1932
0
  1. Home
  2. A-Z Publications
  3. Annual Review of Pharmacology and Toxicology
  4. Volume 64, 2024
  5. Article

Annual Review of Pharmacology and Toxicology

Volume 64, 2024

LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics

Abstract

Lipoprotein(a) [Lp(a)] is a molecule bound to apolipoprotein(a) with some similarity to low-density lipoprotein cholesterol (LDL-C), which has been found to be a risk factor for cardiovascular disease (CVD). Lp(a) appears to induce inflammation, atherogenesis, and thrombosis. Approximately 20% of the world's population has increased Lp(a) levels, determined predominantly by genetics. Current clinical practices for the management of dyslipidemia are ineffective in lowering Lp(a) levels. Evolving RNA-based therapeutics, such as the antisense oligonucleotide pelacarsen and small interfering RNA olpasiran, have shown promising results in reducing Lp(a) levels. Phase III pivotal cardiovascular outcome trials [Lp(a)HORIZON and OCEAN(a)] are ongoing to evaluate their efficacy in secondary prevention of major cardiovascular events in patients with elevated Lp(a). The future of cardiovascular residual risk reduction may transition to a personalized approach where further lowering of either LDL-C, triglycerides, or Lp(a) is selected after high-intensity statin therapy based on the individual risk profile and preferences of each patient.

Keyword(s): antisense oligonucleotides, atherosclerosis, cardiovascular disease, clinical trial, lipoprotein(a), therapy
Loading

Article metrics loading...

/content/journals/10.1146/annurev-pharmtox-031023-100609
2024-01-23
2024-05-09
Loading full text...

Full text loading...

/deliver/fulltext/pharmtox/64/1/annurev-pharmtox-031023-100609.html?itemId=/content/journals/10.1146/annurev-pharmtox-031023-100609&mimeType=html&fmt=ahah

