Emerging therapies targeting lipoprotein(a): the next frontier in cardiovascular risk reduction

Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein particle composed of apolipoprotein B-100 covalently linked to apolipoprotein(a) [apo(a)] via a disulfide bond. The Lp(a) particle is enriched with oxidized phospholipids (OxPLs), which confer enhanced atherogenic and pro-inflammatory properties compared with low-density lipoprotein (LDL). Robust genetic and epidemiologic evidence demonstrates that elevated Lp(a) levels are independently associated with atherosclerotic cardiovascular disease and calcific aortic valve stenosis. However, no pharmacologic therapy has yet been approved that specifically lower Lp(a) or to demonstrate a reduction in cardiovascular events. Antisense oligonucleotides (e.g., pelacarsen), small-interfering RNAs (e.g., olpasiran, lepodisiran, and zerlasiran), and oral small-molecule Lp(a) inhibitors (e.g., muvalaplin) have demonstrated profound reductions in circulating Lp(a) concentrations, typically achieving decreases of 80–90%. In some studies, the reductions approached or achieved a near-complete suppression. Current genetic and modeling evidence suggests that an absolute reduction of at least 50 mg/dL in Lp(a) levels is required to achieve meaningful cardiovascular benefits. Large-scale outcome trials are now underway to assess the effects of these emerging therapies on cardiovascular and valvular outcomes. Early findings indicate favorable effects on oxidized phospholipids and vascular inflammation, suggesting broader anti-atherogenic potential. As these agents progress toward clinical use, routine Lp(a) measurement and risk stratification will become increasingly essential for personalized cardiovascular prevention. This review summarizes the molecular biology of Lp(a), highlights the limitations of current therapies, and discusses emerging RNA-based and small-molecule approaches with the potential to redefine the management of residual cardiovascular risk.

1 Structure and biochemistry of Lp(a)

Lp(a) is an LDL-like particle composed of apolipoprotein B-100 (apoB-100) covalently linked to apo(a) via a disulfide bond (1, 2). Apo(a) shares structural homology with plasminogen but lacks several functional domains (3). The apo(a) component contains 10 distinct kringle IV subtypes (KIV-1 through KIV-10), a kringle V domain, and an inactive protease-like domain (1–3). The KIV-2 domain exhibits marked copy-number variation that substantially influences both the molecular size of apo(a) and circulating Lp(a) levels (1–3). Figure 1 illustrates the structural features of Lp(a). The size of the apo(a) isoform reflects the KIV-2 copy number and is inversely related to plasma Lp(a) concentrations; individuals with fewer KIV-2 repeats produce a smaller apo(a) isoform that is more efficiently secreted, resulting in higher circulating Lp(a) levels (4).

Figure 1

Figure 1. Structure of Lp(a). apo(a), apolipoprotein (a); apo(B), apolipoprotein B; KIV, Kringle IV domain; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); OxPLs, oxidized phospholipids.

2 Pathogenic mechanisms of Lp(a) in cardiovascular disease

Lp(a) is a key mediator of atherosclerotic cardiovascular disease through three principal pathogenic pathways. First, Lp(a) exerts a prothrombotic effect, largely attributable to the structural homology between apo(a) and plasminogen, which interferes with fibrinolysis and promotes thrombus formation (5). Second, Lp(a) is proatherogenic, as its LDL-like moiety facilitates cholesterol deposition within the arterial intima (5). Third, Lp(a) carries OxPLs on both the LDL-like moiety and kringle V of apo(a), serving as a major plasma carrier of OxPLs (1–3, 5, 6). These oxidized lipids trigger vascular inflammation, promote monocyte recruitment, accelerate atherogenesis, and contribute to plaque instability (5). On a molar basis, Lp(a) exhibits approximately 5- to 6-fold greater atherogenic potency than LDL, primarily due to its OxPL enrichment and pronounced proinflammatory potential (7).

3 Lipoprotein(a) as an independent risk factor for cardiovascular and valvular disease

The Copenhagen General Population Study demonstrated a progressive, concentration-dependent association between circulating Lp(a) levels and cardiovascular risk. Among approximately 70,000 participants followed for a median of 7.4 years, individuals with Lp(a) concentrations ≥50 mg/dL (>105 nmol/L) had a markedly higher incidence of major cardiovascular events than those with levels <10 mg/dL. This association persisted even among participants with well-controlled LDL-cholesterol concentrations (8).

