Advertisement

Tackling Residual Atherosclerotic Risk in Statin-Treated Adults: Focus on Emerging Drugs

  • Kohei Takata
  • Stephen J. Nicholls
Review Article
  • 35 Downloads

Abstract

Epidemiological studies and meta-analyses have consistently suggested the importance of lowering low-density lipoprotein cholesterol (LDL-C) to reduce cardiovascular (CV) events. However, these studies and mechanistic studies using intracoronary imaging modalities have reported patients who continue to experience CV events or disease progression despite optimal LDL-C levels on statins. These findings, including statin intolerance, have highlighted the importance of exploring additional potential therapeutic targets to reduce CV risk. Genomic insights have presented a number of additional novel targets in lipid metabolism. In particular, proprotein convertase subtilisin/kexin type 9 inhibitors have rapidly developed and recently demonstrated their beneficial impact on CV outcomes. Triglyceride (TG)-rich lipoproteins have been recently reported as a causal factor of atherosclerotic cardiovascular disease (ASCVD). Indeed, several promising TG-targeting therapies are being tested at various clinical stages. In this review, we present the evidence to support targeting atherogenic lipoproteins to target residual ASCVD risk in statin-treated patients.

Notes

Compliance with Ethical Standards

Funding

None.

Conflict of interest

Stephen J. Nicholls has received speaking honoraria from AstraZeneca, Pfizer, Merck Schering-Plough and Takeda, consulting fees from AstraZeneca, Abbott, Atheronova, Esperion, Amgen, Novartis, Omthera, CSL Behring, Boehringer Ingelheim, Pfizer, Merck Schering-Plough, Takeda, Roche, Novo Nordisk, LipoScience and Anthera, and research support from the National Health and Medical Research Council of Australia, Anthera, AstraZeneca, Cerenis, Eli Lilly, InfraReDx, Roche, Resverlogix, Novartis, Amgen, and LipoScience. Kohei Takata has reported that he has no relationships to disclose.

References

  1. 1.
    Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–322.PubMedGoogle Scholar
  2. 2.
    Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372:2387–97.PubMedCrossRefGoogle Scholar
  3. 3.
    Bayturan O, Kapadia S, Nicholls SJ, et al. Clinical predictors of plaque progression despite very low levels of low-density lipoprotein cholesterol. J Am Coll Cardiol. 2010;55:2736–42.PubMedCrossRefGoogle Scholar
  4. 4.
    Catapano AL, Graham I, De Backer G et al. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J 2016;37:2999–3058.PubMedCrossRefGoogle Scholar
  5. 5.
    Tremblay AJ, Lamarche B, Lemelin V, et al. Atorvastatin increases intestinal expression of NPC1L1 in hyperlipidemic men. J Lipid Res. 2011;52:558–65.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Sharma M, Ansari MT, Abou-Setta AM, et al. Systematic review: comparative effectiveness and harms of combination therapy and monotherapy for dyslipidemia. Ann Intern Med. 2009;151:622–30.PubMedCrossRefGoogle Scholar
  7. 7.
    Rossebo AB, Pedersen TR, Boman K, et al. Intensive lipid lowering with simvastatin and ezetimibe in aortic stenosis. N Engl J Med. 2008;359:1343–56.PubMedCrossRefGoogle Scholar
  8. 8.
    Baigent C, Landray MJ, Reith C, et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet. 2011;377:2181–92.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Wanner C, Krane V, Marz W, et al. Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238–48.PubMedCrossRefGoogle Scholar
  10. 10.
    Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med. 2009;360:1395–407.PubMedCrossRefGoogle Scholar
  11. 11.
    Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). Circulation. 2018;137:1571–82.PubMedCrossRefGoogle Scholar
  12. 12.
    Tsujita K, Sugiyama S, Sumida H, et al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol. 2015;66:495–507.PubMedCrossRefGoogle Scholar
  13. 13.
    Bays HE, Jones PH, Orringer CE, Brown WV, Jacobson TA. National lipid association annual summary of clinical lipidology 2016. J Clin Lipidol. 2016;10:S1–43.PubMedCrossRefGoogle Scholar
  14. 14.
    Petersen DN, Hawkins J, Ruangsiriluk W, et al. A small-molecule anti-secretagogue of PCSK9 targets the 80S ribosome to inhibit PCSK9 protein translation. Cell Chem Biol. 2016;23:1362–71.PubMedCrossRefGoogle Scholar
  15. 15.
    Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–6.PubMedCrossRefGoogle Scholar
  16. 16.
    Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–72.PubMedCrossRefGoogle Scholar
  17. 17.
    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.PubMedCrossRefGoogle Scholar
  18. 18.
    McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. 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.PubMedCrossRefGoogle Scholar
  19. 19.
    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.PubMedCrossRefGoogle Scholar
  20. 20.
    Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36:2996–3003.PubMedPubMedCentralGoogle Scholar
  21. 21.
    Dias CS, Shaywitz AJ, Wasserman SM, 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. 2012;60:1888–98.PubMedCrossRefGoogle Scholar
  22. 22.
    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.PubMedCrossRefGoogle Scholar
  23. 23.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311:1870–82.PubMedCrossRefGoogle Scholar
  25. 25.
    Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63:2531–40.PubMedCrossRefGoogle Scholar
  26. 26.
    Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–99.PubMedCrossRefGoogle Scholar
  27. 27.
    Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–9.PubMedCrossRefGoogle Scholar
  28. 28.
    Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–22.PubMedCrossRefGoogle Scholar
  29. 29.
    Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016;316:1289–97.PubMedCrossRefGoogle Scholar
  30. 30.
    Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107.CrossRefGoogle Scholar
  31. 31.
    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.PubMedCrossRefGoogle Scholar
  32. 32.
    Maki KC. The ODYSSEY Outcomes trial: Clinical implications and exploration of the limits of what can be achieved through lipid lowering. J Clin Lipidol 2018;12:1102–5.CrossRefGoogle Scholar
  33. 33.
    Ridker PM, Tardif JC, Amarenco P, et al. Lipid-Reduction Variability and Antidrug-Antibody Formation with Bococizumab. N Engl J Med. 2017;376:1517–26.PubMedCrossRefGoogle Scholar
  34. 34.
    Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376:1527–39.PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Ference BA, Cannon CP, Landmesser U, Luscher TF, Catapano AL, Ray KK. Reduction of low density lipoprotein-cholesterol and cardiovascular events with proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and statins: an analysis of FOURIER, SPIRE, and the Cholesterol Treatment Trialists Collaboration. Eur Heart J 2017;39:2540–5.PubMedCentralCrossRefGoogle Scholar
  36. 36.
    Sattar N, Toth PP, Blom DJ, et al. Effect of the proprotein convertase subtilisin/kexin type 9 inhibitor evolocumab on glycemia, body weight, and new-onset diabetes mellitus. Am J Cardiol. 2017;120:1521–7.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    de Carvalho LSF, Campos AM, Sposito AC. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and incident type 2 diabetes mellitus: a systematic review and meta-analysis with over 96,000 patient-years. Diabetes Care 2018;41:364–7.PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5:941–50.PubMedCrossRefGoogle Scholar
  39. 39.
    Colhoun HM, Ginsberg HN, Robinson JG, et al. No effect of PCSK9 inhibitor alirocumab on the incidence of diabetes in a pooled analysis from 10 ODYSSEY Phase 3 studies. Eur Heart J. 2016;37:2981–9.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 2016;375:2144–53.PubMedCrossRefGoogle Scholar
  41. 41.
    Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316:2373–84.PubMedCrossRefGoogle Scholar
  42. 42.
    Gaudet D, Kereiakes DJ, McKenney JM, et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol. 2014;114:711–5.PubMedCrossRefGoogle Scholar
  43. 43.
    Gaudet D, Watts GF, Robinson JG, et al. Effect of alirocumab on lipoprotein(a) over >/=1.5 years (from the phase 3 ODYSSEY program). Am J Cardiol. 2017;119:40–6.PubMedCrossRefGoogle Scholar
  44. 44.
    Raal FJ, Giugliano RP, Sabatine MS, et al. PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the LDL receptor’s role. J Lipid Res. 2016;57:1086–96.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Reyes-Soffer G, Pavlyha M, Ngai C, et al. Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans. Circulation. 2017;135:352–62.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Bernick C, Katz R, Smith NL, et al. Statins and cognitive function in the elderly: the Cardiovascular Health Study. Neurology. 2005;65:1388–94.PubMedCrossRefGoogle Scholar
  47. 47.
    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.PubMedCrossRefGoogle Scholar
  48. 48.
    Khan AR, Bavishi C, Riaz H et al. Increased risk of adverse neurocognitive outcomes with proprotein convertase subtilisin-kexin type 9 inhibitors. Circ Cardiovasc Qual Outcomes 2017;10:e003153.PubMedCrossRefGoogle Scholar
  49. 49.
    Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017;377:633–43.PubMedCrossRefGoogle Scholar
  50. 50.
