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PCSK9抑制剂在脂质代谢和动脉粥样硬化中的应用
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Abstract:
自2003年在家族性高胆固醇血症中发现致病基因前蛋白转化酶枯草杆菌素9 (PCSK9)以来，以PCSK9为靶点的研究进展迅速。近年来PCSK9抑制剂被证实具有良好的降低血脂作用，还有潜在的抗炎、降低心血管风险作用，已经作为一种新型降脂药物应用于心血管疾病。现对PCSK9基因与脂质代谢的关系、PCSK9抑制剂的临床研究进展和PCSK9抑制剂的安全性等进行综述。
Since the discovery of the pathogenic gene proprotein convertase subtilisin 9 (PCSK9) in familial hypercholesterolemia in 2003, studies of targeting PCSK9 have progressed rapidly. In recent years, PCSK9 inhibitors have been proven to have good lipid-lowering effects, as well as potential an-ti-inflammatory and cardiovascular risk-reducing effects, and have been used as a new type of li-pid-lowering drugs in cardiovascular diseases. This article reviews the relationship between PCSK9 gene and lipid metabolism, the clinical research progress of PCSK9 inhibitors and the safety of PCSK9 inhibitors.
| [1] | 胡盛寿, 高润霖, 刘力生, 等. 《中国心血管病报告2018》概要[J]. 中国循环杂志, 2019, 34(3): 209-220. |
| [2] | Nicholls, S.J., Kataoka, Y., Nissen, S.E., et al. (2022) Effect of Evolocumab on Coronary Plaque Phe-notype and Burden in Statin-Treated Patients Following Myocardial Infarction. JACC: Cardiovascular Imaging, 15, 1308-1321.
https://doi.org/10.1016/j.jcmg.2022.03.002 |
| [3] | Khatana, C., Saini, N.K., Chakrabarti, S., et al. (2020) Mechanistic Insights into the Oxidized Low-Density Lipoprotein-Induced Atherosclerosis. Oxidative Medicine and Cellular Longevity, 2020, Article ID: 5245308.
https://doi.org/10.1155/2020/5245308 |
| [4] | Giugliano, R.P., Wiviott, S.D., Blazing, M.A., et al. (2017) Long-Term Safety and Efficacy of Achieving Very Low Levels of Low-Density Lipoprotein Cholesterol: A Prespecified Analysis of the IMPROVE-IT Trial. JAMA Cardiology, 2, 547-555. https://doi.org/10.1001/jamacardio.2017.0083 |
| [5] | Yusuf, S., Hawken, S., Ounpuu, S., et al. (2004) Effect of Potentially Modifiable Risk Factors Associated with Myocardial In-farction in 52 Countries (the INTERHEART Study): Case-Control Study. Lancet, 364, 937-952.
https://doi.org/10.1016/S0140-6736(04)17018-9 |
| [6] | Sung, K.-C., Huh, J.H., Ryu, S., et al. (2019) Low Levels of Low-Density Lipoprotein Cholesterol and Mortality Outcomes in Non-Statin Users. Journal of Clinical Medicine, 8, Ar-ticle No. 1571. https://doi.org/10.3390/jcm8101571 |
| [7] | Ference, B.A., Ginsberg, H.N., Graham, I., et al. (2017) 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. European Heart Journal, 38, 2459-2472.
https://doi.org/10.1093/eurheartj/ehx144 |
| [8] | Saavedra, Y.G.L., Dufour, R., Davignon, J. and Baass, A. (2014) PCSK9 R46L, Lower LDL, and Cardiovascular Disease Risk in Familial Hypercholesterolemia: A Cross-Sectional Co-hort Study. Arteriosclerosis, Thrombosis, and Vascular Biology, 34, 2700-2705. https://doi.org/10.1161/ATVBAHA.114.304406 |
| [9] | Libby, P., Buring, J.E., Badimon, L., et al. (2019) Atherosclerosis. Nature Reviews Disease Primers, 5, Article No. 56.
https://doi.org/10.1038/s41572-019-0106-z |
| [10] | Koo, B.K. (2014) Statin for the Primary Prevention of Cardiovas-cular Disease in Patients with Diabetes Mellitus. Diabetes & Metabolism Journal, 38, 32-34. https://doi.org/10.4093/dmj.2014.38.1.32 |
| [11] | Page, M.M. and Watts, G.F. (2018) PCSK9 in Context: A Contem-porary Review of an Important Biological Target for the Prevention and Treatment of Atherosclerotic Cardiovascular Disease. Diabetes, Obesity and Metabolism, 20, 270-282.
