Targeting Lipoprotein (a): an Evolving Therapeutic Landscape

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• 作者：Lillian C. Man (1)
  Erik Kelly (2)
  Danielle Duffy (3)
  
  1. Department of Medicine ; Thomas Jefferson University Hospital ; 1025 Walnut Street ; Room 805 ; Philadelphia ; PA ; 19107 ; USA
  2. Department of Medicine ; Massachusetts General Hospital ; 55 Fruit Street ; GRB 730 ; Boston ; MA ; 02114 ; USA
  3. Division of Cardiology ; Sidney Kimmel Medical College at Thomas Jefferson University ; 925 Chestnut Street ; Mezzanine Level ; Philadelphia ; PA ; 19107 ; USA
  
• 关键词：Lipoprotein (a) ; Cardiovascular disease ; Apolipoprotein (a) ; Nicotinic acid ; Apheresis ; Antisense oligonucleotides
• 刊名：Current Atherosclerosis Reports
• 出版年：2015
• 出版时间：May 2015
• 年：2015
• 卷：17
• 期：5
• 全文大小：1,231 KB
• 参考文献：1. Tsimikas S, Hall JL. Lipoprotein(a) as a potential causal genetic risk factor of cardiovascular disease: a rationale for increased efforts to understand its pathophysiology and develop targeted therapies. J Am Coll Cardiol. 2012;60(8):716鈥?1. / This is a comprehensive and up to date review that highlights the role of Lp(a) in CVD risk and introduces recent therapies to lower Lp(a).
  2. Bennet, A, Angelantonio, E, Erqou, S (2008) Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med 168: pp. 598-608 CrossRef
  3. Erqou, S, Kaptoge, S, Perry, PL (2009) Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302: pp. 412-23 CrossRef
  4. Kamstrup, PR, Tybjaerg-Hansen, A, Steffensen, R, Nordestgaard, BG (2009) Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301: pp. 2331-9 CrossRef
  5. Kamstrup, PR, Benn, M, Tybjaerg-Hansen, A, Nordestgaard, BG (2008) Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation 117: pp. 176-84 CrossRef
  6. Thanassoulis, G, Campbell, CY, Owens, DS (2013) Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 368: pp. 503-12 CrossRef
  7. Kolski, B, Tsimikas, S (2012) Emerging therapeutic agents to lower lipoprotein (a) levels. Curr Opin Lipidol 23: pp. 560-8 CrossRef
  8. Ohira, T, Schreiner, PJ, Morrisett, JD, Chambless, LE, Rosamond, WD, Folsom, AR (2006) Lipoprotein(a) and incident ischemic stroke: the Atherosclerosis Risk in Communities (ARIC) study. Stroke 37: pp. 1407-12 CrossRef
  9. Alonso, R, Andres, E, Mata, N (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: pp. 1982-9 CrossRef
  10. Nielsen, LB (1999) Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux. Atherosclerosis 143: pp. 229-43 CrossRef
  11. Taleb, A, Witztum, JL, Tsimikas, S (2011) Oxidized phospholipids on apoB-100-containing lipoproteins: a biomarker predicting cardiovascular disease and cardiovascular events. Biomark Med 5: pp. 673-94 CrossRef
  12. Tsimikas, S, Brilakis, ES, Miller, ER (2005) Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 353: pp. 46-57 CrossRef
  13. Bergmark, C, Dewan, A, Orsoni, A (2008) A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res 49: pp. 2230-9 CrossRef
  14. Tsimikas, S, Kiechl, S, Willeit, J (2006) Oxidized phospholipids predict the presence and progression of carotid and femoral atherosclerosis and symptomatic cardiovascular disease: five-year prospective results from the Bruneck study. J Am Coll Cardiol 47: pp. 2219-28 CrossRef
  15. Tsimikas, S, Witztum, JL (2008) The role of oxidized phospholipids in mediating lipoprotein(a) atherogenicity. Curr Opin Lipidol 19: pp. 369-77 CrossRef
  16. Marcovina, SM, Koschinsky, ML (2003) Evaluation of lipoprotein(a) as a prothrombotic factor: progress from bench to bedside. Curr Opin Lipidol 14: pp. 361-6 CrossRef
  17. Kang, C, Dominguez, M, Loyau, S, Miyata, T, Durlach, V, Angles-Cano, E (2002) Lp(a) particles mold fibrin-binding properties of apo(a) in size-dependent manner: a study with different-length recombinant apo(a), native Lp(a), and monoclonal antibody. Arterioscler Thromb Vasc Biol 22: pp. 1232-8 CrossRef
