'LDL-C'=LDL-C+Lp(a)-C: Implications of achieved ultra-low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering

Current Opinion in Pediatrics

Volumn 26, Issue 3, 2015, Pages 169-178

  Yeang, Calvin ^a   Witztum, Joseph L ^a   Tsimikas, Sotirios ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

cardiovascular disease; LDL C; lipoprotein(a); PCSK9

Indexed keywords

INTERMEDIATE DENSITY LIPOPROTEIN; KEXIN; LIPOPROTEIN A; LOW DENSITY LIPOPROTEIN CHOLESTEROL; SUBTILISIN; VERY LOW DENSITY LIPOPROTEIN; EZETIMIBE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; PCSK9 PROTEIN, HUMAN; SERINE PROTEINASE; ENZYME INHIBITOR; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9 INHIBITOR; UNCLASSIFIED DRUG;

ATHEROSCLEROSIS; CEREBROVASCULAR ACCIDENT; CORONARY ARTERY DISEASE; DENSITY GRADIENT CENTRIFUGATION; HUMAN; LIMIT OF QUANTITATION; LIPOPROTEIN BLOOD LEVEL; PATHOPHYSIOLOGY; PERIPHERAL OCCLUSIVE ARTERY DISEASE; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN MODIFICATION; REVIEW; VERTICAL AUTO PROFILE; ANIMAL; ANTAGONISTS AND INHIBITORS; BLOOD; CLINICAL TRIAL (TOPIC); HYPERCHOLESTEROLEMIA; TREATMENT OUTCOME; BLOOD SAMPLING; CHOLESTEROL BLOOD LEVEL; CLINICAL RESEARCH; FEASIBILITY STUDY; METHODOLOGY; NONHUMAN; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC);

ANIMALS; CHOLESTEROL, LDL; CLINICAL TRIALS AS TOPIC; EZETIMIBE; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERCHOLESTEROLEMIA; LIPOPROTEIN(A); PROPROTEIN CONVERTASES; SERINE ENDOPEPTIDASES; TREATMENT OUTCOME;

EID: 84960119350     PISSN: 10408703     EISSN: 1531698X     Source Type: Journal    
DOI: 10.1097/MOL.0000000000000171     Document Type: Review

References (72)