https://doi.org/10.1111/dom.13070 |
| [12] | Seidah, N.G., Awan, Z., Chrétien, M. and Mbikay, M. (2014) PCSK9: A Key Modulator of Cardiovascular Health. Circulation Research, 114, 1022-1036. https://doi.org/10.1161/CIRCRESAHA.114.301621 |
| [13] | Pijlman, A.H., Huijgen, R., Verhagen, S.N., et al. (2010) Evaluation of Cholesterol Lowering Treatment of Patients with Familial Hypercholesterolemia: A Large Cross-Sectional Study in the Netherlands. Atherosclerosis, 209, 189-194.
https://doi.org/10.1016/j.atherosclerosis.2009.09.014 |
| [14] | 郑祥珍, 王炳香, 秦树存. 前蛋白转化酶枯草溶菌素9参与动脉粥样硬化的研究进展[J]. 中华老年心脑血管病杂志, 2019, 21(1): 87-89. |
| [15] | 中华医学会心血管病学分会动脉粥样硬化与冠心病学组, 中华心血管病杂志编辑委员会. 超高危动脉粥样硬化性心血管疾病患者血脂管理中国专家共识[J]. 中华心血管病杂志, 2020, 48(4): 280-286. |
| [16] | Tavori, H., Fan, D., Blakemore, J.L., et al. (2013) Serum Proprotein Convertase Subtilisin/Kexin Type 9 and Cell Surface Low-Density Lip-oprotein Receptor: Evidence for a Reciprocal Regulation. Circulation, 127, 2403-2413.
https://doi.org/10.1161/CIRCULATIONAHA.113.001592 |
| [17] | Mihaylova, B., Emberson, J., Blackwell, L., et al. (2012) 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, 380, 581-590. https://doi.org/10.1016/S0140-6736(12)60367-5 |
| [18] | Cui, C.-J., Li, S. and Li, J.-J. (2015) PCSK9 and Its Modulation. Clinica Chimica Acta, 440, 79-86.
https://doi.org/10.1016/j.cca.2014.10.044 |
| [19] | Abifadel, M., Varret, M., Rabes, J.-P., et al. (2003) Muta-tions in PCSK9 Cause Autosomal Dominant Hypercholesterolemia. Nature Genetics, 34, 154-156. https://doi.org/10.1038/ng1161 |
| [20] | Schluter, K.-D., Wolf, A. and Schreckenberg, R. (2020) Coming Back to Physiology: Extra Hepatic Functions of Proprotein Convertase Subtilisin/Kexin Type 9. Frontiers in Physiology, 11, Article 598649.
https://doi.org/10.3389/fphys.2020.598649 |
| [21] | Seidah, N.G., Benjannet, S., Wickham, L., et al. (2003) The Secretory Propro-tein Convertase Neural Apoptosis-Regulated Convertase 1 (NARC-1): Liver Regeneration and Neuronal Differentiation. Proceedings of the National Academy of Sciences of the United States of America, 100, 928-933. https://doi.org/10.1073/pnas.0335507100 |
| [22] | Goldstein, J.L. and Brown, M.S. (2015) A Century of Cholesterol and Coronaries: From Plaques to Genes to Statins. Cell, 161, 161-172. https://doi.org/10.1016/j.cell.2015.01.036 |
| [23] | Lambert, G., Petrides, F., Chatelais, M., et al. (2014) Elevated Plasma PCSK9 Level Is Equally Detrimental for Patients with Nonfamilial Hypercholesterolemia and Heterozygous Fa-milial Hypercholesterolemia, Irrespective of Low-Density Lipoprotein Receptor Defects. Journal of the American College of Cardiology, 63, 2365-2373.
https://doi.org/10.1016/j.jacc.2014.02.538 |
| [24] | Uribe, K.B., Chemello, K., Larrea-Sebal, A., et al. (2021) A Sys-tematic Approach to Assess the Activity and Classification of PCSK9 Variants. International Journal of Molecular Sci-ences, 22, Article No. 13602.
https://doi.org/10.3390/ijms222413602 |
| [25] | Shapiro, M.D., Tavori, H. and Fazio, S. (2018) PCSK9: From Basic Science Discoveries to Clinical Trials. Circulation Research, 122, 1420-1438. https://doi.org/10.1161/CIRCRESAHA.118.311227 |
| [26] | Macchi, C., Ferri, N., Sirtori, C.R., et al. (2021) Propro-tein Convertase Subtilisin/Kexin Type 9: A View beyond the Canonical Cholesterol-Lowering Impact. The American Journal of Pathology, 191, 1385-1397.
