apo(a) and LDL particles. Initial studies have demonstrated robust reductions in Lp(a) concentrations [39,101] as an oral agent offering advantages in terms of accessibility and adherence.

In summary, the therapeutic landscape for elevated Lp(a) is rapidly evolving. While current options provide modest reductions and remain adjunctive to traditional risk factor control, the advent of Lp(a)-specific agents currently being investigated holds potential for more targeted cardiovascular risk reduction. However, it remains unknown whether profound reductions in Lp(a) will translate into clinical benefit or reveal unanticipated adverse effects. Observational data on such low achieved levels are lacking, and the only reassurance comes from the fact that many individuals worldwide naturally have very low Lp(a) without apparent harm.

6. Future Directions: Advancing the Role of Lp(a) in ASCVD Prevention

As the scientific understanding of Lp(a) matures and the therapeutic pipeline advances, several critical future directions must be addressed to fully integrate Lp(a) into the paradigm of preventive cardiology.

6.1. Cost-effectiveness analyses and health economic modeling

The economic viability of routine Lp(a) testing and subsequent intervention remains a key question for widespread clinical adoption. Although Lp(a) assays are relatively inexpensive (∼$25–$100), the broader economic implications hinge on the cost of therapies and the ability of early intervention to prevent high-cost cardiovascular events. Preliminary modeling studies suggest that targeted Lp(a) screening, especially among individuals with intermediate risk or a family history of premature ASCVD, could be cost-effective if it leads to enhanced risk factor control or earlier initiation of statins and other preventive therapies [102,103]. Cost-effectiveness will be further influenced by the pricing of novel Lp(a)-lowering agents, dosing schedules (e.g., quarterly or semi-annual injections), and their demonstrated ability to reduce major cardiovascular events in outcome trials such as Lp(a)HORIZON (NCT04023552) and OCEAN(a)-Outcomes (NCT05581303). However, emerging data raise considerations about potential adverse effects such as alterations in insulin sensitivity indices (HOMA-IR) associated with Lp(a) lowering [104]. There are speculative concerns about impaired wound healing due to evolutionary functions of Lp(a) [105]. Thus, while therapy may bring economic value through event prevention, safety monitoring and further evaluation of unintended biological trade-offs will be essential to fully understand the health economic balance.

Future analyses must also incorporate societal perspectives, including the potential benefits of reducing health disparities, given the disproportionate burden and clinical significance of elevated Lp(a) among different ethnic groups [48,82]. Health economic models tailored to different healthcare systems will be essential to inform reimbursement strategies and guideline updates.

6.2. Integration into EHR systems

Embedding Lp(a) into EHR-based risk assessment tools represents a practical and scalable approach to enhance adoption [106]. The potential strategies include: 1) Automated prompts: Triggering Lp(a) measurement in patients with premature ASCVD, strong family history, or intermediate pooled cohort equation scores; 2) Risk-enhancer flags: Highlighting elevated Lp(a) as a risk-enhancing factor during preventive care visits, 3) Decision support pathways: Guiding clinicians on interpretation and recommended management steps based on Lp(a) levels. Pilot programs utilizing EHR integration for other biomarkers, such as coronary calcium scoring and genetic risk scores, have demonstrated feasibility and impact [107,108]. A similar approach for Lp(a) could dramatically increase clinician awareness and testing rates, bridging the gap between evidence and practice.

6.3. Updating risk prediction models to incorporate Lp(a)

Current ASCVD risk calculators, such as the pooled cohort equations (PCE) and and PREVENT risk score do not formally integrate Lp(a) as a variable [80,81]. As a result, individuals with substantial genetically mediated risk may be misclassified, particularly if traditional risk factors are absent. Emerging data support the development of revised risk models that explicitly incorporate Lp(a) as a continuous or categorical variable. Studies suggest that inclusion of Lp(a) modestly improves both discrimination (C-statistics) and reclassification (net reclassification index) beyond traditional factors quantified by ACC/AHA Pooled Cohorts Equation or the new AHA PREVENT Risk Equation [32,81,109]. Particularly in younger patients and women, where conventional risk scores may underestimate risk, Lp(a)-adjusted models could better guide preventive interventions. Several academic consortia and industry partnerships are actively working on the next generation of personalized risk calculators that integrate genetic markers, imaging, and biomarkers such as Lp(a) [110]. An example of this is the Ferrence Lp(a) Risk Assessment Calculator (www.lpaclinicalguidance.com). The clinical adoption of such tools would represent a major advance in precision prevention.

