Emerging drugs for hyperlipidaemia: An update

Expert Opinion on Emerging Drugs

Volumn 19, Issue 4, 2014, Pages 471-488

  Florentin, Matilda ^a   Kostapanos, Michael S ^a   Kei, Anastazia ^a   Elisaf, Moses S ^a  

^a UNIVERSITY OF IOANNINA   (Greece)

Author keywords

Anacetrapib; Evacetrapib; Microsomal triglyceride transfer protein inhibitors; Mipomersen; Pre protein convertase subtilisin kexin 9 inhibitors

Indexed keywords

ALIROCUMAB; ANACETRAPIB; ANTISENSE OLIGONUCLEOTIDE; APABETALONE; APOLIPOPROTEIN A1; APOLIPOPROTEIN B; BILE ACID SEQUESTRANT; CHOLESTEROL; CHOLESTEROL ESTER TRANSFER PROTEIN INHIBITOR; EVACETRAPIB; EVOLOCUMAB; EZETIMIBE; FIBRIC ACID DERIVATIVE; HIGH DENSITY LIPOPROTEIN; HORMONE DERIVATIVE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN INHIBITOR; MIPOMERSEN; NICOTINIC ACID; OMEGA 3 FATTY ACID; PROTEIN INHIBITOR; SQUALENE SYNTHASE INHIBITOR; TRIACYLGLYCEROL; ANTILIPEMIC AGENT;

ABSORPTION; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL METABOLISM; CLINICAL PRACTICE; CLINICAL RESEARCH; HUMAN; HYPERCHOLESTEROLEMIA; HYPERLIPIDEMIA; MORBIDITY; MORTALITY; NONHUMAN; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); REVIEW; RISK FACTOR; ANIMAL; BLOOD; CARDIOVASCULAR DISEASES; COMPLICATION; DRUG DESIGN; HYPERLIPIDEMIAS;

ANIMALS; CARDIOVASCULAR DISEASES; CHOLESTEROL, LDL; DRUG DESIGN; HUMANS; HYDROXYMETHYLGLUTARYL-COA REDUCTASE INHIBITORS; HYPERLIPIDEMIAS; HYPOLIPIDEMIC AGENTS; RISK FACTORS;

EID: 84912087757     PISSN: 14728214     EISSN: 17447623     Source Type: Journal    
DOI: 10.1517/14728214.2014.976553     Document Type: Review

References (173)

1. Lewington S, Whitlock G, Clarke R, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55, 000 vascular deaths. Lancet 2007;370:1829-39
2. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90, 056 participants in 14 randomised trials of statins. Lancet 2005;366:1267-78
3. Barter P, Gotto AM, LaRosa JC, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10
4. Drexel H. Statins, fibrates, nicotinic acid, cholesterol absorption inhibitors, anion-exchange resins, omega-3 fatty acids: which drugs for which patients? Fundam Clin Pharmacol 2009;23:687-92
5. Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22
6. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008;358:1431-43
7. About heart disease & stroke. Available from: http://millionhearts.hhs.gov/abouthds/cost-consequences.html [Last accessed 10 September 2014]
8. Cardiovascular disease statistics. Available from: http://www.bhf.org.uk/heart-health/heart-statistics.aspx [Last accessed 10 September 2014]
9. Bhatt DL, Steg PG, Ohman EM, et al. International prevalence, recognition, and treatment of cardiovascular risk factors in outpatients with atherothrombosis. JAMA 2006;295:180-9
10. Kotseva K, Wood D, De Backer G, et al. EUROASPIRE III. Management of cardiovascular risk factors in asymptomatic high-risk patients in general practice: cross-sectional survey in 12 European countries. Eur J Cardiovasc Prev Rehabil 2010;17:530-40
11. Watts GF, Karpe F. Triglycerides and atherogenic dyslipidaemia: extending treatment beyond statins in the high-risk cardiovascular patient. Heart 2011;97:350-6
12. 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
13. Mikhailidis DP, Elisaf M, Rizzo M, et al. "European panel on low density lipoprotein (LDL) subclasses": a statement on the pathophysiology, atherogenicity and clinical significance of LDL subclasses: executive summary. Curr Vasc Pharmacol 2011;9:531-2
14. Holmes MV, Asselbergs FW, Palmer TM, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J 2014. [Epub ahead of print]
15. Cederberg H, Saukkonen T, Laakso M, et al. Postchallenge glucose, A1C, and fasting glucose as predictors of type 2 diabetes and cardiovascular disease: a 10-year prospective cohort study. Diabetes Care 2010;33:2077-83