Literature Cited

  1. 1.
    Olson RE. 1998. Discovery of the lipoproteins, their role in fat transport and their significance as risk factors. J. Nutr. 128:2439S–43S
     [Google Scholar]
  2. 2.
    Berg K. 1963. A new serum type system in man—the Lp system. Acta Pathol. Microbiol. Scand. 59:3369–82
     [Google Scholar]
  3. 3.
    Danesh J, Collins R, Peto R. 2000. Lipoprotein(a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 102:101082–85
     [Google Scholar]
  4. 4.
    Kamstrup PR, Tybjærg-Hansen A, Nordestgaard BG. 2014. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J. Am. Coll. Cardiol. 63:5470–77
     [Google Scholar]
  5. 5.
    Kamstrup PR, Nordestgaard BG. 2016. Elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population. JACC Heart Fail. 4:178–87
     [Google Scholar]
  6. 6.
    Thanassoulis G, Campbell CY, Owens DS, Smith JG, Smith AV et al. 2013. Genetic associations with valvular calcification and aortic stenosis. N. Engl. J. Med. 368:503–12
     [Google Scholar]
  7. 7.
    Burgess S, Ference BA, Staley JR, Freitag DF, Mason AM et al. 2018. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 3:7619–27
     [Google Scholar]
  8. 8.
    Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F et al. 2010. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31:232844–53
     [Google Scholar]
  9. 9.
    Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM et al. 2018. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet 392:101551311–20
     [Google Scholar]
  10. 10.
    O'Donoghue M, Giugliano R, Keech A, Kanevsky E, Im K et al. 2018. Lipoprotein(a), PCSK9 inhibition and cardiovascular risk: insights from the FOURIER trial Paper presented at the European Atherosclerosis Society Congress Lisbon, Portugal: May 7
  11. 11.
    Boffa MB. 2022. Beyond fibrinolysis: the confounding role of Lp(a) in thrombosis. Atherosclerosis 349:72–81
     [Google Scholar]
  12. 12.
    Maranhão RC, Carvalho PO, Strunz CC, Pileggi F. 2014. Lipoprotein(a): structure, pathophysiology and clinical implications. Arq. Bras. Cardiol. 103:176–84
     [Google Scholar]
  13. 13.
    McLean JW, Tomlinson JE, Kuang WJ, Eaton DL, Chen EY et al. 1987. cDNA sequence of human apolipoprotein(a) is homologous to plasminogen. Nature 330:6144132–37
     [Google Scholar]
  14. 14.
    Lawn RM, Schwartz K, Patthy L. 1997. Convergent evolution of apolipoprotein(a) in primates and hedgehog. PNAS 94:2211992–97
     [Google Scholar]
  15. 15.
    Boffelli D, Cheng JF, Rubin EM. 2004. Convergent evolution in primates and an insectivore. Genomics 83:119–23
     [Google Scholar]
  16. 16.
    Krempler F, Kostner G, Bolzano K, Sandhofer F. 1979. Lipoprotein(a) is not a metabolic product of other lipoproteins containing apolipoprotein B. Biochim. Biophys. Acta 575:163–70
     [Google Scholar]
  17. 17.
    Romagnuolo R, Marcovina SM, Boffa MB, Koschinsky ML. 2014. Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a). J. Lipid Res. 55:4625–34
     [Google Scholar]
  18. 18.
    Dentali F, Gessi V, Marcucci R, Gianni M, Grandi AM, Franchini M. 2017. Lipoprotein(a) as a risk factor for venous thromboembolism: a systematic review and meta-analysis of the literature. Semin. Thromb. Hemost. 43:6614–20
     [Google Scholar]
  19. 19.
    Miles LA, Fless GM, Levin EG, Scanu AM, Plow EF. 1989. A potential basis for the thrombotic risks associated with lipoprotein(a). Nature 339:6222301–3
     [Google Scholar]
  20. 20.
    Kuijpers MJ, Gilio K, Reitsma S, Nergiz-Unal R, Prinzen L et al. 2009. Complementary roles of platelets and coagulation in thrombus formation on plaques acutely ruptured by targeted ultrasound treatment: a novel intravital model. J. Thromb. Haemost. 7:1152–61
     [Google Scholar]
  21. 21.
    Kuijpers MJ, van der Meijden PE, Feijge MA, Mattheij NJ, May F et al. 2014. Factor XII regulates the pathological process of thrombus formation on ruptured plaques. Arterioscler. Thromb. Vasc. Biol. 34:81674–80
