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Annual Review of Medicine

Volume 72, 2021

Treating Coronary Artery Disease: Beyond Statins, Ezetimibe, and PCSK9 Inhibition

Abstract

Statins, ezetimibe, and PCSK9 inhibitors are currently the standard of care for the prevention and treatment of coronary artery disease. Despite their widespread use, coronary artery disease remains the leading cause of death worldwide, a fact that pleads for the development of new protective therapies. In no small part due to advances in the field of human genetics, many new therapies targeting various lipid traits or inflammation have recently received approval from regulatory agencies such as the US Food and Drug Administration or fared favorably in clinical trials. This wave of new therapies promises to transform the care of patients at risk for life-threatening coronary events.

Keyword(s): cholesterol, coronary artery disease, genetics, inflammation, lipoproteins, triglycerides
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/content/journals/10.1146/annurev-med-080819-044918
2021-01-27
2024-04-19
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Literature Cited

  1. 1. 
    Lloyd-Jones DM, Larson MG, Beiser A et al. 1999. Lifetime risk of developing coronary heart disease. Lancet 353:89–92
     [Google Scholar]
  2. 2. 
    Virani SS, Alonso A, Benjamin EJ et al. 2020. Heart disease and stroke statistics—2020 update: a report from the American Heart Association. Circulation 141:e139–e596
     [Google Scholar]
  3. 3. 
    Grundy SM, Stone NJ, Bailey AL et al. 2019. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 139:e1082–e1143
     [Google Scholar]
  4. 4. 
    Ference BA, Robinson JG, Brook RD et al. 2016. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N. Engl. J. Med. 375:2144–53
     [Google Scholar]
  5. 5. 
    Cannon CP, Blazing MA, Giugliano RP et al. 2015. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372:2387–97
     [Google Scholar]
  6. 6. 
    Stitziel NO, Won HH, Morrison AC et al.Myocard. Infarction Genet. Consort 2014. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N. Engl. J. Med. 371:2072–82
     [Google Scholar]
  7. 7. 
    Abifadel M, Varret M, Rabès JP et al. 2003. Mutations in PCSK9 cause autosomal dominant hyper-cholesterolemia. Nat. Genet. 34:154–56
     [Google Scholar]
  8. 8. 
    Cohen J, Pertsemlidis A, Kotowski IK et al. 2005. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37:161–65
     [Google Scholar]
  9. 9. 
    Cohen JC, Boerwinkle E, Mosley TH Jr. et al. 2006. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354:1264–72
     [Google Scholar]
  10. 10. 
    Zhao Z, Tuakli-Wosornu Y, Lagace TA et al. 2006. Molecular characterization of loss-of-function mutations in PCSK9 and identification of a compound heterozygote. Am. J. Hum. Genet. 79:514–23
     [Google Scholar]
  11. 11. 
    Hooper AJ, Marais AD, Tanyanyiwa DM et al. 2007. The C679X mutation in PCSK9 is present and lowers blood cholesterol in a Southern African population. Atherosclerosis 193:445–48
     [Google Scholar]
  12. 12. 
    Natarajan P, Kathiresan S. 2016. PCSK9 inhibitors. Cell 165:1037
     [Google Scholar]
  13. 13. 
    Sabatine MS, Giugliano RP, Keech AC et al. 2017. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376:1713–22
     [Google Scholar]
  14. 14. 
    Schwartz GG, Steg PG, Szarek M et al. 2018. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N. Engl. J. Med. 379:2097–107
     [Google Scholar]
  15. 15. 
    Fitzgerald K, White S, Borodovsky A et al. 2017. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med. 376:41–51
     [Google Scholar]
  16. 16. 
    Ray KK, Landmesser U, Leiter LA et al. 2017. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 376:1430–40
     [Google Scholar]
  17. 17. 
    Lehrman MA, Schneider WJ, Südhof TC et al. 1985. Mutation in LDL receptor: Alu-Alu recombination deletes exons encoding transmembrane and cytoplasmic domains. Science 227:140–46
     [Google Scholar]
  18. 18. 
