The severe hypercholesterolemia phenotype: Clinical diagnosis, management, and emerging therapies

Journal of the American College of Cardiology

Volumn 63, Issue 19, 2014, Pages 1935-1947

  Sniderman, Allan D ^a   Tsimikas, Sotirios ^b   Fazio, Sergio ^c  

^a ROYAL VICTORIA HOSPITAL   (Canada)

^b UNIVERSITY OF CALIFORNIA SAN DIEGO   (United States)

^c VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

Author keywords

familial hypercholesterolemia; genetics; LDL receptor; lipoproteins; statins

Indexed keywords

ANTISENSE OLIGONUCLEOTIDE; APOLIPOPROTEIN B; HIGH DENSITY LIPOPROTEIN; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; KEXIN; LOMITAPIDE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; LOW DENSITY LIPOPROTEIN RECEPTOR; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN INHIBITOR; MIPOMERSEN; PCSK9 INHIBITOR; PROPROTEIN CONVERTASE SUBTILISIN KEXIN TYPE 9; UNCLASSIFIED DRUG; VERY LOW DENSITY LIPOPROTEIN; ALIROCUMAB; ANTILIPEMIC AGENT; APOLIPOPROTEIN B100; BILE ACID SEQUESTRANT; EVOLOCUMAB; EZETIMIBE; FIBRIC ACID DERIVATIVE; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; NICOTINIC ACID; SUBTILISIN;

APHERESIS; ARTICLE; AUTOSOMAL DOMINANT DISORDER; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL METABOLISM; CORONARY ARTERY DISEASE; DIAGNOSTIC PROCEDURE; DIARRHEA; DISEASE SEVERITY; DRUG DOSE ESCALATION; DRUG TOLERANCE; FAMILIAL HYPERCHOLESTEROLEMIA; GENE MUTATION; GENETIC SCREENING; HIGH RISK PATIENT; HUMAN; HYPERCHOLESTEROLEMIA; LIPOPROTEIN APHERESIS; NAUSEA; PATHOPHYSIOLOGY; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHENOTYPE; PREVALENCE; PRIORITY JOURNAL; RISK REDUCTION; TREATMENT INDICATION; ACUTE CORONARY SYNDROME; AGE DISTRIBUTION; AUTOSOMAL DOMINANT INHERITANCE; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; CLINICAL EFFECTIVENESS; DISEASE CLASSIFICATION; DRUG SAFETY; DRUG TOLERABILITY; ERYTHEMA; FAMILY ASSESSMENT; FATTY LIVER; HEREDITY; INJECTION SITE REACTION; LIFESTYLE MODIFICATION; PAIN; PRURITUS; RISK FACTOR; SCREENING; SEX DIFFERENCE; SKIN SWELLING; TREATMENT RESPONSE; UNSPECIFIED SIDE EFFECT;

FAMILIAL HYPERCHOLESTEROLEMIA; GENETICS; LDL RECEPTOR; LIPOPROTEINS; STATINS;

ANIMALS; ANTICHOLESTEREMIC AGENTS; CHOLESTEROL, LDL; CLINICAL TRIALS AS TOPIC; DISEASE MANAGEMENT; ENZYME INHIBITORS; HUMANS; HYPERCHOLESTEROLEMIA; PHENOTYPE; PROPROTEIN CONVERTASES; RECEPTORS, LDL; RISK FACTORS; SERINE ENDOPEPTIDASES; SEVERITY OF ILLNESS INDEX;

EID: 84900832381     PISSN: 07351097     EISSN: 15583597     Source Type: Journal    
DOI: 10.1016/j.jacc.2014.01.060     Document Type: Review

References (91)