    Giugliano RP, Pedersen TR, Park JG, et al. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390:1962–71.PubMedCrossRefGoogle Scholar
  51. 51.
    Mefford MT, Rosenson RS, Cushman M et al. PCSK9 variants, LDL-cholesterol, and neurocognitive impairment: the REasons for Geographic and Racial Differences in Stroke (REGARDS) Study. Circulation 2018;137:1260–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk open-label extension. https://ClinicalTrials.gov/show/NCT02867813.
  53. 53.
    Pijlman AH, Huijgen R, Verhagen SN, et al. Evaluation of cholesterol lowering treatment of patients with familial hypercholesterolemia: a large cross-sectional study in The Netherlands. Atherosclerosis. 2010;209:189–94.PubMedCrossRefGoogle Scholar
  54. 54.
    Vishwanath R, Hemphill LC. Familial hypercholesterolemia and estimation of US patients eligible for low-density lipoprotein apheresis after maximally tolerated lipid-lowering therapy. J Clin Lipidol. 2014;8:18–28.PubMedCrossRefGoogle Scholar
  55. 55.
    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.PubMedCrossRefGoogle Scholar
  56. 56.
    Hovingh GK, Raal FJ, Dent R, et al. Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017;11:1448–57.PubMedCrossRefGoogle Scholar
  57. 57.
    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.PubMedCrossRefGoogle Scholar
  58. 58.
    Raal FJ, Hovingh GK, Blom D, et al. Long-term treatment with evolocumab added to conventional drug therapy, with or without apheresis, in patients with homozygous familial hypercholesterolaemia: an interim subset analysis of the open-label TAUSSIG study. Lancet Diabetes Endocrinol. 2017;5:280–90.PubMedCrossRefGoogle Scholar
  59. 59.
    Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J. 2016;37:3588–95.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Arch Med Sci. 2015;11:1–23.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Moriarty PM, Thompson PD, Cannon CP, 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.PubMedCrossRefGoogle Scholar
  63. 63.
    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.PubMedCrossRefGoogle Scholar
  64. 64.
    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.PubMedCrossRefGoogle Scholar
  65. 65.
    Nissen SE, Stroes E, Dent-Acosta RE, et al. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA. 2016;315:1580–90.PubMedCrossRefGoogle Scholar
  66. 66.
    Landlinger C, Pouwer MG, Juno C, et al. The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden CETP mice. Eur Heart J. 2017;38:2499–507.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Frank-Kamenetsky M, Grefhorst A, Anderson NN, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci USA. 2008;105:11915–20.PubMedCrossRefGoogle Scholar
  68. 68.
    Fitzgerald K, White S, Borodovsky A, et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N Engl J Med. 2017;376:41–51.PubMedCrossRefGoogle Scholar
  69. 69.
    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.PubMedCrossRefGoogle Scholar
  70. 70.
    Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376:1430–40.PubMedCrossRefGoogle Scholar
  71. 71.
    Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Intern Med. 2013;158:526–34.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Kazi DS, Penko J, Coxson PG, et al. Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial. JAMA. 2017;318:748–50.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Robinson JG, Huijgen R, Ray K, Persons J, Kastelein JJ, Pencina MJ. Determining when to add nonstatin therapy: a quantitative approach. J Am Coll Cardiol. 2016;68:2412–21.PubMedCrossRefGoogle Scholar
  74. 74.
    Annemans L, Packard CJ, Briggs A, Ray KK. ‘Highest risk-highest benefit’ strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J. 2018;39:2546–50.PubMedCrossRefGoogle Scholar
  75. 75.
    Ballantyne CM, McKenney JM, MacDougall DE, et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving statin therapy. Am J Cardiol. 2016;117:1928–33.PubMedCrossRefGoogle Scholar
  76. 76.
    Pinkosky SL, Newton RS, Day EA, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Lemus HN, Mendivil CO. Adenosine triphosphate citrate lyase: emerging target in the treatment of dyslipidemia. J Clin Lipidol. 2015;9:384–9.PubMedCrossRefGoogle Scholar
  78. 78.
    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.PubMedCrossRefGoogle Scholar
  79. 79.
    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.PubMedCrossRefGoogle Scholar
  80. 80.
    Thompson PD, Rubino J, Janik MJ, et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol. 2015;9:295–304.PubMedCrossRefGoogle Scholar
  81. 81.
    Thompson PD, MacDougall DE, Newton RS, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016;10:556–67.PubMedCrossRefGoogle Scholar
  82. 82.