    Soria LF, Ludwig EH, Clarke HR et al. 1989. Association between a specific apolipoprotein B mutation and familial defective apolipoprotein B-100. PNAS 86:587–91
     [Google Scholar]
  19. 19. 
    Voight BF, Peloso GM, Orho-Melander M et al. 2012. Plasma HDL cholesterol and risk of myocardial infarction: a Mendelian randomisation study. Lancet 380:572–80
     [Google Scholar]
  20. 20. 
    Cuchel M, Bloedon LT, Szapary PO et al. 2007. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N. Engl. J. Med. 356:148–56
     [Google Scholar]
  21. 21. 
    Sharp D, Blinderman L, Combs KA et al. 1993. Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 365:65–69
     [Google Scholar]
  22. 22. 
    Raal FJ, Santos RD, Blom DJ et al. 2010. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet 375:998–1006
     [Google Scholar]
  23. 23. 
    Young SG, Northey ST, McCarthy BJ 1988. Low plasma cholesterol levels caused by a short deletion in the apolipoprotein B gene. Science 241:591–93
     [Google Scholar]
  24. 24. 
    Ray KK, Bays HE, Catapano AL et al. 2019. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N. Engl. J. Med. 380:1022–32
     [Google Scholar]
  25. 25. 
    Goldberg AC, Leiter LA, Stroes ESG et al. 2019. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial. JAMA 322:1780–88
     [Google Scholar]
  26. 26. 
    Ference BA, Ray KK, Catapano AL et al. 2019. Mendelian randomization study of ACLY and cardiovascular disease. N. Engl. J. Med. 380:1033–42
     [Google Scholar]
  27. 27. 
    Di Angelantonio E, Sarwar N, Perry P et al.Emerg. Risk Factors Collab 2009. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 302:1993–2000
     [Google Scholar]
  28. 28. 
    Boden WE, Probstfield JL, Anderson T et al.AIM-HIGH Investig 2011. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N. Engl. J. Med. 365:2255–67
     [Google Scholar]
  29. 29. 
    Landray MJ, Haynes R, Hopewell JC et al.HPS2-THRIVE Collab. Group 2014. Effects of extended-release niacin with laropiprant in high-risk patients. N. Engl. J. Med 371:203–12
     [Google Scholar]
  30. 30. 
    Barter PJ, Caulfield M, Eriksson M et al. 2007. Effects of torcetrapib in patients at high risk for coronary events. N. Engl. J. Med. 357:2109–22
     [Google Scholar]
  31. 31. 
    Schwartz GG, Olsson AG, Abt M et al. 2012. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N. Engl. J. Med. 367:2089–99
     [Google Scholar]
  32. 32. 
    Lincoff AM, Nicholls SJ, Riesmeyer JS et al. 2017. Evacetrapib and cardiovascular outcomes in high-risk vascular disease. N. Engl. J. Med. 376:1933–42
     [Google Scholar]
  33. 33. 
    Bowman L, Hopewell JC, Chen F et al.HPS3/TIMI55-REVEAL Collab. Group 2017. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med 377:1217–27
     [Google Scholar]
  34. 34. 
    Utermann G. 1989. The mysteries of lipoprotein(a). Science 246:904–10
     [Google Scholar]
  35. 35. 
    Erqou S, Kaptoge S, Perry PL et al.Emerg. Risk Factors Collab 2009. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA 302:412–23
     [Google Scholar]
  36. 36. 
    Clarke R, Peden JF, Hopewell JC et al. 2009. Genetic variants associated with Lp(a) lipoprotein level and coronary disease. N. Engl. J. Med. 361:2518–28
     [Google Scholar]
  37. 37. 
    Kamstrup PR, Tybjaerg-Hansen A, Steffensen R et al. 2009. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA 301:2331–39
     [Google Scholar]
  38. 38. 
