Lp(a) affects approximately 1.5 billion people globally. Despite being present in 20% of populations worldwide, recent data indicate that only 0.3% of adults underwent screening between 2012 and 2021 [10], creating a profound gap between epidemiological significance and clinical implementation.

Global prevalence patterns of Lp(a) levels vary significantly by ethnicity, sex, and age. Ethnic disparities in median Lp(a) levels follow a distinct pattern: individuals of African descent exhibit the highest levels (median 75 nmol/L), followed by South Asian populations (median 31 nmol/L), White individuals (median 19 nmol/L), and East Asian individuals (median 16 nmol/L) [11]. Race-specific 90th percentile thresholds demonstrate statistical significance across all ethnic groups [11]. Despite substantial ethnic differences in baseline Lp(a) levels, the relative cardiovascular risk per unit increase appears consistent across ethnic groups [11]. The distribution of apo(a) isoform size also varies by ancestry: African populations show a single peak distribution, South Asian populations demonstrate equal distribution of large and small isoforms, European populations exhibit a biphasic pattern with higher peaks on smaller isoforms, and East Asian populations display a biphasic distribution with higher peaks on larger isoforms [12].

Sex-based differences in Lp(a) levels are modest but consistent, with females demonstrating concentrations approximately 5–10% higher than males [13, 14]. Large-scale studies indicate that Lp(a) levels are generally similar between men and women before menopause but tend to be modestly higher in women afterward [11, 15, 16, 17]. Meta-analyses show that postmenopausal tibolone treatment significantly reduces Lp(a) levels by 25%, and that postmenopausal increases appear to be due to aging rather than menopause itself [18, 19].

Age-related patterns of Lp(a) levels are unique among lipoproteins: primarily genetically determined, they rise rapidly after birth, with the LPA gene fully expressed by age 2 and adult-like concentrations achieved by age 5 [20, 21]. After this point, Lp(a) levels remain largely unchanged throughout life, except in specific physiological or disease states [12].

The evolution of Lp(a) recommendations from 2018 to 2024 reflects the field’s transition from uncertainty to clinical readiness (Table 2, Ref. [12, 22, 23, 24, 25]) [12, 22, 23, 26]. The 2018 American College of Cardiology/American Heart Association (ACC/AHA) guidelines adopted selective screening for high-risk individuals [23], while the 2019 European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) pivotally endorsed population-wide screening, recognizing Lp(a)’s genetic determination warranted early identification regardless of therapeutic availability [24]. The 2022 EAS and 2024 National Lipid Association (NLA) guidelines marked critical inflection points by establishing detailed laboratory standards and elevating screening to a Class I recommendation, respectively [12, 22]. This progression—from selective to universal measurement with standardized protocols—coincided with promising results from phase 2 RNA-targeted intervention trials [6, 7, 9, 27].

The standardization of Lp(a) testing is essential for reliable clinical implementation. Current standardization follows International Organization for Standardization (ISO) 17511:2020 guidelines with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC)/World Health Organization (WHO) reference material, Standard Reference Material 2B (SRM2B), serving as the primary standard [28, 29, 30]. A major advancement is the liquid chromatography-multiple reaction monitoring-mass spectrometry (LC-MRM-MS) based reference measurement procedure that measures apo(a) peptides independent of size polymorphism, offering extended measuring range up to 600 nmol/L and traceability to international standards [25]. Laboratory medicine organizations now recommend reporting in molar units (nmol/L) rather than mass concentrations (mg/dL), as mass measurements are inherently flawed due to variable apo(a) molecular weights [12]. This shift represents a paradigm change essential for accurate risk assessment across populations with different apo(a) isoform distributions. Clinically, physicians must recognize that the traditional 50 mg/dL threshold corresponds to approximately 100–125 nmol/L, with variation due to apo(a) size polymorphism, complicating risk assessment during the transition period.