     [Google Scholar]
  22. 22.
    Boffa MB, Marar TT, Yeang C, Viney NJ, Xia S et al. 2019. Potent reduction of plasma lipoprotein(a) with an antisense oligonucleotide in human subjects does not affect ex vivo fibrinolysis. J. Lipid Res. 60:122082–89
     [Google Scholar]
  23. 23.
    Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP et al. 2022. 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. 42:1e48–60
     [Google Scholar]
  24. 24.
    Guerra R, Yu Z, Marcovina S, Peshock R, Cohen JC, Hobbs HH. 2005. Lipoprotein(a) and apolipoprotein(a) isoforms. Circulation 111:121471–79
     [Google Scholar]
  25. 25.
    Patel AP, Wang M, Pirruccello JP, Ellinor PT, Ng K et al. 2021. Lp(a) (Lipoprotein[a]) concentrations and incident atherosclerotic cardiovascular disease. Arterioscler. Thromb. Vasc. Biol. 41:1465–74
     [Google Scholar]
  26. 26.
    Reyes-Soffer G. 2021. The impact of race and ethnicity on lipoprotein(a) levels and cardiovascular risk. Curr. Opin. Lipidol. 32:3163–66
     [Google Scholar]
  27. 27.
    Lee SR, Prasad A, Choi YS, Xing C, Clopton P et al. 2017. LPA gene, ethnicity, and cardiovascular events. Circulation 135:3251–63
     [Google Scholar]
  28. 28.
    Khovidhunkit W, Kim M-S, Memon RA, Shigenaga JK, Moser AH et al. 2004. Effects of infection and inflammation on lipid and lipoprotein metabolism mechanisms and consequences to the host. J. Lipid Res. 45:71169–96
     [Google Scholar]
  29. 29.
    Vavuranakis MA, Jones SR, Ziogos E, Blaha MJ, Williams MS et al. 2022. The trajectory of lipoprotein(a) during the peri- and early postinfarction period and the impact of proprotein convertase subtilisin/kexin type 9 inhibition. Am. J. Cardiol. 171:1–6
     [Google Scholar]
  30. 30.
    Mooser V, Berger MM, Tappy L, Cayeux C, Marcovina SM et al. 2000. Major reduction in plasma Lp(a) levels during sepsis and burns. Arterioscler. Thromb. Vasc. Biol. 20:41137–42
     [Google Scholar]
  31. 31.
    Andreassen AK, Berg K, Torsvik H. 1994. Changes in Lp(a) lipoprotein and other plasma proteins during acute myocardial infarction. Clin. Genet. 46:6410–16
     [Google Scholar]
  32. 32.
    Maeda S, Abe A, Seishima M, Makino K, Noma A, Kawade M. 1989. Transient changes of serum lipoprotein(a) as an acute phase protein. Atherosclerosis 78:2–3145–50
     [Google Scholar]
  33. 33.
    Wållberg-Jonsson S, Uddhammar A, Dahlen G, Rantapää-Dahlqvist S. 1995. Lipoprotein(a) in relation to acute phase reaction in patients with rheumatoid arthritis and polymyalgia rheumatica. Scand. . J. Clin. Lab. Investig. 55:4309–15
     [Google Scholar]
  34. 34.
    Honigberg MC, Trinder M, Natarajan P. 2022. Lipoprotein(a), menopausal hormone therapy, and risk of coronary heart disease in postmenopausal individuals. JAMA Cardiol. 7:5565–68
     [Google Scholar]
  35. 35.
    Anagnostis P, Antza C, Trakatelli C, Lambrinoudaki I, Goulis DG, Kotsis V. 2023. The effect of menopause on lipoprotein(a) concentrations: a systematic review and meta-analysis. Maturitas 167:39–45
     [Google Scholar]
  36. 36.
    Anagnostis P, Galanis P, Chatzistergiou V, Stevenson JC, Godsland IF et al. 2017. The effect of hormone replacement therapy and tibolone on lipoprotein(a) concentrations in postmenopausal women: a systematic review and meta-analysis. Maturitas 99:27–36
     [Google Scholar]
  37. 37.
    Khoudary SRE, Aggarwal B, Beckie TM, Hodis HN, Johnson AE et al. 2020. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation 142:25e506–32
     [Google Scholar]
  38. 38.
    Jenner JL, Ordovas JM, Lamon-Fava S, Schaefer MM, Wilson PW et al. 1993. Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study. Circulation 87:41135–41
     [Google Scholar]
  39. 39.
    Akita H, Matsubara M, Shibuya H, Fuda H, Chiba H. 2002. Effect of ageing on plasma lipoprotein(a) levels. Ann. Clin. Biochem. 39:Pt. 3237–40
     [Google Scholar]