1. M.S. Brown, and J.L. Goldstein A receptor-mediated pathway for cholesterol homeostasis Science 232 1986 34 47
2. P.N. Hopkins, P.P. Toth, C.M. Ballantyne, and D.J. Rader Familial hypercholesterolemias: prevalence, genetics, diagnosis and screening recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia J Clin Lipidol 5 2011 S9 S17
3. F.R. Maxfield, and G. van Meer Cholesterol, the central lipid of mammalian cells Curr Opin Cell Bio 22 2010 422 429
4. P.J. Talmud, S. Shah, and R. Whittall et al. Use of low-density lipoprotein cholesterol gene score to distinguish patients with polygenic and monogenic familial hypercholesterolaemia: a case-control study Lancet 381 2013 1293 1301
5. E.A. Stein, and F.J. Raal Polygenic familial hypercholesterolaemia: does it matter? Lancet 381 2013 1255 1257
6. B.G. Nordestgaard, M.J. Chapman, and S.E. Humphries et al. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society Eur Heart J 34 2013 3478 3490
7. J.D. Horton, J.C. Cohen, and H.H. Hobbs PCSK9: a convertase that coordinates LDL catabolism J Lipid Res 50 Suppl 2009 S172 S177
8. F.J. Raal, and R.D. Santos Homozygous familial hypercholesterolemia: current perspectives on diagnosis and treatment Atherosclerosis 223 2012 262 268
9. D.L. Sprecher, E.J. Schaefer, and K.M. Kent et al. Cardiovascular features of homozygous familial hypercholesterolemia: analysis of 16 patients Am J Cardiol 54 1984 20 30
10. J.M. Allen, G.R. Thompson, N.B. Myant, R. Steiner, and C.M. Oakley Cardiovascular complications of homozygous familial hypercholesterolaemia Br Heart J 44 1980 361 368
11. J.L. Goldstein, H.G. Schrott, W.R. Hazzard, E.L. Bierman, and A.G. Motulsky Hyperlipidemia in coronary heart disease. II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia J Clin Invest 52 1973 1544 1568
12. D. Gaudet, M.C. Vohl, and P. Julien et al. Relative contribution of low-density lipoprotein receptor and lipoprotein lipase gene mutations to angiographically assessed coronary artery disease among French Canadians Am J Cardiol 82 1998 299 305
13. L.S. Rallidis, J. Lekakis, and D. Panagiotakos et al. Long-term prognostic factors of young patients (
14. J.T. Real, F.J. Chaves, I. Martinez-Uso, A.B. Garcia-Garcia, J.F. Ascaso, and R. Carmena Importance of HDL cholesterol levels and the total/ HDL cholesterol ratio as a risk factor for coronary heart disease in molecularly defined heterozygous familial hypercholesterolaemia Eur Heart J 22 2001 465 471
15. A.C. Jansen, E.S. van Aalst-Cohen, and M.W. Tanck et al. The contribution of classical risk factors to cardiovascular disease in familial hypercholesterolaemia: data in 2400 patients J Int Med 256 2004 482 490
16. S. Tsimikas, and J.H. Hall 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 60 2012 716 721
17. H.G. Kraft, A. Lingenhel, F.J. Raal, M. Hohenegger, and G. Utermann Lipoprotein(a) in homozygous familial hypercholesterolemia Arterioscler Thromb Vasc Biol 20 2000 522 528
18. D.J. Rader, W.A. Mann, and W. Cain et al. The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans J Clin Invest 95 1995 1403 1408
19. W.J. Cain, J.S. Millar, and A.S. Himebauch et al. Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a] J Lipid Res 46 2005 2681 2691
20. S.M. Grundy, G.L. Vega, and D.W. Bilheimer Kinetic mechanisms determining variability in low density lipoprotein levels and rise with age Arteriosclerosis 5 1985 623 630
21. A.D. Sniderman, X.J. Zhang, and K. Cianflone Governance of the concentration of plasma LDL: a reevaluation of the LDL receptor paradigm Atherosclerosis 148 2000 215 229
22. J. Twisk, D.L. Gillian-Daniel, A. Tebon, L. Wang, P.H. Barrett, and A.D. Attie The role of the LDL receptor in apolipoprotein B secretion J Clin Invest 105 2000 521 532
23. D.A. Blasiole, A.T. Oler, and A.D. Attie Regulation of ApoB secretion by the low density lipoprotein receptor requires exit from the endoplasmic reticulum and interaction with ApoE or ApoB J Biol Chem 283 2008 11374 11381