Implementation of these advances faces several challenges: many laboratories still use older assays lacking proper standardization, creating significant inter-laboratory variation. The transition from mass to molar reporting requires both technical changes and clinician education for those accustomed to mg/dL thresholds. Furthermore, establishing metrological traceability chains requires coordination between manufacturers, reference laboratories, and clinical facilities—a process still in progress globally [29].

Multiple systemic barriers perpetuate the implementation gap between guidelines and clinical practice. First, reimbursement challenges create fundamental access barriers. Despite test costs of $\$$ 20–100, Lp(a) testing faces critical reimbursement barriers globally. In the United States, Medicare explicitly does not cover Lp(a) testing, the Current Procedural Terminology (CPT) code 83695, despite covering standard lipid panels, and many private insurers classify it as ‘investigational and not medically necessary’. Similarly, in South Korea, Lp(a) measurement is not reimbursed by the National Health Insurance Service and is classified as a non-covered service. Patients must pay out-of-pocket for Lp(a) testing, which serves as a major barrier to routine screening. This creates a fundamental disconnect—recent cost-effectiveness analysis demonstrated that Lp(a) screening is cost-effective to cost-saving, with incremental cost-effectiveness ratios of 12,134 AUD/Quality-Adjusted Life Year (QALY) in Australia and actual cost savings in the UK healthcare system [31]. The Brussels International Declaration explicitly called for “systematic Lp(a) testing at least once during a person’s lifetime with full reimbursement”, representing unprecedented international consensus on the need for policy action [32].

Second, knowledge gaps among providers hinder implementation. Surveys indicate that many healthcare providers remain uncertain about how to manage patients once Lp(a) results are obtained. This uncertainty stems from the absence of specific therapies until recently and the lack of clear management algorithms. Only 4.6% of primary care providers and 14.1% of cardiologists ordered even a single Lp(a) test during the recent study periods [10].

Third, laboratory standardization issues create measurement challenges. Many laboratories still use older assays that lack proper standardization, potentially misclassifying patients as high or low risk depending on which laboratory performs the test. The transition from mass (mg/dL) to molar (nmol/L) reporting adds complexity for clinicians accustomed to traditional thresholds.

Finally, limited patient awareness reduces demand for testing. Unlike cholesterol, patients are rarely aware of Lp(a), which limits demand for testing and reduces the opportunity for cascade screening in affected families. This knowledge gap is particularly problematic given the genetic nature of elevated Lp(a) and the importance of family screening.

Despite emerging consensus on universal screening and the establishment of robust metrological standards, several fundamental questions remain hotly debated in the clinical community, reflecting the complexity of translating genetic insights and analytical precision into practical care.

Reference standards and risk thresholds present a major area of ongoing debate. While current guidelines favor universal thresholds ($\ge$125 nmol/L or $\ge$50 mg/dL), the substantial ethnic differences in baseline levels—with African populations having 4-fold higher median levels than East Asians—challenge this approach. This is particularly critical for sub-Saharan African populations, where applying universal thresholds would classify 40–50% as high-risk, yet most outcome data come from African Americans with different genetic admixture rather than continental African populations [11]. Despite these elevated levels, the clinical significance of Lp(a) in sub-Saharan African populations remains uncertain, though some evidence suggests that the predictive value for cardiovascular diseases may not vary sufficiently across ancestries to warrant different thresholds [11]. Critics argue that universal thresholds may lead to over-screening in some populations and under-screening in others. The question remains: Should risk stratification be ancestry-specific to account for population differences, sex-specific to address hormonal influences, or maintain universal standards for clinical simplicity? Recent genetic studies suggest that relative risk per unit increase remains consistent across ethnicities, supporting universal thresholds, but this remains an active area of investigation.

Measurement frequency and timing represent another major point of contention. While guidelines recommend “once in a lifetime” measurement based on genetic stability [12, 22, 24, 33], accumulating evidence challenges this assumption, as Lp(a) levels can fluctuate significantly during acute conditions, with certain medications, and during physiological transitions. This raises critical questions: Should Lp(a) be remeasured after major cardiovascular events? Should women be retested post-menopause? How do we account for medication-induced changes when assessing baseline risk? Current guidelines provide little guidance on these scenarios, leaving clinicians to navigate these decisions empirically.