    Evaluation of major cardiovascular events in patients with, or at high risk for, cardiovascular disease who are statin intolerant treated with bempedoic acid (ETC-1002) or placebo. https://ClinicalTrials.gov/show/NCT02993406.
  83. 83.
    Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–31.CrossRefGoogle Scholar
  84. 84.
    Sniderman AD, Tsimikas S, Fazio S. The severe hypercholesterolemia phenotype: clinical diagnosis, management, and emerging therapies. J Am Coll Cardiol. 2014;63:1935–47.PubMedCrossRefGoogle Scholar
  85. 85.
    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.PubMedCrossRefGoogle Scholar
  86. 86.
    Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJP. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol. 2016;10:1011–21.PubMedCrossRefGoogle Scholar
  87. 87.
    Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol. 2015;35:689–99.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Reyes-Soffer G, Ginsberg HN, Ramakrishnan R. The metabolism of lipoprotein (a): an ever-evolving story. J Lipid Res. 2017;58:1756–64.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Cuchel M, Bruckert E, Ginsberg HN, et al. Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society. Eur Heart J. 2014;35:2146–57.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Cuchel M, Meagher EA, du Toit Theron H, 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.PubMedCrossRefGoogle Scholar
  91. 91.
    Blom DJ, Fayad ZA, Kastelein JJ, et al. LOWER, a registry of lomitapide-treated patients with homozygous familial hypercholesterolemia: rationale and design. J Clin Lipidol. 2016;10:273–82.PubMedCrossRefGoogle Scholar
  92. 92.
    Tardif JC, Rheaume E, Lemieux Perreault LP, et al. Pharmacogenomic determinants of the cardiovascular effects of dalcetrapib. Circ Cardiovasc Genet. 2015;8:372–82.PubMedCrossRefGoogle Scholar
  93. 93.
    Ference BA, Kastelein JJP, Ginsberg HN, et al. Association of genetic variants related to CETP inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 2017;318:947–56.PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Stone NJ, Robinson JG, 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:S1–45.PubMedCrossRefGoogle Scholar
  95. 95.
    Nordestgaard BG. Triglyceride-rich lipoproteins and atherosclerotic cardiovascular disease: new insights from epidemiology, genetics, and biology. Circ Res. 2016;118:547–63.PubMedCrossRefGoogle Scholar
  96. 96.
    Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk: new insights from human genetics. Arterioscler Thromb Vasc Biol. 2015;35:e3–9.PubMedCrossRefGoogle Scholar
  97. 97.
    Shearer GC, Savinova OV, Harris WS. Fish oil—how does it reduce plasma triglycerides? Biochem Biophys Acta. 2012;1821:843–51.PubMedGoogle Scholar
  98. 98.
    Mozaffarian D, Wu JH. Omega-3 fatty acids and cardiovascular disease: effects on risk factors, molecular pathways, and clinical events. J Am Coll Cardiol. 2011;58:2047–67.PubMedCrossRefGoogle Scholar
  99. 99.
    Kris-Etherton PM, Harris WS, Appel LJ. Fish consumption, fish oil, omega-3 fatty acids, and cardiovascular disease. Circulation. 2002;106:2747–57.PubMedCrossRefGoogle Scholar
  100. 100.
    Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1—executive summary. J Clin Lipidol. 2014;8:473–88.PubMedCrossRefGoogle Scholar
  101. 101.
    GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico. Lancet 1999;354:447–55.CrossRefGoogle Scholar
  102. 102.
    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.PubMedCrossRefGoogle Scholar
  103. 103.
    Roncaglioni MC, Tombesi M, Avanzini F, et al. n-3 fatty acids in patients with multiple cardiovascular risk factors. N Engl J Med. 2013;368:1800–8.PubMedCrossRefGoogle Scholar
  104. 104.
    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.PubMedCrossRefGoogle Scholar
  105. 105.
    Siscovick DS, Barringer TA, Fretts AM, et al. Omega-3 polyunsaturated fatty acid (fish oil) supplementation and the prevention of clinical cardiovascular disease: a science advisory from the American Heart Association. Circulation. 2017;135:e867–84.PubMedCrossRefGoogle Scholar
  106. 106.
    Bowman L, Mafham M, Wallendszus K, et al. Effects of n-3 fatty acid supplements in diabetes mellitus. N Engl J Med. 2018;379:1540–50.PubMedCrossRefGoogle Scholar
  107. 107.
    Bhatt DL, Steg PG, Brinton EA, et al. Rationale and design of REDUCE-IT: reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial. Clin Cardiol. 2017;40:138–48.PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    AstraZeneca, Clinic TC, Quintiles I. Outcomes Study to assess statin residual risk reduction with EpaNova in high CV risk patients with hypertriglyceridemia. https://ClinicalTrials.gov/show/NCT02104817. 2014.