https://doi.org/10.1016/j.ajpath.2021.04.016 |
| [27] | Wu, N.-Q., Shi, H.-W. and Li, J.-J. (2022) Proprotein Convertase Subtilisin/Kexin Type 9 and Inflammation: An Updated Review. Frontiers in Cardiovascular Medicine, 9, Article 763516. https://doi.org/10.3389/fcvm.2022.763516 |
| [28] | Geovanini, G.R. and Libby, P. (2018) Atherosclerosis and Inflammation: Overview and Updates. Clinical Science, 132, 1243-1252. https://doi.org/10.1042/CS20180306 |
| [29] | Tang, Z.-H., Peng, J., Ren, Z., et al. (2017) New Role of PCSK9 in Atherosclerotic Inflammation Promotion Involving the TLR4/NF-κB Pathway. Atherosclerosis, 262, 113-122. https://doi.org/10.1016/j.atherosclerosis.2017.04.023 |
| [30] | Ricci, C., Ruscica, M., Camera, M., et al. (2018) PCSK9 Induces a Pro-Inflammatory Response in Macrophages. Scientific Reports, 8, Article No. 2267. https://doi.org/10.1038/s41598-018-20425-x |
| [31] | Badimon, L., Luquero, A., Crespo, J., Pe？a, E. and Bor-rell-Pages, M. (2021) PCSK9 and LRP5 in Macrophage Lipid Internalization and Inflammation. Cardiovascular Re-search, 117, 2054-2068. https://doi.org/10.1093/cvr/cvaa254 |
| [32] | Ding, Z., Wang, X., Liu, S., et al. (2018) PCSK9 Expression in the Ischaemic Heart and Its Relationship to Infarct Size, Cardiac Function, and Development of Autophagy. Cardiovascular Research, 114, 1738-1751.
https://doi.org/10.1093/cvr/cvy128 |
| [33] | Boyd, J.H., Fjell, C.D., Russell, J.A., et al. (2016) Increased Plasma PCSK9 Levels Are Associated with Reduced Endotoxin Clearance and the Development of Acute Organ Failures during Sepsis. Journal of Innate Immunity, 8, 211-220.
https://doi.org/10.1159/000442976 |
| [34] | Sabatine, M.S., Giugliano, R.P., Keech, A.C., et al. (2017) Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. New England Journal of Medicine, 376, 1713-1722. https://doi.org/10.1056/NEJMoa1615664 |
| [35] | Park, K.-H. and Park, W.J. (2015) Endothelial Dysfunction: Clinical Implications in Cardiovascular Disease and Therapeutic Approaches. Journal of Korean Medical Science, 30, 1213-1225. https://doi.org/10.3346/jkms.2015.30.9.1213 |
| [36] | Yurtseven, E., Ural, D., Baysal, K. and Tokg？zo？lu, L. (2020) An Update on the Role of PCSK9 in Atherosclerosis. Journal of Atherosclerosis and Thrombosis, 27, 909-918. https://doi.org/10.5551/jat.55400 |
| [37] | Roche-Molina, M., Sanz-Rosa, D., Cruz, F.M., et al. (2015) Induction of Sustained Hypercholesterolemia by Single Adeno-Associated Virus-Mediated Gene Transfer of Mutant hPCSK9. Arte-riosclerosis, Thrombosis, and Vascular Biology, 35, 50-59. https://doi.org/10.1161/ATVBAHA.114.303617 |
| [38] | Adhyaru, B.B. and Jacobson, T.A. (2018) Safety and Effi-cacy of Statin Therapy. Nature Reviews Cardiology, 15, 757-769.
https://doi.org/10.1038/s41569-018-0098-5 |
| [39] | Lebeau, P.F., Wassef, H., Byun, J.H., et al. (2021) The Loss-of-Function PCSK9Q152H Variant Increases ER Chaperones GRP78 and GRP94 and Protects against Liver Injury Journal of Clinical Investigation, 131, e128650.
https://doi.org/10.1172/JCI128650 |
| [40] | Mayne, J., Dewpura, T., Raymond, A., et al. (2011) Novel Loss-of-Function PCSK9 Variant Is Associated with Low Plasma LDL Cholesterol in a French-Canadian Family and with Impaired Processing and Secretion in Cell Culture. Clinical Chemistry, 57, 1415-1423. https://doi.org/10.1373/clinchem.2011.165191 |
| [41] | Rosenson, R.S., Hegele, R.A. and Koenig, W. (2019) Choles-terol-Lowering Agents. Circulation Research, 124, 364-385. https://doi.org/10.1161/CIRCRESAHA.118.313238 |
| [42] | Seidah, N.G., Prat, A., Pirillo, A., Catapano, A.L. and Norata, G.D. (2019) Novel Strategies to Target Proprotein Convertase Subtilisin Kexin 9: Beyond Monoclonal Antibod-ies. Cardiovascular Research, 115, 510-518.