The clinical significance of measurement variability also remains unresolved. While standardized assays exist, clinicians face unanswered questions: Is the 5–15% inter-assay variation clinically acceptable when making treatment decisions [12, 22]? Should clinicians request apo(a) isoform size testing in addition to concentration, given that smaller isoforms may confer higher risk? When patients present with results in different units (mg/dL vs nmol/L), how should clinicians interpret risk given that conversion factors vary from 2.0–2.5 depending on isoform size [12, 22]? These measurement uncertainties directly impact clinical decision-making, particularly for patients with borderline elevations where assay variability could alter risk classification.

Lp(a) has been firmly established as an independent biomarker for cardiovascular risk through decades of large-scale observational studies. The evidence base demonstrates consistent, dose-dependent associations across diverse populations and cardiovascular outcomes.

Three landmark observational studies exemplify this evidence. The Copenhagen City Heart Study (9330 participants, 10-year follow-up) demonstrated extreme Lp(a) levels predicted a 3- to 4-fold increase in myocardial infarction risk, with hazard ratios (HR) increasing stepwise from 1.2 to 2.6 across Lp(a) percentiles (trend p 0.001) [34]. The Atherosclerosis Risk in Communities (ARIC) study (14,221 participants, 13.5-year follow-up) showed individuals with Lp(a) $\ge$30 mg/dL had 79% higher ischemic stroke risk than those 10 mg/dL, with comparable associations in African Americans and Caucasians, establishing Lp(a) as a universal biomarker across ancestries [35]. More recently, the Mass General Brigham Lp(a) Registry (16,419 participants, median 11.9-year follow-up) confirmed these associations in a large contemporary U.S. cohort, demonstrating that elevated Lp(a) independently predicts major adverse cardiovascular events in both primary and secondary prevention populations [36]. Notably, primary prevention patients with Lp(a) in the highest decile show markedly elevated cardiovascular risk, underscoring the clinical importance of identifying these individuals [36]. This recognition has led to Lp(a) being described as a biomarker whose time has come by the NLA, reflecting its maturation from research curiosity to clinical tool.

Mendelian randomization (MR) uses genetic variants as ‘nature’s randomized trial’. Since genes are randomly assigned at conception, they’re not influenced by lifestyle or other factors that confound observational studies. If genetic variants that raise Lp(a) also increase atherosclerotic cardiovascular disease (ASCVD) risk, this strongly suggests Lp(a) causes the disease rather than just marking it. Because Lp(a) levels are largely genetically determined—primarily by LPA gene variants, including KIV-2 repeats and specific single nucleotide polymorphisms (SNPs)—MR is a particularly powerful tool for establishing causality [32].

Table 3 (Ref. [37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50]) summarizes key MR studies demonstrating causal relationships between Lp(a) and ASCVD (Coronary heart disease [37, 38, 39, 40], multiple cardiovascular diseases [41, 42, 43, 44, 45, 46], ischemic stroke [41, 42, 43, 44, 45, 46], and peripheral arterial disease [50]), while Table 4 (Ref. [41, 42, 43, 44, 45, 46, 47, 48, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61]) presents MR evidence for non-atherosclerotic outcomes including valvular heart disease [41, 42, 43, 44, 51, 52, 53], heart failure [41, 43, 45, 46, 48, 54, 55, 56], atrial fibrillation [41, 43, 45, 46, 48, 55, 56, 57], non-ASCVD stroke [42, 45, 47], and other non-ASCVD outcomes [41, 42, 43, 46, 58, 59, 60, 61]. The MR evidence demonstrates robust causal relationships across the ASCVD outcomes. Multiple large-scale MR studies consistently show causal relationships between Lp(a) and coronary heart disease. The 2018 Burgess et al. study [40] notably found that a 100 mg/dL Lp(a) reduction would provide cardiovascular benefits equivalent to a 38.67 mg/dL LDL-cholesterol (LDL-C) reduction. Importantly, MR studies reveal differential effects by stroke subtype, with stronger associations for large-artery stroke (odds ratio, OR 1.20, 95% CI 1.11–1.30) [47] and null or protective effects for small-vessel stroke, suggesting distinct pathophysiological mechanisms underlying Lp(a)’s vascular effects.

