The pharmacology of cholesterol-lowering drugs

The pharmacology of cholesterol-lowering drugs

Christie M. Ballantyne
Department of Medicine, Baylor College of Medicine, Houston, TX, USA
Alberico L. Catapano
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy

Abstract

The causal role of low-density lipoprotein cholesterol LDL-C in atherosclerotic-related cardiovascular disease (ASCVD) has been undoubtedly established over the last decades, and lowering plasma LDL-C levels represents the main approach to reduce the risk of cardiovascular (CV) events. A large number of observations has definitely proven that the protective effect is independent of the drug used to lower LDL-C, with a continuous linear reduction of CV risk with further LDL-C reductions. Although high-intensity statin therapy may significantly reduce CV event incidence, frequently statins are insufficient to achieve the large reductions recommended by current guidelines for high and very high risk patients.
Several non-statin drugs, having mechanisms of action complementary to that of statins, are now available, and include ezetimibe, monoclonal antibodies targeting PCSK9, and, more recently, inclisiran, bempedoic acid, and evinacumab. Combining these drugs based on the recommendations by current and future guidelines should be considered for optimal risk reduction, although several gaps in clinical practice remain to be filled.

References

  1. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017; 38:2459-72. https://doi.org/10.1093/eurheartj/ehx144
  2. Boren J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2020; 41:2313-30. https://doi.org/10.1093/eurheartj/ehz962
  3. 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. https://doi.org/10.1001/jama.2016.13985
  4. Koskinas KC, Siontis GCM, Piccolo R, et al. Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials. Eur Heart J 2018; 39:1172-80. https://doi.org/10.1093/eurheartj/ehx566
  5. Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005; 366:1267-78. https://doi.org/10.1016/S0140-6736(05)67394-1
  6. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020; 41:111-88. https://doi.org/10.1093/eurheartj/ehz455
  7. Packard C, Chapman MJ, Sibartie M, et al. Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges. Heart 2021; 107:1369-75. https://doi.org/10.1136/heartjnl-2020-318760
  8. Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet 2010; 376:1670-81. https://doi.org/10.1016/S0140-6736(10)61350-5
  9. Chan DK, O'Rourke F, Shen Q, et al. Meta-analysis of the cardiovascular benefits of intensive lipid lowering with statins. Acta Neurol Scand 2011; 124:188-95. https://doi.org/10.1111/j.1600-0404.2010.01450.x
  10. Mills EJ, O'Regan C, Eyawo O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of >40 000 patients. Eur Heart J 2011; 32:1409-15. https://doi.org/10.1093/eurheartj/ehr035
  11. Mills EJ, Wu P, Chong G, et al. Efficacy and safety of statin treatment for cardiovascular disease: a network meta-analysis of 170,255 patients from 76 randomized trials. QJM 2011; 104:109-24. https://doi.org/10.1093/qjmed/hcq165
  12. Naci H, Brugts JJ, Fleurence R, et al. Comparative benefits of statins in the primary and secondary prevention of major coronary events and all-cause mortality: a network meta-analysis of placebo-controlled and active-comparator trials. Eur J Prev Cardiol 2013; 20:641-57. https://doi.org/10.1177/2047487313480435
  13. Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013; 1:CD004816. https://doi.org/10.1002/14651858.CD004816.pub5
  14. Fulcher J, O'Connell R, Voysey M, et al. Efficacy and safety of LDL-lowering therapy among men and women: meta-analysis of individual data from 174,000 participants in 27 randomised trials. Lancet 2015; 385:1397-405. https://doi.org/10.1016/S0140-6736(14)61368-4