16. Lorenzo C, Wagenknecht LE, Hanley AJ, et al. A1C between 5.7 and 6.4% as a marker for identifying pre-diabetes, insulin sensitivity and secretion, and cardiovascular risk factors: the Insulin Resistance Atherosclerosis Study (IRAS). Diabetes Care 2010;33:2104-9
17. Rader DJ, Cohen J, Hobbs HH. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 2003;111:1795-803
18. Gagne C, Gaudet D, Bruckert E. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002;105:2469-75
19. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). JAMA 2001;285:2486-97
20. Grundy SM, Cleeman JI, Merz CN, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. J Am Coll Cardiol 2004;44:720-32
21. Law M, Rudnicka AR. Statin safety: a systematic review. Am J Cardiol 2006;97:52C-60C
22. Altmann SW, Davis HR Jr, Zhu LJ, et al. Niemann-Pick C1 Like 1 protein is critical for intestinal cholesterol absorption. Science 2004;303:1201-4
23. Katsiki N, Theocharidou E, Karagiannis A, et al. Ezetimibe therapy for dyslipidemia: an update. Curr Pharm Des 2013;19:3107-14
24. Cannon CP, Giugliano RP, Blazing MA, et al. Rationale and design of IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin Efficacy International Trial): comparison of ezetimibe/simvastatin versus simvastatin monotherapy on cardiovascular outcomes in patients with acute coronary syndromes. Am Heart J 2008;156:826-32
25. Chiang JY. Bile acid regulation of gene expression: roles of nuclear hormone receptors. Endocr Rev 2002;23:443-63
26. Andrade SE, Walker AM, Gottlieb LK, et al. Discontinuation of antihyperlipidemic drugs-do rates reported in clinical trials reflect rates in primary care settings? N Engl J Med 1995;332:1125-31
27. Florentin M, Liberopoulos EN, Mikhailidis DP, et al. Colesevelam hydrochloride in clinical practice: a new approach in the treatment of hypercholesterolaemia. Curr Med Res Opin 2008;24:995-1009
28. Davidson MH, Dillon MA, Gordon B, et al. Colesevelam hydrochloride (Cholestagel): a new, potent bile acid sequestrant associated with a low incidence of gastrointestinal side effects. Arch Intern Med 1999;159:1893-900
29. Aggarwal S, Loomba RS, Arora RR. Efficacy of colesevelam on lowering glycemia and lipids. J Cardiovasc Pharmacol 2012;59:198-205
30. Welchol. Available from: http://www. rxlist.com/welchol-drug/indications-dosage.htm [Last accessed 10 September 2014]
31. Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002;53:409-35
32. Ghani RA, Bin Yaakob I, Wahab NA, et al. The influence of fenofibrate on lipid profile, endothelial dysfunction, and inflammatory markers in type 2 diabetes mellitus patients with typical and mixed dyslipidemia. J Clin Lipidol 2013;7:446-53
33. Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61
34. Gazi IF, Tsimihodimos V, Tselepis AD, et al. Clinical importance and therapeutic modulation of small dense low-density lipoprotein particles. Expert Opin Biol Ther 2007;7:53-72
35. Frick MH, Elo O, Haapa K, et al. Helsinki Heart Study: primary-prevention trial with gemfibrozil in middle-aged men with dyslipidemia. Safety of treatment, changes in risk factors, and incidence of coronary heart disease. N Engl J Med 1987;317:1237-45
36. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-18
37. The Bezafibrate Infarction Prevention Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery disease. Circulation 2000;102:21-7
38. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74
39. Ansquer JC, Foucher C, Aubonnet P, et al. Fibrates and microvascular complications in diabetes-insight from the FIELD study. Curr Pharm Des 2009;15:537-52
40. Robins SJ, Rubins HB, Faas FH, et al. Insulin resistance and cardiovascular events with low HDL cholesterol: the Veterans Affairs HDL Intervention Trial (VA-HIT). Diabetes Care 2003;26:1513-17
