An overview of the new frontiers in the treatment of atherogenic dyslipidemias

Clinical Pharmacology and Therapeutics

Volumn 96, Issue 1, 2014, Pages 57-63

  Rached, F H ^a,b   Chapman, M J ^a   Kontush, A ^a  

^a INSERM   (France)

^b UNIVERSITY OF SÃO PAULO   (Brazil)

Author keywords

[No Author keywords available]

Indexed keywords

ANIMALS; ATHEROSCLEROSIS; CHOLESTEROL ESTER TRANSFER PROTEINS; DYSLIPIDEMIAS; HUMANS; HYPOLIPIDEMIC AGENTS; LIPOPROTEINS, HDL; MICRORNAS; MOLECULAR TARGETED THERAPY; OLIGONUCLEOTIDES;

EID: 84903626957     PISSN: 00099236     EISSN: 15326535     Source Type: Journal    
DOI: 10.1038/clpt.2014.85     Document Type: Review

References (80)

1. Perk, J. et al.; European Association for Cardiovascular Prevention & Rehabilitation (EACPR); ESC Committee for Practice Guidelines (CPG) European Guidelines on cardiovascular disease prevention in clinical practice (version 2012) The Fifth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of nine societies and by invited experts) Eur. Heart J. 33, 1635-1701 (2012)
2. Baigent, C. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-Analysis of data from 170,000 participants in 26 randomised trials. Lancet 376, 1670-1681 (2010)
3. Fruchart, J.C. et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am. J. Cardiol. 102, 1K-34K (2008)
4. Teslovich, T.M. et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 466, 707-713 (2010)
5. Seidah, N.G. et al. The secretory proprotein convertase neural apoptosisregulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc. Natl. Acad. Sci. USA 100, 928-933 (2003)
6. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154-156 (2003)
7. Cohen, J., Pertsemlidis, A., Kotowski, I.K., Graham, R., Garcia, C.K. & Hobbs, H.H. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161-165 (2005)
8. Zhao, Z. et al. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet. 79, 514-523 (2006)
9. Tibolla, G., Norata, G.D., Artali, R., Meneghetti, F. & Catapano, A.L. Proprotein convertase subtilisin/kexin type 9 (PCSK9): from structure-function relation to therapeutic inhibition. Nutr. Metab. Cardiovasc. Dis. 21, 835-843 (2011)
10. Artenstein, A.W. & Opal, S.M. Proprotein convertases in health and disease. N. Engl. J. Med. 365, 2507-2518 (2011)
11. Park, S.W., Moon, Y.A. & Horton, J.D. Post-Transcriptional regulation of low density lipoprotein receptor protein by proprotein convertase subtilisin/kexin type 9a in mouse liver. J. Biol. Chem. 279, 50630-50638 (2004)
12. Seidah, N.G. & Prat, A. The biology and therapeutic targeting of the proprotein convertases. Nat. Rev. Drug Discov. 11, 367-383 (2012)
13. Kwon, H.J., Lagace, T.A., McNutt, M.C., Horton, J.D. & Deisenhofer, J. Molecular basis for LDL receptor recognition by PCSK9. Proc. Natl. Acad. Sci. USA 105, 1820-1825 (2008)
14. Benjannet, S. et al. NARC-1/PCSK9 and its natural mutants: zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol. J. Biol. Chem. 279, 48865-48875 (2004)
15. Cunningham, D. et al. Structural and biophysical studies of PCSK9 and its mutants linked to familial hypercholesterolemia. Nat. Struct. Mol. Biol. 14, 413-419 (2007)
16. Duff, C.J., Scott, M.J., Kirby, I.T., Hutchinson, S.E., Martin, S.L. & Hooper, N.M. Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochem. J. 419, 577-584 (2009)
17. Stroes, E. 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) doi: 10.1016/j. jacc.2014.03.019 (e-pub ahead of print)
18. Giugliano, R.P. et al.; LAPLACE-TIMI 57 Investigators. 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, 2007-2017 (2012)
19. Stein, E.A. et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N. Engl. J. Med. 366, 1108-1118 (2012)
20. Koren, M.J. 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, placebocontrolled, phase 2 study. Lancet 380, 1995-2006 (2012)
21. Davidson, M.H. Emerging low-density lipoprotein therapies: Targeting PCSK9 for low-density lipoprotein reduction. J. Clin. Lipidol. 7, S11-S15 (2013)
22. Graham, M.J. et al. Antisense inhibition of proprotein convertase subtilisin/kexin type 9 reduces serum LDL in hyperlipidemic mice. J. Lipid Res. 48, 763-767 (2007)
23. Frank-Kamenetsky, M. et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc. Natl. Acad. Sci. USA 105, 11915-11920 (2008)
24. Oberbauer, R. Not nonsense but antisense-Applications of antisense oligonucleotides in different fields of medicine. Wien. Klin. Wochenschr. 109, 40-46 (1997)