  15. Kearney PM, Blackwell L, Collins R, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet 2008; 371:117-25. https://doi.org/10.1016/S0140-6736(08)60104-X
  16. Mihaylova B, Emberson J, Blackwell L, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380:581-90. https://doi.org/10.1016/S0140-6736(12)60367-5
  17. Cholesterol Treatment Trialists C, Herrington WG, Emberson J, et al. Impact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol 2016; 4:829-39. https://doi.org/10.1016/S2213-8587(16)30156-5
  18. Banach M, Rizzo M, Toth PP, et al. Statin intolerance - an attempt at a unified definition. Position paper from an International Lipid Expert Panel. Expert Opin Drug Saf 2015; 14:935-55. https://doi.org/10.1517/14740338.2015.1039980
  19. Toth PP. That Myalgia of Yours Is Not From Statin Intolerance. J Am Coll Cardiol 2021; 78:1223-6. https://doi.org/10.1016/j.jacc.2021.07.025
  20. Banach M, Stulc T, Dent R, Toth PP. Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement. Int J Cardiol 2016; 225:184-96. https://doi.org/10.1016/j.ijcard.2016.09.075
  21. Rajpathak SN, Kumbhani DJ, Crandall J, et al. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care 2009; 32:1924-9. https://doi.org/10.2337/dc09-0738
  22. Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375:735-42. https://doi.org/10.1016/S0140-6736(09)61965-6
  23. Wang S, Cai R, Yuan Y, et al. Association between reductions in low-density lipoprotein cholesterol with statin therapy and the risk of new-onset diabetes: a meta-analysis. Sci Rep 2017; 7:39982. https://doi.org/10.1038/srep39982
  24. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305:2556-64. https://doi.org/10.1001/jama.2011.860
  25. Casula M, Mozzanica F, Scotti L, et al. Statin use and risk of new-onset diabetes: a meta-analysis of observational studies. Nutr Metab Cardiovasc Dis 2017; 27:396-406. https://doi.org/10.1016/j.numecd.2017.03.001
  26. Betteridge DJ, Carmena R. The diabetogenic action of statins - mechanisms and clinical implications. Nat Rev Endocrinol 2016; 12:99-110. https://doi.org/10.1038/nrendo.2015.194
  27. 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. https://doi.org/10.1056/NEJMoa1604304
  28. Wang DQ. Regulation of intestinal cholesterol absorption. Annu Rev Physiol 2007; 69:221-48. https://doi.org/10.1146/annurev.physiol.69.031905.160725
  29. Wang LJ, Song BL. Niemann-Pick C1-Like 1 and cholesterol uptake. Biochim Biophys Acta 2012; 1821:964-72. https://doi.org/10.1016/j.bbalip.2012.03.004
  30. Stitziel NO, Won HH, Morrison AC, et al. Inactivating mutations in NPC1L1 and protection from coronary heart disease. N Engl J Med 2014; 371:2072-82. https://doi.org/10.1056/NEJMoa1405386
  31. Descamps OS, De Sutter J, Guillaume M, Missault L. Where does the interplay between cholesterol absorption and synthesis in the context of statin and/or ezetimibe treatment stand today? Atherosclerosis 2011; 217:308-21. https://doi.org/10.1016/j.atherosclerosis.2011.06.010
  32. Catapano A, Brady WE, King TR, Palmisano J. Lipid altering-efficacy of ezetimibe co-administered with simvastatin compared with rosuvastatin: a meta-analysis of pooled data from 14 clinical trials. Curr Med Res Opin 2005; 21:1123-30. https://doi.org/10.1185/030079905X50642
  33. Catapano AL, Davidson MH, Ballantyne CM, et al. Lipid-altering efficacy of the ezetimibe/simvastatin single tablet versus rosuvastatin in hypercholesterolemic patients. Curr Med Res Opin 2006; 22:2041-53. https://doi.org/10.1185/030079906X132721
  34. Mikhailidis DP, Sibbring GC, Ballantyne CM, et al. Meta-analysis of the cholesterol-lowering effect of ezetimibe added to ongoing statin therapy. Curr Med Res Opin 2007; 23:2009-26. https://doi.org/10.1185/030079907X210507
