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PCSK9 inhibitors: clinical evidence and implementation

Abstract

The gene encoding PCSK9 was first identified and linked to the phenotype of familial hypercholesterolaemia approximately 15 years ago. Soon after, studies uncovered the role of PCSK9 in the regulation of LDL-receptor recycling and identified loss-of-function variants of PCSK9 that were associated with low circulating levels of LDL cholesterol (LDL-C) and a reduced risk of coronary artery disease. With amazing rapidity, monoclonal antibodies against PCSK9 were developed and studied in large clinical programmes. These PCSK9 inhibitors lowered plasma LDL-C levels by approximately 60%, even in patients already receiving maximum-dose statin therapy. In the past year, three cardiovascular outcome trials were completed and showed that PCSK9 inhibitors significantly reduce the risk of major vascular events. Reassuringly, this benefit comes with no major offsetting adverse events, such as an excess of myalgias, elevation of hepatic aminotransferases levels in the plasma, incident diabetes mellitus or neurocognitive adverse events. The clinical benefit of PCSK9 inhibitors seen in these trials occurred in the setting of reducing LDL-C levels to unprecedentedly low levels, suggesting that more aggressive LDL-C targets should be adopted. New technologies to inhibit PCSK9 are now being harnessed and might further revolutionize our treatment of dyslipidaemia.

Key points

  • Monoclonal antibodies targeting PCSK9 can lower plasma LDL-cholesterol (LDL-C) levels by approximately 60%.

  • In dedicated cardiovascular outcome trials, PCSK9 inhibitors significantly reduced the risk of major adverse cardiovascular events.

  • This benefit was consistent in patients with a baseline LDL-C level <70 mg/dl, who achieved an LDL-C level of approximately 20 mg/dl, which is well below the current guideline-recommended targets.

  • No offsetting safety concerns were reported in these trials over the timeframes studied.

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Fig. 1: Clinical benefit of PCSK9 inhibition relative to the benefit of statin therapy over time.
Fig. 2: Efficacy of LDL-C-lowering therapy in patients with very low baseline levels of LDL-C.
Fig. 3: Cumulative burden of LDL-C.

References

  1. Varret, M. et al. A third major locus for autosomal dominant hypercholesterolemia maps to 1p34.1-p32. Am. J. Hum. Genet. 64, 1378–1387 (1999).

    CAS  Article  Google Scholar 

  2. Abifadel, M. et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat. Genet. 34, 154–156 (2003).

    CAS  Article  Google Scholar 

  3. Horton, J. D., Cohen, J. C. & Hobbs, H. H. PCSK9: a convertase that coordinates LDL catabolism. J. Lipid Res. 50, S172–S177 (2009).

    Article  Google Scholar 

  4. Maxwell, K. N. & Breslow, J. L. Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype. Proc. Natl Acad. Sci. USA 101, 7100–7105 (2004).

    CAS  Article  Google Scholar 

  5. Maxwell, K. N., Fisher, E. A. & Breslow, J. L. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc. Natl Acad. Sci. USA 102, 2069–2074 (2005).

    CAS  Article  Google Scholar 

  6. Cohen, J. et al. Low LDL cholesterol in individuals of African descent resulting from frequent nonsense mutations in PCSK9. Nat. Genet. 37, 161–165 (2005).

    CAS  Article  Google Scholar 

  7. Cohen, J. C. et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N. Engl. J. Med. 354, 1264–1272 (2006).

    CAS  Article  Google Scholar 

  8. Kathiresan, S. & Myocardial Infarction Genetics, C. A. PCSK9 missense variant associated with a reduced risk of early-onset myocardial infarction. N. Engl. J. Med. 358, 2299–2300 (2008).

    CAS  Article  Google Scholar 

  9. Ference, B. A. et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N. Engl. J. Med. 375, 2144–2153 (2016).

    CAS  Article  Google Scholar 

  10. Wasserman, S. et al. Comparison of LDL-C reduction using different evolocumab doses and intervals: biological insights and treatment implications. J. Cardiovasc. Pharmacol. Ther. 23, 423–432 (2018).

    CAS  Article  Google Scholar 

  11. Koren, M. J. et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled phase III clinical trial of evolocumab. J. Am. Coll. Cardiol. 63, 2531–2540 (2014).