41. Tenenbaum A, Motro M, Fisman EZ, et al. Bezafibrate for the secondary prevention of myocardial infarction in patients with metabolic syndrome. Arch Intern Med 2005;165:1154-60
42. Lincoff AM, Tardif JC, Schwartz GG, et al. Effect of aleglitazar on cardiovascular outcomes after acute coronary syndrome in patients with type 2 diabetes mellitus: the AleCardio randomized clinical trial. JAMA 2014;311:1515-25
43. Gazi I, Liberopoulos EN, Saougos VG, et al. Beneficial effects of omega-3 fatty acids: the current evidence. Hellenic J Cardiol 2006;47:223-31
44. Papazafiropoulou AK, Kardara MS, Pappas SI. Pleiotropic effects of omega-3 fatty acids. Recent Pat Endocr Metab Immune Drug Discov 2012;6:40-6
45. Morris MC, Sacks F, Rosner B. Does fish oil lower blood pressure? A meta-analysis of controlled trials. Circulation 1993;88:523-33
46. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 2002;105:1897-903
47. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3 polyunsaturated fatty acids in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1223-30
48. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet 2007;369:1090-8
49. Kromhout D, Giltay EJ, Geleijnse JM. n-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010;363:2015-26
50. Bosch J, Gerstein HC, Dagenais GR, et al. n-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012;367:309-18
51. Rizos EC, Ntzani EE, Bika E, et al. Association between omega-3 fatty acid supplementation and risk of major cardiovascular disease events: a systematic review and meta-analysis. JAMA 2012;308:1024-33
52. Kwak SM, Myung SK, Lee YJ, et al. Efficacy of omega-3 fatty acid supplements (eicosapentaenoic acid and docosahexaenoic acid) in the secondary prevention of cardiovascular disease: a meta-analysis of randomized, double-blind, placebo-controlled trials. Arch Intern Med 2012;172:686-94
53. Catapano AL, Reiner Z, De Backer G, et al. ESC/EAS Guidelines for the management of dyslipidaemias The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Atherosclerosis 2011;217:3-46
54. A study of AMR101 to evaluate its ability to reduce cardiovascular events in high risk patients with hypertriglyceridemia and on statin. Available from: http://www.clinicaltrials. gov/ct2/results?term=NCT01492361&Search=Search [Last accessed 10 September 2014]
55. Outcomes study to assess STatin residual risk reduction with epanova in high CV risk patients with hypertriglyceridemia. Available from: http://www.clinicaltrials.gov/ct2/results?term=NCT02104817&Search=Search [Last accessed 10 September 2014]
56. Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem 1955;54:558-9
57. Guyton JR. Extended-release niacin for modifying the lipoprotein profile. Expert Opin Pharmacother 2004;5:1385-98
58. Merck Announces HPS2-THRIVE Study of TREDAPTIVETM (Extended-Release Niacin/Laropiprant) did not achieve primary endpoint. Available from: http://www.mercknewsroom.com/pressrelease/prescription-medicine-news/merck-announces-hps2-thrive-study-tredaptive-extended-relea [Last accessed 10 September 2014]
59. Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67
60. Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med 2014;371:203-12
61. Lloyd-Jones DM. Niacin and HDL cholesterol-time to face facts. N Engl J Med 2014;371:271-3
62. Anderson TJ, Boden WE, Desvigne-Nickens P, et al. Safety profile of extended-release niacin in the AIM-HIGH trial. N Engl J Med 2014;371:288-90
63. El Harchaoui K, Akdim F, Stroes ES, et al. Current and future pharmacologic options for the management of patients unable to achieve low-density lipoprotein-cholesterol goals with statins. Am J Cardiovasc Drugs 2008;8:233-42
64. Nicolosi RJ, Wilson TA, Krause BR. The ACAT inhibitor, CI-1011 is effective in the prevention and regression of aortic fatty streak area in hamsters. Atherosclerosis 1998;137:77-85