Despite substantial LDL-cholesterol reduction achieved with rosuvastatin in the ASTRONOMER trial, no attenuation in the progression of aortic valve disease was observed (9). This finding indicates that Lp(a) functions as an LDL-independent predictor of calcific aortic valve disease progression (5). Participants with elevated baseline Lp(a) concentrations (>58.5 mg/dL) exhibited a significantly greater annual increase in aortic valve stenosis severity (p = 0.005) and an approximately 2-fold higher risk of aortic valve replacement or death compared with those in the lower tertiles (HR = 2.0; 95% CI: 1.1 to 3.7; p = 0.02) (5). Moreover, individuals with elevated Lp(a) concentrations (≥50 mg/dL) and high coronary artery calcium (CAC) scores (≥100 Agatston units) had a markedly greater 10-year ASCVD incidence compared with those with low Lp(a) and zero CAC (adjusted HR: 4.71; 95% CI: 3.01 to 7.40).

4 Epidemiology and genetic determinants of Lp(a)

Elevated Lp(a) is among the most common inherited lipid disorders. It is estimated that more than 1.4 billion people worldwide—approximately one-fifth of the global population—have Lp(a) concentrations above 125 nmol/L (50 mg/dL) (10). In the United States, approximately 35% of individuals have Lp(a) concentrations above 75 nmol/L (30 mg/dL) (11). Importantly, the atherothrombotic effects of Lp(a) may manifest at concentrations above 75 nmol/L (30 mg/dL) (10).

Plasma Lp(a) concentrations are primarily genetically determined, with more than 90% of interindividual variability explained by polymorphisms within the LPA gene (4, 12). Differences in KIV-2 repeat number determine apo(a) isoform size and drive most of the variation in circulating Lp(a) (4, 12). Therefore, substantial differences in Lp(a) distribution exist among ethnic groups, largely due to population-level variation in LPA allele frequencies (8, 10, 13, 14).

In the UK Biobank cohort, median Lp(a) concentrations were highest among Black participants (75 nmol/L), followed by South Asian (31 nmol/L), White (19 nmol/L), and Chinese (16 nmol/L) individuals (15). Although these ethnic disparities are well documented, current guidelines adopt a unified approach. The 2018 AHA/ACC Multisociety Cholesterol Guideline considers Lp(a) concentrations above 125 nmol/L (50 mg/dL) as a risk-enhancing factor in primary prevention (16).

5 Clinical assessment of Lp(a) in cardiovascular risk stratification

The epidemiologic and genetic characteristics of Lp(a) make measurements essential to identify individuals at increased cardiovascular risk. Plasma Lp(a) concentrations typically peak by approximately 5 years of age and remain relatively stable throughout life (4, 12). Therefore, most clinical guidelines recommend at least one lifetime measurement for clinical assessment and cardiovascular risk stratification (1, 8, 16–19). Nonetheless, certain non-genetic determinants can influence circulating Lp(a) concentrations. These include environmental, physiological, and pathological conditions such as aging, sex differences, menopause, inflammation, and kidney or liver disease (4, 8, 20).

Reassessment may be warranted in selected patient populations, particularly those at intermediate cardiovascular risk (8). For example, changes related to these non-genetic determinants may increase Lp(a) concentrations, potentially shifting an individual from an intermediate- to a higher-risk category. Therefore, measuring Lp(a) remains clinically important for cardiovascular risk assessment and for guiding the intensity of preventive interventions (1).

6 Underutilization of Lp(a) testing in clinical practice

Real-world data indicate that Lp(a) testing remains markedly underutilized in clinical practice (21–24). In an analysis of more than 5.5 million adults across six University of California health systems from 2012 to 2021, only 0.3% of all adults underwent Lp(a) testing (21). Even among higher-risk populations, testing was performed in only 3% of individuals with a family history of cardiovascular disease and in fewer than 4% of those with a personal history of cardiovascular disease (21). Recent data also show that fewer than 1% of adults in the United States have ever undergone Lp(a) measurement, with substantially lower testing rates among non-Hispanic Black individuals (OR: 0.68; 95% CI: 0.58 to 0.81) (22).

7 Analytical challenges in Lp(a) quantification

Accurate assessment of Lp(a) requires direct measurement, as standard lipid panels do not differentiate cholesterol derived from LDL particles from that transported by Lp(a) (25). Other circulating biomarkers, including apolipoprotein B and C-reactive protein, also do not typically capture the unique proatherogenic and procalcific properties of Lp(a) and are therefore inadequate substitutes for its measurement (26, 27).

The quantification of Lp(a) concentrations can be performed using either mass-based or particle-based assays (1). Mass assays report Lp(a) levels in milligrams per deciliter (mg/dL) and measure the total protein-lipid mass of circulating particles. Although mass assays are widely used in clinical laboratories, they are substantially influenced by apo(a) isoform size heterogeneity, which limits accuracy when estimating the true particle number (5, 28).