24. A.C. Goldberg, P.N. Hopkins, and P.P. Toth et al. 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 2011 S1 S8
25. S. Calandra, P. Tarugi, H.E. Speedy, A.F. Dean, S. Bertolini, and C.C. Shoulders Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk J Lipid Res 52 2011 1885 1926
26. A. Haase, and A.C. Goldberg Identification of people with heterozygous familial hypercholesterolemia Curr Opin Lipidol 23 2012 282 289
27. T.L. Innerarity, R.W. Mahley, and K.H. Weisgraber et al. Familial defective apolipoprotein B-100: a mutation of apolipoprotein B that causes hypercholesterolemia J Lipid Res 31 1990 1337 1349
28. C.K. Garcia, K. Wilund, and M. Arca et al. Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein Science 292 2001 1394 1398
29. J. Wang, T. Joy, D. Mymin, J. Frohlich, and R.A. Hegele Phenotypic heterogeneity of sitosterolemia J Lipid Res 45 2004 2361 2367
30. G. Lambert, B. Sjouke, B. Choque, J.J. Kastelein, and G.K. Hovingh The PCSK9 decade J Lipid Res 53 2012 2515 2524
31. J.C. Cohen, E. Boerwinkle, T.H. Mosley Jr., and H.H. Hobbs Sequence variations in PCSK9, low LDL, and protection against coronary heart disease N Engl J Med 354 2006 1264 1272
32. Z. Ahmad, B. Adams-Huet, C. Chen, and A. Garg Low prevalence of mutations in known loci for autosomal dominant hypercholesterolemia in a multiethnic patient cohort Circ Cardiovasc Genet 5 2012 666 675
33. K. Harders-Spengel, C.B. Wood, G.R. Thompson, N.B. Myant, and A.K. Soutar Difference in saturable binding of low density lipoprotein to liver membranes from normocholesterolemic subjects and patients with heterozygous familial hypercholesterolemia Proc Natl Acad Sci U S A 79 1982 6355 6359
34. L.M. Havekes, H. Verboom, E. de Wit, S.H. Yap, and H.M. Princen Regulation of low density lipoprotein receptor activity in primary cultures of human hepatocytes by serum lipoproteins Hepatology 6 1986 1356 1360
35. N. Zelcer, C. Hong, R. Boyadjian, and P. Tontonoz LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor Science 325 2009 100 104
36. A.D. Sniderman, Y. Qi, and C.I. Ma et al. Hepatic cholesterol homeostasis: is the low-density lipoprotein pathway a regulatory or a shunt pathway? Arterioscler Thromb Vasc Biol 33 2013 2481 2490
37. D.W. Bilheimer, N.J. Stone, and S.M. Grundy Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo J Clin Invest 64 1979 524 533
38. E.D. Janus, A. Nicoll, R. Wootton, P.R. Turner, P.J. Magill, and B. Lewis Quantitative studies of very low density lipoprotein: conversion to low density lipoprotein in normal controls and primary hyperlipidaemic states and the role of direct secretion of low density lipoprotein in heterozygous familial hypercholesterolaemia Eur J Clin Invest 10 1980 149 159
39. A.K. Soutar, N.B. Myant, and G.R. Thompson Simultaneous measurement of apolipoprotein B turnover in very-low-and low-density lipoproteins in familial hypercholesterolaemia Atherosclerosis 28 1977 247 256
40. B. Teng, A.D. Sniderman, A.K. Soutar, and G.R. Thompson Metabolic basis of hyperapobetalipoproteinemia. Turnover of apolipoprotein B in low density lipoprotein and its precursors and subfractions compared with normal and familial hypercholesterolemia J Clin Invest 77 1986 663 672
41. J.S. Millar, C. Maugeais, and K. Ikewaki et al. Complete deficiency of the low-density lipoprotein receptor is associated with increased apolipoprotein B-100 production Arterioscler Thromb Vasc Biol 25 2005 560 565
42. Y.A. Kesaniemi, and S.M. Grundy Significance of low density lipoprotein production in the regulations of plasma cholesterol level in man J Clin Invest 70 1982 13 22
43. N. Bellanger, A. Orsoni, and Z. Julia et al. Atheroprotective reverse cholesterol transport pathway is defective in familial hypercholesterolemia Arterioscler Thromb Vasc Biol 31 2011 1675 1681