While MR studies provide compelling evidence for Lp(a) causality in atherosclerotic outcomes (Table 3), the evidence for non-atherosclerotic cardiovascular outcomes presents a more complex picture (Table 4). Strong evidence supports Lp(a) causality for calcific aortic valve stenosis [41, 42, 44, 51, 52, 53]. For heart failure, the MR evidence shows significant heterogeneity that appears population-dependent, with European populations showing mostly positive associations [43, 54] or null effects [45, 55], while African [43] and Chinese [48] ancestry show null effects, with meta-analysis revealing extreme heterogeneity (I² = 97.6%) [56]. This variation may suggest that Lp(a)’s effect on heart failure may be modified by genetic background or environmental factors. Similarly, atrial fibrillation shows modest positive associations in European [43, 55, 57] but null effects in African ancestry (OR 1.06, 95% CI 0.99–1.14) [43] and protective effects in Han Chinese (OR 0.94, 95% CI 0.90–0.99) [48], highlighting striking population-specific differences.

Notably, multiple MR studies consistently show no causal relationship between Lp(a) and type 2 diabetes (OR 0.97–1.08 across studies) [41, 58, 59, 60]. This null association distinguishes Lp(a) from triglyceride-rich lipoproteins. Unlike metabolically active lipoproteins that affect insulin signaling, Lp(a) primarily drives vascular inflammation through oxidized phospholipids without affecting glucose metabolism—suggesting Lp(a)-lowering therapies will be metabolically neutral, unlike statins. MR analysis does not support a causal relationship between Lp(a) and immune-mediated inflammatory diseases [61]. Lp(a) is causally linked to both thrombosis (especially arterial) and inflammation [62]. Its prothrombotic effects are mediated by impaired fibrinolysis and increased tissue factor, while its pro-inflammatory properties are largely due to its carriage of oxidized phospholipids and stimulation of vascular immune responses. For venous thromboembolism, MR evidence has been inconsistent—studies of individual components showed null associations [41, 42], while recent combined VTE analysis found a modest increased risk [46]. The smaller and less consistent effect sizes for non-atherosclerotic outcomes may reflect that Lp(a)’s thrombotic and inflammatory effects are primarily pathogenic in the arterial circulation or require the presence of atherosclerotic plaque to manifest their full clinical impact. This mechanistic understanding supports the focus on ASCVD as the primary target for Lp(a)-lowering interventions.

The convergence of observational and genetic evidence establishes Lp(a) as both a biomarker and causal factor. This dual validation provides the scientific foundation for both current screening recommendations and the ongoing development of Lp(a)-targeted therapies [4]. As a biomarker, Lp(a) identifies high-risk individuals who benefit from aggressive management of modifiable risk factors; as a causal factor, it represents a valid therapeutic target, justifying the ongoing clinical trials of Lp(a)-lowering approaches.

Looking forward, Lp(a) is poised to play a central role in multi-biomarker approaches to cardiovascular risk assessment. Its genetic determination and lifelong stability make it an ideal complement to dynamic biomarkers such as high-sensitivity troponin, N-terminal pro-B-type natriuretic peptide, and C-reactive protein. Such integrated biomarker panels could enable more precise identification of patients with residual cardiovascular risk despite optimal management of traditional risk factors, ultimately guiding both risk stratification and the selection of targeted interventions in precision cardiovascular medicine.

Conventional lipid-lowering therapies demonstrate limited efficacy against Lp(a), with some paradoxically increasing levels despite their cardiovascular benefits. Table 5 (Ref. [64]) summarizes these effects across drug classes: statin [65], PCSK9 monoclonal antibody inhibitors [66, 67, 68], PCSK9 small interfering RNA (siRNA) [69], ezetimibe [70], bempedoic acid [71], fibrates [64], niacin [72], and lomitapide [73].