  18. Clarke, R, Peden, JF, Hopewell, JC (2009) Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 361: pp. 2518-28 CrossRef
  19. Li, Y, Luke, MM, Shiffman, D, Devlin, JJ (2011) Genetic variants in the apolipoprotein(a) gene and coronary heart disease. Circ Cardiovasc Genet 4: pp. 565-73 CrossRef
  20. Chasman, DI, Shiffman, D, Zee, RY (2009) Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy. Atherosclerosis 203: pp. 371-6 CrossRef
  21. Deo, RC, Wilson, JG, Xing, C (2011) Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans. PLoS One 6: pp. e14581 CrossRef
  22. Virani, SS, Brautbar, A, Davis, BC (2012) Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study. Circulation 125: pp. 241-9 CrossRef
  23. Matthews, KA, Sowers, MF, Derby, CA (2005) Ethnic differences in cardiovascular risk factor burden among middle-aged women: Study of Women鈥檚 Health Across the Nation (SWAN). Am Heart J 149: pp. 1066-73 CrossRef
  24. Kathiresan, S (2009) Lp(a) lipoprotein redux鈥攆rom curious molecule to causal risk factor. N Engl J Med 361: pp. 2573-4 CrossRef
  25. Utermann, G (1989) The mysteries of lipoprotein(a). Science 246: pp. 904-10 CrossRef
  26. Marcovina, SM, Albers, JJ, Scanu, AM (2000) Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem 46: pp. 1956-67
  27. Erqou, S, Thompson, A, Angelantonio, E (2010) Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants. J Am Coll Cardiol 55: pp. 2160-7 CrossRef
  28. Marcovina, SM, Koschinsky, ML, Albers, JJ, Skarlatos, S (2003) Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions. Clin Chem 49: pp. 1785-96 CrossRef
  29. McConnell, JP, Guadagno, PA, Dayspring, TD, Hoefner, DM, Thiselton, DL, Warnick, GR (2014) Lipoprotein(a) mass: a massively misunderstood metric. J Clin Lipidol 8: pp. 550-3 CrossRef
  30. Davidson, MH, Ballantyne, CM, Jacobson, TA (2011) Clinical utility of inflammatory markers and advanced lipoprotein testing: advice from an expert panel of lipid specialists. J Clin Lipidol 5: pp. 338-67 CrossRef
  31. Nordestgaard, BG, Chapman, MJ, Ray, K (2010) Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 31: pp. 2844-53 CrossRef
  32. Wang, W, Hu, D, Lee, ET (2002) Lipoprotein(a) in American Indians is low and not independently associated with cardiovascular disease. The Strong Heart Study. Ann Epidemiol 12: pp. 107-14 CrossRef
  33. Banerjee, D, Wong, EC, Shin, J, Fortmann, SP, Palaniappan, L (2011) Racial and ethnic variation in lipoprotein (a) levels among Asian Indian and Chinese patients. J Lipids 2011: pp. 291954 CrossRef
  34. Tavridou, A, Unwin, N, Bhopal, R, Laker, MF (2003) Predictors of lipoprotein(a) levels in a European and South Asian population in the Newcastle Heart Project. Eur J Clin Invest 33: pp. 686-92 CrossRef
  35. Stone, NJ, Robinson, JG, Lichtenstein, AH (2014) 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 129: pp. S1-45 CrossRef
  36. Anderson, TJ, Gregoire, J, Hegele, RA (2013) 2012 update of the Canadian Cardiovascular Society guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Can J Cardiol 29: pp. 151-67 CrossRef
  37. Luc, G, Bard, JM, Arveiler, D (2002) Lipoprotein (a) as a predictor of coronary heart disease: the PRIME Study. Atherosclerosis 163: pp. 377-84 CrossRef
  38. Maher, VM, Brown, BG, Marcovina, SM, Hillger, LA, Zhao, XQ, Albers, JJ (1995) Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a). JAMA 274: pp. 1771-4 CrossRef
  39. Jacobson, TA (2013) Lipoprotein(a), cardiovascular disease, and contemporary management. Mayo Clin Proc 88: pp. 1294-311 CrossRef
  40. Akaike, M, Azuma, H, Kagawa, A (2002) Effect of aspirin treatment on serum concentrations of lipoprotein(a) in patients with atherosclerotic diseases. Clin Chem 48: pp. 1454-9
  41. Creider, JC, Hegele, RA, Joy, TR (2012) Niacin: another look at an underutilized lipid-lowering medication. Nat Rev Endocrinol 8: pp. 517-28 CrossRef