In contrast, particle-based assays quantify Lp(a) in nanomoles per liter (nmol/L), representing the molar concentration of Lp(a) particles rather than their aggregate mass. This approach is considered analytically superior, as it provides a more accurate estimation of particle burden and associated cardiovascular risk (5, 28). Nevertheless, particle-based assays remain less commonly available for routine use due to ongoing standardization challenges.

While direct conversions between mg/dL and nmol/L measurements are not scientifically valid, approximate conversions are sometimes used in clinical and research contexts to facilitate interpretation. Such estimates should be interpreted cautiously, given the inherent analytical imprecision.

8 Clinical management of patients with elevated lipoprotein(a)

The management of elevated Lp(a) requires a comprehensive approach that combines precise cardiovascular risk assessment, lifestyle optimization, and aggressive control of modifiable risk factors (1). In the primary prevention setting, Lp(a) measurement serves as an adjunct to conventional ASCVD risk estimation, particularly in individuals with a family history of premature ASCVD or elevated CAC scores (16). Although Lp(a) is currently considered a risk-enhancing marker, it is anticipated to become a therapeutic target as ongoing trials of Lp(a)-lowering agents report their outcomes. In patients with established ASCVD, elevated Lp(a) highlights the need for aggressive residual-risk reduction as part of secondary prevention (16).

To date, no pharmacologic agent has been approved specifically for the reduction of Lp(a) concentrations. The effects of existing lipid-lowering therapies on Lp(a) are variable and generally insufficient to meaningfully reduce Lp(a)-associated cardiovascular risk. Table 1 summarizes the effects of currently available lipid-lowering agents on circulating Lp(a) levels. Until targeted therapies become available, prevention management should emphasize comprehensive lifestyle interventions alongside optimal management of coexisting cardiometabolic conditions such as dyslipidemia, hypertension, and diabetes mellitus.

Table 1

Table 1. Effects of available lipid-lowering therapies on lipoprotein(a) and ASCVD risk.

Early identification of individuals with elevated Lp(a) enables the timely implementation of preventive strategies that may mitigate future cardiovascular risk. Management should incorporate shared decision-making, particularly when considering cascade screening of first-degree relatives. Data from the UK Biobank cohort demonstrated a strong familial association with elevated Lp(a) levels, with elevated concentrations observed in more than 40% of first-degree and approximately 30% of second-degree relatives (29).

9 Emerging Lp(a)-lowering therapies

Emerging therapies targeting Lp(a) act through three main mechanisms of action (Figure 2) (30). Antisense oligonucleotides (ASO), such as pelacarsen, consist of single-stranded nucleotides conjugated to N-acetylgalactosamine (GalNAc), which facilitates targeted delivery to hepatocytes via the asialoglycoprotein (ASGPR) receptors (1). Once internalized, these agents hybridize with LPA messenger RNA to form a duplex that recruits RNase H, leading to selective cleavage of the mRNA strand and inhibition of apo(a) protein synthesis (1).

Figure 2

Figure 2. Emerging therapeutic approaches targeting lipoprotein(a). apo(a), apolipoprotein(a); apo(B), apolipoprotein B; ASO, Antisense oligonucleotide; RISC, RNA-induced silencing complex; siRNAs, Small interfering RNAs; Lp(a), lipoprotein(a).

Small interfering RNAs (siRNAs), including olpasiran, lepodisiran, and zerlasiran, follow a complementary pathway. These double-stranded, GalNAc-conjugated molecules are processed intracellularly, where the antisense strand is incorporated into the RNA-induced silencing complex (RISC), which subsequently guides it to LPA mRNA for cleavage and degradation, thereby silencing apo(a) production (1).

In addition to these gene-silencing strategies, muvalaplin introduces a third mechanism by disrupting Lp(a) particle assembly. As the first oral small-molecule Lp(a) inhibitor, muvalaplin prevents the binding of apo(a) to apo(B), thereby blocking the formation of the mature Lp(a) complex (30).

These therapeutic approaches have demonstrated substantial efficacy, reducing circulating Lp(a) concentrations by approximately 80–90%, with some regimens achieving near-complete suppression (Table 2). However, whether these biochemical reductions will translate into meaningful reductions in cardiovascular events remains to be determined, pending results from large-scale outcome trials. Nevertheless, early-phase clinical studies have reported favorable safety profiles across all classes of these investigational agents. Mild injection site reactions were the most frequently observed adverse events. Long-term use data are still needed to establish a more definitive understanding of the overall safety profile of these emerging therapies.

Table 2

Table 2. Emerging pharmacological agents targeting Lp(a) reduction.

