Targeting Lipoprotein(a): A New Era in Cardiovascular Disease Prevention
References
- Mensah GA, Wei GS, Sorlie PD, et al. Decline in cardiovascular mortality: possible causes and implications. Circ Res. 2017 Jan 20;120(2):366-380. doi: 10.1161/CIRCRESAHA.116.309115
- Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019 Sep 10;140(11):e596-e646. doi: 10.1161/CIR.0000000000000678
- Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664
- Gomez-Delgado F, Raya-Cruz M, Katsiki N, Delgado-Lista J, Perez-Martinez P. Residual cardiovascular risk: when should we treat it? Eur J Intern Med. 2024 Feb;120:17-24. doi: 10.1016/j.ejim.2023.10.013
- Berg K. A new serum type system in man--the LP system. Acta Pathol Microbiol Scand. 1963;59:369-382. doi: 10.1111/j.1699-0463.1963.tb01808.x
- Reyes-Soffer G, Ginsberg HN, Berglund L, 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 Jan;42(1):e48-e60. doi: 10.1161/ATV.0000000000000147
- Kronenberg F, Utermann G. Lipoprotein(a): resurrected by genetics. J Intern Med. 2013;273(1):6-30. doi: 10.1111/j.1365-2796.2012.02592.x
- McLean JW, Tomlinson JE, Kuang WJ, et al. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature. 1987 Nov;330(6144):132-137. doi: 10.1038/330132a0
- Lawn RM, Schwartz K, Patthy L. Convergent evolution of apolipoprotein(a) in primates and hedgehog. Proc Nat Acad Sci. 1997 Oct 28;94(22):11992-11997. doi: 10.1073/pnas.94.22.11992
- Lackner C, Boerwinkle E, Leffert CC, Rahmig T, Hobbs HH. Molecular basis of apolipoprotein (a) isoform size heterogeneity as revealed by pulsed-field gel electrophoresis. J Clin Invest. 1991 Jun;87(6):2153-2161. doi: 10.1172/JCI115248
- Hoekstra M, Chen HY, Rong J, et al. Genome-wide association study highlights APOH as a novel locus for lipoprotein(a) levels. Arterioscler Thromb Vasc Biol. 2021 Jan;41(1):458-464. doi: 10.1161/ATVBAHA.120.314965
- Mack S, Coassin S, Rueedi R, et al. A genome-wide association meta-analysis on lipoprotein (a) concentrations adjusted for apolipoprotein (a) isoforms. J Lipid Res. 2017 Sep;58(9):1834-1844. doi: 10.1194/jlr.M076232
- Köchl S, Fresser F, Lobentanz E, Baier G, Utermann G. Novel interaction of apolipoprotein(a) with β-2 glycoprotein i mediated by the kringle iv domain. Blood. 1997 Aug 15;90(4):1482-1489. doi: 10.1182/blood.V90.4.1482
- Trinder M, Uddin MM, Finneran P, Aragam KG, Natarajan P. Clinical utility of lipoprotein(a) and LPA genetic risk score in risk prediction of incident atherosclerotic cardiovascular disease. JAMA Cardiol. 2021 Mar 1;6(3):287-295. doi: 10.1001/jamacardio.2020.5398
- Tsimikas S, Marcovina SM. Ancestry, lipoprotein(a), and cardiovascular risk thresholds. J Am Coll Cardiol. 2022 Aug 30;80(9):934-946. doi: 10.1016/j.jacc.2022.06.019
- Tselepis AD. Oxidized phospholipids and lipoprotein-associated phospholipase A2 as important determinants of Lp(a) functionality and pathophysiological role. J Biomed Res. 2018 Jan 26;32(1):13-22. doi: 10.7555/JBR.31.20160009
- Schmidt K, Noureen A, Kronenberg F, Utermann G. Structure, function, and genetics of lipoprotein (a). J Lipid Res. 2016 Aug;57(8):1339-1359. doi: 10.1194/jlr.R067314
- Mukamel RE, Handsaker RE, Sherman MA, et al. Protein-coding repeat polymorphisms strongly shape diverse human phenotypes. Science. 2021 Sep 24;373(6562):1499-1505. doi: 10.1126/science.abg8289
- Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017 Feb 14;69(6):692-711. doi: 10.1016/j.jacc.2016.11.042
- Kraft HG, Menzel HJ, Hoppichler F, Vogel W, Utermann G. Changes of genetic apolipoprotein phenotypes caused by liver transplantation. Implications for apolipoprotein synthesis. J Clin Invest. 1989 Jan;83(1):137-142. doi: 10.1172/JCI113849