  35. Lorenzi M, Ambegaonkar B, Baxter CA, et al. Ezetimibe in high-risk, previously treated statin patients: a systematic review and network meta-analysis of lipid efficacy. Clin Res Cardiol 2019; 108:487-509. https://doi.org/10.1007/s00392-018-1379-z
  36. Foody JM, Toth PP, Tomassini JE, et al. Changes in LDL-C levels and goal attainment associated with addition of ezetimibe to simvastatin, atorvastatin, or rosuvastatin compared with titrating statin monotherapy. Vasc Health Risk Manag 2013; 9:719-27. https://doi.org/10.2147/VHRM.S49840
  37. Sakamoto K, Kawamura M, Kohro T, et al. Effect of ezetimibe on LDL-C lowering and atherogenic lipoprotein profiles in type 2 diabetic patients poorly controlled by statins. PLoS One 2015; 10:e0138332. https://doi.org/10.1371/journal.pone.0138332
  38. Sakamoto K, Kawamura M, Watanabe T, et al. Effect of ezetimibe add-on therapy over 52 weeks extension analysis of prospective randomized trial (RESEARCH study) in type 2 diabetes subjects. Lipids Health Dis 2017; 16:122. https://doi.org/10.1186/s12944-017-0508-4
  39. Gagne C, Gaudet D, Bruckert E, Ezetimibe Study G. Efficacy and safety of ezetimibe coadministered with atorvastatin or simvastatin in patients with homozygous familial hypercholesterolemia. Circulation 2002; 105:2469-75. https://doi.org/10.1161/01.cir.0000018744.58460.62
  40. Pisciotta L, Fasano T, Bellocchio A, et al. Effect of ezetimibe coadministered with statins in genotype-confirmed heterozygous FH patients. Atherosclerosis 2007; 194:e116-22. https://doi.org/10.1016/j.atherosclerosis.2006.10.036
  41. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or without ezetimibe in familial hypercholesterolemia. N Engl J Med 2008; 358:1431-43. https://doi.org/10.1056/NEJMoa0800742
  42. 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. https://doi.org/10.1056/NEJMoa1410489
  43. Kato ET, Cannon CP, Blazing MA, et al. Efficacy and Safety of Adding Ezetimibe to Statin Therapy Among Women and Men: Insight From IMPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial). J Am Heart Assoc 2017; 6:e006901. https://doi.org/10.1161/JAHA.117.006901
  44. 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. https://doi.org/10.1161/CIRCULATIONAHA.117.030950
  45. Bach RG, Cannon CP, Giugliano RP, et al. Effect of Simvastatin-Ezetimibe Compared With Simvastatin Monotherapy After Acute Coronary Syndrome Among Patients 75 Years or Older: A Secondary Analysis of a Randomized Clinical Trial. JAMA Cardiol 2019; 4:846-54. https://doi.org/10.1001/jamacardio.2019.2306
  46. 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. https://doi.org/10.1073/pnas.0335507100
  47. Leren TP. Sorting an LDL receptor with bound PCSK9 to intracellular degradation. Atherosclerosis 2014; 237:76-81. https://doi.org/10.1016/j.atherosclerosis.2014.08.038
  48. Norata GD, Tavori H, Pirillo A, et al. Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering. Cardiovasc Res 2016; 112:429-42. https://doi.org/10.1093/cvr/cvw194
  49. Seidah NG, Prat A, Pirillo A, et al. Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. Cardiovasc Res 2019; 115:510-8. https://doi.org/10.1093/cvr/cvz003
  50. 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. https://doi.org/10.1056/NEJMoa054013
  51. Cohen J, Pertsemlidis A, Kotowski IK, et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat Genet 2005; 37:161-5. https://doi.org/10.1038/ng1509
  52. Kathiresan S. A PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N Engl J Med 2008; 358:2299-300. https://doi.org/10.1056/NEJMc0707445
