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Future Lipid-Altering Therapeutic Options Targeting Residual Cardiovascular Risk

  • Lipid Abnormalities and Cardiovascular Prevention (G De Backer, Section Editor)
  • Published:
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Abstract

Low-density lipoproteins (LDL) play a causal role in the development of atherosclerosis, and reduction of LDL cholesterol with a statin is a cornerstone in prevention of cardiovascular disease. However, it remains an unmet need to reduce the residual risk on maximally tolerated statin alone or in combination with other drugs such as ezetimibe. Among the new LDL-lowering therapies, PCSK9 inhibitors appear the most promising class. Genetic studies suggest that triglyceride-rich lipoproteins are associated with cardiovascular risk and several promising triglyceride-lowering therapies are at various stages of development. At the opposite end, high-density lipoprotein (HDL) cholesterol seems to not be causally associated with cardiovascular risk, and thus far, trials designed to reduce cardiovascular risk by mainly raising HDL cholesterol levels have been disappointing. Nevertheless, new drugs targeting HDL are still in development. This review describes the new drugs reducing LDL, apolipoprotein(a), and triglyceride-rich lipoproteins, and the strategies to modulate HDL metabolism.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Catapano AL, Ference BA. IMPROVE-IT and genetics reaffirm the causal role of LDL in cardiovascular disease. Atherosclerosis. 2015;241:498–501.

    Article  CAS  PubMed  Google Scholar 

  2. Cholesterol Treatment Trialists’ (CTT) Collaborators. 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.

    Article  Google Scholar 

  3. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376:1670–81.

    Article  Google Scholar 

  4. 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). European guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J. 2012;33:1635–701.

    Article  Google Scholar 

  5. Stone NJ, Robinson J, Lichtenstein AH, 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. Circulation. 2014;129(25 Suppl 2):S1–45.

    Article  PubMed  Google Scholar 

  6. Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events. J Am Coll Cardiol. 2014;64:485–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cannon CP, Blazing MA, Giugliano RP, for the IMPROVE-IT investigators, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.

    Article  CAS  PubMed  Google Scholar 

  8. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy - European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36:1012–22.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Seidah NG, Awan Z, Chrétien M, et al. PCSK9. A key modulator of cardiovascular health. Circ Res. 2014;114:1022–36.

    Article  CAS  PubMed  Google Scholar 

  10. Norata GD, Tibolla G, Catapano AL. PCSK9 inhibition for the treatment of hypercholesterolemia: promises and emerging challenges. Vascul Pharmacol. 2014;62:103–11.

    Article  CAS  PubMed  Google Scholar 

  11. Marais AD, Kim JB, Wasserman SM, et al. PCSK9 inhibition in LDL cholesterol reduction: genetics and therapeutic implications of very low plasma lipoprotein levels. Pharmacol Ther. 2015;145:58–66.

    Article  CAS  PubMed  Google Scholar 

  12. Shimada YJ, Cannon CP. PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors: past, present, and the future. Eur Heart J. 2015;36:2415–24.

    Article  PubMed  Google Scholar 

  13. Bergeron N, Phan BAP, Ding Y, et al. Proprotein convertase subtilisin/kexin type 9 inhibition. A new therapeutic mechanism for reducing cardiovascular disease risk. Circulation. 2015;132:1648–66. A recent comprehensive review on PCSK9 function and PCSK9 inhibition.

    Article  CAS  PubMed  Google Scholar 

  14. Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100:928–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.

    Article  CAS  PubMed  Google Scholar 

  16. Cohen JC, Boerwinkle E, Mosley Jr TH, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.

    Article  CAS  PubMed  Google Scholar 

  17. 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;55:2833–42.

    Article  CAS  PubMed  Google Scholar 

  18. Hedrick JA. Targeting PCSK9 for the treatment of hypercholesterolemia. Curr Opin Invest Drugs. 2009;10:938–46.

    CAS  Google Scholar 

  19. Turner T, Stein EA. Non-statin treatments for managing LDL cholesterol and their outcomes. Clin Ther. 2015;37:2751–69. Good review on new treatments targeting LDL metabolism.