10 Magnitude of Lp(a) reduction required for clinical benefits

Accumulating genetic evidence indicates that substantial absolute reductions in Lp(a) levels are necessary to achieve measurable cardiovascular benefits. A landmark Mendelian randomization analysis demonstrated a linear, dose-dependent association between genetically determined Lp(a) concentrations and the risk of coronary heart disease (CHD) (31). The study suggested that the cardiovascular benefit is proportional to the absolute magnitude of Lp(a) lowering rather than to relative percentage change. Each 10 mg/dL decrement in genetically predicted Lp(a) corresponded to an approximately 5.8% reduction in CHD odds (OR 0.94; 95% CI 0.93–0.95) (31).

Modeling of this relationship indicated that an absolute reduction of approximately 100 mg/dL would be required to achieve a CHD risk reduction comparable to lowering LDL-cholesterol by 38.67 mg/dL (1 mmol/L)—a degree of LDL-cholesterol lowering consistently associated with a 20–25% decrease in major cardiovascular events (32). Therefore, achieving meaningful cardiovascular benefit likely requires lowering Lp(a) by approximately 105–210 nmol/L (50–100 mg/dL) (7). This finding may provide a mechanistic rationale for the neutral outcomes observed in earlier trials of agents such as niacin, which reduced Lp(a) by 20–30% yet produced limited absolute changes and, consequently, no discernible Lp(a)-specific benefit.

11 Conclusions and future directions

Although novel Lp(a)-lowering agents have demonstrated marked efficacy, often achieving reductions of 80–90%, it remains uncertain whether these substantial biochemical effects will translate into proportional reductions in cardiovascular events. Additionally, these therapies have been shown to lower OxPLs and vascular inflammation, suggesting additive cardiovascular benefits beyond Lp(a) lowering (7, 33–35).

Ongoing cardiovascular outcome trials will be essential to determine whether achieving such profound decreases in Lp(a) can meaningfully modify residual cardiovascular risk and confirm the predictions derived from genetic modeling. If these trials confirm its clinical benefit, Lp(a)-targeted therapy may become available in routine practice within the next few years, shifting Lp(a) from a risk modifier to a treatable therapeutic target.

Author contributions

IA: Conceptualization, Data curation, Investigation, Methodology, Project administration, Resources, Supervision, Validation, Visualization, Writing – original draft, Writing – review & editing.

Funding

The author(s) declared that financial support was received for this work and/or its publication. The APC was funded by the Deanship of Graduate Studies and Scientific Research at Qassim University (QU-APC-2025).

Acknowledgments

The researcher would like to thank the Deanship of Graduate Studies and Scientific Research at Qassim University for financial support (QU-APC-2025).

Conflict of interest

The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that Generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

1. Alhomoud, IS, Talasaz, A, Mehta, A, Kelly, MS, Sisson, EM, Bucheit, JD, et al. Role of lipoprotein(a) in atherosclerotic cardiovascular disease: a review of current and emerging therapies. Pharmacotherapy. (2023) 43:1051–63. doi: 10.1002/phar.2851,

PubMed Abstract | Crossref Full Text | Google Scholar

2. Koschinsky, ML, and Boffa, MB. Oxidized phospholipid modification of lipoprotein(a): epidemiology, biochemistry and pathophysiology. Atherosclerosis. (2022) 349:92–100. doi: 10.1016/j.atherosclerosis.2022.04.001,

PubMed Abstract | Crossref Full Text | Google Scholar

3. Boffa, MB, and Koschinsky, ML. Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease. Nat Rev Cardiol. (2019) 16:305–18. doi: 10.1038/s41569-018-0153-2,

PubMed Abstract | Crossref Full Text | Google Scholar

4. Enkhmaa, B, Anuurad, E, and Berglund, L. Lipoprotein (a): impact by ethnicity and environmental and medical conditions. J Lipid Res. (2016) 57:1111–25. doi: 10.1194/jlr.R051904,

PubMed Abstract | Crossref Full Text | Google Scholar

5. Tsimikas, S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. (2017) 69:692–711. doi: 10.1016/j.jacc.2016.11.042,

PubMed Abstract | Crossref Full Text | Google Scholar

6. Mehta, A, and Shapiro, MD. Apolipoproteins in vascular biology and atherosclerotic disease. Nat Rev Cardiol. (2022) 19:168–79. doi: 10.1038/s41569-021-00613-5,

PubMed Abstract | Crossref Full Text | Google Scholar

7. Greco, A, Finocchiaro, S, Spagnolo, M, Faro, DC, Mauro, MS, Raffo, C, et al. Lipoprotein(a) as a pharmacological target: premises, promises, and prospects. Circulation. (2025) 151:400–15. doi: 10.1161/CIRCULATIONAHA.124.069210,