Statins exemplify this paradox, increasing Lp(a) levels by 10–20% through upregulation of LPA gene expression—potentially undermining their cardiovascular benefits in patients with elevated Lp(a) levels [12, 65]. This phenomenon represents a cardiologist’s dilemma: the very medications proven to reduce cardiovascular events may simultaneously elevate a potent genetic risk factor. Despite this paradox, statins remain indicated in patients with elevated Lp(a) because their cardiovascular benefits through LDL-C reduction substantially outweigh the possible modest Lp(a) increase. MR studies suggest the cardiovascular benefit from a 38.67 mg/dL LDL-C reduction (achievable with statins) is equivalent to a 100 mg/dL Lp(a) reduction [40]—far exceeding the 10–20% Lp(a) increase caused by statins. Thus, withholding statins from high Lp(a) patients would result in net cardiovascular harm.

PCSK9 inhibitors achieve modest Lp(a) reductions, though reporting varies across studies. A meta-analysis demonstrated that these agents reduce Lp(a) by a weighted mean difference of –12.55 mg/dL (95% CI: –17.05 to –8.04 mg/dL) and are associated with reduced major adverse cardiac events (MACE) (RR 0.86, 95% CI: 0.81–0.91) in patients with coronary heart disease, though the analysis did not establish whether Lp(a) reduction independently contributes to cardiovascular benefit [67]. Similarly, while the ODYSSEY OUTCOMES trial with alirocumab demonstrated 25–30% Lp(a) reduction, it did not prove this reduction significantly contributed to cardiovascular benefits, leaving the relationship correlative rather than causal [68]. In contrast, the FOURIER trial provided stronger evidence for Lp(a)’s independent contribution, showing that evolocumab reduced Lp(a) by a median of 26.9% (interquartile range: 6.2–46.7%) at 48 weeks, with a 15% cardiovascular risk reduction per 25 nmol/L decrease in Lp(a) independent of LDL-C changes [66]. Despite these benefits, PCSK9 inhibitors are still not considered a primary Lp(a)-targeted therapy due to their modest effect compared to newer RNA-targeted therapies, which achieve reductions exceeding 95%.

Inclisiran, a PCSK9 siRNA, reduces Lp(a) by 15–25% [69], similar to monoclonal antibodies evolocumab and alirocumab, likely through enhanced LDL receptor-mediated clearance. Like ODYSSEY OUTCOMES, the ORION trials have not analyzed whether this Lp(a) reduction independently contributes to cardiovascular benefit. The ongoing ORION-4 cardiovascular outcomes trial, with results expected around 2026, will determine whether inclisiran reduces MACE.

Niacin reduces Lp(a) levels via decreasing apo(a) production rate. Extended-release niacin was associated with a significant 23% reduction in Lp(a) levels in a meta-analysis [72]. The Coronary Drug Project demonstrated the benefit of niacin monotherapy for ASCVD in men [74]; however, a combination of statin and niacin did not show clinical benefit [75, 76]. The 2024 NLA guidelines explicitly recommend against its use for ASCVD risk reduction (Class III recommendation) [22].

Lipoprotein apheresis is the first Food and Drug Administration (FDA)-approved Lp(a)-lowering intervention [33, 77]. The 2024 NLA provides a Class IIa recommendation: Lipoprotein apheresis is reasonable for high-risk patients with familial hypercholesterolemia and ASCVD (coronary or peripheral arteries) whose Lp(a) level remains $\ge$60 mg/dL (150 nmol/L) and LDL-C $\ge$100 mg/dL on maximally tolerated lipid-lowering therapy [22]. While effective at acutely lowering Lp(a) through non-specific apoB particle removal, the procedure’s benefits are transient, requiring frequent repetition.