44. S.R. Daniels, S.S. Gidding, and S.D. de Ferranti Pediatric aspects of familial hypercholesterolemias: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia J Clin Lipidol 5 2011 S30 S37
45. E.S. van Aalst-Cohen, A.C. Jansen, and M.W. Tanck et al. Diagnosing familial hypercholesterolaemia: The relevance of genetic testing Eur Heart J 27 2006 2240 2246
46. Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group BMJ 303 1991 893 896
47. B. Thorsson, G. Sigurdsson, and V. Gudnason Systematic family screening for familial hypercholesterolemia in Iceland Arterioscler Thromb Vasc Biol 23 2003 335 338
48. J.P. Kane, M.J. Malloy, T.A. Ports, N.R. Phillips, J.C. Diehl, and R.J. Havel Regression of coronary atherosclerosis during treatment of familial hypercholesterolemia with combined drug regimens JAMA 264 1990 3007 3012
49. F.J. Raal, G.J. Pilcher, and V.R. Panz et al. Reduction in mortality in subjects with homozygous familial hypercholesterolemia associated with advances in lipid-lowering therapy Circulation 124 2011 2202 2207
50. A. Neil, J. Cooper, and J. Betteridge et al. Reductions in all-cause, cancer, and coronary mortality in statin-treated patients with heterozygous familial hypercholesterolaemia: a prospective registry study Eur Heart J 29 2008 2625 2633
51. J. Versmissen, D.M. Oosterveer, and M. Yazdanpanah et al. Efficacy of statins in familial hypercholesterolaemia: a long term cohort study BMJ 337 2008 a2423
52. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S) Lancet 344 1994 1383 1389
53. J. Shepherd, S.M. Cobbe, and I. Ford et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group N Engl J Med 333 1995 1301 1307
54. The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease JAMA 251 1984 351 364
55. N.J. Stone, J. Robinson, and A.H. Lichtenstein et al. 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 J Am Coll Cardiol 2013 Nov 7 [E-pub ahead of print] doi: 10.1016/j.jacc.2013.11.002
56. A.H. Pijlman, R. Huijgen, and S.N. Verhagen et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands Atherosclerosis 209 2010 189 194
57. M.K. Ito, M.P. McGowan, and P.M. Moriarty Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia J Clin Lipidol 5 2011 S38 S45
58. E.A. Stein, K. Strutt, H. Southworth, P.J. Diggle, and E. Miller Comparison of rosuvastatin versus atorvastatin in patients with heterozygous familial hypercholesterolemia Am J Cardiol 92 2003 1287 1293
59. L. Pisciotta, T. Fasano, and A. Bellocchio et al. Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients Atherosclerosis 194 2007 e116 e122
60. A. van der Graaf, C. Cuffie-Jackson, and M.N. Vissers et al. Efficacy and safety of coadministration of ezetimibe and simvastatin in adolescents with heterozygous familial hypercholesterolemia J Am Coll Cardiol 52 2008 1421 1429
61. H.H. Knapp, H. Schrott, and P. Ma et al. Efficacy and safety of combination simvastatin and colesevelam in patients with primary hypercholesterolemia Am J Med 110 2001 352 360
62. M.P. McGowan Emerging low-density lipoprotein (LDL) therapies: management of severely elevated LDL cholesterol - the role of LDL-apheresis J Clin Lipidol 7 2013 S21 S26
63. K. Arai, A. Orsoni, and Z. Mallat et al. Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia J Lipid Res 53 2012 1670 1678
64. C. Otto, J. Berster, B. Otto, and K.G. Parhofer Effects of two whole blood systems (DALI and Liposorber D) for LDL apheresis on lipids and cardiovascular risk markers in severe hypercholesterolemia J Clin Apher 22 2007 301 305
65. B.R. Jaeger, Y. Richter, and D. Nagel et al. 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 2009 229 239
66. J1. Leebmann, E. Roeseler, and U. Julius et al. for the Pro(a)LiFe Study Group. Lipoprotein apheresis in patients with maximally tolerated lipid-lowering therapy, lipoprotein(a)-hyperlipoproteinemia and progressive cardiovascular disease: prospective observational multicenter study Circulation 128 2013 2567 2576