PubMed Abstract | Crossref Full Text | Google Scholar

8. Kronenberg, F, Mora, S, Stroes, ESG, Ference, BA, Arsenault, BJ, Berglund, L, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European atherosclerosis society consensus statement. Eur Heart J. (2022) 43:3925–46. doi: 10.1093/eurheartj/ehac361,

PubMed Abstract | Crossref Full Text | Google Scholar

9. Chan, KL, Teo, K, Dumesnil, JG, Ni, A, and Tam, J. Effect of lipid lowering with Rosuvastatin on progression of aortic stenosis: results of the aortic stenosis progression observation: measuring effects of Rosuvastatin (ASTRONOMER) trial. Circulation. (2010) 121:306–14. doi: 10.1161/CIRCULATIONAHA.109.900027,

PubMed Abstract | Crossref Full Text | Google Scholar

10. Tsimikas, S, Fazio, S, Ferdinand, KC, Ginsberg, HN, Koschinsky, ML, Marcovina, SM, et al. NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol. (2018) 71:177–92. doi: 10.1016/j.jacc.2017.11.014,

PubMed Abstract | Crossref Full Text | Google Scholar

11. Varvel, S, McConnell, JP, and Tsimikas, S. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler Thromb Vasc Biol. (2016) 36:2239–45. doi: 10.1161/ATVBAHA.116.308011,

PubMed Abstract | Crossref Full Text | Google Scholar

12. Tsimikas, S, Moriarty, PM, and Stroes, ES. Emerging RNA therapeutics to lower blood levels of Lp(a): JACC focus seminar 2/4. J Am Coll Cardiol. (2021) 77:1576–89. doi: 10.1016/j.jacc.2021.01.051,

PubMed Abstract | Crossref Full Text | Google Scholar

13. Guan, W, Cao, J, Steffen, BT, Post, WS, Stein, JH, Tattersall, MC, et al. Race is a key variable in assigning lipoprotein(a) cutoff values for coronary heart disease risk assessment: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol. (2015) 35:996–1001. doi: 10.1161/ATVBAHA.114.304785,

PubMed Abstract | Crossref Full Text | Google Scholar

14. Virani, SS, Brautbar, A, Davis, BC, Nambi, V, Hoogeveen, RC, Sharrett, AR, et al. Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the atherosclerosis risk in communities (ARIC) study. Circulation. (2012) 125:241–9. doi: 10.1161/CIRCULATIONAHA.111.045120,

PubMed Abstract | Crossref Full Text | Google Scholar

15. Patel, AP, Wang, M, Pirruccello, JP, Ellinor, PT, Ng, K, Kathiresan, S, et al. Lp(a) (lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease: new insights from a large national biobank. Arterioscler Thromb Vasc Biol. (2021) 41:465–74. doi: 10.1161/ATVBAHA.120.315291,

PubMed Abstract | Crossref Full Text | Google Scholar

16. Grundy, SM, Stone, NJ, Bailey, AL, Beam, C, Birtcher, KK, Blumenthal, RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. (2019) 139. doi: 10.1161/CIR.0000000000000625

Crossref Full Text | Google Scholar

17. Mach, F, Baigent, C, Catapano, AL, Koskinas, KC, Casula, M, Badimon, L, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. (2020) 41:111–88. doi: 10.1093/eurheartj/ehz455,

PubMed Abstract | Crossref Full Text | Google Scholar

18. Koschinsky, ML, Bajaj, A, Boffa, MB, Dixon, DL, Ferdinand, KC, Gidding, SS, et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol. (2024) 18:e308–19. doi: 10.1016/j.jacl.2024.03.001,

PubMed Abstract | Crossref Full Text | Google Scholar

19. Reyes-Soffer, G, Ginsberg, HN, Berglund, L, Duell, PB, Heffron, SP, Kamstrup, PR, et al. Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. (2022) 42:e48–60. doi: 10.1161/ATV.0000000000000147,

PubMed Abstract | Crossref Full Text | Google Scholar

20. Simony, SB, Mortensen, MB, Langsted, A, Afzal, S, Kamstrup, PR, and Nordestgaard, BG. Sex differences of lipoprotein(a) levels and associated risk of morbidity and mortality by age: the Copenhagen general population study. Atherosclerosis. (2022) 355:76–82. doi: 10.1016/j.atherosclerosis.2022.06.1023,

PubMed Abstract | Crossref Full Text | Google Scholar

21. Bhatia, HS, Hurst, S, Desai, P, Zhu, W, and Yeang, C. Lipoprotein(a) testing trends in a large academic health system in the United States. J Am Heart Assoc. (2023) 12:e031255. doi: 10.1161/JAHA.123.031255,