  40. 40.
    Lin L, Deng K-Q, Chen Z, Lei F, Qin J-J et al. 2023. Lipoprotein(a) distribution and its association with carotid arteriopathy in the Chinese population. Atherosclerosis 372:1–9
     [Google Scholar]
  41. 41.
    Lippi G, Targher G, Salvagno GL, Montagnana M, Franchini M, Guidi GC. 2010. Lipoprotein(a) and ageing. Clin. Lab. 56:9–10463–66
     [Google Scholar]
  42. 42.
    de Boer LM, Hof MH, Wiegman A, Stroobants AK, Kastelein JJP, Hutten BA. 2022. Lipoprotein(a) levels from childhood to adulthood: data in nearly 3,000 children who visited a pediatric lipid clinic. Atherosclerosis 349:227–32
     [Google Scholar]
  43. 43.
    Enkhmaa B, Petersen KS, Kris-Etherton PM, Berglund L. 2020. Diet and Lp(a): Does dietary change modify residual cardiovascular risk conferred by Lp(a)?. Nutrients 12:72024
     [Google Scholar]
  44. 44.
    Jang AY, Han SH, Sohn IS, Oh PC, Koh KK. 2020. Lipoprotein(a) and cardiovascular diseases—revisited. Circ. J. 84:6867–74
     [Google Scholar]
  45. 45.
    Saleheen D, Haycock PC, Zhao W, Rasheed A, Taleb A et al. 2017. Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis. Lancet Diabetes Endocrinol. 5:7524–33
     [Google Scholar]
  46. 46.
    Koller D, Hackl H, Bogner-Strauß JG, Hermetter A. 2014. Effects of oxidized phospholipids on gene expression in RAW 264.7 macrophages: a microarray study. PLOS ONE 9:10e110486
     [Google Scholar]
  47. 47.
    Rawther T, Tabet F. 2019. Biology, pathophysiology and current therapies that affect lipoprotein(a) levels. J. Mol. Cell Cardiol. 131:1–11
     [Google Scholar]
  48. 48.
    Bhatia HS, Wilkinson MJ. 2022. Lipoprotein(a): evidence for role as a causal risk factor in cardiovascular disease and emerging therapies. J. Clin. Med. 11:206040
     [Google Scholar]
  49. 49.
    Duarte Lau F, Giugliano RP 2022. Lipoprotein(a) and its significance in cardiovascular disease: a review. JAMA Cardiol. 7:7760–69
     [Google Scholar]
  50. 50.
    Vuorio A, Watts GF, Schneider WJ, Tsimikas S, Kovanen PT. 2020. Familial hypercholesterolemia and elevated lipoprotein(a): double heritable risk and new therapeutic opportunities. J. Intern. Med. 287:12–18
     [Google Scholar]
  51. 51.
    Tsimikas S. 2017. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J. Am. Coll. Cardiol. 69:6692–711
     [Google Scholar]
  52. 52.
    Sebestjen M, Zegura B, Guzic-Salobir B, Keber I. 2001. Fibrinolytic parameters and insulin resistance in young survivors of myocardial infarction with heterozygous familial hypercholesterolemia. Wien. Klin. Wochenschr. 113:3–4113–18
     [Google Scholar]
  53. 53.
    Alonso R, Andres E, Mata N, Fuentes-Jiménez F, Badimón L et al. 2014. Lipoprotein(a) levels in familial hypercholesterolemia: an important predictor of cardiovascular disease independent of the type of LDL receptor mutation. J. Am. Coll. Cardiol. 63:191982–89
     [Google Scholar]
  54. 54.
    Ellis KL, Pérez de Isla L, Alonso R, Fuentes F, Watts GF, Mata P 2019. Value of measuring lipoprotein(a) during cascade testing for familial hypercholesterolemia. J. Am. Coll. Cardiol. 73:91029–39
     [Google Scholar]
  55. 55.
    Ong KL, McClelland RL, Allison MA, Cushman M, Garg PK et al. 2021. Lipoprotein(a) and coronary artery calcification: prospective study assessing interactions with other risk factors. Metabolism 116:154706
     [Google Scholar]
  56. 56.
    Sung KC, Wild SH, Byrne CD. 2013. Lipoprotein(a), metabolic syndrome and coronary calcium score in a large occupational cohort. Nutr. Metab. Cardiovasc. Dis. 23:121239–46
     [Google Scholar]
  57. 57.
    Greif M, Arnoldt T, von Ziegler F, Ruemmler J, Becker C et al. 2013. Lipoprotein(a) is independently correlated with coronary artery calcification. Eur. J. Intern. Med. 24:175–79
     [Google Scholar]
  58. 58.
    Pechlivanis S, Mahabadi AA, Hoffmann P, Nöthen MM, Broecker-Preuss M et al. 2020. Association between lipoprotein(a) (Lp(a)) levels and Lp(a) genetic variants with coronary artery calcification. BMC Med. Genet. 21:162