    Tsimikas S, Viney NJ, Hughes SG et al. 2015. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 386:1472–83
     [Google Scholar]
  39. 39. 
    Viney NJ, van Capelleveen JC, Geary RS et al. 2016. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet 388:2239–53
     [Google Scholar]
  40. 40. 
    Do R, Willer CJ, Schmidt EM et al. 2013. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat. Genet. 45:1345–52
     [Google Scholar]
  41. 41. 
    ACCORD Study Group Ginsberg HN, Elam MB et al. 2010. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362:1563–74
     [Google Scholar]
  42. 42. 
    ASCEND Study Collaborative Group Bowman L, Mafham M et al. 2018. Effects of n-3 fatty acid supplements in diabetes mellitus. N. Engl. J. Med. 379:1540–50
     [Google Scholar]
  43. 43. 
    Manson JE, Cook NR, Lee IM et al. 2019. Marine n-3 fatty acids and prevention of cardiovascular disease and cancer. N. Engl. J. Med. 380:23–32
     [Google Scholar]
  44. 44. 
    AstraZeneca 2020. Update on phase III STRENGTH trial for Epanova in mixed dyslipidaemia Press Release Jan. 13. https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html
  45. 45. 
    Bhatt DL, Steg PG, Miller M et al. 2019. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N. Engl. J. Med. 380:11–22
     [Google Scholar]
  46. 46. 
    Mach F, Baigent C, Catapano AL et al. 2019. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Atherosclerosis 290:140–205
     [Google Scholar]
  47. 47. 
    American Diabetes Association 2019. 10. Cardiovascular disease and risk management: standards of medical care in diabetes—2019. Diabetes Care 42:Suppl. 1S103–23
     [Google Scholar]
  48. 48. 
    Stitziel NO, Stirrups KE, Masca NG et al.Myocard. Infarction Genet. and CARDIoGRAM Exome Consortia 2016. Coding variation in ANGPTL4, LPL, and SVEP1 and the risk of coronary disease. N. Engl. J. Med. 374:1134–44
     [Google Scholar]
  49. 49. 
    Sarwar N, Sandhu MS, Ricketts SL et al.Triglyceride Coron. Dis. Genet. Consort. and Emerg. Risk Factors Collab 2010. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 375:1634–39
     [Google Scholar]
  50. 50. 
    Jørgensen AB, Frikke-Schmidt R, West AS et al. 2013. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur. Heart J. 34:1826–33
     [Google Scholar]
  51. 51. 
    Do R, Stitziel NO, Won HH et al. 2015. Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction. Nature 518:102–6
     [Google Scholar]
  52. 52. 
    Pollin TI, Damcott CM, Shen H et al. 2008. A null mutation in human APOC3 confers a favorable plasma lipid profile and apparent cardioprotection. Science 322:1702–5
     [Google Scholar]
  53. 53. 
    Crosby J, Peloso GM, Auer PL et al.TG and HDL Work. Group Exome Seq. Proj., Natl. Heart Lung Blood Inst 2014. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N. Engl. J. Med 371:22–31
     [Google Scholar]
  54. 54. 
    Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG et al. 2014. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N. Engl. J. Med. 371:32–41
     [Google Scholar]
  55. 55. 
    Dewey FE, Gusarova V, O'Dushlaine C et al. 2016. Inactivating variants in ANGPTL4 and risk of coronary artery disease. N. Engl. J. Med. 374:1123–33
     [Google Scholar]
  56. 56. 
    Stitziel NO, Khera AV, Wang X et al. 2017. ANGPTL3 deficiency and protection against coronary artery disease. J. Am. Coll. Cardiol. 69:2054–63
     [Google Scholar]
  57. 57. 
    Dewey FE, Gusarova V, Dunbar RL et al. 2017. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N. Engl. J. Med. 377:211–21
     [Google Scholar]
  58. 58. 
    Saleheen D, Natarajan P, Armean IM et al. 2017. Human knockouts and phenotypic analysis in a cohort with a high rate of consanguinity. Nature 544:235–39
     [Google Scholar]
  59. 59. 