- Jawi MM, Frohlich J, Chan SY. Lipoprotein(a) the insurgent: a new insight into the structure, function, metabolism, pathogenicity, and medications affecting lipoprotein(a) molecule. J Lipids. 2020;2020:3491764. doi: 10.1155/2020/3491764
- Bhatia HS, Becker RC, Leibundgut G, et al. Lipoprotein(a), platelet function and cardiovascular disease. Nat Rev Cardiol. 2024 May;21(5):299-311. doi: 10.1038/s41569-023-00947-2
- Duarte Lau F, Giugliano RP. Lipoprotein(a) and its significance in cardiovascular disease: a review. JAMA Cardiol. 2022 Jul 1;7(7):760-769. doi: 10.1001/jamacardio.2022.0987
- Langsted A, Nordestgaard BG. Lipoprotein(a): is it more, less or equal to LDL as a causal factor for cardiovascular disease and mortality? Curr Opin Lipidol. 2020 Jun;31(3):125-131. doi: 10.1097/MOL.0000000000000681
- Björnson E, Adiels M, Taskinen MR, et al. Lipoprotein(a) is markedly more atherogenic than LDL: an apolipoprotein B-based genetic analysis. J Am Coll Cardiol. 2024 Jan 23;83(3):385-395. doi: 10.1016/j.jacc.2023.10.039
- Marston NA, Melloni GEM, Murphy SA, et al. Per-Particle Cardiovascular Risk of Lipoprotein(a) vs Non-Lp(a) Apolipoprotein B-Containing Lipoproteins. J Am Coll Cardiol. 2024 Jan 23;83(3):470-472. doi: 10.1016/j.jacc.2023.09.836
- Ridker PM, Devalaraja M, Baeres FMM, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet. 2021 May 29;397(10289):2060-2069. doi: 10.1016/S0140-6736(21)00520-1
- Yu MM, Wang ML, Wang JJ, et al. Association of Lipoprotein(a) Levels With Myocardial Infarction in Patients With Low-Attenuation Plaque. J Am Coll Cardiol. 2024 May 7;83(18):1743-1755. doi: 10.1016/j.jacc.2024.03.367
- Jackson CL, Garg PK, Guan W, et al. Lipoprotein(a) and coronary artery calcium in comparison with other lipid biomarkers: The multi-ethnic study of atherosclerosis. J Clin Lipidol. 2023 Jul 1;17(4):538-548. doi: 10.1016/j.jacl.2023.06.002
- Kaiser Y, Daghem M, Tzolos E, et al. Association of Lipoprotein(a) With Atherosclerotic Plaque Progression. JACC. 2022 Jan 25;79(3):223-233. doi: 10.1016/j.jacc.2021.10.044
- Kim BJ, Kang J. Association of lipoprotein(a) and coronary artery calcium with atherosclerotic cardiovascular disease. J Clin Lipidol. 2025 May 1;19(3):521-530. doi: 10.1016/j.jacl.2025.02.007
- Mehta A, Vasquez N, Ayers CR, et al. Independent Association of Lipoprotein(a) and Coronary Artery Calcification With Atherosclerotic Cardiovascular Risk. JACC. 2022 Mar;79(8):757-768. doi: 10.1016/j.jacc.2021.11.058
- Greco A, Finocchiaro S, Spagnolo M, et al. Lipoprotein(a) as a Pharmacological Target: Premises, Promises, and Prospects. Circulation. 2025 Feb 11;151(6):400-415. doi: 10.1161/CIRCULATIONAHA.124.069210
- Koschinsky ML, Bajaj A, Boffa MB, et al. A focused update to the 2019 NLA scientific statement on use of lipoprotein(a) in clinical practice. J Clin Lipidol. 2024;18(3):e308-e319. doi: 10.1016/j.jacl.2024.03.001
- Enkhmaa B, Anuurad E, Berglund L. Lipoprotein (a): impact by ethnicity and environmental and medical conditions. J Lipid Res. 2016 Jul 1;57(7):1111-1125. doi: 10.1194/jlr.R051904
- Derby CA, Crawford SL, Pasternak RC, Sowers M, Sternfeld B, Matthews KA. Lipid Changes During the Menopause Transition in Relation to Age and Weight. Am J Epidemiol. 2009 Jun 1;169(11):1352-1361. doi: 10.1093/aje/kwp043
- Paré G, Çaku A, McQueen M, et al. Lipoprotein(a) Levels and the Risk of Myocardial Infarction Among 7 Ethnic Groups. Circulation. 2019 Mar 19;139(12):1472-1482. doi: 10.1161/CIRCULATIONAHA.118.034311
- Mehta A, Jain V, Saeed A, et al. Lipoprotein(a) and ethnicities. Atherosclerosis. 2022 May;349:42-52. doi: 10.1016/j.atherosclerosis.2022.04.005
- Rubin J, Paultre F, Tuck CH, et al. Apolipoprotein [a] genotype influences isoform dominance pattern differently in African Americans and Caucasians. J Lipid Res. 2002 Feb ;43(2):234-244. PMID: 11861665.