     [Google Scholar]
  59. 59.
    Naami R, Miller DM, Al-Kindi S, Neeland IJ. 2022. Coronary artery calcium scoring as a tool for risk stratification in patients with an elevated lipoprotein(a) level. Front. Cardiovasc. Med. 9:1084814
     [Google Scholar]
  60. 60.
    Mehta A, Vasquez N, Ayers CR, Patel J, Hooda A et al. 2022. Independent association of lipoprotein(a) and coronary artery calcification with atherosclerotic cardiovascular risk. J. Am. Coll. Cardiol. 79:8757–68
     [Google Scholar]
  61. 61.
    Patel J, Pallazola VA, Dudum R, Greenland P, McEvoy JW et al. 2021. Assessment of coronary artery calcium scoring to guide statin therapy allocation according to risk-enhancing factors: the multi-ethnic study of atherosclerosis. JAMA Cardiol. 6:101161–70
     [Google Scholar]
  62. 62.
    Obisesan OH, Kou M, Wang FM, Boakye E, Honda Y et al. 2022. Lipoprotein(a) and subclinical vascular and valvular calcification on cardiac computed tomography: the Atherosclerosis Risk in Communities Study. J. Am. Heart Assoc. 11:11e024870
     [Google Scholar]
  63. 63.
    Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK et al. 2019. 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 139:25e1082–143
     [Google Scholar]
  64. 64.
    Kronenberg F, Mora S, Stroes ESG, Ference BA, Arsenault BJ et al. 2022. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur. Heart J. 43:393925–46
     [Google Scholar]
  65. 65.
    Kronenberg F. 2022. Lipoprotein(a) measurement issues: Are we making a mountain out of a molehill?. Atherosclerosis 349:123–35
     [Google Scholar]
  66. 66.
    Nordestgaard BG, Chapman MJ, Ray K, Borén J, Andreotti F et al. 2010. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur. Heart J. 31:232844–53
     [Google Scholar]
  67. 67.
    Varvel S, McConnell JP, Tsimikas S. 2016. Prevalence of elevated Lp(a) mass levels and patient thresholds in 532 359 patients in the United States. Arterioscler. Thromb. Vasc. Biol. 36:112239–45
     [Google Scholar]
  68. 68.
    Saeedi R, Frohlich J. 2016. Lipoprotein(a), an independent cardiovascular risk marker. Clin. Diabetes Endocrinol. 2:17
     [Google Scholar]
  69. 69.
    Welsh P, Welsh C, Celis-Morales CA, Brown R, Ho FK et al. 2022. Lipoprotein(a) and cardiovascular disease: prediction, attributable risk fraction, and estimating benefits from novel interventions. Eur. J. Prev. Cardiol. 28:181991–2000
     [Google Scholar]
  70. 70.
    Afshar M, Rong J, Zhan Y, Chen HY, Engert JC et al. 2020. Risks of incident cardiovascular disease associated with concomitant elevations in lipoprotein(a) and low-density lipoprotein cholesterol—the Framingham Heart Study. J. Am. Heart Assoc. 9:18e014711
     [Google Scholar]
  71. 71.
    Rikhi R, Hammoud A, Ashburn N, Snavely AC, Michos ED et al. 2022. Relationship of low-density lipoprotein-cholesterol and lipoprotein(a) to cardiovascular risk: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 363:102–8
     [Google Scholar]
  72. 72.
    Liu Q, Yu Y, Xi R, Li J, Lai R et al. 2022. Association between lipoprotein(a) and calcific aortic valve disease: a systematic review and meta-analysis. Front. Cardiovasc. Med. 9:877140
     [Google Scholar]
  73. 73.
    Zheng KH, Tsimikas S, Pawade T, Kroon J, Jenkins WSA et al. 2019. Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis. J. Am. Coll. Cardiol. 73:172150–62
     [Google Scholar]
  74. 74.
    Marcovina SM, Albers JJ. 2016. Lipoprotein(a) measurements for clinical application. J. Lipid Res. 57:4526–37
     [Google Scholar]
  75. 75.
    Albers JJ, Adolphson JL, Hazzard WR. 1977. Radioimmunoassay of human plasma Lp(a) lipoprotein. J. Lipid Res. 18:3331–38
     [Google Scholar]
  76. 76.
    Reyes-Soffer G, Ginsberg HN, Berglund L, Duell PB, Heffron SP et al. 2022. 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. 42:1e48–60