    CAS  Article  Google Scholar 

  12. Robinson, J. G. 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 311, 1870–1882 (2014).

    Article  Google Scholar 

  13. Stroes, E. et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J. Am. Coll. Cardiol. 63, 2541–2548 (2014).

    CAS  Article  Google Scholar 

  14. Nissen, S. E. et al. Efficacy and tolerability of evolocumab versus ezetimibe in patients with muscle-related statin intolerance: the GAUSS-3 randomized clinical trial. JAMA 315, 1580–1590 (2016).

    CAS  Article  Google Scholar 

  15. Raal, F. J. et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet 385, 331–340 (2015).

    CAS  Article  Google Scholar 

  16. Stein, E. A. et al. Efficacy and safety of evolocumab (AMG 145), a fully human monoclonal antibody to PCSK9, in hyperlipidaemic patients on various background lipid therapies: pooled analysis of 1359 patients in four phase 2 trials. Eur. Heart J. 35, 2249–2259 (2014).

    CAS  Article  Google Scholar 

  17. Desai, N. R. et al. Association between circulating baseline proprotein convertase subtilisin kexin type 9 levels and efficacy of evolocumab. JAMA Cardiol. 2, 556–560 (2017).

    Article  Google Scholar 

  18. Raal, F. J. et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA part B): a randomised, double-blind, placebo-controlled trial. Lancet 385, 341–350 (2015).

    CAS  Article  Google Scholar 

  19. Raal, F. J. 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. 5, 280–290 (2017).

    CAS  Article  Google Scholar 

  20. Roth, E. M. et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized phase 3 trial. Int. J. Cardiol. 176, 55–61 (2014).

    Article  Google Scholar 

  21. Kereiakes, D. J. 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. 169, 906–915.e13 (2015).

    CAS  Article  Google Scholar 

  22. Cannon, C. P. 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. 36, 1186–1194 (2015).

    CAS  Article  Google Scholar 

  23. Moriarty, P. M. et al. Efficacy and safety of alirocumab versus ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J. Clin. Lipidol. 9, 758–769 (2015).

    Article  Google Scholar 

  24. Robinson, J. G. et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N. Engl. J. Med. 372, 1489–1499 (2015).

    CAS  Article  Google Scholar 

  25. Roth, E. M. et al. A phase III randomized trial evaluating alirocumab 300 mg every 4 weeks as monotherapy or add-on to statin: ODYSSEY CHOICE I. Atherosclerosis 254, 254–262 (2016).

    CAS  Article  Google Scholar 

  26. Kastelein, J. J. et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur. Heart J. 36, 2996–3003 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Ginsberg, H. N. et al. Efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia and LDL-C of 160 mg/dl or higher. Cardiovasc. Drugs Ther. 30, 473–483 (2016).

    CAS  Article  Google Scholar 

  28. Hartgers, M. L. et al. Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia. J. Clin. Lipidol. 12, 390–396.e8 (2018).

    Article  Google Scholar 

  29. US Department of Health & Human Services. Highlights of prescribing information: LIPITOR®. FDA.gov https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020702s056lbl.pdf (2009).

  30. Sabatine, M. S. et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N. Engl. J. Med. 376, 1713–1722 (2017).

    CAS  Article  Google Scholar 

  31. Cannon, C. P. et al. Ezetimibe added to statin therapy after acute coronary syndromes. N. Engl. J. Med. 372, 2387–2397 (2015).

    CAS  Article  Google Scholar 

  32. Desai, N. R. et al. AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9, significantly reduces lipoprotein(a) in hypercholesterolemic patients receiving statin therapy. Circulation 128, 962–969 (2013).

    CAS  Article  Google Scholar 

  33. Bohula, E. A. et al. Inflammatory and cholesterol risk in the FOURIER trial (further cardiovascular outcomes research with PCSK9 inhibition in patients with elevated risk). Circulation 138, 131–140 (2018).

    CAS  Article  Google Scholar 

  34. Sabatine, M. S. et al. Rationale and design of the Further cardiovascular OUtcomes Research with PCSK9 Inhibition in subjects with Elevated Risk trial. Am. Heart J. 173, 94–101 (2016).