65. Asami Y, Yamagishi I, Akiyoshi K, et al. Inhibitory effect of TS-962 on the formation of early atherosclerotic lesions in high fat-fed hyperlipidemic hamsters. Atherosclerosis 1999;146:237-42
66. Tardif JC, Gregoire J, L'Allier PL, et al. Effects of the acyl coenzyme A: cholesterol acyltransferase inhibitor avasimibe on human atherosclerotic lesions. Circulation 2004;110:3372-7
67. Nissen SE, Tuzcu EM, Brewer HB, et al. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N Engl J Med 2006;354:1253-63
68. Meuwese MC, de Groot E, Duivenvoorden R, et al. ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial. JAMA 2009;301:1131-9
69. A trial of the safety and efficacy of K-604 for the treatment of atherosclerosis. Available from: http://clinicaltrials.gov/ct2/show/NCT00851500?term=k604&rank=1 [Last accessed 10 September 2014]
70. Hussain MM, Rava P, Walsh M, et al. Multiple functions of microsomal triglyceride transfer protein. Nutr Metab (Lond) 2012;9:14
71. Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 2003;44:22-32
72. Kostapanos MS, Rizos EC, Papanas N, et al. Mitochondrial triglyceride transfer protein inhibition: new achievements in the treatment of dyslipidemias. Curr Pharm Des 2013;19:3150-60
73. Luscher TF, Taddei S, Kaski JC, et al. Vascular effects and safety of dalcetrapib in patients with or at risk of coronary heart disease: the dal-VESSEL randomized clinical trial. Eur Heart J 2012;33:857-65
74. Meruvu S, Ayers SD, Winnier G, et al. Thyroid hormone analogues: where do we stand in 2013? Thyroid 2013;23:1333-44
75. Seiki S, Frishman WH. Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia. Cardiol Rev 2009;17:70-6
76. Seidah NG, Prat A. The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov 2012;11:367-83
77. Park SW, Moon YA, Horton JD. Post-transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J Biol Chem 2004;279:50630-8
78. Cariou B, Le May C, Costet P. Clinical aspects of PCSK9. Atherosclerosis 2011;216:258-65
79. Toth PP, Barter PJ, Rosenson RS, et al. High-density lipoproteins: a consensus statement from the National Lipid Association. J Clin Lipidol 2013;7:484-525
80. Tall AR, Yvan-Charvet L, Wang N. The failure of torcetrapib: was it the molecule or the mechanism? Arterioscler Thromb Vasc Biol 2007;27:257-60
81. McLure KG, Gesner EM, Tsujikawa L, et al. RVX-208, an inducer of ApoA-I in humans, is a BET bromodomain antagonist. PLoS One 2013;8:e83190
82. Nicholls SJ, Gordon A, Johannson J, et al. ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies. Cardiovasc Drugs Ther 2012;26:181-7
83. Franceschini G, Sirtori CR, Capurso A II, et al. A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family. J Clin Invest 1980;66:892-900
84. Tardif JC, Gregoire J, L'Allier PL, et al. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 2007;297:1675-82
85. Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-300
86. Waksman R, Torguson R, Kent KM, et al. A first-in-man, randomized, placebo-controlled study to evaluate the safety and feasibility of autologous delipidated high-density lipoprotein plasma infusions in patients with acute coronary syndrome. J Am Coll Cardiol 2010;55:2727-35
87. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res 1993;34:1255-74
88. de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, et al. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation 2002;105:2159-65
89. Hermann F, Enseleit F, Spieker LE, et al. Cholesterylestertransfer protein inhibition and endothelial function in type II hyperlipidemia. Thromb Res 2009;123:460-5
90. Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med 2012;367:2089-99
91. Schwartz GG, Olsson AG, Ballantyne CM, et al. Rationale and design of the dal-OUTCOMES trial: efficacy and safety of dalcetrapib in patients with recent acute coronary syndrome. Am Heart J 2009;158:896-901; e3