https://doi.org/10.1093/cvr/cvz003 |
| [43] | Sabatine, M.S., Giugliano, R.P., Wiviott, S.D., et al. (2015) Efficacy and Safety of Evolocumab in Reducing Lipids and Cardiovascular Events. New England Journal of Medicine, 372, 1500-1509.
https://doi.org/10.1056/NEJMoa1500858 |
| [44] | Robinson, J.G., Farnier, M., Krempf, M., et al. (2015) Efficacy and Safety of Alirocumab in Reducing Lipids and Cardiovascular Events. New England Journal of Medicine, 372, 1489-1499. https://doi.org/10.1056/NEJMoa1501031 |
| [45] | Raal, F.J., Stein, E.A., Dufour, R., et al. (2015) PCSK9 Inhibition with Evolocumab (AMG 145) in Heterozygous Familial Hypercholesterolaemia (RUTHERFORD-2): A Randomised, Double-Blind, Placebo-Controlled Trial. Lancet, 385, 331-340.
https://doi.org/10.1016/S0140-6736(14)61399-4 |
| [46] | Koren, M.J., Giugliano, R.P., Raal, F.J., et al. (2014) Effi-cacy and Safety of Longer-Term Administration of Evolocumab (AMG 145) in Patients with Hypercholesterolemia: 52-Week Results from the Open-Label Study of Long-Term Evaluation against LDL-C (OSLER) Randomized Trial. Circulation, 129, 234-243.
https://doi.org/10.1161/CIRCULATIONAHA.113.007012 |
| [47] | Blom, D.J., Hala, T., Bolognese, M., et al. (2014) A 52-Week Placebo-Controlled Trial of Evolocumab in Hyperlipidemia. New England Journal of Medicine, 370, 1809-1819. https://doi.org/10.1056/NEJMoa1316222 |
| [48] | Robinson, J.G., Nedergaard, B.S., Rogers, W.J., et al. (2014) 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. https://doi.org/10.1001/jama.2014.4030 |
| [49] | Stroes, E., Colquhoun, D., Sullivan, D., et al. (2014) Anti-PCSK9 Antibody Effectively Lowers Cholesterol in Patients with Statin Intolerance: The GAUSS-2 Randomized, Place-bo-Controlled Phase 3 Clinical Trial of Evolocumab. Journal of the American College of Cardiology, 63, 2541-2548. https://doi.org/10.1016/j.jacc.2014.03.019 |
| [50] | Blom, D.J., Djedjos, C.S., Monsalvo, M.L., et al. (2015) Effects of Evolocumab on Vitamin E and Steroid Hormone Levels: Results from the 52-Week, Phase 3, Double-Blind, Randomized, Placebo-Controlled DESCARTES Study. Circulation Research, 117, 731-741. https://doi.org/10.1161/CIRCRESAHA.115.307071 |
| [51] | Koren, M.J., Sabatine, M.S., Giugliano, R.P., et al. (2017) Long-Term Low-Density Lipoprotein Cholesterol-Lowering Efficacy, Persistence, and Safety of Evolocumab in Treat-ment of Hypercholesterolemia: Results up to 4 Years from the Open-Label OSLER-1 Extension Study. JAMA Cardiolo-gy, 2, 598-607.
https://doi.org/10.1001/jamacardio.2017.0747 |
| [52] | Sabatine, M.S., Leiter, L.A., Wiviott, S.D., et al. (2017) Cardi-ovascular 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. The Lancet Diabetes and Endocrinology, 5, 941-950. https://doi.org/10.1016/S2213-8587(17)30313-3 |
| [53] | Deedwania, P., Murphy, S.A., Scheen, A., et al. (2021) Ef-ficacy and Safety of PCSK9 Inhibition with Evolocumab in Reducing Cardiovascular Events in Patients with Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis from the FOURIER Randomized Clinical Trial. JAMA Cardi-ology, 6, 139-147.
https://doi.org/10.1001/jamacardio.2020.3151 |
| [54] | Giugliano, R.P., Pedersen, T.R., Saver, J.L., et al. (2020) Stroke Prevention with the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients with Stable Atherosclerosis. Stroke, 51, 1546-1554. https://doi.org/10.1161/STROKEAHA.119.027759 |
| [55] | Cannon, C.P., Cariou, B., Blom, D., et al. (2015) 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. European Heart Journal, 36, 1186-1194.