    CAS  Article  Google Scholar 

  35. Wiviott, S. D. The effects of adding the CETP inhibitor anacetrapib to statin on urgent and routine revascularization: results from the HPS 3/TIMI 55-REVEAL trial. J. Am. Coll. Cardiol. 71, A107 (2018).

    Article  Google Scholar 

  36. Collins, R. et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 388, 2532–2561 (2016).

    CAS  Article  Google Scholar 

  37. Giugliano, R. P. et al. Clinical efficacy and safety of evolocumab in high-risk patients receiving a statin: secondary analysis of patients with low LDL cholesterol levels and in those already receiving a maximal-potency statin in a randomized clinical trial. JAMA Cardiol. 2, 1385–1391 (2017).

    Article  Google Scholar 

  38. Ridker, P. M., Pradhan, A., MacFadyen, J. G., Libby, P. & Glynn, R. J. Cardiovascular benefits and diabetes risks of statin therapy in primary prevention: an analysis from the JUPITER trial. Lancet 380, 565–571 (2012).

    CAS  Article  Google Scholar 

  39. Sabatine, M. S. 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. 5, 941–950 (2017).

    CAS  Article  Google Scholar 

  40. Giugliano, R. P. et al. Design and rationale of the EBBINGHAUS trial: a phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy — a cognitive study of patients enrolled in the FOURIER trial. Clin. Cardiol. 40, 59–65 (2017).

    Article  Google Scholar 

  41. Giugliano, R. P., Sabatine, M. S. & Ott, B. R. Cognitive function in a randomized trial of evolocumab. N. Engl. J. Med. 377, 1997 (2017).

    Article  Google Scholar 

  42. Ridker, P. M. et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N. Engl. J. Med. 376, 1517–1526 (2017).

    CAS  Article  Google Scholar 

  43. Ridker, P. M. et al. Evaluating bococizumab, a monoclonal antibody to PCSK9, on lipid levels and clinical events in broad patient groups with and without prior cardiovascular events: rationale and design of the studies of PCSK9 inhibition and the reduction of vascular events (SPIRE) lipid lowering and SPIRE cardiovascular outcomes trials. Am. Heart J. 178, 135–144 (2016).

    Article  Google Scholar 

  44. Ridker, P. M. et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N. Engl. J. Med. 376, 1527–1539 (2017).

    CAS  Article  Google Scholar 

  45. Schwartz, G. G. 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. 168, 682–689 (2014).

    CAS  Article  Google Scholar 

  46. Schwartz, G. et al. The ODYSSEY OUTCOMES trial: topline results — alirocumab in patients after acute coronary syndrome. Presented at the 67th Scientific Sessions of the American College of Cardiology (2018).

  47. Wiviott, S. D. et al. A tale of two trials: a comparison of the post-acute coronary syndrome lipid-lowering trials A to Z and PROVE IT-TIMI 22. Circulation 113, 1406–1414 (2006).

    CAS  Article  Google Scholar 

  48. Silverman, M. G. et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA 316, 1289–1297 (2016).

    CAS  Article  Google Scholar 

  49. Ference, B. A. et al. 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. 39, 2540–2545 (2018).

    Article  Google Scholar 

  50. Sacks, F. M. et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N. Engl. J. Med. 335, 1001–1009 (1996).

    CAS  Article  Google Scholar 

  51. Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N. Engl. J. Med. 339, 1349–1357 (1998).

    Article  Google Scholar 

  52. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 360, 7–22 (2002).

    Article  Google Scholar 

  53. LaRosa, J. C. et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N. Engl. J. Med. 352, 1425–1435 (2005).

    CAS  Article  Google Scholar 

  54. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 344, 1383–1389 (1994).

    Google Scholar 

  55. Hps Timi Reveal Collaborative Group, Bowman, L. et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N. Engl. J. Med. 377, 1217–1227 (2017).

    Google Scholar 

  56. Giugliano, R. P. 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 390, 1962–1971 (2017).

    CAS  Article  Google Scholar 

  57. Kazi, D. S. et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA 316, 743–753 (2016).

    CAS  Article  Google Scholar 

  58. Kazi, D. S. et al. Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial. JAMA 318, 748–750 (2017).

    Article  Google Scholar 

  59. Fonarow, G. C. et al. Cost-effectiveness of evolocumab therapy for reducing cardiovascular events in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2, 1069–1078 (2017).