92. Miller M, Stone NJ, Ballantyne C, et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333
93. Yao Z, Wang Y. Apolipoprotein C-III and hepatic triglyceride-rich lipoprotein production. Curr Opin Lipidol 2012;23:206-12
94. Kawakami A, Aikawa M, Alcaide P, et al. Apolipoprotein CIII induces expression of vascular cell adhesion molecule-1 in vascular endothelial cells and increases adhesion of monocytic cells. Circulation 2006;114:681-7
95. Graham MJ, Lee RG, Bell TA III, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013;112:1479-90
96. Chen HC, Farese RV Jr. Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler Thromb Vasc Biol 2005;25:482-6
97. Le Bloc'h J, Leray V, Chetiveaux M, et al. Nicotinic acid decreases apolipoprotein B100-containing lipoprotein levels by reducing hepatic very low density lipoprotein secretion through a possible diacylglycerol acyltransferase 2 inhibition in obese dogs. J Pharmacol Exp Ther 2010;334:583-9
98. Available from: http://clinicaltrials.gov/ct2/results?term=lcq908&Search=Search Last accessed 10 September 2014
99. Kulinski A, Rustaeus S, Vance JE. Microsomal triacylglycerol transfer protein is required for lumenal accretion of triacylglycerol not associated with ApoB, as well as for ApoB lipidation. J Biol Chem 2002;277:31516-25
100. Shiomi M, Ito T. MTP inhibitor decreases plasma cholesterol levels in LDL receptor-deficient WHHL rabbits by lowering the VLDL secretion. Eur J Pharmacol 2001;431:127-31
101. Cuchel M, Bloedon LT, Szapary PO, et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 2007;356:148-56
102. Samaha FF, McKenney J, Bloedon LT, et al. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Clin Pract Cardiovasc Med 2008;5:497-505
103. Available form www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm333285.htm. [Last accessed 10 September 2014]
104. Available from: http://www.ema.europa. eu Last accessed 10 September 2014
105. Funatsu T, Kakuta H, Takasu T, et al. Atorvastatin increases hepatic fatty acid beta-oxidation in sucrose-fed rats: comparison with an MTP inhibitor. Eur J Pharmacol 2002;455:161-7
106. Angulo P, Lindor KD. Non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2002;17(Suppl):S186-90
107. Cuadrado A, Orive A, Garcia-Suarez C, et al. Non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma. Obes Surg 2005;15:442-6
108. Kostapanos MS, Katsiki N, Elisaf MS, et al. Editorial: reducing cardiovascular risk: is low-density lipoprotein-cholesterol (LDL-C) lowering enough? Curr Vasc Pharmacol 2012;10:173-7
109. Bennett CF, Swayze EE. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu Rev Pharmacol Toxicol 2010;50:259-93
110. Akdim F, Visser ME, Tribble DL, et al. Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia. Am J Cardiol 2010;105:1413-19
111. Akdim F, Stroes ES, Sijbrands EJ, et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J Am Coll Cardiol 2010;55:1611-18
112. Akdim F, Tribble DL, Flaim JD, et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-to-moderate hyperlipidaemia. Eur Heart J 2011;32:2650-9
113. Visser ME, Akdim F, Tribble DL, et al. Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. J Lipid Res 2010;51:1057-62
114. Stein EA, Dufour R, Gagne C, 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 2012;126:2283-92
115. Raal FJ, Santos RD, Blom DJ, 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 2010;375:998-1006
116. Thomas GS, Cromwell WC, Ali S, et al. 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 2013;62:2178-84
117. McGowan MP, Tardif JC, Ceska R, et al. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One 2012;7:e49006
118. Visser ME, Wagener G, Baker BF, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, lowers low-density lipoprotein cholesterol in high-risk statin-intolerant patients: a randomized, double-blind, placebo-controlled trial. Eur Heart J 2012;33:1142-9