25. Bennett, C.F. & Swayze, E.E. RNA targeting therapeutics: molecular mechanisms of antisense oligonucleotides as a therapeutic platform. Annu. Rev. Pharmacol. Toxicol. 50, 259-293 (2010)
26. Wierzbicki, A.S., Hardman, T. & Prince, W.T. Future challenges for microsomal transport protein inhibitors. Curr. Vasc. Pharmacol. 7, 277-286 (2009)
27. Raal, F.J. et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebocontrolled trial. Lancet 375, 998-1006 (2010)
28. Akdim, F. et al. Efficacy and safety of mipomersen, an antisense inhibitor of apolipoprotein B, in hypercholesterolemic subjects receiving stable statin therapy. J. Am. Coll. Cardiol. 55, 1611-1618 (2010)
29. Akdim, F. et al. Efficacy of apolipoprotein B synthesis inhibition in subjects with mild-To-moderate hyperlipidaemia. Eur. Heart J. 32, 2650-2659 (2011)
30. Parhofer, K.G. Lipoprotein(a): medical treatment options for an elusive molecule. Curr. Pharm. Des. 17, 871-876 (2011)
31. Visser, M.E. et al. Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. J. Lipid Res. 51, 1057-1062 (2010)
32. Pollin, T.I. et al. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322, 1702-1705 (2008)
33. Visser, M.E., Witztum, J.L., Stroes, E.S. & Kastelein, J.J. Antisense oligonucleotides for the treatment of dyslipidaemia. Eur. Heart J. 33, 1451-1458 (2012)
34. Graham, M.J. et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ. Res. 112, 1479-1490 (2013)
35. Clarke, R. et al.; PROCARDIS Consortium. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361, 2518-2528 (2009)
36. Ginsberg, H.N. & Fisher, E.A. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J. Lipid Res. 50 (suppl.), S162-S166 (2009)
37. Cuchel, M. & Rader, D.J. Microsomal transfer protein inhibition in humans. Curr. Opin. Lipidol. 24, 246-250 (2013)
38. Wetterau, J.R. et al. An MTP inhibitor that normalizes atherogenic lipoprotein levels in WHHL rabbits. Science 282, 751-754 (1998)
39. Cuchel, M. et al. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N. Engl. J. Med. 356, 148-156 (2007)
40. Samaha, F.F., McKenney, J., Bloedon, L.T., Sasiela, W.J. & Rader, D.J. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat. Clin. Pract. Cardiovasc. Med. 5, 497-505 (2008)
41. Taghibiglou, C., Van Iderstine, S.C., Kulinski, A., Rudy, D. & Adeli, K. Intracellular mechanisms mediating the inhibition of apoB-containing lipoprotein synthesis and secretion in HepG2 cells by avasimibe (CI-1011), a novel acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor. Biochem. Pharmacol. 63, 349-360 (2002)
42. Nissen, S.E. et al.; ACAT Intravascular Atherosclerosis Treatment Evaluation (ACTIVATE) Investigators. Effect of ACAT inhibition on the progression of coronary atherosclerosis. N. Engl. J. Med. 354, 1253-1263 (2006)
43. Meuwese, M.C. et al.; CAPTIVATE Investigators. ACAT inhibition and progression of carotid atherosclerosis in patients with familial hypercholesterolemia: the CAPTIVATE randomized trial. JAMA 301, 1131-1139 (2009)
44. Y oshinaka, Y. et al. A selective ACAT-1 inhibitor, K-604, stimulates collagen production in cultured smooth muscle cells and alters plaque phenotype in apolipoprotein E-knockout mice. Atherosclerosis 213, 85-91 (2010)
45. Tziomalos, K., Athyros, V.G. & Mikhailidis, D.P. Fish oils and vascular disease prevention: an update. Curr. Med. Chem. 14, 2622-2628 (2007)
46. Kataoka, Y., Uno, K., Puri, R. & Nicholls, S.J. Epanova(®) and hypertriglyceridemia: pharmacological mechanisms and clinical efficacy. Future Cardiol. 9, 177-186 (2013)
47. Wierzbicki, A.S., Clarke, R.E., Viljoen, A. & Mikhailidis, D.P. Triglycerides: a case for treatment? Curr. Opin. Cardiol. 27, 398-404 (2012)
48. Chen, H.C. & Farese, R.V. Jr. Inhibition of triglyceride synthesis as a treatment strategy for obesity: lessons from DGAT1-deficient mice. Arterioscler. Thromb. Vasc. Biol. 25, 482-486 (2005)
49. Kim, E. et al. A small-molecule inhibitor of enterocytic microsomal triglyceride transfer protein, SLx-4090: biochemical, pharmacodynamic, pharmacokinetic, and safety profile. J. Pharmacol. Exp. Ther. 337, 775-785 (2011)
50. Castelli, W.P. et al. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation 55, 767-772 (1977)
51. Castelli, W.P., Anderson, K., Wilson, P.W. & Levy, D. Lipids and risk of coronary heart disease. The Framingham Study. Ann. Epidemiol. 2, 23-28 (1992)
52. Sharrett, A.R. et al.; Atherosclerosis Risk in Communities Study Group. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 104, 1108-1113 (2001)