- Helmhold M, Bigge J, Muche R, et al. Contribution of the apo[a] phenotype to plasma Lp[a] concentrations shows considerable ethnic variation. J Lipid Res. 1991 Dec 1;32(12):1919-1928. PMID: 1840066.
- Erhart G, Lamina C, Lehtimäki T, et al. Genetic Factors Explain a Major Fraction of the 50% Lower Lipoprotein(a) Concentrations in Finns. Arterioscler Thromb Vasc Biol. 2018 May;38(5):1230-1241. doi: 10.1161/ATVBAHA.118.310865
- Berg K, Dahlén G, Frick MH. Lp(a) lipoprotein and pre-β1-lipoprotein in patients with coronary heart disease. Clinical Genetics. 1974;6(3):230-235. doi: 10.1111/j.1399-0004.1974.tb00657.x
- Djurovic S, Berg K. Review: Epidemiology of Lp(a) lipoprotein: its role in atherosclerotic/thrombotic disease. Clinical Genetics. 1997;52(5):281-292. doi: 10.1111/j.1399-0004.1997.tb04345.x
- Bostom AG, Cupples LA, Jenner JL, et al. Elevated plasma lipoprotein(a) and coronary heart disease in men aged 55 years and younger. A prospective study. JAMA. 1996 Aug 21;276(7):544-548. doi: 10.1001/jama.1996.03540070040028
- Welsh P, Welsh C, Celis-Morales CA, et al. Lipoprotein(a) and cardiovascular disease: prediction, attributable risk fraction, and estimating benefits from novel interventions. Eur J Prev Cardiol. 2022 Feb 9;28(18):1991-2000. doi: 10.1093/eurjpc/zwaa063
- Kamstrup PR, Nordestgaard BG. Elevated Lipoprotein(a) Levels, LPA Risk Genotypes, and Increased Risk of Heart Failure in the General Population. JACC Heart Fail. 2016 Jan;4(1):78-87. doi: 10.1016/j.jchf.2015.08.006
- Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009 Jun 10;301(22):2331-2339. doi: 10.1001/jama.2009.801
- Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022 Oct 14;43(39):3925-3946. doi: 10.1093/eurheartj/ehac361
- Ohira T, Schreiner PJ, Morrisett JD, Chambless LE, Rosamond WD, Folsom AR. Lipoprotein(a) and Incident Ischemic Stroke. Stroke. 2006 Jun;37(6):1407-1412. doi: 10.1161/01.STR.0000222666.21482.b6
- Ariyo AA, Thach C, Tracy R. Lp(a) Lipoprotein, Vascular Disease, and Mortality in the Elderly. New Engl J Med. 2003 Nov 27;349(22):2108-2115. doi: 10.1056/NEJMoa001066
- Golledge J, Rowbotham S, Velu R, et al. Association of Serum Lipoprotein (a) With the Requirement for a Peripheral Artery Operation and the Incidence of Major Adverse Cardiovascular Events in People With Peripheral Artery Disease. J Am Heart Assoc. 2020 Mar 17;9(6):
e015355 . doi: 10.1161/JAHA.119.015355 - Ridker PM, Stampfer MJ, Rifai N. Novel Risk Factors for Systemic AtherosclerosisA Comparison of C-Reactive Protein, Fibrinogen, Homocysteine, Lipoprotein(a), and Standard Cholesterol Screening as Predictors of Peripheral Arterial Disease. JAMA. 2001 May 16;285(19):2481-2485. doi: 10.1001/jama.285.19.2481
- Zheng KH, Tsimikas S, Pawade T, et al. Lipoprotein(a) and Oxidized Phospholipids Promote Valve Calcification in Patients With Aortic Stenosis. JACC. 2019 May 7;73(17):2150-2162. doi: 10.1016/j.jacc.2019.01.070
- Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. Elevated Lipoprotein(a) and Risk of Aortic Valve Stenosis in the General Population. JACC. 2014 Feb 11;63(5):470-477. doi: 10.1016/j.jacc.2013.09.038