    Article  CAS  PubMed  Google Scholar 

  20. Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, 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. 2014;383:60–8.

    Article  CAS  PubMed  Google Scholar 

  21. Fitzgerald K, Simon A, White S, et al. ALN-PCSsc, an RNAi investigational agent that inhibits PCSK9 synthesis with the potential for effective bi-annual dosing. Presented at AHA scientific session 2015.

  22. Galabova G, Brunner S, Winsauer G, et al. Peptide-based anti-PCSK9 vaccines – An approach for long-term LDLc management. PLoS One. 2014;9:e114469.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Farnier M. An evaluation of alirocumab for the treatment of hypercholesterolemia. Expert Rev Cardiovasc Ther. 2015;13:1307–23. Recent review on alirocumab.

    Article  CAS  PubMed  Google Scholar 

  24. Langslet G, Emery M, Wasserman SM. Evolocumab (AMG 145) for primary hypercholesterolemia. Expert Rev Cardiovasc Ther. 2015;13:477–88. Recent review on evolocumab.

    Article  CAS  PubMed  Google Scholar 

  25. Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging, study in statin-treated subjects with hypercholesterolemia. Am J Cardiol. 2015;115:1212–21.

    Article  CAS  PubMed  Google Scholar 

  26. Kastelein JJP, Nissen SE, Rader DJ, et al. Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled phase 2 study. Eur Heart J. 2016; Jan 12: online.

  27. Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78-week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolemia. Eur Heart J. 2015;36:2996–3003. Studies evaluating efficacy of alirocumab in two large cohorts of heterozygous FH.

    PubMed  PubMed Central  Google Scholar 

  28. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolemia (RUTHERFORD-2): a randomized, double-blind, placebo-controlled trial. Lancet. 2015;385:331–40.

    Article  CAS  PubMed  Google Scholar 

  29. 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. 2015;385:341–50. Study showing a significant effect of evolocumab for homozygous FH with residual LDL receptor activity.

    Article  CAS  PubMed  Google Scholar 

  30. Robinson JG, Farnier M, Krempf M, et al. For the ODYSSEY LONG TERM Investigators. Efficacy and safety of Alirocumab in reducing lipids and cardiovascular events. New Engl J Med. 2015;372:1489–99. Important phase III trial evaluating long term efficacy and safety of alirocumab, with a post-hoc analysis suggesting a cardiovascular benefit.

  31. Kereiakes DJ, Robinson JG, Cannon CP, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab among high cardiovascular risk patients on maximally tolerated statin therapy: the ODYSSEY COMBO I study. Am Heart J. 2015;169:906–15.

    Article  CAS  PubMed  Google Scholar 

  32. Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36:1186–94.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 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. JAMA. 2014;311:1870–82.

    Article  PubMed  Google Scholar 

  34. Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370:1809–19.

    Article  CAS  PubMed  Google Scholar 

  35. Farnier M, Jones P, Severance R, et al. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: the ODYSSEY OPTIONS II randomized trial. Atherosclerosis. 2016;244:138–46.

    Article  CAS  PubMed  Google Scholar 

  36. Bays H, Gaudet D, Weiss R, et al. Alirocumab as add-on to atorvastatin versus other lipid treatment strategies: ODYSSEY OPTIONS I randomized trial. J Clin Endocrinol Metab. 2015;100:3140–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014;176:55–61.

    Article  PubMed  Google Scholar 

  38. Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia – the MENDEL-2 randomized, controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531–40.

    Article  CAS  PubMed  Google Scholar 

  39. 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;63:2541–8.

    Article  CAS  PubMed  Google Scholar 

  40. Moriarty PM, Thompson PD, Cannon CP, for the ODYSSEY ALTERNATIVE Investigators, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9:758–69.

    Article  PubMed  Google Scholar 

  41. Sabatine MS, Giugliano RP, Wiviott SD, for the Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9. Important phase III trial suggesting a cardiovascular benefit after one year of evolocumab treatment.