1. Myocardial Infarction Genetics Consortium Investigators. Stitziel NO, Won HH, Morrison AC, et al. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med 2014; 371:2072-2082.
2. Cannon CP. IMPROVE-IT trial: a comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes after acute coronary syndromes. In: AHA presentation 2014.
3. Dadu RT, Ballantyne CM. Lipid lowering with PCSK9 inhibitors. Nat Rev Cardiol 2014; 11:563-575.
4. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet 2003; 34:154-156.
5. Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med 2006; 354:1264-1272.
6. Benn M, Nordestgaard BG, Grande P, et al. PCSK9 R46L, low-density lipoprotein cholesterol levels, and risk of ischemic heart disease: 3 independent studies and meta-analyses. J Am Coll Cardiol 2010; 55:2833-2842.
7. Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet 2012; 380:1995-2006.
8. Raal F, Scott R, Somaratne R, et al. Low-density lipoprotein cholesterollowering effects ofAMG145, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease in patients with heterozygous familial hypercholesterolemia: the Reduction of LDL-C with PCSK9 Inhibition in Heterozygous Familial Hypercholesterolemia Disorder (RUTHERFORD) randomized trial. Circulation 2012; 126:2408-2417.
9. Sullivan D, Olsson AG, Scott R, et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial. JAMA 2012; 308:2497-2506.
10. Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation 2014; 129:234-243.
11. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012; 367:1891-1900.
12. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012; 59:2344-2353.
13. Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet 2012; 380:29-36.
14. Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate-or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA 2014; 311:1870-1882.
15. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol 2014; 63:2531-2540.
16. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2014.
17. Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2014.
18. Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol 2014; 63:2541-2548.
19. Roth EM, McKenney JM. ODYSSEY MONO: effect of alirocumab 75mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol 2015; 11:27-37.
20. Robinson J, Farnier M, Chaudhari U et al. Adverse events in patients with lowdensity lipoprotein cholesterol levels <25 or <15 mg/dl on at least two consecutive visits in fourteen randomized, controlled, clinical trials of alirocumab. American College of Cardiology Presentation 2015
21. Lamon-Fava S, Marcovina SM, Albers JJ, et al. Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study. J Lipid Res 2011; 52:1181-1187.
22. Konerman M, Kulkarni K, Toth PP, Jones SR. Lipoprotein(a) particle concentration and lipoprotein(a) cholesterol assays yield discordant classification of patients into four physiologically discrete groups. J Clin Lipidol 2012; 6:368-373.
23. Tsimikas S, Hall JH. 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; 60:716-721.
24. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010; 31:2844-2853.
25. Ravandi A, Leibundgut G, Hung MY, et al. Release and capture of bioactive oxidized phospholipids and oxidized cholesteryl esters during percutaneous coronary and peripheral arterial interventions in humans. J Am Coll Cardiol 2014; 63:1961-1971.
26. Erqou S, Kaptoge S, Perry PL, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 2009; 302:412-423.
27. Gurdasani D, Sjouke B, Tsimikas S, et al. Lipoprotein(a) and risk of coronary, cerebrovascular, and peripheral artery disease: The EPIC-Norfolk Prospective Population Study. Arterioscler Thromb Vasc Biol 2012; 32:3058-3065.
28. Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med 2009; 361:2518-2528.
29. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 2009; 301:2331-2339.
30. Tregouet DA, Konig IR, Erdmann J, et al. Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease. Nat Genet 2009; 41:283-285.
31. Schunkert H, Konig IR, Kathiresan S, et al. Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011; 43:333-338.
32. CARDIoGRAMplusC4D Consortium. Deloukas P, Kanoni S, Willenborg C, et al. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 2013; 45:25-33.
33. Willeit P, Kiechl S, Kronenberg F, et al. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol 2014; 64:851-860.
34. Tsimikas S, Mallat Z, Talmud PJ, et al. Oxidation-specific biomarkers, lipoprotein( a), and risk of fatal and nonfatal coronary events. J Am Coll Cardiol 2010; 56:946-955.
35. Tsimikas S, Duff GW, Berger PB, et al. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 2014; 63:1724-1734.
36. Kamstrup PR, Tybjaerg-Hansen A, Nordestgaard BG. Elevated lipoprotein(a) and risk of aortic valve stenosis in the general population. J Am Coll Cardiol 2014; 63:470-477.
37. Arsenault BJ, Boekholdt SM, Dube MP, et al. Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective mendelian randomization study and replication in a case-control cohort. Circ Cardiovasc Genet 2014; 7:304-310.
38. Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med 2013; 368:503-512.
39. Hung MY, Witztum JL, Tsimikas S. New therapeutic targets for calcific aortic valve stenosis: the lipoprotein(a)-lipoprotein-associated phospholipase A2-oxidized phospholipid axis. J Am Coll Cardiol 2014; 63:478-480.
40. Steinberg D, Witztum JL. Oxidized low-density lipoprotein and atherosclerosis. Arterioscler Thromb Vasc Biol 2010; 30:2311-2316.