119. An open-label extension study to assess the long-term safety and efficacy of ISIS 301012 (Mipomersen) in patients with familial hypercholesterolemia or severe-hypercholesterolemia. Available from: http://clinicaltrials.gov/ct2/show/NCT00694109?term=mipomersen&rank=15 [Last accessed 10 September 2014]
120. A study of the safety and efficacy of two different regimens of mipomersen in patients with familial hypercholesterolemia and inadequately controlled low-density lipoprotein cholesterol (FOCUS FH). Available from: http://clinicaltrials.gov/ct2/show/NCT01475825?term=mipomersen&rank=2 [Last accessed 10 September 2014]
121. Effect of mipomersen on LDL-cholesterol levels in patients treated by regular apheresis (MICA). Available from: http://clinicaltrials.gov/ct2/show/NCT01598948?term=mipomersen&rank=7 [Last accessed 10 September 2014]
122. Raal F, Scott R, Somaratne R, 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 2012;126:2408-17
123. Giugliano RP, Desai NR, Kohli P, 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 2012;380:2007-17
124. 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;308:2497-506
125. 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
126. Stein EA, Honarpour N, Wasserman SM, et al. Effect of the Proprotein Convertase Subtilisin/Kexin 9 Monoclonal Antibody, AMG 145, in Homozygous familial hypercholesterolemia. Circulation 2013;128:2113-20
127. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53
128. Reduction of LDL-C with PCSK9 inhibition in heterozygous familial hypercholesterolemia disorder study-2 (RUTHERFORD-2). Available from: http://clinicaltrials.gov/ct2/show/NCT01763918?term=RUTHERFORD2&rank=1 [Last accessed 10 September 2014]
129. Trial evaluating PCSK9 antibody in subjects with LDL receptor abnormalities (TESLA). Available from: http://clinicaltrials.gov/ct2/show/NCT01588496?term=tesla+and+evolocumab&rank=1 [Last accessed 10 September 2014]
130. Trial assessing long term use of PCSK9 inhibition in subjects with genetic LDL disorders (TAUSSIG). Available from: http://clinicaltrials.gov/ct2/show/NCT01624142?term=taussig&rank=1 [Last accessed 10 September 2014]
131. Goal achievement after utilizing an anti-PCSK9 antibody in statin intolerant subjects-3. Available from: http://clinicaltrials.gov/ct2/show/NCT01984424?term=evolocumab&rank=2 [Last accessed 10 September 2014]
132. GLobal assessment of plaque regression with a PCSK9 antibody as measured by intravascular ultrasound (GLAGOV). Available from: http://clinicaltrials.gov/ct2/show/NCT01813422?term=glagov&rank=1 [Last accessed 10 September 2014]
133. Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER). Available from: http://clinicaltrials.gov/ct2/show/NCT01764633?term=fourier&rank=1 [Last accessed 10 September 2014]
134. Open label study of long term evaluation against LDL-C Trial-2 (OSLER-2). Available from: http://clinicaltrials.gov/ct2/show/NCT01854918? term=osler2&rank=1 [Last accessed 10 September 2014]
135. 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;59:2344-53
136. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012;367:1891-900
137. 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
138. Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med 2012;366:1108-18
139. Study to Evaluate the efficacy and safety of an every four weeks treatment regimen of alirocumab (REGN727/SAR236553) in patients with primary hypercholesterolemia (ODYSSEY CHOICE 1). Available from: http://clinicaltrials.gov/ct2/show/NCT01926782?term=alirocumab&rank=14 [Last accessed 10 September 2014]
140. Phase III study to evaluate alirocumab in patients with hypercholesterolemia not treated with a statin (ODYSSEY CHOICE II). Available from: http://clinicaltrials.gov/ct2/show/NCT02023879?term=alirocumab&rank=4 [Last accessed 10 September 2014]