67. H. Tavori, I. Giunzioni, M.F. Linton, and S. Fazio Loss of plasma proprotein convertase subtilisin/kexin 9 (PCSK9) after lipoprotein apheresis Circ Res 113 2013 1290 1295
68. A. Brautbar, and C.M. Ballantyne Pharmacological strategies for lowering LDL cholesterol: statins and beyond Nat Rev Cardiol 8 2011 253 265
69. M.M. Hussain, J. Iqbal, K. Anwar, P. Rava, and K. Dai Microsomal triglyceride transfer protein: a multifunctional protein Front Biosci 8 2003 s500 s506
70. M. Cuchel, L.T. Bloedon, and P.O. Szapary et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia N Engl J Med 356 2007 148 156
71. M. Cuchel, E.A. Meagher, and H. du Toit Theron 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 381 2013 40 46
72. F.F. Samaha, J. McKenney, L.T. Bloedon, W.J. Sasiela, and D.J. Rader Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia Nat Clin Pract Cardiovasc Med 5 2008 497 505
73. S. Tsimikas, J. Witztum, and A. Catapano Effect of mipomersen on lipoprotein(a) in patients with hypercholesterolemia across four phase III studies (abstr) J Am Coll Cardiol 59 2012 E1494
74. F.J. Raal, R.D. Santos, and D.J. Blom et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial Lancet 375 2010 998 1006
75. E.A. Stein, R. Dufour, and C. Gagne et al. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease Circulation 126 2012 2283 2292
76. M.P. McGowan, J.C. Tardif, and R. Ceska et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy PloS One 7 2012 e49006
77. G.S. Thomas, W.C. Cromwell, S. Ali, W. Chin, J.D. Flaim, and M. Davidson Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial J Am Coll Cardiol 62 2013 2178 2184
78. R.D. Santos, P.B. Duell, and C. East et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension Eur Heart J 2013 Dec 23 [E-pub ahead of print]
79. M. Abifadel, M. Varret, and J.P. Rabes et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia Nat Genet 34 2003 154 156
80. E.A. Stein, S. Mellis, and G.D. Yancopoulos et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol N Engl J Med 366 2012 1108 1118
81. E.M. Roth, J.M. McKenney, C. Hanotin, G. Asset, and E.A. Stein Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia N Engl J Med 367 2012 1891 1900
82. J.M. McKenney, M.J. Koren, D.J. Kereiakes, C. Hanotin, A.C. Ferrand, and E.A. Stein 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 59 2012 2344 2353
83. E.A. Stein, D. Gipe, and J. Bergeron 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 380 2012 29 36
84. M.J. Koren, R. Scott, and J.B. Kim 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 380 2012 1995 2006
85. C.S. Dias, A.J. Shaywitz, and S.M. Wasserman et al. Effects of AMG 145 on low-density lipoprotein cholesterol levels: results from 2 randomized, double-blind, placebo-controlled, ascending-dose phase 1 studies in healthy volunteers and hypercholesterolemic subjects on statins J Am Coll Cardiol 60 2012 1888 1898
86. F. Raal, R. Scott, and R. Somaratne et al. Low-density lipoprotein cholesterol-lowering effects of AMG 145, 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 126 2012 2408 2417
87. R.P. Giugliano, N.R. Desai, and P. Kohli et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study Lancet 380 2012 2007 2017
88. D. Sullivan, A.G. Olsson, and R. Scott et al. Effect of a monoclonal antibody to PCSK9 on low-density lipoprotein cholesterol levels in statin-intolerant patients: the GAUSS randomized trial JAMA 308 2012 2497 2506
89. E.A. Stein, N. Honarpour, S.M. Wasserman, F. Xu, R. Scott, and F.J. Raal Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia Circulation 128 2013 2113 2120
90. K. Fitzgerald, M. Frank-Kamenetsky, and S. Shulga-Morskaya et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial Lancet 383 2014 60 68
91. N.R. Desai, P. Kohli, and R.P. Giugliano et al. 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 2013 962 969