  42. The Coronary Drug Project Research Group. Clofibrate and niacin in coronary heart disease. JAMA. 1975;231(4):360鈥?1.
  43. Canner, PL, Berge, KG, Wenger, NK (1986) Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol 8: pp. 1245-55 CrossRef
  44. Capuzzi, DM, Guyton, JR, Morgan, JM (1998) Efficacy and safety of an extended-release niacin (Niaspan): a long-term study. Am J Cardiol 82: pp. 74U-81 CrossRef
  45. Carlson, LA, Hamsten, A, Asplund, A (1989) Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid. J Intern Med 226: pp. 271-6 CrossRef
  46. Albers, JJ, Slee, A, O鈥橞rien, KD (2013) Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol 62: pp. 1575-9 CrossRef
  47. Landray, MJ, Haynes, R, Hopewell, JC (2014) Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 371: pp. 203-12 CrossRef
  48. Lavigne, PM, Karas, RH (2013) The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression. J Am Coll Cardiol 61: pp. 440-6 CrossRef
  49. Thompson, GR, Barbir, M, Davies, D (2010) Efficacy criteria and cholesterol targets for LDL apheresis. Atherosclerosis 208: pp. 317-21 CrossRef
  50. McGowan, MP (2013) Emerging low-density lipoprotein (LDL) therapies: management of severely elevated LDL cholesterol鈥攖he role of LDL-apheresis. J Clin Lipidol 7: pp. S21-6 CrossRef
  51. Schwartz, J, Winters, JL, Padmanabhan, A (2013) Guidelines on the use of therapeutic apheresis in clinical practice鈥攅vidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher 28: pp. 145-284 CrossRef
  52. Leebmann, J, Roeseler, E, Julius, U (2013) Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia, and progressive cardiovascular disease: prospective observational multicenter study. Circulation 128: pp. 2567-76 CrossRef
  53. Thompson, GR (2008) Recommendations for the use of LDL apheresis. Atherosclerosis 198: pp. 247-55 CrossRef
  54. Jaeger, BR, Richter, Y, Nagel, D (2009) Longitudinal cohort study on the effectiveness of lipid apheresis treatment to reduce high lipoprotein(a) levels and prevent major adverse coronary events. Nat Clin Pract Cardiovasc Med 6: pp. 229-39 CrossRef
  55. Taskinen, MR, Puolakka, J, Pyorala, T (1996) Hormone replacement therapy lowers plasma Lp(a) concentrations. Comparison of cyclic transdermal and continuous estrogen-progestin regimens. Arterioscler Thromb Vasc Biol 16: pp. 1215-21 CrossRef
  56. Espeland, MA, Marcovina, SM, Miller, V (1998) Effect of postmenopausal hormone therapy on lipoprotein(a) concentration. PEPI Investigators. Postmenopausal Estrogen/Progestin Interventions. Circulation 97: pp. 979-86 CrossRef
  57. Soma, MR, Meschia, M, Bruschi, F (1994) Hormonal agents used in lowering lipoprotein(a). Chem Phys Lipids 67鈥?8: pp. 345-50 CrossRef
  58. Sacks, FM, McPherson, R, Walsh, BW (1994) Effect of postmenopausal estrogen replacement on plasma Lp(a) lipoprotein concentrations. Arch Intern Med 154: pp. 1106-10 CrossRef
  59. Hoover-Plow, J, Huang, M (2013) Lipoprotein(a) metabolism: potential sites for therapeutic targets. Metabolism 62: pp. 479-91 CrossRef
  60. Manson, JE, Hsia, J, Johnson, KC (2003) Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 349: pp. 523-34 CrossRef
  61. Hulley, S, Grady, D, Bush, T (1998) Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 280: pp. 605-13 CrossRef
  62. Grady, D, Herrington, D, Bittner, V (2002) Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 288: pp. 49-57 CrossRef
  63. Suk Danik, J, Rifai, N, Buring, JE, Ridker, PM (2008) Lipoprotein(a), hormone replacement therapy, and risk of future cardiovascular events. J Am Coll Cardiol 52: pp. 124-31 CrossRef
  64. Kynamro^TM (mipomersen sodium) injection [package insert]. Cambridge, MA; Genzyme. Revised January 2015.
  65. Visser, ME, Witztum, JL, Stroes, ES, Kastelein, JJ (2012) Antisense oligonucleotides for the treatment of dyslipidaemia. Eur Heart J 33: pp. 1451-8 CrossRef