141. Efficacy and safety of alirocumab SAR236553 (REGN727) versus placebo on top of lipid-modifying therapy in patients with heterozygous familial hypercholesterolemia not adequately controlled with their lipid-modifying therapy (ODYSSEY FH I). Available from: http://clinicaltrials.gov/ct2/show/NCT01623115?term=alirocumab&rank=18 [Last accessed 10 September 2014]
142. Study of alirocumab (REGN727/SAR236553) in patients with heFH (Heterozygous Familial Hypercholesterolemia) who are not adequately controlled with their LMT (Lipid-Modifying Therapy) (Odyssey FH II). Available from: http://clinicaltrials.gov/ct2/show/NCT01709500?term=odyssey&rank=4 [Last accessed 10 September 2014]
143. Alirocumab effectively lowers LDL cholesterol in nine trials: top-line results from ODYSSEY. Available from: http://www.medscape.com/viewarticle/829130 [Last accessed 7 October 2014]
144. Open label study of long term safety evaluation of alirocumab (ODYSSEY OLE). Available from: http://clinicaltrials.gov/ct2/show/NCT0 1954394?term=odyssey&rank=3 [Last accessed 10 September 2014]
145. Efficacy and safety of alirocumab SAR236553 (REGN727) versus placebo on top of lipid-modifying therapy in patients with heterozygous familial hypercholesterolemia (ODYSSEY High FH). Available from: http://clinicaltrials. gov/ct2/show/NCT01617655? term=alirocumab&rank=16 [Last accessed 10 September 2014]
146. Efficacy and safety of alirocumab SAR236553 (REGN727) versus placebo on top of lipid-modifying therapy in patients with high cardiovascular risk and hypercholesterolemia (ODYSSEY Combo I). Available from: http://clinicaltrials. gov/ct2/show/NCT01644175? term=odyssey+combo&rank=2 [Last accessed 10 September 2014]
147. Efficacy and safety of alirocumab SAR236553 (REGN727) versus ezetimibe on top of statin in high cardiovascular risk patients with hypercholesterolemia (ODYSSEY Combo II). Available from: http://clinicaltrials. gov/ct2/show/NCT01644188? term=alirocumab&rank=11 [Last accessed 10 September 2014]
148. Study of alirocumab (REGN727/SAR236553) in patients with primary hypercholesterolemia and moderate, high, or very high cardiovascular (CV) risk, who are intolerant to statins (Odyssey Alternative). Available from: http://clinicaltrials.gov/ct2/show/NCT01709513?term=alirocumab&rank=20 [Last accessed 10 September 2014]
149. Long-term safety and tolerability of alirocumab SAR236553 (REGN727) versus placebo on top of lipid-modifying therapy in high cardiovascular risk patients with hypercholesterolemia (ODYSSEY long term). Available from: http://clinicaltrials.gov/ct2/show/NCT01507831?term=alirocumab&rank=19 [Last accessed 10 September 2014]
150. Schwartz GG, Bessac L, Berdan LG, et al. Effect of alirocumab, a monoclonal antibody to PCSK9, on long-term cardiovascular outcomes following acute coronary syndromes: rationale and design of the ODYSSEY Outcomes trial. Am Heart J 2014;0:1-8; e1 In press
151. RVX-208 & MOA. Available from: http://www.resverlogix.com [Last accessed 10 September 2014]
152. Keyserling CH, Hunt TL, Klepp HM, et al. Abstract 15525: CER-001, a synthetic HDL-mimetic, safely mobilizes cholesterol in healthy dyslipidemic volunteers. Circulation 2011;124:A15525
153. Hovingh GK, Stroes ES, Gaudet D, et al. Effects of CER-001 on carotid atherosclerosis by 3TMRI in homozygous familial hypercholesterolaemia (HOFH): the modifying orphan disease evaluation (MODE) study. 82nd Congress of the European Atherosclerosis Society, Madrid, Spain; 2014
154. Tardif JC, Ballantyne CM, Barter P, et al. Effects of the high-density lipoprotein mimetic agent CER-001 on coronary atherosclerosis in patients with acute coronary syndromes: a randomized trial. Eur Heart J 2014. [Epub ahead of print]
155. Gille A, Easton R, D'Andrea D, et al. CSL112 Enhances Biomarkers of Reverse Cholesterol Transport After Single and Multiple Infusions in Healthy Subjects. Arterioscler Thromb Vasc Biol 2014;34:2106-14