  109. 109.
    Morton AM, Furtado JD, Lee J, Amerine W, Davidson MH, Sacks FM. The effect of omega-3 carboxylic acids on apolipoprotein CIII-containing lipoproteins in severe hypertriglyceridemia. J Clin Lipidol. 2016;10(1442–1451):e4.Google Scholar
  110. 110.
    Bhatt DL, Steg PG, Miller M et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Eng J Med 2018 Nov 10. [Epub ahead of print].Google Scholar
  111. 111.
    Ference BA. Using genetic variants in the targets of lipid lowering therapies to inform drug discovery and development: current and future treatment options. Clin Pharmacol Ther 2018 Jun 28. [Epub ahead of print].Google Scholar
  112. 112.
    Sahebkar A, Chew GT, Watts GF. Recent advances in pharmacotherapy for hypertriglyceridemia. Prog Lipid Res. 2014;56:47–66.PubMedCrossRefGoogle Scholar
  113. 113.
    Bays HE, Braeckman RA, Ballantyne CM, et al. Icosapent ethyl, a pure EPA omega-3 fatty acid: effects on lipoprotein particle concentration and size in patients with very high triglyceride levels (the MARINE study). J Clin Lipidol. 2012;6:565–72.PubMedCrossRefGoogle Scholar
  114. 114.
    Ballantyne CM, Braeckman RA, Bays HE, et al. Effects of icosapent ethyl on lipoprotein particle concentration and size in statin-treated patients with persistent high triglycerides (the ANCHOR Study). J Clin Lipidol. 2015;9:377–83.PubMedCrossRefGoogle Scholar
  115. 115.
    Ishida T, Ohta M, Nakakuki M, et al. Distinct regulation of plasma LDL cholesterol by eicosapentaenoic acid and docosahexaenoic acid in high fat diet-fed hamsters: participation of cholesterol ester transfer protein and LDL receptor. Prostaglandins Leukot Essent Fatty Acids. 2013;88:281–8.PubMedCrossRefGoogle Scholar
  116. 116.
    Kastelein JJ, Maki KC, Susekov A, et al. Omega-3 free fatty acids for the treatment of severe hypertriglyceridemia: the Epanova for lowering very high triglyceridEs (EVOLVE) trial. J Clin Lipidol. 2014;8:94–106.PubMedCrossRefGoogle Scholar
  117. 117.
    Dunbar RL, Nicholls SJ, Maki KC, et al. Effects of omega-3 carboxylic acids on lipoprotein particles and other cardiovascular risk markers in high-risk statin-treated patients with residual hypertriglyceridemia: a randomized, controlled, double-blind trial. Lipids Health Dis. 2015;14:98.PubMedPubMedCentralCrossRefGoogle Scholar
  118. 118.
    Davidson MH, Johnson J, Rooney MW, Kyle ML, Kling DF. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova((R)) compared to Lovaza((R)) in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol. 2012;6:573–84.PubMedCrossRefGoogle Scholar
  119. 119.
    Blair HA, Dhillon S. Omega-3 carboxylic acids (Epanova): a review of its use in patients with severe hypertriglyceridemia. Am J Cardiovasc Drugs. 2014;14:393–400.PubMedCrossRefGoogle Scholar
  120. 120.
    Ballantyne CM, Bays HE, Braeckman RA, et al. Icosapent ethyl (eicosapentaenoic acid ethyl ester): effects on plasma apolipoprotein C-III levels in patients from the MARINE and ANCHOR studies. J Clin Lipidol. 2016;10(635–645):e1.Google Scholar
  121. 121.
    Maki KC, Bays HE, Dicklin MR, Johnson SL, Shabbout M. Effects of prescription omega-3-acid ethyl esters, coadministered with atorvastatin, on circulating levels of lipoprotein particles, apolipoprotein CIII, and lipoprotein-associated phospholipase A2 mass in men and women with mixed dyslipidemia. J Clin Lipidol. 2011;5:483–92.PubMedCrossRefGoogle Scholar
  122. 122.
    Davidson MH, Maki KC, Bays H, Carter R, Ballantyne CM. Effects of prescription omega-3-acid ethyl esters on lipoprotein particle concentrations, apolipoproteins AI and CIII, and lipoprotein-associated phospholipase A (2) mass in statin-treated subjects with hypertriglyceridemia. J Clin Lipidol. 2009;3:332–40.PubMedCrossRefGoogle Scholar
  123. 123.