- Thanassoulis G, Campbell CY, Owens DS, et al. Genetic Associations with Valvular Calcification and Aortic Stenosis. New Engl J Med. 2013 Feb 7;368(6):503-512. doi: 10.1056/NEJMoa1109034
- Capoulade R, Chan KL, Yeang C, et al. Oxidized Phospholipids, Lipoprotein(a), and Progression of Calcific Aortic Valve Stenosis. JACC. 2015 Sep 15;66(11):1236-1246. doi: 10.1016/j.jacc.2015.07.020
- Bergmark BA, O’Donoghue ML, Murphy SA, et al. An Exploratory Analysis of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition and Aortic Stenosis in the FOURIER Trial. JAMA Cardiol. 2020 Jun 1;5(6):709-713. doi: 10.1001/jamacardio.2020.0728
- Kronenberg F. Lipoprotein(a) measurement issues: Are we making a mountain out of a molehill? Atherosclerosis. 2022 May;349:123-135. doi: 10.1016/j.atherosclerosis.2022.04.008
- Scharnagl H, Stojakovic T, Dieplinger B, et al. Comparison of lipoprotein (a) serum concentrations measured by six commercially available immunoassays. Atherosclerosis. 2019 Oct 1;289:206-213. doi: 10.1016/j.atherosclerosis.2019.08.015
- Marcovina SM, Navabi N, Allen S, Gonen A, Witztum JL, Tsimikas S. Development and validation of an isoform-independent monoclonal antibody-based ELISA for measurement of lipoprotein(a). J Lipid Res. 2022 Aug;63(8):100239. doi: 10.1016/j.jlr.2022.100239
- Marcovina SM, Shapiro MD. Measurement of lipoprotein(a): a once in a lifetime opportunity. J Am Coll Cardiol. 2022;79:629-631. doi: 10.1016/j.jacc.2021.11.053.
- Cobbaert CM, Althaus H, Begcevic Brkovic I, et al. Towards an SI-Traceable Reference Measurement System for Seven Serum Apolipoproteins Using Bottom-Up Quantitative Proteomics: Conceptual Approach Enabled by Cross-Disciplinary/Cross-Sector Collaboration. Clin Chem. 2021 Mar 1;67(3):478-489. doi: 10.1093/clinchem/hvaa239
- Writing Committee Members, Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2026 Apr 28;153(17):e1154-e1276. doi: 10.1161/CIR.0000000000001423
- Bene-Alhasan Y, Sun C, Hamid A, et al. Correlation between serum and plasma lipoprotein(a) measurements: ARIC Study. J Clin Lipidol. 2026 July;20(7):1498-1502. doi: 10.1016/j.jacl.2026.05.226.
- Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2020 Jan 1;41(1):111-188. doi: 10.1093/eurheartj/ehz455
- Pearson GJ, Thanassoulis G, Anderson TJ, et al. 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults. Can J Cardiol. 2021 Aug 1;37(8):1129-1150. doi: 10.1016/j.cjca.2021.03.016
- Morton JI, Kronenberg F, Daccord M, et al. Lp(a) testing for the primary prevention of cardiovascular disease in high-income countries: a cost-effectiveness analysis. Atherosclerosis. 2025 Oct 1;409. doi: 10.1016/j.atherosclerosis.2025.120447
- Bene-Alhasan Y, Al Osta S, Issaka Y, et al. Persistent gaps in management and risk factor control among patients with atherosclerotic cardiovascular disease: All of Us Research Program. Atherosclerosis. 2026 Jul;418:120794. doi: 10.1016/j.atherosclerosis.2026.120794.