53. Barter, P. et al.; Treating to New Targets Investigators. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N. Engl. J. Med. 357, 1301-1310 (2007)
54. Barter, P.J. et al.; ILLUMINATE Investigators. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357, 2109-2122 (2007)
55. Schwartz, G.G. et al.; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367, 2089-2099 (2012)
56. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebocontrolled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur. Heart J. 34, 1279-1291 (2013)
57. Brousseau, M.E. et al. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler. Thromb. Vasc. Biol. 25, 1057-1064 (2005)
58. Nissen, S.E. et al.; ILLUSTRATE Investigators. Effect of torcetrapib on the progression of coronary atherosclerosis. N. Engl. J. Med. 356, 1304-1316 (2007)
59. Kastelein, J.J. et al.; RADIANCE 1 Investigators. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N. Engl. J. Med. 356, 1620-1630 (2007)
60. Bots, M.L. et al.; RADIANCE 2 Investigators. Torcetrapib and carotid intimamedia thickness in mixed dyslipidaemia (RADIANCE 2 study): a randomised, double-blind trial. Lancet 370, 153-160 (2007)
61. Vergeer, M. et al. Cholesteryl ester transfer protein inhibitor torcetrapib and off-Target toxicity: a pooled analysis of the rating atherosclerotic disease change by imaging with a new CETP inhibitor (RADIANCE) trials. Circulation 118, 2515-2522 (2008)
62. Lüscher, T.F. et al.; dal-VESSEL Investigators. 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. 33, 857-865 (2012)
63. Cannon, C.P. et al.; Determining the Efficacy and Tolerability Investigators. Safety of anacetrapib in patients with or at high risk for coronary heart disease. N. Engl. J. Med. 363, 2406-2415 (2010)
64. Nicholls, S.J. 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 306, 2099-2109 (2011)
65. Nicholls, S.J. Evacetrapib. Curr. Cardiol. Rep. 14, 245-250 (2012)
66. Nissen, S.E. et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 290, 2292-2300 (2003)
67. Tardif, J.C. et al.; Effect of rHDL on Atherosclerosis-Safety and Efficacy (ERASE) Investigators. Effects of reconstituted high-density lipoprotein infusions on coronary atherosclerosis: a randomized controlled trial. JAMA 297, 1675-1682 (2007)
68. Diditchenko, S. et al. Novel formulation of a reconstituted high-density lipoprotein (CSL112) dramatically enhances ABCA1-dependent cholesterol efflux. Arterioscler. Thromb. Vasc. Biol. 33, 2202-2211 (2013)
69. Tardy, C. et al. CER-001, a HDL-mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice. Atherosclerosis 232, 110-118 (2014)
70. Navab, M. et al. Oral administration of an Apo A-I mimetic Peptide synthesized from D-Amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 105, 290-292 (2002)
71. Navab, M. et al. D-4F and statins synergize to render HDL antiinflammatory in mice and monkeys and cause lesion regression in old apolipoprotein E-null mice. Arterioscler. Thromb. Vasc. Biol. 25, 1426-1432 (2005)
72. Bielicki, J.K. et al. A new HDL mimetic peptide that stimulates cellular cholesterol efflux with high efficiency greatly reduces atherosclerosis in mice. J. Lipid Res. 51, 1496-1503 (2010)
73. Uehara, Y. et al. FAMP, a novel apoA-I mimetic peptide, suppresses aortic plaque formation through promotion of biological HDL function in ApoEdeficient mice. J. Am. Heart Assoc. 2, e000048 (2013)
74. Waksman, R. 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. 55, 2727-2735 (2010)
75. Bartel, D.P. MicroRNAs: target recognition and regulatory functions. Cell 136, 215-233 (2009)
76. Moore, K.J., Rayner, K.J., Suárez, Y. & Fernández- Hernando, C. The role of microRNAs in cholesterol efflux and hepatic lipid metabolism. Annu. Rev. Nutr. 31, 49-63 (2011)
77. Rayner, K.J. & Moore, K.J. The plaque micro environment: microRNAs control the risk and the development of atherosclerosis. Curr. Atheroscler. Rep. 14, 413-421 (2012)
78. Rayner, K.J. et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature 478, 404-407 (2011)
79. Soh, J., Iqbal, J., Queiroz, J., Fernandez-Hernando, C. & Hussain, M.M. MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion. Nat. Med. 19, 892-900 (2013)
80. Kingwell, B.A. & Chapman, M.J. Future of high-density lipoprotein infusion therapies: potential for clinical management of vascular disease. Circulation 128, 1112-1121 (2013)