     [Google Scholar]
  77. 77.
    Lackner C, Cohen JC, Hobbs HH. 1993. Molecular definition of the extreme size polymorphism in apolipoprotein(a). Hum. Mol. Genet. 2:7933–40
     [Google Scholar]
  78. 78.
    Cao J 2018. Understanding lipoprotein(a) testing: ask the expert: November 2018. Am. Assoc. Clin. Chem. https://www.aacc.org/cln/articles/2018/november/understanding-lipoprotein-a-testing
    [Google Scholar]
  79. 79.
    Brown WV, Ballantyne CM, Jones PH, Marcovina S. 2010. Management of Lp(a). J. Clin. Lipidol. 4:4240–47
     [Google Scholar]
  80. 80.
    Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK et al. 2019. 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. J. Am. Coll. Cardiol. 73:24e285–350
     [Google Scholar]
  81. 81.
    Pearson GJ, Thanassoulis G, Anderson TJ, Barry AR, Couture P et al. 2021. 2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can. J. Cardiol. 37:81129–50
     [Google Scholar]
  82. 82.
    Wilson PWF, Jacobson TA, Martin SS, Jackson EJ, Le N-A et al. 2021. Lipid measurements in the management of cardiovascular diseases: practical recommendations a scientific statement from the national lipid association writing group. J. Clin. Lipidol. 15:5629–48
     [Google Scholar]
  83. 83.
    Cegla J, Neely RDG, France M, Ferns G, Byrne CD et al. 2019. HEART UK consensus statement on Lipoprotein(a): a call to action. Atherosclerosis 291:62–70
     [Google Scholar]
  84. 84.
    Newman CB, Blaha MJ, Boord JB, Cariou B, Chait A et al. 2020. Lipid management in patients with endocrine disorders: an Endocrine Society Clinical Practice Guideline. J. Clin. Endocrinol. Metab. 105:123613–82
     [Google Scholar]
  85. 85.
    Khera AV, Everett BM, Caulfield MP, Hantash FM, Wohlgemuth J et al. 2014. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation 129:6635–42
     [Google Scholar]
  86. 86.
    de Boer LM, Oorthuys AOJ, Wiegman A, Langendam MW, Kroon J et al. 2022. Statin therapy and lipoprotein(a) levels: a systematic review and meta-analysis. Eur. J. Prev. Cardiol. 29:5779–92
     [Google Scholar]
  87. 87.
    Wang X, Li J, Ju J, Fan Y, Xu H. 2021. Effect of different types and dosages of statins on plasma lipoprotein(a) levels: a network meta-analysis. Pharmacol. Res. 163:105275
     [Google Scholar]
  88. 88.
    Wilson DP, Jacobson TA, Jones PH, Koschinsky ML, McNeal CJ et al. 2019. Use of Lipoprotein(a) in clinical practice: a biomarker whose time has come. A scientific statement from the National Lipid Association. J. Clin. Lipidol. 13:3374–92
     [Google Scholar]
  89. 89.
    Sahebkar A, Simental-Mendía LE, Pirro M, Banach M, Watts GF et al. 2018. Impact of ezetimibe on plasma lipoprotein(a) concentrations as monotherapy or in combination with statins: a systematic review and meta-analysis of randomized controlled trials. Sci. Rep. 8:117887
     [Google Scholar]
  90. 90.
    Sahebkar A, Reiner Ž, Simental-Mendía LE, Ferretti G, Cicero AF. 2016. Effect of extended-release niacin on plasma lipoprotein(a) levels: a systematic review and meta-analysis of randomized placebo-controlled trials. Metabolism 65:111664–78
     [Google Scholar]
  91. 91.
    AIM-HIGH Investig 2011. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365:242255–67
     [Google Scholar]
  92. 92.
    HPS2-THRIVE Collab. Group 2014. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med. 371:3203–12
     [Google Scholar]
  93. 93.
    Warden BA, Minnier J, Watts GF, Fazio S, Shapiro MD. 2019. Impact of PCSK9 inhibitors on plasma lipoprotein(a) concentrations with or without a background of niacin therapy. J. Clin. Lipidol. 13:4580–85
     [Google Scholar]
  94. 94.
    Desai NR, Kohli P, Giugliano RP, O'Donoghue ML, Somaratne R et al. 2013. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy: an analysis from the LDL-C Assessment with Proprotein Convertase Subtilisin Kexin Type 9 Monoclonal Antibody Inhibition Combined with Statin Therapy (LAPLACE)-Thrombolysis in Myocardial Infarction (TIMI) 57 trial. Circulation 128:9962–69