    Article  CAS  PubMed  Google Scholar 

  42. Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia. A systematic review and meta-analysis. Ann Intern Med. 2015;163:40–51.

    Article  PubMed  Google Scholar 

  43. Lipinski MJ, Benedetto U, Escarcega RO, et al. The impact of proprotein convertase subtilisin-kexin type 9 serine protease inhibitors on lipid levels and outcomes in patients with primary hypercholesterolaemia: a network meta-analysis. Eur Heart J. 2016;37:536–45.

    Article  PubMed  Google Scholar 

  44. Sabatine MS, Giugliano RP, Keech A, et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk (FOURIER) trial. Am Heart J. 2016;173:94–101.

  45. 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;168:682–9.e1.

    Article  CAS  PubMed  Google Scholar 

  46. SPIRE-1: The evaluation of Bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects. www.clinicaltrials.gov, NCT 01975376, accessed on February 2016.

  47. SPIRE-2: The evaluation of Bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects. www.clinicaltrials.gov, NCT 01975389, accessed on February 2016.

  48. EBBINGHAUS: Evaluating PCSK9 Binding antiBody Influence oN cognitive HeAlth in High cardiovascular Risk Subjects. www.clinicaltrials.gov, NCT02207634, accessed on February 2016.

  49. Giugliano RP, Sabatine MS. Are PCSK9 inhibitors the next breakthrough in the cardiovascular field ? J Am Coll Cardiol. 2015;65:2638–51.

    Article  CAS  PubMed  Google Scholar 

  50. Tice JA, Kazi DS, Pearson SD. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors for treatment of high cholesterol levels. Effectiveness and value. JAMA Intern Med. 2016;176:107–8.

    Article  PubMed  Google Scholar 

  51. Agarwala A, Jones P, Nambi V. The role of antisense oligonucleotide therapy in patients with familial hypercholesterolemia: risks, benefits, and management recommendations. Curr Atheroscler Rep. 2015;17:467.

    Article  PubMed  Google Scholar 

  52. Santos RD, Duell PB, East C, 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. 2015;36:566–75.

    Article  PubMed  Google Scholar 

  53. 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.

    Article  CAS  PubMed  Google Scholar 

  54. Ahmad Z, Khera A. The role of microsomal triglyceride transfer protein inhibitors in the treatment of patients with familial hypercholesterolemia: risks, benefits, and management. Curr Atheroscler Rep. 2015;17:469.

    Article  PubMed  Google Scholar 

  55. Cuchel M, Meagher EA, du Toit Theron H, for the phase 3 HoFH Lomitapide Study Investigators, 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. 2013;381:40–6.

    Article  CAS  PubMed  Google Scholar 

  56. Stefanutti C, Blom DJ, Averna MR, for the phase 3 HoFH Lomitapide Study Investigators, et al. The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia – A post-hoc analysis of a Phase 3, single-arm, open-label trial. Atherosclerosis. 2015;240:408–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Gutierrez MJ, Rosenberg NL, MacDougall DE, et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2014;34:676–83.

    Article  CAS  PubMed  Google Scholar 

  58. Ballantyne CM, Davidson MH, MacDougall DE, et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia. Results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62:1154–62.

    Article  CAS  PubMed  Google Scholar 

  59. Thompson P, Ballantyne C, McKenney J, et al. ETC-1002 lowers LDL-C more than ezetimibe in patients with hypercholesterolemia with or without statin intolerance and has a similar safety and tolerability profile. J Am Coll Cardiol. 2015;65:A345.

    Article  Google Scholar 

  60. Bays HE, McKenney JM, Dujovne CA, et al. Effectiveness and tolerance of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Am J Cardiol. 2003;92:538–43.

    Article  CAS  PubMed  Google Scholar 

  61. Donovan JM, Mancini M, Sanabria C, et al. Phase 1 study of CAT-2054, an oral modulator of SREBP. J Clin Lipidol. 2015;9:474–5.