- Marcovina SM, Viney NJ, Hughes SG, Xia S, Witztum JL, Tsimikas S. Temporal variability in lipoprotein(a) levels in patients enrolled in the placebo arms of IONIS-APO(a)Rx and IONIS-APO(a)-LRx antisense oligonucleotide clinical trials. J Clin Lipidol. 2018;12(1):122-129.e2. doi: 10.1016/j.jacl.2017.10.024
- Deshotels MR, Sun C, Nambi V, et al. Temporal Trends in Lipoprotein(a) Concentrations: The Atherosclerosis Risk in Communities Study. J Am Heart Assoc. 2022 Oct 26;11(21):
e026762 . doi: 10.1161/JAHA.122.026762 - Xie S, Galimberti F, Olmastroni E, Carugo S, Catapano AL, Casula M. Effect of lipid-lowering therapies on lipoprotein(a) levels: a comprehensive meta-analysis of randomized controlled trials. Atherosclerosis. 2025 Sep 1;408. doi: 10.1016/j.atherosclerosis.2025.120420
- Chennamsetty I, Kostner KM, Claudel T, et al. Nicotinic acid inhibits hepatic APOA gene expression: studies in humans and in transgenic mice. J Lipid Res. 2012 Nov;53(11):2405-2412. doi: 10.1194/jlr.M029769
- HPS2-THRIVE Collaborative Group. Effects of Extended-Release Niacin with Laropiprant in High-Risk Patients. New Engl J Med. 2014 Jul 17;371(3):203-212. doi: 10.1056/NEJMoa1300955
- Mansfield BS, Bene-Alhasan Y, Ballantyne CM, Raal FJ. The evolving therapeutic landscape of PCSK9 inhibition. Atherosclerosis. 2026 Mar 1;414:120670. doi: 10.1016/j.atherosclerosis.2026.120670
- Desai NR, Kohli P, Giugliano RP, et al. AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy. Circulation. 2013 Aug 27;128(9):962-969. doi: 10.1161/CIRCULATIONAHA.113.001969
- O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk. Circulation. 2019 Mar 19;139(12):1483-1492. doi: 10.1161/CIRCULATIONAHA.118.037184
- Bittner VA, Szarek M, Aylward PE, et al. Effect of Alirocumab on Lipoprotein(a) and Cardiovascular Risk After Acute Coronary Syndrome. J Am Coll Cardiol. 2020 Jan 21;75(2):133-144. doi: 10.1016/j.jacc.2019.10.057
- Kaur G, Abdelrahman K, Berman AN, et al. Lipoprotein(a): Emerging insights and therapeutics. Am J Prev Cardiol. 2024 Jun 1;18:100641. doi: 10.1016/j.ajpc.2024.100641
- Ballantyne CM, Norata GD. The evolving landscape of targets for lipid lowering: from molecular mechanisms to translational implications. Eur Heart J. 2025 Nov 21;46(44):4737-4750. doi: 10.1093/eurheartj/ehaf606. PMID: 40911366.
- Nicholls SJ, Ni W, Rhodes GM, et al. Oral muvalaplin for lowering of lipoprotein(a): a randomized clinical trial. JAMA. 2025 Jan 21;333(3):222-231. doi: 10.1001/jama.2024.24017
DOI: https://doi.org/10.14797/mdcvj.1836 | Journal eISSN: 1947-6108
Language: English
Page range: 28 - 39
Submitted on: Apr 2, 2026
Accepted on: Jul 21, 2026
Published on: Sep 15, 2026
Published by: Houston Methodist DeBakey Heart & Vascular Center
In partnership with: Paradigm Publishing Services
Keywords:
© 2026 Yakubu Bene-Alhasan, Vijay Nambi, Layla A. Abushamat, Christie M. Ballantyne, published by Houston Methodist DeBakey Heart & Vascular Center
This work is licensed under the Creative Commons Attribution-NonCommercial 4.0 License.