     [Google Scholar]
  95. 95.
    O'Donoghue ML, Fazio S, Giugliano RP, Stroes ESG, Kanevsky E et al. 2019. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 139:121483–92
     [Google Scholar]
  96. 96.
    Bittner VA, Szarek M, Aylward PE, Bhatt DL, Diaz R et al. 2020. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J. Am. Coll. Cardiol. 75:2133–44
     [Google Scholar]
  97. 97.
    Farmakis I, Doundoulakis I, Pagiantza A, Zafeiropoulos S, Antza C et al. 2021. Lipoprotein(a) reduction with proprotein convertase subtilisin/kexin type 9 inhibitors: a systematic review and meta-analysis. J. Cardiovasc. Pharmacol. 77:3397–407
     [Google Scholar]
  98. 98.
    Ray KK, Stoekenbroek RM, Kallend D, Leiter LA, Landmesser U et al. 2018. Effect of an siRNA therapeutic targeting PCSK9 on atherogenic lipoproteins: prespecified secondary end points in ORION 1. Circulation 138:131304–16
     [Google Scholar]
  99. 99.
    Raal FJ, Kallend D, Ray KK, Turner T, Koenig W et al. 2020. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N. Engl. J. Med. 382:161520–30
     [Google Scholar]
  100. 100.
    Ray KK, Raal FJ, Kallend DG, Jaros MJ, Koenig W et al. 2023. Inclisiran and cardiovascular events: a patient-level analysis of phase III trials. Eur. Heart J. 44:2129–38
     [Google Scholar]
  101. 101.
    Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R et al. 2015. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart J. 36:432996–3003
     [Google Scholar]
  102. 102.
    Raal FJ, Hovingh GK, Blom D, Santos RD, Harada-Shiba M et al. 2017. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 5:4280–90
     [Google Scholar]
  103. 103.
    Li N, Li Q, Tian XQ, Qian HY, Yang YJ. 2014. Mipomersen is a promising therapy in the management of hypercholesterolemia: a meta-analysis of randomized controlled trials. Am. J. Cardiovasc. Drugs 14:5367–76
     [Google Scholar]
  104. 104.
    Waldmann E, Parhofer KG. 2016. Lipoprotein apheresis to treat elevated lipoprotein(a). J. Lipid Res. 57:101751–57
     [Google Scholar]
  105. 105.
    Thompson GR, Lowenthal R, Myant NB. 1975. Plasma exchange in the management of homozygous familial hypercholesterolaemia. Lancet 1:79181208–11
     [Google Scholar]
  106. 106.
    Stoffel W, Borberg H, Greve V. 1981. Application of specific extracorporeal removal of low density lipoprotein in familial hypercholesterolaemia. Lancet 2:82541005–7
     [Google Scholar]
  107. 107.
    Goldberg AC, Hopkins PN, Toth PP, Ballantyne CM, Rader DJ et al. 2011. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients: clinical guidance from the National Lipid Association expert panel on familial hypercholesterolemia. J. Clin. Lipidol. 5:3133–40
     [Google Scholar]
  108. 108.
    Jamialahmadi T, Reiner Ž, Alidadi M, Kroh M, Almahmeed W et al. 2022. The effect of bariatric surgery on circulating levels of lipoprotein(a): a meta-analysis. Biomed. Res. Int. 2022:8435133
     [Google Scholar]
  109. 109.
    Reyes-Soffer G, Westerterp M. 2021. Beyond lipoprotein(a) plasma measurements: lipoprotein(a) and inflammation. Pharmacol. Res. 169:105689
     [Google Scholar]
  110. 110.
    Rao SR. 2012. Inflammatory markers and bariatric surgery: a meta-analysis. Inflamm. Res. 61:789–807
     [Google Scholar]
  111. 111.
    Wade DP, Clarke JG, Lindahl GE, Liu AC, Zysow BR et al. 1993. 5′ Control regions of the apolipoprotein(a) gene and members of the related plasminogen gene family. PNAS 90:41369–73
     [Google Scholar]
  112. 112.
    Lacaze P, Bakshi A, Riaz M, Polekhina G, Owen A et al. 2022. Aspirin for primary prevention of cardiovascular events in relation to lipoprotein(a) genotypes. J. Am. Coll. Cardiol. 80:141287–98
     [Google Scholar]
  113. 113.