  53. Kent ST, Rosenson RS, Avery CL, et al. PCSK9 Loss-of-Function Variants, Low-Density Lipoprotein Cholesterol, and Risk of Coronary Heart Disease and Stroke: Data From 9 Studies of Blacks and Whites. Circ Cardiovasc Genet 2017; 10:e001632. https://doi.org/10.1161/CIRCGENETICS.116.001632
  54. 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. https://doi.org/10.1016/j.jacc.2010.02.044
  55. Hopkins PN, Defesche J, Fouchier SW, et al. Characterization of Autosomal Dominant Hypercholesterolemia Caused by PCSK9 Gain of Function Mutations and Its Specific Treatment With Alirocumab, a PCSK9 Monoclonal Antibody. Circ Cardiovasc Genet 2015; 8:823-31. https://doi.org/10.1161/CIRCGENETICS.115.001129
  56. Qiu C, Zeng P, Li X, et al. What is the impact of PCSK9 rs505151 and rs11591147 polymorphisms on serum lipids level and cardiovascular risk: a meta-analysis. Lipids Health Dis 2017; 16:111. https://doi.org/10.1186/s12944-017-0506-6
  57. Naoumova RP, Tosi I, Patel D, et al. Severe hypercholesterolemia in four British families with the D374Y mutation in the PCSK9 gene: long-term follow-up and treatment response. Arterioscler Thromb Vasc Biol 2005; 25:2654-60. https://doi.org/10.1161/01.ATV.0000190668.94752.ab
  58. 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. https://doi.org/10.1001/jama.2012.25790
  59. 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. https://doi.org/10.1161/CIRCULATIONAHA.112.144055
  60. Stein EA, Honarpour N, Wasserman SM, et al. Effect of the proprotein convertase subtilisin/kexin 9 monoclonal antibody, AMG 145, in homozygous familial hypercholesterolemia. Circulation 2013; 128:2113-20. https://doi.org/10.1161/CIRCULATIONAHA.113.004678
  61. 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. https://doi.org/10.1016/j.jacc.2014.03.018
  62. 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. https://doi.org/10.1001/jama.2014.4030
  63. 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. https://doi.org/10.1016/j.jacc.2014.03.019
  64. Nissen SE, Dent-Acosta RE, Rosenson RS, et al. Comparison of PCSK9 Inhibitor Evolocumab vs Ezetimibe in Statin-Intolerant Patients: Design of the Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin-Intolerant Subjects 3 (GAUSS-3) Trial. Clin Cardiol 2016; 39:137-44. https://doi.org/10.1002/clc.22518
  65. Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 2015; 385:331-40. https://doi.org/10.1016/S0140-6736(14)61399-4
  66. 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. https://doi.org/10.1016/S0140-6736(14)61374-X
  67. Santos RD, Stein EA, Hovingh GK, et al. Long-Term Evolocumab in Patients With Familial Hypercholesterolemia. J Am Coll Cardiol 2020; 75:565-74. https://doi.org/10.1016/j.jacc.2019.12.020
  68. Koren MJ, Sabatine MS, Giugliano RP, et al. Long-Term Efficacy and Safety of Evolocumab in Patients With Hypercholesterolemia. J Am Coll Cardiol 2019; 74:2132-46. https://doi.org/10.1016/j.jacc.2019.08.1024
  69. 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. https://doi.org/10.1056/NEJMoa1615664
  70. 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. https://doi.org/10.1016/S2213-8587(17)30313-3
  71. Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). Circulation 2018; 137:338-50. https://doi.org/10.1161/CIRCULATIONAHA.117.032235
  72. Charytan DM, Sabatine MS, Pedersen TR, et al. Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial. J Am Coll Cardiol 2019; 73:2961-70. https://doi.org/10.1016/j.jacc.2019.03.513
  73. Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease. Circulation 2018; 138:756-66. https://doi.org/10.1161/CIRCULATIONAHA.118.034309
  74. Marston NA, Kamanu FK, Nordio F, et al. Predicting benefit from evolocumab therapy in patients with atherosclerotic disease using a genetic risk score: results from the FOURIER Trial. Circulation 2020; 141:616-23. https://doi.org/10.1161/CIRCULATIONAHA.119.043805