    Gaudet D, Alexander VJ, Baker BF et al. 2015. Antisense inhibition of apolipoprotein C-III in patients with hypertriglyceridemia. N. Engl. J. Med. 373:438–47
     [Google Scholar]
  60. 60. 
    Witztum JL, Gaudet D, Freedman SD et al. 2019. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N. Engl. J. Med. 381:531–42
     [Google Scholar]
  61. 61. 
    Koishi R, Ando Y, Ono M et al. 2002. Angptl3 regulates lipid metabolism in mice. Nat. Genet. 30:151–57
     [Google Scholar]
  62. 62. 
    Musunuru K, Pirruccello JP, Do R et al. 2010. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N. Engl. J. Med. 363:2220–27
     [Google Scholar]
  63. 63. 
    Gaudet D, Gipe DA, Pordy R et al. 2017. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N. Engl. J. Med. 377:296–97
     [Google Scholar]
  64. 64. 
    Graham MJ, Lee RG, Brandt TA et al. 2017. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N. Engl. J. Med. 377:222–32
     [Google Scholar]
  65. 65. 
    Ridker PM, Rifai N, Rose L et al. 2002. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N. Engl. J. Med. 347:1557–65
     [Google Scholar]
  66. 66. 
    Zacho J, Tybjaerg-Hansen A, Jensen JS et al. 2008. Genetically elevated C-reactive protein and ischemic vascular disease. N. Engl. J. Med. 359:1897–908
     [Google Scholar]
  67. 67. 
    Elliott P, Chambers JC, Zhang W et al. 2009. Genetic loci associated with C-reactive protein levels and risk of coronary heart disease. JAMA 302:37–48
     [Google Scholar]
  68. 68. 
    Ridker PM, Everett BM, Pradhan A et al. 2019. Low-dose methotrexate for the prevention of atherosclerotic events. N. Engl. J. Med. 380:752–62
     [Google Scholar]
  69. 69. 
    O'Donoghue ML, Braunwald E, White HD et al. 2014. Effect of darapladib on major coronary events after an acute coronary syndrome: the SOLID-TIMI 52 randomized clinical trial. JAMA 312:1006–15
     [Google Scholar]
  70. 70. 
    O'Donoghue ML, Glaser R, Cavender MA et al. 2016. Effect of losmapimod on cardiovascular outcomes in patients hospitalized with acute myocardial infarction: a randomized clinical trial. JAMA 315:1591–99
     [Google Scholar]
  71. 71. 
    Sarwar N, Butterworth AS, Freitag DF et al.IL6R Genet. Consort. Emerg. Risk Factors Collab 2012. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet 379:1205–13
     [Google Scholar]
  72. 72. 
    Swerdlow DI, Holmes MV, Kuchenbaecker KB et al.[Interleukin-6 Recept. Mendel. Randomisation Anal. (IL6R MR) Consort.] 2012. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet 379:1214–24
     [Google Scholar]
  73. 73. 
    Ridker PM, Everett BM, Thuren T et al. 2017. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377:1119–31
     [Google Scholar]
  74. 74. 
    Tardif JC, Kouz S, Waters DD et al. 2019. Efficacy and safety of low-dose colchicine after myocardial infarction. N. Engl. J. Med. 381:2497–505
     [Google Scholar]
  75. 75. 
    Chadwick AC, Evitt NH, Lv W, Musunuru K 2018. Reduced blood lipid levels with in vivo CRISPR-Cas9 base editing of ANGPTL3. Circulation 137:975–77
     [Google Scholar]
/content/journals/10.1146/annurev-med-080819-044918
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Treating Coronary Artery Disease: Beyond Statins, Ezetimibe, and PCSK9 Inhibition
Annual Review of Medicine 72, 447 (2021); https://doi.org/10.1146/annurev-med-080819-044918
/content/journals/10.1146/annurev-med-080819-044918
/content/journals/10.1146/annurev-med-080819-044918
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