6.4. Expanding family Cascade screening

Given the high heritability of Lp(a), cascade screening of first-degree relatives when elevated Lp(a) is identified offers an efficient and impactful strategy for early risk detection [12,16,18,43,75]. Family-based screening models have been highly successful for other inherited lipid disorders such as familial hypercholesterolemia. The cascade screening entails 1) recommending testing to all first-degree relatives of affected individuals, 2) educating families about the genetic basis and lifelong nature of Lp(a)-mediated risk, and 3) instituting early preventive strategies for relatives found to have elevated Lp(a). Population health models predict that cascade screening could identify a substantial number of at-risk individuals before the onset of clinical disease, enabling decades-long opportunities for risk modification.

6.5. Public health initiatives and advocacy

The wider adoption of Lp(a) testing and management will require concerted public health advocacy. This includes:

• •Efforts by professional societies (e.g., AHA, ACC, EAS) to update guideline recommendations and educational materials.
• •Initiatives to enhance insurance coverage and reimbursement for Lp(a) testing and emerging therapies.
• •Collaboration with community organizations to promote awareness, particularly in populations at higher risk for elevated Lp(a).
• •Policy initiatives to ensure equitable access to testing and future treatments.
• •Support from advocacy groups such as the Family Heart Foundation, which has played a leading role in education, outreach, and provision of free Lp(a) testing for at-risk individuals.

Ultimately, positioning Lp(a) as a recognized, routinely measured risk factor, akin to LDL-C or blood pressure, requires broad cultural shifts within clinical medicine and public health.

7. Conclusions

The convergence of robust epidemiologic, genetic, and mechanistic evidence firmly establishes elevated Lp(a) as a causal, independent risk factor for ASCVD and CAVS. This genetically determined risk manifests early, remains relatively stable across the lifespan, and eludes detection by traditional risk calculators. Identifying elevated Lp(a) in individuals with premature ASCVD, strong family histories, intermediate risk profiles, or unexplained residual risk enables earlier intervention. This includes intensified lipid-lowering, selective aspirin use, lifestyle modification, and enhanced surveillance. Cascade screening extends these preventive opportunities across families, amplifying impact. Emerging therapies, promise transformative reductions in Lp(a) levels. However, Lp(a) testing today provides actionable information that should inform preventive strategies without awaiting novel drug approvals. Hence, Lp(a) is actionable today. Cardiologists, internists, and primary care providers must recognize elevated Lp(a) as a call to intensified prevention as it holds the potential to meaningfully reduce the global burden of ASCVD for generations to come.

CRediT authorship contribution statement

Vibhu Parcha: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Visualization, Writing – original draft, Writing – review & editing. Vera A. Bittner: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

Ethics approval

This study did not require an IRB approval.

Ethics statement

The authors would like to certify that:

• •the work described has not been published previously except in the form of a preprint, an abstract, a published lecture, academic thesis or registered report.
• •the article is not under consideration for publication elsewhere.
• •the article's publication is approved by all authors and tacitly or explicitly by the responsible authorities where the work was carried out.
• •if accepted, the article will not be published elsewhere in the same form, in English or in any other language, including electronically, without the written consent of the copyright-holder.

Funding

This work is not supported by any funding.

Declaration of competing interest

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: VB serves on Data and Safety Monitoring Boards for Verve Therapeutics and Eli Lilly; is a site Principal Investigator for Amgen (EVOLVE-MI) and Novartis (ORION-IV); serves as Senior Guest Editor for Circulation (American Heart Association); and is Editor-in-Chief of the ACC Self-Assessment Program (SAP) for the American College of Cardiology. VP has no relevant disclosures of conflicts of interest.