PubMed Abstract | Crossref Full Text | Google Scholar

22. Razavi, AC, Richardson, LC, Coronado, F, Vesper, HW, Lyle, A, Bhatia, HS, et al. Prevalence and correlates of lipoprotein(a) testing in a diverse cohort of U.S. adults. JACC Adv. (2025) 4:101826. doi: 10.1016/j.jacadv.2025.101826,

PubMed Abstract | Crossref Full Text | Google Scholar

23. Alotaibi, AS, Albekery, MA, Alanazi, AA, Alhomoud, IS, Alamer, KA, Shawaqfeh, M, et al. Evaluation of statins use in hemodialysis patients: a retrospective analysis of clinical and safety outcomes. Pharmaceuticals. (2025) 18:911. doi: 10.3390/ph18060911,

PubMed Abstract | Crossref Full Text | Google Scholar

24. Altuwalah, A, Alfehaid, L, Alhmoud, H, Alrasheedy, A, and Alhomoud, I. ApoB testing in dyslipidemia management: knowledge and practices of healthcare providers in Saudi Arabia. J Multidiscip Healthc. (2025) 18:6667–79. doi: 10.2147/JMDH.S560362,

PubMed Abstract | Crossref Full Text | Google Scholar

25. Viney, NJ, Yeang, C, Yang, X, Xia, S, Witztum, JL, and Tsimikas, S. Relationship between “LDL-C”, estimated true LDL-C, apolipoprotein B-100, and PCSK9 levels following lipoprotein(a) lowering with an antisense oligonucleotide. J Clin Lipidol. (2018) 12:702–10. doi: 10.1016/j.jacl.2018.02.014,

PubMed Abstract | Crossref Full Text | Google Scholar

26. Small, AM, Pournamdari, A, Melloni, GEM, Scirica, BM, Bhatt, DL, Raz, I, et al. Lipoprotein(a), C-reactive protein, and cardiovascular risk in primary and secondary prevention populations. JAMA Cardiol. (2024) 9:385–91. doi: 10.1001/jamacardio.2023.5605,

PubMed Abstract | Crossref Full Text | Google Scholar

27. Tsimikas, S, and Bittner, V. Particle number and characteristics of lipoprotein(a), LDL, and apoB: perspectives on contributions to ASCVD. J Am Coll Cardiol. (2024) 83:396–400. doi: 10.1016/j.jacc.2023.11.008,

PubMed Abstract | Crossref Full Text | Google Scholar

28. Nordestgaard, BG, Chapman, MJ, Ray, K, Borén, J, Andreotti, F, Watts, GF, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. (2010) 31:2844–53. doi: 10.1093/eurheartj/ehq386,

PubMed Abstract | Crossref Full Text | Google Scholar

29. Reeskamp, LF, Tromp, TR, Patel, AP, Ibrahim, S, Trinder, M, Haidermota, S, et al. Concordance of a high lipoprotein(a) concentration among relatives. JAMA Cardiol. (2023) 8:1111–8. doi: 10.1001/jamacardio.2023.3548,

PubMed Abstract | Crossref Full Text | Google Scholar

30. Kaur, G, Abdelrahman, K, Berman, AN, Biery, DW, Shiyovich, A, Huck, D, et al. Lipoprotein(a): emerging insights and therapeutics. Am J Prev Cardiol. (2024) 18:100641. doi: 10.1016/j.ajpc.2024.100641,

PubMed Abstract | Crossref Full Text | Google Scholar

31. Burgess, S, Ference, BA, Staley, JR, Freitag, DF, Mason, AM, Nielsen, SF, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. (2018) 3:619–27. doi: 10.1001/jamacardio.2018.1470,

PubMed Abstract | Crossref Full Text | Google Scholar

32. Ference, BA, Yoo, W, Alesh, I, Mahajan, N, Mirowska, KK, Mewada, A, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol. (2012) 60:2631–9. doi: 10.1016/j.jacc.2012.09.017,

PubMed Abstract | Crossref Full Text | Google Scholar

33. Stiekema, LCA, Prange, KHM, Hoogeveen, RM, Verweij, SL, Kroon, J, Schnitzler, JG, et al. Potent lipoprotein(a) lowering following apolipoprotein(a) antisense treatment reduces the pro-inflammatory activation of circulating monocytes in patients with elevated lipoprotein(a). Eur Heart J. (2020) 41:2262–71. doi: 10.1093/eurheartj/ehaa171,

PubMed Abstract | Crossref Full Text | Google Scholar

34. O’Donoghue, ML, Rosenson, RS, Gencer, B, López, JAG, Lepor, NE, Baum, SJ, et al. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N Engl J Med. (2022) 387:1855–64. doi: 10.1056/NEJMoa2211023,