  75. 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. https://doi.org/10.1016/S0140-6736(17)32290-0
  76. Giugliano RP, Mach F, Zavitz K, et al. Cognitive Function in a Randomized Trial of Evolocumab. N Engl J Med 2017; 377:633-43. https://doi.org/10.1056/NEJMoa1701131
  77. McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012; 59:2344-53. https://doi.org/10.1016/j.jacc.2012.03.007
  78. Roth EM, McKenney JM, Hanotin C, et al. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med 2012; 367:1891-900. https://doi.org/10.1056/NEJMoa1201832
  79. 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. https://doi.org/10.1016/S0140-6736(12)60771-5
  80. Dufour R, Bergeron J, Gaudet D, et al. Open-label therapy with alirocumab in patients with heterozygous familial hypercholesterolemia: Results from three years of treatment. Int J Cardiol 2017; 228:754-60. https://doi.org/10.1016/j.ijcard.2016.11.046
  81. Roth EM, McKenney JM. ODYSSEY MONO: effect of alirocumab 75 mg subcutaneously every 2 weeks as monotherapy versus ezetimibe over 24 weeks. Future Cardiol 2015; 11:27-37. https://doi.org/10.2217/fca.14.82
  82. 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 e13. https://doi.org/10.1016/j.ahj.2015.03.004
  83. 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. https://doi.org/10.1056/NEJMoa1501031
  84. 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. https://doi.org/10.1093/eurheartj/ehv028
  85. 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. https://doi.org/10.1210/jc.2015-1520
  86. 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. https://doi.org/10.1016/j.atherosclerosis.2015.11.010
  87. 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. https://doi.org/http://dx.doi.org/10.1016/j.jacl.2015.08.006
  88. 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. https://doi.org/10.1093/eurheartj/ehv370
  89. Kastelein JJ, Robinson JG, Farnier M, et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia not adequately controlled with current lipid-lowering therapy: design and rationale of the ODYSSEY FH studies. Cardiovasc Drugs Ther 2014; 28:281-9. https://doi.org/10.1007/s10557-014-6523-z
  90. Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018; 379:2097-107. https://doi.org/10.1056/NEJMoa1801174
  91. Diaz R, Li QH, Bhatt DL, et al. Intensity of statin treatment after acute coronary syndrome, residual risk, and its modification by alirocumab: insights from the ODYSSEY OUTCOMES trial. Eur J Prev Cardiol 2021; 28:33-43. https://doi.org/10.1177/2047487320941987
  92. Sinnaeve PR, Schwartz GG, Wojdyla DM, et al. Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis. Eur Heart J 2020; 41:2248-58. https://doi.org/10.1093/eurheartj/ehz809
  93. Damask A, Steg PG, Schwartz GG, et al. Patients With High Genome-Wide Polygenic Risk Scores for Coronary Artery Disease May Receive Greater Clinical Benefit From Alirocumab Treatment in the ODYSSEY OUTCOMES Trial. Circulation 2020; 141:624-36. https://doi.org/10.1161/CIRCULATIONAHA.119.044434
  94. Perego C, Da Dalt L, Pirillo A, et al. Cholesterol metabolism, pancreatic beta-cell function and diabetes. Biochim Biophys Acta Mol Basis Dis 2019; 1865:2149-56. https://doi.org/10.1016/j.bbadis.2019.04.012
  95. Da Dalt L, Ruscica M, Bonacina F, et al. PCSK9 deficiency reduces insulin secretion and promotes glucose intolerance: the role of the low-density lipoprotein receptor. Eur Heart J 2019; 40:357-68. https://doi.org/10.1093/eurheartj/ehy357
  96. 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. https://doi.org/10.1093/eurheartj/ehw292