    Article  Google Scholar 

  62. Nordestgaard B, Varbo A. Lipids and cardiovascular disease 3. Triglycerides and cardiovascular disease. Lancet. 2014;384:626–35.

    Article  CAS  PubMed  Google Scholar 

  63. Di Angelantonio E, Sarwar N, Perry P, et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009;302:1993–2000.

    Article  PubMed  Google Scholar 

  64. Miller M, Cannon CP, Murphy SA, for the PROVE-IT-TIMI 22 Investigations, et al. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE-IT TIMI 22 trial. J Am Coll Cardiol. 2008;51:724–30.

    Article  CAS  PubMed  Google Scholar 

  65. Schwartz GG, Abt M, Bao W, et al. Fasting triglycerides predict recurrent ischemic events in patients with acute coronary syndrome treated with statins. J Am Coll Cardiol. 2015;65:2267–75.

    Article  CAS  PubMed  Google Scholar 

  66. Varbo A, Benn M, Tybjærg-Hansen A, et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–36.

    Article  CAS  PubMed  Google Scholar 

  67. Holmes MV, Asselbergs FW, Palmer TM, et al. Mendelian randomization of blood lipids for coronary heart disease. Eur Heart J. 2015;36:539–50.

    Article  PubMed  Google Scholar 

  68. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet. 2010;375:1634–39.

    Article  PubMed Central  Google Scholar 

  69. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, et al. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41.

    Article  PubMed  Google Scholar 

  70. The TG and HDL Working Group off the Exome Sequencing Project, National Heart, Lung, and Blood Institute. Loss-of-function mutations in APOC3, triglycerides and coronary disease. N Engl J Med. 2014;371:22–31.

    Article  Google Scholar 

  71. Gryn SE, Hegele RA. Novel therapeutics in hypertriglyceridemia. Curr Opin Lipidol. 2015;26:484–91.

    Article  CAS  PubMed  Google Scholar 

  72. Sahebkar A, Chew GT, Watts GF. Recent advances in pharmacotherapy for hypertriglyceridemia. Prog Lipid Res. 2014;56:47–66.

    Article  CAS  PubMed  Google Scholar 

  73. REDUCE-IT: A study of AMR101 to evaluate its ability to reduce cardiovascular events in high risk patients with hypertriglyceridemia and on statin. www.clinicaltrials.gov, NCT 01492361, accessed on February 2016.

  74. STRENGTH: Outcomes study to assess statin residual risk reduction with Epanova in high CV risk patients with hypertriglyceridemia. www.clinicaltrials.gov, NCT 02104817, accessed on February 2016.

  75. Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200–6. Proof-of-concept trial demonstrating ApoC3 inhibition would be effective to treat hyperchylomicronemia.

    Article  PubMed  Google Scholar 

  76. Gaudet D, Alexander VJ, Baker BF, et al. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N Engl J Med. 2015;373:438–47. Important trial showing positive effects of ASO apoC3 inhibitor.

    Article  CAS  PubMed  Google Scholar 

  77. Gusarova V, Alexa CA, Wang Y, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res. 2015;56:1308–17.

    Article  CAS  PubMed  Google Scholar 

  78. Wang Y, Gusarova V, Banfi S, et al. Inactivation if ANGPTL3 reduces hepatic VLDL- triglyceride secretion. J Lipid Res. 2015;56:1296–307.

    Article  CAS  PubMed  Google Scholar 

  79. Liu ZM, Hu M, Chan P, et al. Early investigational drugs targeting PPAR-alpha for the treatment of metabolic disease. Expert Opin Investig Drugs. 2015;24:611–21.

    Article  CAS  PubMed  Google Scholar 

  80. Ferreira W, Twisk J, Kwikkers K, et al. Immune responses to intramuscular administration of alipogene tiparvocec (AAV1-LPL(S447X)) in a phase II clinical trial of lipoprotein lipase deficiency gene therapy. Hum Gene Ther. 2014;25:180–8.