    Pechlaner R, Tsimikas S, Yin X, et al. Very-low-density lipoprotein-associated apolipoproteins predict cardiovascular events and are lowered by inhibition of APOC-III. J Am Coll Cardiol. 2017;69:789–800.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Zheng C, Khoo C, Furtado J, Sacks FM. Apolipoprotein C-III and the metabolic basis for hypertriglyceridemia and the dense low-density lipoprotein phenotype. Circulation. 2010;121:1722–34.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Kawakami A, Aikawa M, Alcaide P, Luscinskas FW, Libby P, Sacks FM. 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.PubMedCrossRefGoogle Scholar
  126. 126.
    Kawakami A, Aikawa M, Nitta N, Yoshida M, Libby P, Sacks FM. Apolipoprotein CIII-induced THP-1 cell adhesion to endothelial cells involves pertussis toxin-sensitive G protein- and protein kinase C alpha-mediated nuclear factor-kappaB activation. Arterioscler Thromb Vasc Biol. 2007;27:219–25.PubMedCrossRefGoogle Scholar
  127. 127.
    Riwanto M, Rohrer L, Roschitzki B, et al. Altered activation of endothelial anti- and proapoptotic pathways by high-density lipoprotein from patients with coronary artery disease: role of high-density lipoprotein-proteome remodeling. Circulation. 2013;127:891–904.PubMedCrossRefGoogle Scholar
  128. 128.
    Luc G, Fievet C, Arveiler D, et al. Apolipoproteins C-III and E in apoB- and non-apoB-containing lipoproteins in two populations at contrasting risk for myocardial infarction: the ECTIM study. Etude Cas Temoins sur ‘Infarctus du Myocarde. J Lipid Res. 1996;37:508–17.PubMedGoogle Scholar
  129. 129.
    Sacks FM, Alaupovic P, Moye LA, et al. VLDL, apolipoproteins B, CIII, and E, and risk of recurrent coronary events in the Cholesterol and Recurrent Events (CARE) trial. Circulation. 2000;102:1886–92.PubMedCrossRefGoogle Scholar
  130. 130.
    Lee SJ, Campos H, Moye LA, Sacks FM. LDL containing apolipoprotein CIII is an independent risk factor for coronary events in diabetic patients. Arterioscler Thromb Vasc Biol. 2003;23:853–8.PubMedCrossRefGoogle Scholar
  131. 131.
    Scheffer PG, Teerlink T, Dekker JM, et al. Increased plasma apolipoprotein C-III concentration independently predicts cardiovascular mortality: the Hoorn Study. Clin Chem. 2008;54:1325–30.PubMedCrossRefGoogle Scholar
  132. 132.
    Crosby J, Peloso GM, Auer PL, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22–31.PubMedCrossRefGoogle Scholar
  133. 133.
    Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjaerg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41.PubMedCrossRefGoogle Scholar
  134. 134.
    Qamar A, Khetarpal SA, Khera AV, Qasim A, Rader DJ, Reilly MP. Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol. 2015;35:1880–8.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Graham MJ, Lee RG, Bell TA 3rd, et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res. 2013;112:1479–90.PubMedCrossRefGoogle Scholar
  136. 136.
    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.PubMedCrossRefGoogle Scholar
  137. 137.
    Gaudet D, Brisson D, Tremblay K, et al. Targeting APOC3 in the familial chylomicronemia syndrome. N Engl J Med. 2014;371:2200–6.PubMedCrossRefGoogle Scholar
  138. 138.
    Rocha NA, East C, Zhang J, McCullough PA. ApoCIII as a cardiovascular risk factor and modulation by the novel lipid-lowering agent volanesorsen. Curr Atheroscler Rep. 2017;19:62.PubMedCrossRefGoogle Scholar
  139. 139.
    Gaudet D, Digenio A, Alexander VJ, et al. The APPROACH study: a randomized, double-blind, placebo-controlled, phase 3 study of volanesorsen administered subcutaneously to patients with familial chylomicronemia syndrome (FCS). J Clin Lipidol. 2017;11:814–5.CrossRefGoogle Scholar
  140. 140.
    Gouni-Berthold I, Alexander V, Digenio A, et al. Apolipoprotein C-III Inhibition With Volanesorsen in Patients With Hypertriglyceridemia (COMPASS): a randomized, double-blind, placebo-controlled trial. J Clin Lipidol. 2017;11:794–5.CrossRefGoogle Scholar
  141. 141.