  97. Leiter LA, Muller-Wieland D, Baccara-Dinet MT, et al. Efficacy and safety of alirocumab in people with prediabetes vs those with normoglycaemia at baseline: a pooled analysis of 10 phase III ODYSSEY clinical trials. Diabet Med 2018; 35:121-30. https://doi.org/10.1111/dme.13450
  98. Cao YX, Liu HH, Dong QT, et al. Effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies on new-onset diabetes mellitus and glucose metabolism: A systematic review and meta-analysis. Diabetes Obes Metab 2018; 20:1391-8. https://doi.org/10.1111/dom.13235
  99. 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. https://doi.org/10.1016/j.amjcard.2017.07.047
  100. Chiu SW, Pratt CM, Feinn R, Chatterjee S. Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and Ezetimibe on Risk of New-Onset Diabetes: A Systematic Review and Meta-Analysis of Large, Double-Blinded Randomized Controlled Trials. J Cardiovasc Pharmacol Ther 2020; 25:409-17. https://doi.org/10.1177/1074248420924983
  101. Tromp TR, Stroes ESG, Hovingh GK. Gene-based therapy in lipid management: the winding road from promise to practice. Expert Opin Investig Drugs 2020; 29:483-93. https://doi.org/10.1080/13543784.2020.1757070
  102. 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 U S A 2008; 105:11915-20. https://doi.org/10.1073/pnas.0805434105
  103. 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. https://doi.org/10.1016/S0140-6736(13)61914-5
  104. 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. https://doi.org/10.1056/NEJMoa1615758
  105. Ray KK, Stoekenbroek RM, Kallend D, et al. Effect of 1 or 2 Doses of Inclisiran on Low-Density Lipoprotein Cholesterol Levels: One-Year Follow-up of the ORION-1 Randomized Clinical Trial. JAMA Cardiol 2019; 4:1067-75. https://doi.org/10.1001/jamacardio.2019.3502
  106. Leiter LA, Teoh H, Kallend D, et al. Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status: the ORION-1 randomized clinical trial. Diabetes Care 2019; 42:173-6. https://doi.org/10.2337/dc18-1491
  107. Kastelein JJP. Late Breakers. Long-term inclisiran in subjects with high CV risk and elevated LDL-C. Presented at: National Lipid Association Scientific Sessions; May 16–19, 2019; Miami. 2019.
  108. Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med 2020; 382:1520-30. https://doi.org/10.1056/NEJMoa1913805
  109. Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med 2020; 382:1507-19. https://doi.org/10.1056/NEJMoa1912387
  110. Hovingh GK, Lepor NE, Kallend D, et al. Inclisiran Durably Lowers Low-Density Lipoprotein Cholesterol and Proprotein Convertase Subtilisin/Kexin Type 9 Expression in Homozygous Familial Hypercholesterolemia: The ORION-2 Pilot Study. Circulation 2020; 141:1829-31. https://doi.org/10.1161/CIRCULATIONAHA.119.044431
  111. 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. https://doi.org/10.1038/ncomms13457
  112. Ference BA, Ray KK, Catapano AL, et al. Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med 2019; 380:1033-42. https://doi.org/10.1056/NEJMoa1806747
  113. 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. https://doi.org/10.1016/j.jacc.2013.05.050
  114. 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. https://doi.org/10.1161/ATVBAHA.113.302677
  115. 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. https://doi.org/10.1016/j.amjcard.2016.03.043
  116. Lalwani ND, Hanselman JC, MacDougall DE, et al. Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) to high-dose atorvastatin background therapy in hypercholesterolemic patients: A randomized placebo-controlled trial. J Clin Lipidol 2019; 13:568-79. https://doi.org/10.1016/j.jacl.2019.05.003
  117. Rubino J, MacDougall DE, Sterling LR, et al. Combination of bempedoic acid, ezetimibe, and atorvastatin in patients with hypercholesterolemia: A randomized clinical trial. Atherosclerosis 2021; 320:122-8. https://doi.org/10.1016/j.atherosclerosis.2020.12.023