156. Florentin M, Liberopoulos EN, Mikhailidis DP, et al. Emerging options in the treatment of dyslipidemias: a bright future? Expert Opin Emerg Drugs 2011;16:247-70
157. Cannon CP, Shah S, Dansky HM, et al. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N Engl J Med 2010;363:2406-15
158. Study to assess the tolerability and efficacy of anacetrapib in patients with coronary heart disease (CHD) or CHD risk-equivalent disease (MK-0859-019) (DEFINE). Available from: http://clinicaltrials.gov/ct2/show/NCT00685776 [Last accessed 10 September 2014]
159. Study to assess the tolerability and efficacy of anacetrapib co-administered with statin in participants with heterozygous familial hypercholesterolemia (MK-0859-020) (REALIZE). Available from: http://clinicaltrials.gov/ct2/show/NCT01524289?term=anacetrapib&rank=10 [Last accessed 10 September 2014]
160. A study of the safety and efficacy of anacetrapib (MK-0859) when added to ongoing statin therapy in Japanese participants with dyslipidemia (MK-0859-051 AM1). Available from: http://clinicaltrials.gov/ct2/show/NCT01760460?term=anacetrapib&rank=3 [Last accessed 10 September 2014]
161. A study of the safety and efficacy of anacetrapib (MK-0859) When added to ongoing statin therapy in Japanese participants with heterozygous familial hypercholesterolemia (MK-0859-050). Available from: http://clinicaltrials.gov/ct2/show/NCT01824238?term=anacetrapib&rank=5 [Last accessed 10 September 2014]
162. Efficacy and tolerability of anacetrapib added to ongoing lipid-lowering therapy in adult participants with homozygous familial hypercholesterolemia (HoFH) (MK-0859-042). Available from: http://clinicaltrials.gov/ct2/show/NCT01841684?term=anacetrapib&rank=8 [Last accessed 10 September 2014]
163. REVEAL: randomized evaluation of the effects of anacetrapib through lipid-modification. Available from: http://clinicaltrials.gov/ct2/show/NCT01252953 [Last accessed 10 September 2014]
164. A Study of the safety and efficacy of anacetrapib (MK-0859) when added to ongoing statin therapy (MK-0859-021). Available from: http://clinicaltrials.gov/ct2/show/NCT01717300? term=anacetrapib&rank=2 [Last accessed 10 September 2014]
165. A study of the safety and efficacy of anacetrapib (MK-0859) among participants with hypercholesterolemia when added to ongoing statin therapy (MK-0859-022 AM4). Available from: http://clinicaltrials.gov/ct2/show/NCT01860729?term=anacetrapib&rank=9 [Last accessed 10 September 2014]
166. Bloomfield D, Carlson GL, Sapre A, et al. Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients. Am Heart J 2009;157:352-60; e2
167. Gurfinkel R, Joy TR. Anacetrapib: hope for CETP inhibitors? Cardiovasc Ther 2011;29:327-39
168. Gotto AM Jr, Cannon CP, Li XS, et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am J Cardiol 2013;113:76-83
169. Nicholls SJ, Brewer HB, Kastelein JJ, et al. Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial. JAMA 2011;306:2099-109
170. A Study of Evacetrapib in high-risk vascular disease (ACCELERATE). Availabe from http://clinicaltrials.gov/ct2/show/NCT01687998? term=evacetrapib&rank=13 [Last accessed 10 September 2014]
171. Dezima Pharma in-licenses CETP Inhibitor Program from Mitsubishi Tanabe Pharma Corp. Available from: http://www.dezimapharma.com/dezima-dez001-in-licensing-final-22-jan-13 [Last accessed 10 September 2014]
172. Boettcher MF, Heinig R, Schmeck C, et al. Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein. Br J Clin Pharmacol 2012;73:210-18
173. A safety and efficacy study of DRL-17822, a Cholesteryl Ester Transfer Protein (CETP) inhibitor, in patients with abnormal cholesterol levels. Available from: http://clinicaltrials.gov/ct2/show/NCT0s1388816 [Last accessed 10 September 2014]