    Kaczmarek JC, Kowalski PS, Anderson DG. Advances in the delivery of RNA therapeutics: from concept to clinical reality. Genome Med. 2017;9:60.PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    Huang Y. Preclinical and Clinical Advances of GalNAc-decorated nucleic acid therapeutics. Mol Therapy Nucleic Acids. 2017;6:116–32.PubMedCrossRefGoogle Scholar
  143. 143.
    Study of ISIS 678354 (AKCEA-APOCIII-LRx) in patients with hypertriglyceridemia and established cardiovascular disease (CVD). https://ClinicalTrials.gov/show/NCT03385239.
  144. 144.
    Safety, tolerability, PK, and pharmacodynamics (PD) of IONIS APOCIII-LRx in healthy volunteers with elevated triglycerides. https://ClinicalTrials.gov/show/NCT02900027.
  145. 145.
    Derosa G, Sahebkar A, Maffioli P. The role of various peroxisome proliferator-activated receptors and their ligands in clinical practice. J Cell Physiol. 2018;233:153–61.PubMedCrossRefGoogle Scholar
  146. 146.
    Staels B, Dallongeville J, Auwerx J, Schoonjans K, Leitersdorf E, Fruchart JC. Mechanism of action of fibrates on lipid and lipoprotein metabolism. Circulation. 1998;98:2088–93.PubMedCrossRefGoogle Scholar
  147. 147.
    Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013;45:1345–52.PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    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.PubMedCrossRefGoogle Scholar
  149. 149.
    Jun M, Foote C, Lv J, et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet. 2010;375:1875–84.PubMedCrossRefGoogle Scholar
  150. 150.
    Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy of fibrates for cardiovascular risk reduction in persons with atherogenic dyslipidemia: a meta-analysis. Atherosclerosis. 2011;217:492–8.PubMedCrossRefGoogle Scholar
  151. 151.
    Bruckert E, Labreuche J, Deplanque D, Touboul PJ, Amarenco P. Fibrates effect on cardiovascular risk is greater in patients with high triglyceride levels or atherogenic dyslipidemia profile: a systematic review and meta-analysis. J Cardiovasc Pharmacol. 2011;57:267–72.PubMedCrossRefGoogle Scholar
  152. 152.
    Hennuyer N, Duplan I, Paquet C, et al. The novel selective PPARalpha modulator (SPPARMalpha) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis. Atherosclerosis. 2016;249:200–8.PubMedCrossRefGoogle Scholar
  153. 153.
    Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S. Efficacy and safety of K-877, a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMalpha), in combination with statin treatment: two randomised, double-blind, placebo-controlled clinical trials in patients with dyslipidaemia. Atherosclerosis. 2017;261:144–52.PubMedCrossRefGoogle Scholar
  154. 154.
    Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol. 2013;61:427–36.PubMedCrossRefGoogle Scholar
  155. 155.
    Jorgensen AB, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Tybjaerg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J. 2013;34:1826–33.PubMedCrossRefGoogle Scholar
  156. 156.
    Araki E, Yamashita S, Arai H et al. Effects of pemafibrate, a novel selective PPARalpha modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 2018;41:538–46.CrossRefGoogle Scholar
  157. 157.
    Ishibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor alpha modulator, in patients with dyslipidemia: Results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol 2017;12:173–84.PubMedCrossRefGoogle Scholar
  158. 158.
    Pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabeTes (PROMINENT). https://ClinicalTrials.gov/show/NCT03071692.
  159. 159.
    Altschul R, Hoffer A, Stephen JD. Influence of nicotinic acid on serum cholesterol in man. Arch Biochem Biophys. 1955;54:558–9.PubMedCrossRefGoogle Scholar
  160. 160.
    Khetarpal SA, Qamar A, Millar JS, Rader DJ. Targeting ApoC-III to reduce coronary disease risk. Curr Atheroscler Rep. 2016;18:54.PubMedCrossRefGoogle Scholar
  161. 161.
    Goel H, Dunbar RL. Niacin alternatives for dyslipidemia: fool’s gold or gold mine? Part II: novel niacin mimetics. Curr Atheroscler Rep. 2016;18:17.PubMedPubMedCentralCrossRefGoogle Scholar
  162. 162.
    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.PubMedCrossRefGoogle Scholar
  163. 163.
    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.PubMedCrossRefPubMedCentralGoogle Scholar
  164. 164.
    Zimmer M, Bista P, Benson EL, et al. CAT-2003: a novel sterol regulatory element-binding protein inhibitor that reduces steatohepatitis, plasma lipids, and atherosclerosis in apolipoprotein E*3-Leiden mice. Hepatol Commun. 2017;1:311–25.PubMedPubMedCentralCrossRefGoogle Scholar
  165. 165.
    Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med. 2017;377:222–32.PubMedCrossRefGoogle Scholar
  166. 166.
    Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377:211–21.PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med. 2010;363:2220–7.PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Xu YX, Redon V, Yu H, et al. Role of angiopoietin-like 3 (ANGPTL3) in regulating plasma level of low-density lipoprotein cholesterol. Atherosclerosis. 2018;268:196–206.PubMedCrossRefGoogle Scholar
  169. 169.
    Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 deficiency and protection against coronary artery disease. J Am Coll Cardiol. 2017;69:2054–63.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Pisciotta L, Favari E, Magnolo L, et al. Characterization of three kindreds with familial combined hypolipidemia caused by loss-of-function mutations of ANGPTL3. Circ Cardiovasc Genet. 2012;5:42–50.PubMedCrossRefGoogle Scholar
  171. 171.
    Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med. 2017;377:296–7.PubMedCrossRefGoogle Scholar
  172. 172.
    Study of evinacumab (REGN1500) in participants with persistent hypercholesterolemia. https://ClinicalTrials.gov/show/NCT03175367.
  173. 173.
    Bisgaier CL, Oniciu DC, Srivastava RAK. Comparative evaluation of gemcabene and peroxisome proliferator-activated receptor ligands in transcriptional assays of peroxisome proliferator-activated receptors: implication for the treatment of hyperlipidemia and cardiovascular disease. J Cardiovasc Pharmacol. 2018;72:3–10.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Cupido AJ, Reeskamp LF, Kastelein JJP. Novel lipid modifying drugs to lower LDL cholesterol. Curr Opin Lipidol. 2017;28:367–73.PubMedCrossRefGoogle Scholar
  175. 175.
    Stein E, Bays H, Koren M, Bakker-Arkema R, Bisgaier C. Efficacy and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients. J Clin Lipidol. 2016;10:1212–22.PubMedCrossRefGoogle Scholar
  176. 176.
    Srivastava RAK, Cornicelli JA, Markham B, Bisgaier CL. Gemcabene, a first-in-class lipid-lowering agent in late-stage development, down-regulates acute-phase C-reactive protein via C/EBP-delta-mediated transcriptional mechanism. Mol Cell Biochem 2018.Google Scholar
  177. 177.
    Bays HE, McKenney JM, Dujovne CA, et al. Effectiveness and tolerability of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Am J Cardiol. 2003;92:538–43.PubMedCrossRefGoogle Scholar
  178. 178.
    Ferretti G, Bacchetti T, Johnston TP, Banach M, Pirro M, Sahebkar A. Lipoprotein(a): a missing culprit in the management of athero-thrombosis? J Cell Physiol. 2018;233:2966–81.PubMedCrossRefGoogle Scholar
  179. 179.
    Bennet A, Di Angelantonio E, Erqou S, et al. Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data. Arch Intern Med. 2008;168:598–608.PubMedCrossRefGoogle Scholar
  180. 180.
    Clarke R, Peden JF, Hopewell JC, et al. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N Engl J Med. 2009;361:2518–28.PubMedCrossRefGoogle Scholar
  181. 181.
    Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, Nordestgaard BG. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009;301:2331–9.PubMedCrossRefGoogle Scholar
  182. 182.
    Albers JJ, Slee A, O’Brien KD, et al. Relationship of apolipoproteins A-1 and B, and lipoprotein(a) to cardiovascular outcomes: the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes). J Am Coll Cardiol. 2013;62:1575–9.PubMedPubMedCentralCrossRefGoogle Scholar
  183. 183.
    Khera AV, Everett BM, Caulfield MP, et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin). Circulation. 2014;129:635–42.PubMedCrossRefGoogle Scholar
  184. 184.
    van Capelleveen JC, van der Valk FM, Stroes ES. Current therapies for lowering lipoprotein (a). J Lipid Res. 2016;57:1612–8.PubMedPubMedCentralCrossRefGoogle Scholar
  185. 185.
    Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3:619–27.PubMedCrossRefGoogle Scholar
  186. 186.
    Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388:2239–53.PubMedCrossRefGoogle Scholar
  187. 187.
    Phase 2 Study of ISIS 681257 (AKCEA-APO(a)-LRx) in patients with hyperlipoproteinemia(a) and cardiovascular disease. https://ClinicalTrials.gov/show/NCT03070782.
  188. 188.
    Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–53.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.South Australian Health and Medical Research InstituteAdelaideAustralia
  2. 2.University of AdelaideAdelaideAustralia

Personalised recommendations