    Article  CAS  PubMed  Google Scholar 

  81. Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380:572–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Nordestgaard BG, Tybjærg-Hansen A. Genetic determinants of LDL, lipoprotein(a), triglyceride-rich lipoproteins and HDL: concordance and discordance with cardiovascular disease risk. Curr Opin Lipidol. 2011;22:113–22.

    Article  CAS  PubMed  Google Scholar 

  83. Kingwell BA, Chapman MJ, Kontush A, et al. HDL-targeted therapies: progress, failures and future. Nat Rev. 2014;13:445–64.

    CAS  Google Scholar 

  84. Saleheen D, Scott R, Javad S, et al. Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol. 2015;3:507–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Gautier T, Masson D, Lagrost L. The potential of cholesteryl ester transfer protein as a therapeutic target. Exper Opin Ther Targets. 2016;20:47–59. Excellent review on the putative role of CETP inhibition.

    Article  CAS  Google Scholar 

  86. Kastelein JJP, Besseling J, Shah S, et al. Anacetrapib as lipid-modifying therapy in patients with heterozygous familial hypercholesterolaemia (REALIZE): a randomized, double-blind, placebo controlled, phase 3 study. Lancet. 2015;385:2153–61.

    Article  CAS  PubMed  Google Scholar 

  87. Howingh GK, Kastelein JP, van Deventer SJH, et al. Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP); a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2015;386:452–60.

    Article  Google Scholar 

  88. REVEAL: Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification. www.clinicaltrials.gov, NCT 01252953, accessed on February 2016.

  89. 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.

    Article  CAS  PubMed  Google Scholar 

  90. Kootte RS, Smits LP, van der Valk FM, et al. Effect of open-label infusion of an apoA-1-containing particle (CER-001) on RCT and artery wall thickness in patients with FHA. J Lipid Res. 2015;56:703–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hovingh GK, Smits LP, Stefanutti C, et al. The effect of an apolipoprotein A-I-containing high-density lipoprotein-mimetic particle (CER-001) on carotid artery wall thickness in patients with homozygous familial hypercholesterolemia: the Modifying Orphan Disease Evaluation (MODE) study. Am Heart J. 2015;169:736–42.e1.

    Article  CAS  PubMed  Google Scholar 

  92. 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.

    Article  CAS  PubMed  Google Scholar 

  93. Bailey D, Jahagirdar R, Gordon A, et al. RVX-208: a small molecule that increases apolipoprotein A-I and high-density lipoprotein cholesterol in vitro and in vivo. J Am Coll Cardiol. 2010;55:2580–9.

    Article  CAS  PubMed  Google Scholar 

  94. Nicholls SJ, Puri R, Wolski K, et al. Effect of the BET protein inhibitor, RVX-208, on progression of coronary atherosclerosis: results of the Phase 2b, randomized, double-blind, multicenter, ASSURE trial. Am J Cardiovasc Drugs. 2016;16:55–65.

    Article  CAS  PubMed  Google Scholar 

  95. Jacobson TA. Lipoprotein(a), cardiovascular disease, and contemporary management. Mayo Clin Proc. 2013;88:1294–311.

    Article  CAS  PubMed  Google Scholar 

  96. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Van Capelleveen JC, van der Valk FM, Stroes ESG. Current therapies for lowering lipoprotein(a). J Lipid Res. 2015 Dec 4.

  98. Tsimikas S, Viney NJ, Hughes SG, et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet. 2015;386:1472–83. First-trial with an ASO blocking apo(a) synthesis.

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Michel Farnier.

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Dr. Farnier reports having received grants, consulting fees, and/or honoraria, and delivering lectures for Abbott/Mylan, Amgen, AstraZeneca, Eli Lilly, Genzyme, Kowa, Merck and Co, Pfizer, Roche, Sanofi/Regeneron, and Servier.

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This article is part of the Topical Collection on Lipid Abnormalities and Cardiovascular Prevention

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Farnier, M. Future Lipid-Altering Therapeutic Options Targeting Residual Cardiovascular Risk. Curr Cardiol Rep 18, 65 (2016). https://doi.org/10.1007/s11886-016-0743-8

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