Emerging observational evidence suggests aspirin may offer benefit for individuals with elevated Lp(a), with a recent propensity-matched study demonstrating a 46% lower risk of coronary events (HR 0.54, 95% CI, 0.32–0.94) among those with Lp(a) $>$50 mg/dL taking aspirin, though randomized trials are needed for confirmation [78]. Overall, these modest effects pale in comparison to the unprecedented potency of emerging RNA-targeted therapies.

The landscape for Lp(a) management is undergoing revolutionary transformation with therapeutic approaches targeting different stages of Lp(a) production. RNA-targeted strategies, including antisense oligonucleotides (ASOs) and siRNAs, prevent apolipoprotein(a) synthesis at the hepatic level, while small molecule inhibitors like muvalaplin disrupt Lp(a) particle assembly. These approaches provide clinicians with tools to meaningfully reduce Lp(a) levels that have remained resistant to conventional lipid-lowering therapies [79, 80].

As shown in Table 5, monthly administered ASOs like pelacarsen achieved dose-dependent Lp(a) reductions of 35–80% in phase 2 trials [6], leading to the ongoing Lp(a)HORIZON phase 3 cardiovascular outcome trial [81]. The siRNA approaches demonstrated even greater potency with extended duration: olpasiran achieved $>$95% reduction with quarterly dosing [7, 27, 82] and is now being evaluated in the OCEAN(a) trial [83]; lepodisiran showed 94% reduction with potential twice-yearly administration [84] and entered the ACCLAIM-Lp(a) trial [85]; while zerlasiran achieved 90% reduction with 4–6 month intervals [9] and recently completed phase 2. All maintained efficacy between doses, representing a major advance over conventional therapies requiring daily or frequent administration.

The emergence of muvalaplin as the first oral Lp(a)-lowering agent represents a pivotal advance in treatment accessibility. This small molecule inhibitor achieved up to 85.8% reductions in the KRAKEN phase 2 trial [8, 86], offering daily oral therapy that could dramatically improve patient acceptance compared to injectable approaches, particularly for primary prevention populations.

Across all RNA-targeted approaches, safety profiles have been reassuring, with mild injection-site reactions as the most common adverse effects and no evidence of off-target toxicity. Importantly, these agents specifically target Lp(a) production rather than having off-target LDL-C effects, unlike PCSK9 inhibitors which affect both.

Despite achieving exceptional biomarker reductions with RNA-targeted therapies, a critical question remains unanswered: will these dramatic biochemical changes translate to reduced cardiovascular events? This fundamental uncertainty represents the current “waiting game” in cardiovascular medicine, where remarkable pharmacological success awaits clinical validation.

The disconnect between proven Lp(a) lowering and unproven clinical outcomes reflects the complexity of cardiovascular therapeutics. History teaches caution—numerous interventions that successfully modified biomarkers failed to improve patient outcomes. Yet the genetic evidence for Lp(a) causality, combined with the magnitude of achievable reductions, provides reason for optimism.

There are three ongoing major phase 3 cardiovascular outcome trials: Lp(a)HORIZON (pelacarsen, completing 2026) [81, 87], OCEAN(a) (olpasiran, completing 2026) [83], and ACCLAIM-Lp(a) (lepodisiran, completing 2029) [85]. These trials should provide definitive evidence whether genetically-targeted Lp(a) reduction translates to cardiovascular benefit—completing the journey from genetic insight to clinical reality.

A practical treatment algorithm for Lp(a) management, based on current evidence and guidelines, is presented in Fig. 1. Universal screening is recommended for all adults $\ge$18 years, at least once in their lifetime. The optimal timing is 40–50 years, which balances early detection with the cardiovascular risk period. If resources are limited, priority testing would be for personal history of premature ASCVD (55 years men, 65 years women), family history of premature ASCVD or elevated Lp(a), familial hypercholesterolemia, recurrent cardiovascular events despite optimal LDL-C control, calcific aortic valve stenosis, and intermediate cardiovascular risk (5–20% 10-year risk) requiring reclassification.