  118. 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. https://doi.org/10.1016/j.jacl.2015.03.003
  119. 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. https://doi.org/10.1016/j.jacl.2015.12.025
  120. Banach M, Duell PB, Gotto AM, Jr., et al. Association of Bempedoic Acid Administration With Atherogenic Lipid Levels in Phase 3 Randomized Clinical Trials of Patients With Hypercholesterolemia. JAMA Cardiol 2020; 5:1124-35. https://doi.org/10.1001/jamacardio.2020.2314
  121. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019; 380:1022-32. https://doi.org/10.1056/NEJMoa1803917
  122. Goldberg AC, Leiter LA, Stroes ESG, et al. 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 2019; 322:1780-8. https://doi.org/10.1001/jama.2019.16585
  123. Laufs U, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc 2019; 8:e011662. https://doi.org/10.1161/JAHA.118.011662
  124. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis 2018; 277:195-203. https://doi.org/10.1016/j.atherosclerosis.2018.06.002
  125. Tikka A, Jauhiainen M. The role of ANGPTL3 in controlling lipoprotein metabolism. Endocrine 2016; 52:187-93. https://doi.org/10.1007/s12020-015-0838-9
  126. Stitziel NO, Khera AV, Wang X, et al. ANGPTL3 Deficiency and Protection Against Coronary Artery Disease. J Am Coll Cardiol 2017; 69:2054-63. https://doi.org/10.1016/j.jacc.2017.02.030
  127. 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. https://doi.org/10.1056/NEJMoa1612790
  128. Wang Y, Gusarova V, Banfi S, et al. Inactivation of ANGPTL3 reduces hepatic VLDL-triglyceride secretion. J Lipid Res 2015; 56:1296-307. https://doi.org/10.1194/jlr.M054882
  129. Gaudet D, Gipe DA, Pordy R, et al. ANGPTL3 inhibition in homozygous familial hypercholesterolemia. N Engl J Med 2017; 377:296-7. https://doi.org/10.1056/NEJMc1705994
  130. Raal FJ, Rosenson RS, Reeskamp LF, et al. Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med 2020; 383:711-20. https://doi.org/10.1056/NEJMoa2004215
  131. Reeskamp LF, Nurmohamed NS, Bom MJ, et al. Marked plaque regression in homozygous familial hypercholesterolemia. Atherosclerosis 2021; 327:13-7. https://doi.org/10.1016/j.atherosclerosis.2021.04.014
  132. Musunuru K, Pirruccello JP, Do R, et al. Exome sequencing, ANGPTL3 mutations, and familial combined hypolipidemia. N Engl J Med 2010; 363:2220-7. https://doi.org/10.1056/NEJMoa1002926
  133. Reeskamp LF, Millar JS, Wu L, et al. ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia-Brief Report. Arterioscler Thromb Vasc Biol 2021; 41:1753-9. https://doi.org/10.1161/ATVBAHA.120.315204
  134. Blaum C, Brunner FJ, Gossling A, et al. Target Populations and Treatment Cost for Bempedoic Acid and PCSK9 Inhibitors: A Simulation Study in a Contemporary CAD Cohort. Clin Ther 2021; 43:1583-600. https://doi.org/10.1016/j.clinthera.2021.07.019
  135. Ray KK, Molemans B, Schoonen WM, et al. EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care: the DA VINCI study. Eur J Prev Cardiol 2021; 28:1279-89. https://doi.org/10.1093/eurjpc/zwaa047
  136. Kotseva K, De Backer G, De Bacquer D, et al. Primary prevention efforts are poorly developed in people at high cardiovascular risk: A report from the European Society of Cardiology EURObservational Research Programme EUROASPIRE V survey in 16 European countries. Eur J Prev Cardiol 2021; 28:370-9. https://doi.org/10.1177/2047487320908698
  137. Ray KK, Reeskamp LF, Laufs U, et al. Combination lipid-lowering therapy as first-line strategy in very high-risk patients. Eur Heart J 2021; in press. https://doi.org/10.1093/eurheartj/ehab718

Send mail to Author


Send Cancel

Custom technologies based on your needs

  • MongoDB
  • ElasticSearch
  • Redis
  • Solr
  • Memcached