  66. 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: pp. 367-76 CrossRef
  67. Juxtapid (lomitapide) capsules [package insert]. Cambridge, MA; Aegerion Pharmaceuticals. Revised August, 2014.
  68. Samaha, FF, McKenney, J, Bloedon, LT, Sasiela, WJ, Rader, DJ (2008) Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med 5: pp. 497-505 CrossRef
  69. Goldberg, AC (2013) Emerging low-density lipoprotein therapies: microsomal triglyceride transfer protein inhibitors. J Clin Lipidol 7: pp. S16-20 CrossRef
  70. Cuchel, M, Meagher, EA, Toit Theron, H (2013) 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 381: pp. 40-6 CrossRef
  71. Urban, D, Poss, J, Bohm, M, Laufs, U (2013) Targeting the proprotein convertase subtilisin/kexin type 9 for the treatment of dyslipidemia and atherosclerosis. J Am Coll Cardiol 62: pp. 1401-8 CrossRef
  72. Sniderman, AD, Tsimikas, S, Fazio, S (2014) The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies. J Am Coll Cardiol 63: pp. 1935-47 CrossRef
  73. Stein, EA, Swergold, GD (2013) Potential of proprotein convertase subtilisin/kexin type 9 based therapeutics. Curr Atheroscler Rep 15: pp. 310 CrossRef
  74. Raal, FJ, Giugliano, RP, Sabatine, MS (2014) Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 63: pp. 1278-88 CrossRef
  75. Gaudet, D, Kereiakes, DJ, McKenney, JM (2014) Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol 114: pp. 711-5 CrossRef
  76. Barter, PJ, Caulfield, M, Eriksson, M (2007) Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 357: pp. 2109-22 CrossRef
  77. Schwartz, GG, Olsson, AG, Abt, M (2012) Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 367: pp. 2089-99 CrossRef
  78. Cannon, CP, Shah, S, Dansky, HM (2010) Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 363: pp. 2406-15 CrossRef
  79. REVEAL: randomized evaluation of the effects of anacetrapib through lipid-modification. https://clinicaltrials.gov/ct2/show/NCT01252953.
  80. Mohammadpour, AH, Akhlaghi, F (2013) Future of cholesteryl ester transfer protein (CETP) inhibitors: a pharmacological perspective. Clin Pharmacokinet 52: pp. 615-26 CrossRef
  81. ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High-Risk for Vascular Outcomes). https://clinicaltrials.gov/ct2/show/study/NCT01687998?term=NCT01687998&rank=1 (ClinicalTrials.gov Identifier: NCT01687998).
  82. Angelin, B, Rudling, M (2010) Lipid lowering with thyroid hormone and thyromimetics. Curr Opin Lipidol 21: pp. 499-506 CrossRef
  83. Ladenson, PW, Kristensen, JD, Ridgway, EC (2010) Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med 362: pp. 906-16 CrossRef
  84. Claudel, T, Sturm, E, Duez, H (2002) Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element. J Clin Invest 109: pp. 961-71 CrossRef
  85. Chennamsetty, I, Claudel, T, Kostner, KM (2011) Farnesoid X receptor represses hepatic human APOA gene expression. J Clin Invest 121: pp. 3724-34 CrossRef
  86. 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: pp. 145-50 CrossRef
  87. Berthold, HK, Laudes, M, Krone, W, Gouni-Berthold, I (2011) Association between the interleukin-6 promoter polymorphism -174G/C and serum lipoprotein(a) concentrations in humans. PLoS One 6: pp. e24719 CrossRef
  88. Schultz, O, Oberhauser, F, Saech, J (2010) Effects of inhibition of interleukin-6 signalling on insulin sensitivity and lipoprotein (a) levels in human subjects with rheumatoid diseases. PLoS One 5: pp. e14328 CrossRef
  89. Merki, E, Graham, M, Taleb, A (2011) Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol 57: pp. 1611-21 CrossRef
  
• 刊物主题：Angiology; Cardiology;
• 出版者：Springer US
• ISSN：1534-6242

文摘

Robust epidemiologic and genetic studies have solidified the role of lipoprotein (a) [Lp(a)] as an independent and causal risk factor for cardiovascular disease. The increased cardiovascular risk of Lp(a) is mediated through both proatherogenic and prothrombotic/antifibrinolytic mechanisms. Several societies recommend Lp(a) screening for patients with high cardiovascular risk, although no consensus exists on the management of patients with elevated Lp(a). However, numerous pharmacologic approaches are being evaluated that have the potential to reduce Lp(a) and will be the focus of this review. The majority of these interventions have been developed for other lipid-lowering indications, but also lower Lp(a). There are also novel therapies in development that specifically target Lp(a). The efficacy of these therapies varies, and their role in the evolving lipoprotein therapeutic landscape has yet to be determined. Nevertheless, targeted Lp(a) reduction is certainly intriguing and will likely continue to be an active area of investigation in the future.