    Article  Google Scholar 

  60. Sabatine, M. S. & Giugliano, R. P. Low-density lipoprotein cholesterol treatment in the proprotein convertase subtilisin/kexin type 9 inhibitor era: getting back on target. JAMA Cardiol. 2, 935–936 (2017).

    Article  Google Scholar 

  61. Navarese, E. P. et al. Association between baseline LDL-C level and total and cardiovascular mortality after LDL-C lowering: a systematic review and meta-analysis. JAMA 319, 1566–1579 (2018).

    CAS  Article  Google Scholar 

  62. Sabatine, M. S., Wiviott, S. D., Im, K. A., Murphy, S. A. & Giugliano, R. P. Efficacy and safety of LDL-cholesterol lowering in patient populations starting with low LDL-cholesterol — a meta-analysis. JAMA Cardiol. 3, 823–828 (2018).

    Article  Google Scholar 

  63. Bonaca, M. P., Braunwald, E. & Sabatine, M. S. Long-term use of ticagrelor in patients with prior myocardial infarction. N. Engl. J. Med. 373, 1274–1275 (2015).

    PubMed  Google Scholar 

  64. Bonaca, M. P. et al. Efficacy and safety of ticagrelor over time in patients with prior MI in PEGASUS-TIMI 54. J. Am. Coll. Cardiol. 70, 1368–1375 (2017).

    CAS  Article  Google Scholar 

  65. Dellborg, M. et al. Efficacy and safety with ticagrelor in patients with prior myocardial infarction in the approved European label: insights from PEGASUS-TIMI 54. Eur. Heart J. 38, P3670 (2017).

    Article  Google Scholar 

  66. Bansilal, S. et al. Ticagrelor for secondary prevention of atherothrombotic events in patients with multivessel coronary disease. J. Am. Coll. Cardiol. 71, 489–496 (2018).

    CAS  Article  Google Scholar 

  67. Sabatine, M. S. et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease: an analysis from FOURIER. Circulation 138, 756–766 (2018).

    CAS  Article  Google Scholar 

  68. Bonaca, M. P. 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 137, 338–350 (2018).

    CAS  Article  Google Scholar 

  69. Fitzgerald, K. et al. A highly durable RNAi therapeutic inhibitor of PCSK9. N. Engl. J. Med. 376, 41–51 (2017).

    CAS  Article  Google Scholar 

  70. Ray, K. K. et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N. Engl. J. Med. 376, 1430–1440 (2017).

    CAS  Article  Google Scholar 

  71. TIMI Study Group. HPS-4/TIMI 65 ORION-4. TIMI.org http://www.timi.org/index.php?page=orion-4 (2018).

  72. Landlinger, 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. 38, 2499–2507 (2017).

    CAS  Article  Google Scholar 

  73. Pan, Y. et al. A therapeutic peptide vaccine against PCSK9. Sci. Rep. 7, 12534 (2017).

    Article  Google Scholar 

  74. Wang, X. et al. CRISPR-Cas9 targeting of PCSK9 in human hepatocytes in vivo — brief report. Arterioscler. Thromb. Vasc. Biol. 36, 783–786 (2016).

    CAS  Article  Google Scholar 

  75. Ding, Q. et al. Permanent alteration of PCSK9 with in vivo CRISPR-Cas9 genome editing. Circ. Res. 115, 488–492 (2014).

    CAS  Article  Google Scholar 

  76. Thakore, P. I. et al. RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors. Nat. Commun. 9, 1674 (2018).

    Article  Google Scholar 

  77. Cholesterol Treatment Trialists’ (CTT) Collaboration. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170 000 participants in 26 randomised trials. Lancet 376, 1670–1681 (2010).

    Article  Google Scholar 

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Correspondence to Marc S. Sabatine.

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M.S. received research grant support through Brigham and Women’s Hospital, Boston, USA, from Amgen, AstraZeneca, Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, MedImmune, Merck, Novartis, Pfizer, Poxel, Takeda and The Medicines Company. M.S. also consulted for Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Esperion, Intarcia, Janssen Research and Development, MedImmune, Merck, Novartis and The Medicines Company.

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Sabatine, M.S. PCSK9 inhibitors: clinical evidence and implementation. Nat Rev Cardiol 16, 155–165 (2019). https://doi.org/10.1038/s41569-018-0107-8

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