Risk stratification based on Lp(a) levels alters several key clinical decisions: (1) cascade family screening becomes mandatory when Lp(a) levels reach 125 nmol/L or higher, necessitating testing of all first-degree relatives given the strong genetic heritability [4, 12, 33]; (2) the threshold for statin initiation shifts in patients with borderline cardiovascular risk, where Lp(a) levels of $\ge$75 nmol/L favor treatment initiation despite otherwise equivocal risk profiles [24]; (3) aspirin for primary prevention requires careful risk-benefit assessment, with consideration warranted when Lp(a) $\ge$125 nmol/L and 10-year ASCVD risk $\ge$10%, or when Lp(a) $\ge$430 nmol/L with 10-year risk $>$7.5% [78]; (4) the addition of PCSK9 inhibitors should be considered at lower LDL-C thresholds in patients with Lp(a) levels above 125 nmol/L, recognizing both the modest Lp(a)-lowering effect and the heightened residual risk [66]; (5) lipoprotein apheresis referral becomes appropriate for patients with Lp(a) levels of 60 mg/dL or higher who experience recurrent cardiovascular events despite guideline-directed medical therapy [22, 33, 77].

Repeated Lp(a) measurements are generally unnecessary given genetic stability [12, 22]; monitoring should focus on modifiable factors like LDL-C, blood pressure, and HbA1c. Rare exceptions for repeat testing include acute phase responses (20–30% elevation during acute myocardial infarction), pregnancy-related fluctuations, verification of extremely high values before initiating apheresis, and certain conditions affecting Lp(a) levels such as declining renal function, post-menopausal status (5–10% increase), or medication effects from niacin and PCSK9 inhibitors (15–30% reduction) [12, 18, 19, 66, 72]. While these variations rarely alter management given Lp(a)’s predominantly genetic determination, clinicians should recognize these potential confounders when interpreting serial measurements.

Healthcare systems must prepare for the imminent availability of RNA-targeted therapies. Key preparatory steps include establishing specialized lipid clinics, training healthcare providers in Lp(a) management, developing patient registries for those with elevated levels, and creating reimbursement pathways. While phase 3 trials have enrolled patients with Lp(a) thresholds as low as 70 mg/dL (175 nmol/L) for secondary prevention (Lp(a)HORIZON) [81] and 175 nmol/L for primary prevention (ACCLAIM-Lp(a)) [85], real-world implementation will likely require more stringent criteria initially.

Based on risk-benefit considerations and cost-effectiveness, patient selection may follow a tiered approach. First priority would be secondary prevention with recurrent ASCVD events and Lp(a) $\ge$125 nmol/L. Second would be secondary prevention with a single event and Lp(a) $\ge$125 nmol/L. Third would be primary prevention for patients with Lp(a) $\ge$180–250 nmol/L, particularly those with additional risk enhancers. These higher thresholds reflect the balance between identifying those at the highest absolute risk while awaiting definitive outcome data [12, 22].

Implementation challenges require immediate attention. Healthcare systems should establish Lp(a) testing infrastructure now, as identifying eligible patients requires systematic screening programs that may take years to implement fully. Clinical protocols must address practical questions, including the timing of therapy initiation relative to acute events, concurrent management with existing lipid-lowering agents, and monitoring requirements during treatment. Patient education programs should also be initiated immediately, as individuals with elevated Lp(a) need an understanding of both current risk management strategies and emerging therapeutic options. Beyond these clinical considerations, economic barriers will be substantial. Cost considerations based on pricing precedents for similar RNA-targeted therapies will necessitate careful patient selection and outcomes documentation to justify expenditure. Healthcare systems must develop prior authorization processes and work with payers to establish reimbursement pathways that balance access with appropriate utilization.

The focus must shift from whether we can lower Lp(a) to how we can efficiently deliver these therapies to the millions who may benefit. Centers should develop referral networks for high-risk patients and create multidisciplinary teams combining lipidology, cardiology, and pharmacy expertise. Success will require coordinated efforts between healthcare systems, payers, and pharmaceutical companies to ensure equitable access while maintaining appropriate utilization.