    Chasman DI, Shiffman D, Zee RY, Louie JZ, Luke MM et al. 2009. Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 203:2371–76
     [Google Scholar]
  114. 114.
    Zhang C, Zhang B. 2023. RNA therapeutics: updates and future potential. Sci. China Life Sci. 66:112–30
     [Google Scholar]
  115. 115.
    Zhang MM, Bahal R, Rasmussen TP, Manautou JE, Zhong X-B. 2021. The growth of siRNA-based therapeutics: updated clinical studies. Biochem. Pharmacol. 189:114432
     [Google Scholar]
  116. 116.
    Sato H, Kato Y, Hayasi E, Tabata T, Suzuki M et al. 2002. A novel hepatic-targeting system for therapeutic cytokines that delivers to the hepatic asialoglycoprotein receptor, but avoids receptor-mediated endocytosis. Pharm. Res. 19:111736–44
     [Google Scholar]
  117. 117.
    Springer AD, Dowdy SF. 2018. GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Ther. 28:3109–18
     [Google Scholar]
  118. 118.
    Nair JK, Willoughby JLS, Chan A, Charisse K, Alam MR et al. 2014. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J. Am. Chem. Soc. 136:4916958–61
     [Google Scholar]
  119. 119.
    Tsimikas S, Viney NJ, Hughes SG, Singleton W, Graham MJ et al. 2015. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386:100021472–83
     [Google Scholar]
  120. 120.
    Viney NJ, van Capelleveen JC, Geary RS, Xia S, Tami JA et al. 2016. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 388:100572239–53
     [Google Scholar]
  121. 121.
    Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, Tardif J-C, Baum SJ et al. 2020. Lipoprotein(a) reduction in persons with cardiovascular disease. N. Engl. J. Med. 382:3244–55
     [Google Scholar]
  122. 122.
    O'Donoghue ML, Rosenson RS, Gencer B, López JAG, Lepor NE et al. 2022. Small interfering RNA to reduce lipoprotein(a) in cardiovascular disease. N. Engl. J. Med. 387:201855–64
     [Google Scholar]
  123. 123.
    Subhan MA, Torchilin VP. 2020. siRNA based drug design, quality, delivery and clinical translation. Nanomed. Nanotechnol. Biol. Med. 29:102239
     [Google Scholar]
  124. 124.
    Sohn W, Winkle P, Neutel J, Wu Y, Jabari F et al. 2022. Pharmacokinetics, pharmacodynamics, and tolerability of olpasiran in healthy Japanese and non-Japanese participants: results from a phase I, single-dose, open-label study. Clin. Ther. 44:91237–47
     [Google Scholar]
  125. 125.
    Nurmohamed NS, Kraaijenhof JM, Stroes ESG. 2022. Lp(a): a new pathway to target?. Curr. Atheroscler. Rep. 24:11831–38
     [Google Scholar]
  126. 126.
    Nissen SE, Wolski K, Balog C, Swerdlow DI, Scrimgeour AC et al. 2022. Single ascending dose study of a short interfering RNA targeting lipoprotein(a) production in individuals with elevated plasma lipoprotein(a) levels. JAMA 327:171679–87
     [Google Scholar]
  127. 127.
    Karwatowska-Prokopczuk E, Lesogor A, Yan J-H, Hurh E, Hoenlinger A et al. 2023. Efficacy and safety of pelacarsen in lowering Lp(a) in healthy Japanese subjects. J. Clin. Lipidol. 17:1181–88
     [Google Scholar]
  128. 128.
    Koren MJ, Moriarty PM, Baum SJ, Neutel J, Hernandez-Illas M et al. 2022. Preclinical development and phase 1 trial of a novel siRNA targeting lipoprotein(a). Nat. Med. 28:196–103
     [Google Scholar]
  129. 129.
    O'Donoghue ML, López JAG, Knusel B, Gencer B, Wang H et al. 2022. Study design and rationale for the Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study (OCEAN(a)-DOSE). Am. Heart J. 251:61–69
     [Google Scholar]
/content/journals/10.1146/annurev-pharmtox-031023-100609
Loading
LP(a): Structure, Genetics, Associated Cardiovascular Risk, and Emerging Therapeutics
Annual Review of Pharmacology and Toxicology 64, 135 (2024); https://doi.org/10.1146/annurev-pharmtox-031023-100609
/content/journals/10.1146/annurev-pharmtox-031023-100609
/content/journals/10.1146/annurev-pharmtox-031023-100609
Loading

Data & Media loading...

  • Article Type: Review Article

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error