https://doi.org/10.1093/eurheartj/ehv028 |
| [56] | Ying, Q., Chan, D.C., Pang, J., et al. (2022) PCSK9 Inhibition with Alirocumab Decreases Plasma Lipoprotein(a) Concentration by a Dual Mechanism of Action in Statin-Treated Patients with Very High Apolipoprotein(a) Concentration. Journal of Internal Medicine, 291, 870-876. https://doi.org/10.1111/joim.13457 |
| [57] | Villard, E.F., Thedrez, A., Blankenstein, J., et al. (2016) PCSK9 Modu-lates the Secretion but Not the Cellular Uptake of Lipoprotein(a) ExVivo: An Effect Blunted by Alirocumab. JACC: Basic to Translational Science, 1, 419-427.
https://doi.org/10.1016/j.jacbts.2016.06.006 |
| [58] | Roth, E.M., Taskinen, M.R., Ginsberg, H.N., et al. (2014) Mon-otherapy with the PCSK9 Inhibitor Alirocumab versus Ezetimibe in Patients with Hypercholesterolemia: Results of a 24week, Double-Blind, Randomized Phase 3 Trial. International Journal of Cardiology, 176, 55-61. https://doi.org/10.1016/j.ijcard.2014.06.049 |
| [59] | Goodman, S.G., Aylward, P.E., Szarek, M., et al. (2019) Effects of Alirocumab on Cardiovascular Events after Coronary Bypass Surgery. Journal of the American College of Cardiology, 74, 1177-1186.
https://doi.org/10.1016/j.jacc.2019.07.015 |
| [60] | Damask, A., Steg, P.G., Schwartz, G.G., et al. (2020) 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, 141, 624-636. https://doi.org/10.1161/CIRCULATIONAHA.119.044434 |
| [61] | Arnett, D.K., Blumenthal, R.S., Albert, M.A., et al. (2019) 2019 ACC/AHA Guideline on the Primary Prevention of Cardiovascular Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation, 140, e596-e646. https://doi.org/10.1161/CIR.0000000000000678 |
| [62] | Raal, F.J., Kallend, D., Ray, K.K., et al. (2020) Inclisiran for the Treatment of Heterozygous Familial Hypercholesterolemia. New England Journal of Medicine, 382, 1520-1530. https://doi.org/10.1056/NEJMoa1913805 |
| [63] | Ray, K.K., Wright, R.S., Kallend, D., et al. (2020) Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol. New England Journal of Medicine, 382, 1507-1519. https://doi.org/10.1056/NEJMoa1912387 |
| [64] | Tucker, T.J., Embrey, M.W., Alleyne, C., et al. (2021) A Series of Novel, Highly Potent, and Orally Bioavailable Next-Generation Tricyclic Peptide PCSK9 Inhibitors. Journal of Medicinal Chemistry, 64, 16770-16800.
https://doi.org/10.1021/acs.jmedchem.1c01599 |
| [65] | Chaudhary, R., Garg, J., Shah, N. and Sumner, A. (2017) PCSK9 inhibitors: A New Era of Lipid Lowering Therapy. World Journal of Cardiology, 9, 76-91. https://doi.org/10.4330/wjc.v9.i2.76 |
| [66] | Hao, Y., Yang, Y.-L., Wang, Y.-C. and Li, J. (2022) Effect of the Early Application of Evolocumab on Blood Lipid Profile and Cardiovascular Prognosis in Patients with Extremely High-Risk Acute Coronary Syndrome. International Heart Journal, 63, 669-677. https://doi.org/10.1536/ihj.22-052 |
| [67] | Squizzato, A., Suter, M.B., Nerone, M., et al. (2017) PCSK9 Inhibitors for Treating Dyslipidemia in Patients at Different Cardiovascular Risk: A Systematic Review and a Meta-Analysis. Internal and Emergency Medicine, 12, 1043-1053.
https://doi.org/10.1007/s11739-017-1708-7 |
| [68] | Abifadel, M., Elbitar, S., El Khoury, P., et al. (2014) Living the PCSK9 Adventure: From the Identification of a New Gene in Familial Hypercholesterolemia towards a Potential New Class of Anticholesterol Drugs. Current Atherosclerosis Reports, 16, Article No. 439. https://doi.org/10.1007/s11883-014-0439-8 |
| [69] | Raccah, B.H., Yanovsky, A., Treves, N., et al. (2021) Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors and the Risk for Neurocognitive Adverse Events: A Systematic Review, Meta-Analysis and Meta-Regression. International Journal of Cardiology, 335, 7-14. https://doi.org/10.1016/j.ijcard.2021.04.025 |