PubMed Abstract | Crossref Full Text | Google Scholar

35. Tsimikas, S, Karwatowska-Prokopczuk, E, Gouni-Berthold, I, Tardif, JC, Baum, SJ, Steinhagen-Thiessen, E, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. (2020) 382:244–55. doi: 10.1056/NEJMoa1905239,

PubMed Abstract | Crossref Full Text | Google Scholar

36. Tsimikas, S, Gordts, PLSM, Nora, C, Yeang, C, and Witztum, JL. Statin therapy increases lipoprotein(a) levels. Eur Heart J. (2020) 41:2275–84. doi: 10.1093/eurheartj/ehz310,

PubMed Abstract | Crossref Full Text | Google Scholar

37. O’Donoghue, ML, Fazio, S, Giugliano, RP, Stroes, ESG, Kanevsky, E, Gouni-Berthold, I, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation. (2019) 139:1483–92. doi: 10.1161/CIRCULATIONAHA.118.037184,

PubMed Abstract | Crossref Full Text | Google Scholar

38. Bittner, VA, Szarek, M, Aylward, PE, Bhatt, DL, Diaz, R, Edelberg, JM, et al. Effect of Alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. (2020) 75:133–44. doi: 10.1016/j.jacc.2019.10.057,

PubMed Abstract | Crossref Full Text | Google Scholar

39. Ray, KK, Wright, RS, Kallend, D, Koenig, W, Leiter, LA, Raal, FJ, et al. Two phase 3 trials of Inclisiran in patients with elevated LDL cholesterol. N Engl J Med. (2020) 382:1507–19. doi: 10.1056/NEJMoa1912387,

PubMed Abstract | Crossref Full Text | Google Scholar

40. ClinicalTrials.gov. Study of Inclisiran to Prevent cardiovascular (CV) events in participants with established cardiovascular disease (VICTORION-2P). Available online at: https://clinicaltrials.gov/study/NCT05030428 (Accessed October 9, 2025)

Google Scholar

41. ClinicalTrials.gov. A randomized trial assessing the effects of Inclisiran on clinical outcomes among people with cardiovascular disease (ORION-4). Available online at: https://clinicaltrials.gov/study/NCT03705234 (Accessed October 9, 2025).

Google Scholar

42. ClinicalTrials.gov. A study of Inclisiran to Prevent cardiovascular events in high-risk primary prevention patients. ClinicalTrials.gov. Available online at: https://clinicaltrials.gov/study/NCT05739383 (Accessed October 9, 2025).

Google Scholar

43. The AIM-HIGH Investigators. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. (2011) 365:2255–67. doi: 10.1056/NEJMoa1107579

Crossref Full Text | Google Scholar

44. Sahebkar, A, Reiner, Ž, Simental-Mendía, LE, Ferretti, G, and Cicero, AFG. Effect of extended-release niacin on plasma lipoprotein(a) levels: a systematic review and meta-analysis of randomized placebo-controlled trials. Metabolism. (2016) 65:1664–78. doi: 10.1016/j.metabol.2016.08.007,

PubMed Abstract | Crossref Full Text | Google Scholar

45. Schettler, VJJ, Peter, C, Zimmermann, T, Julius, U, Roeseler, E, Schlieper, G, et al. The German lipoprotein apheresis registry-summary of the ninth annual report. Ther Apher Dial. (2022) 26:81–8. doi: 10.1111/1744-9987.13780

Crossref Full Text | Google Scholar

46. Awad, K, Mikhailidis, DP, Katsiki, N, Muntner, P, and Banach, M. Effect of ezetimibe monotherapy on plasma lipoprotein(a) concentrations in patients with primary hypercholesterolemia: a systematic review and meta-analysis of randomized controlled trials. Drugs. (2018) 78:453–62. doi: 10.1007/s40265-018-0870-1

Crossref Full Text | Google Scholar

47. Cannon, CP, Blazing, MA, Giugliano, RP, McCagg, A, White, JA, Theroux, P, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. (2015) 372:2387–97. doi: 10.1056/NEJMoa1410489,

PubMed Abstract | Crossref Full Text | Google Scholar

48. Rubino, J, MacDougall, DE, Sterling, LR, Kelly, SE, McKenney, JM, and Lalwani, ND. Lipid lowering with bempedoic acid added to a proprotein convertase subtilisin/kexin type 9 inhibitor therapy: a randomized, controlled trial. J Clin Lipidol. (2021) 15:593–601. doi: 10.1016/j.jacl.2021.05.002,

PubMed Abstract | Crossref Full Text | Google Scholar

49. Ridker, PM, Lei, L, Ray, KK, Ballantyne, CM, Bradwin, G, and Rifai, N. Effects of bempedoic acid on CRP, IL-6, fibrinogen and lipoprotein(a) in patients with residual inflammatory risk: a secondary analysis of the CLEAR harmony trial. J Clin Lipidol. (2023) 17:297–302. doi: 10.1016/j.jacl.2023.02.002,