41. Di Angelantonio E, Gao P, Pennells L, et al. Lipid-related markers and cardiovascular disease prediction. JAMA 2012; 307:2499-2506.
42. Seman LJ, Breckenridge WC. Isolation and partial characterization of apolipoprotein (a) from human lipoprotein (a). Biochem Cell Biol 1986; 64:999-1009.
43. Jenner JL, Ordovas JM, Lamon-Fava S, et al. Effects of age, sex, and menopausal status on plasma lipoprotein(a) levels. The Framingham Offspring Study. Circulation 1993; 87:1135-1141.
44. Marcovina SM, Albers JJ, Scanu AM, et al. 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). Clinical chemistry 2000; 46:1956-1967.
45. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972; 18:499-502.
46. Martin SS, Blaha MJ, Elshazly MB, et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol 2013; 62:732-739.
47. Li KM, Wilcken DE, Dudman NP. Effect of serum lipoprotein(a) on estimation of low-density lipoprotein cholesterol by the Friedewald formula. Clinical chemistry 1994; 40:571-573.
48. Contois JH, Warnick GR, Sniderman AD. Reliability of low-density lipoprotein cholesterol, nonhigh-density lipoprotein cholesterol, and apolipoprotein B measurement. J Clin Lipidol 2011; 5:264-272.
49. Miller WG, Myers GL, Sakurabayashi I, et al. Seven direct methods for measuring HDL and LDL cholesterol compared with ultracentrifugation reference measurement procedures. Clin Chem 2010; 56:977-986.
50. Kulkarni KR, Garber DW, Marcovina SM, Segrest JP. Quantification of cholesterol in all lipoprotein classes by the VAP-II method. J Lipid Res 1994; 35:159-168.
51. Konerman M, Kulkarni K, Toth PP, Jones SR. Evidence of dependence of lipoprotein(a) on triglyceride and high-density lipoprotein metabolism. J Clin Lipidol 2012; 6:27-32.
52. Sharma S, Merchant J, Fleming SE. Lp(a)-cholesterol is associated with HDLcholesterol in overweight and obese African American children and is not an independent risk factor for CVD. Cardiovasc Diabetol 2012; 11:10.
53. Chapman MJ, Goldstein S, Lagrange D, Laplaud PM. A density gradient ultracentrifugal procedure for the isolation of the major lipoprotein classes from human serum. J Lipid Res 1981; 22:339-358.
54. Menzel HJ, Dieplinger H, Lackner C, et al. Abetalipoproteinemia with an ApoB-100-lipoprotein(a) glycoprotein complex in plasma. Indication for an assembly defect. J Biol Chem 1990; 265:981-986.
55. Merki E, Graham M, Taleb A, et al. Antisense oligonucleotide lowers plasma levels of apolipoprotein (a) and lipoprotein (a) in transgenic mice. J Am Coll Cardiol 2011; 57:1611-1621.
56. Merki E, Graham MJ, Mullick AE, et al. Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice. Circulation 2008; 118:743-753.
57. O'Donoghue ML, Morrow DA, Tsimikas S, et al. Lipoprotein(a) for risk assessment in patients with established coronary artery disease. J Am Coll Cardiol 2014; 63:520-527.
58. Tsimikas S, Witztum JL, Miller ER, et al. High-dose atorvastatin reduces total plasma levels of oxidized phospholipids and immune complexes present on apolipoprotein B-100 in patients with acute coronary syndromes in the MIRACL trial. Circulation 2004; 110:1406-1412.
59. Rodenburg J, Vissers MN, Wiegman A, et al. Oxidized low-density lipoprotein in children with familial hypercholesterolemia and unaffected siblings: effect of pravastatin. J Am Coll Cardiol 2006; 47:1803-1810.
60. Kostner GM, Gavish D, Leopold B, et al. HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation 1989; 80: 1313-1319.
61. Choi SH, Chae A, Miller E, et al. Relationship between biomarkers of oxidized low-density lipoprotein, statin therapy, quantitative coronary angiography, and atheroma: volume observations from the REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study. J Am Coll Cardiol 2008; 52:24-32.
62. Ky B, Burke A, Tsimikas S, et al. The influence of pravastatin and atorvastatin on markers of oxidative stress in hypercholesterolemic humans. J Am Coll Cardiol 2008; 51:1653-1662.
63. Tsimikas S, Willeit P, Willeit J, et al. Oxidation-specific biomarkers, prospective 15-year cardiovascular and stroke outcomes, and net reclassification of cardiovascular events. J Am Coll Cardiol 2012; 60:2218-2229.
64. Tsimikas S, Brilakis ES, Miller ER, et al. Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease. N Engl J Med 2005; 353: 46-57.
65. Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1300 patients in 4 phase II trials. J Am Coll Cardiol 2014; 63:1278-1288.
66. Stein EA, Giugliano RP, Koren MJ, et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur Heart J 2014; 35:2249-2259.
67. Fless GM, ZumMallen ME, Scanu AM. Physicochemical properties of apolipoprotein(a) and lipoprotein(a-) derived from the dissociation of human plasma lipoprotein (a). J Biol Chem 1986; 261:8712-8718.
68. Bergmark C, Dewan A, Orsoni A, et al. A novel function of lipoprotein [a] as a preferential carrier of oxidized phospholipids in human plasma. J Lipid Res 2008; 49:2230-2239.
69. Leibundgut G, Scipione C, Yin H, et al. Determinants of binding of oxidized phospholipids on apolipoprotein (a) and lipoprotein (a). J Lipid Res 2013; 54:2815-2830.
70. Kronenberg F, Kuen E, Ritz E, et al. Lipoprotein(a) serum concentrations and apolipoprotein(a) phenotypes in mild and moderate renal failure. J Am Soc Nephrol 2000; 11:105-115.
71. Arai K, Orsoni A, Mallat Z, et al. Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia. J Lipid Res 2012; 53:1670-1678.
72. Mooser V, Seabra MC, Abedin M, et al. Apolipoprotein(a) kringle 4-containing fragments in human urine. Relationship to plasma levels of lipoprotein(a). J Clin Investig 1996; 97:858-864.