PubMed Abstract | Crossref Full Text | Google Scholar

50. Nissen, SE, Lincoff, AM, Brennan, D, Ray, KK, Mason, D, Kastelein, JJP, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. (2023) 388:1353–64. doi: 10.1056/NEJMoa2215024,

PubMed Abstract | Crossref Full Text | Google Scholar

51. Cuchel, M, Meagher, EA, du Toit Theron, H, Blom, DJ, Marais, AD, Hegele, RA, et al. Efficacy and safety of a microsomal triglyceride transfer protein inhibitor in patients with homozygous familial hypercholesterolaemia: a single-arm, open-label, phase 3 study. Lancet. (2013) 381:40–6. doi: 10.1016/S0140-6736(12)61731-0,

PubMed Abstract | Crossref Full Text | Google Scholar

52. Raal, FJ, Rosenson, RS, Reeskamp, LF, Hovingh, GK, Kastelein, JJP, Rubba, P, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. (2020) 383:711–20. doi: 10.1056/NEJMoa2004215,

PubMed Abstract | Crossref Full Text | Google Scholar

53. ClinicalTrials.gov. Assessing the impact of lipoprotein (a) lowering with Pelacarsen (TQJ230) on major cardiovascular events in patients with CVD (Lp(a)HORIZON). Available online at: https://clinicaltrials.gov/study/NCT04023552 (Accessed October 11, 2025).

Google Scholar

54. ClinicalTrials.gov. A multicenter trial assessing the impact of lipoprotein(a) lowering with Pelacarsen (TQJ230) on the progression of calcific aortic valve stenosis. Available online at: https://clinicaltrials.gov/study/NCT05646381 (Accessed October 11, 2025).

Google Scholar

55. ClinicalTrials.gov. Olpasiran trials of cardiovascular events and lipoprotein(a) reduction (OCEAN(a)) - outcomes trial. Available online at: https://clinicaltrials.gov/study/NCT05581303 (Accessed November 10, 2025).

Google Scholar

56. Nissen, SE, Linnebjerg, H, Shen, X, Wolski, K, Ma, X, Lim, S, et al. Lepodisiran, an extended-duration short interfering RNA targeting lipoprotein(a): a randomized dose-ascending clinical trial. JAMA. (2023) 330:2075–83. doi: 10.1001/jama.2023.21835,

PubMed Abstract | Crossref Full Text | Google Scholar

57. Nissen, SE, Ni, W, Shen, X, Wang, Q, Navar, AM, Nicholls, SJ, et al. Lepodisiran - a long-duration Small interfering RNA targeting lipoprotein(a). N Engl J Med. (2025) 392:1673–83. doi: 10.1056/NEJMoa2415818,

PubMed Abstract | Crossref Full Text | Google Scholar

58. ClinicalTrials.gov. A study to investigate the effect of Lepodisiran on the reduction of major adverse cardiovascular events in adults with elevated lipoprotein(a) - ACCLAIM-Lp(a). Available online at: https://clinicaltrials.gov/study/NCT06292013 (Accessed December 10, 2025).

Google Scholar

59. Nissen, SE, Wolski, K, Watts, GF, Koren, MJ, Fok, H, Nicholls, SJ, et al. Single ascending and multiple-dose trial of Zerlasiran, a short interfering RNA targeting lipoprotein(a): a randomized clinical trial. JAMA. (2024) 331:1534–43. doi: 10.1001/jama.2024.4504,

PubMed Abstract | Crossref Full Text | Google Scholar

60. ClinicalTrials.gov. Evaluate SLN360 in participants with elevated lipoprotein(a) at high risk of atherosclerotic cardiovascular disease events. Available online at: https://www.clinicaltrials.gov/study/NCT05537571 (Accessed December 10, 2025).

Google Scholar

61. Nicholls, SJ, Nissen, SE, Fleming, C, Urva, S, Suico, J, Berg, PH, et al. Muvalaplin, an Oral Small molecule inhibitor of lipoprotein(a) formation: a randomized clinical trial. JAMA. (2023) 330:1042–53. doi: 10.1001/jama.2023.16503,

PubMed Abstract | Crossref Full Text | Google Scholar

62. Nicholls, SJ, Ni, W, Rhodes, GM, Nissen, SE, Navar, AM, Michael, LF, et al. Oral muvalaplin for lowering of lipoprotein(a): a randomized clinical trial. JAMA. (2025) 333:222. doi: 10.1001/jama.2024.24017,

PubMed Abstract | Crossref Full Text | Google Scholar