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(32):2459–72. https://doi.org/10.1093/eurheartj/ehx144.

CAS  Article  PubMed  PubMed Central  Google Scholar 

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(24):2313–30. https://doi.org/10.1093/eurheartj/ehz962.

CAS  Article  PubMed  PubMed Central  Google Scholar 

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(9753):1670–81. https://doi.org/10.1016/S0140-6736(10)61350-5.

CAS  Article  PubMed  Google Scholar 

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(9493):1267–78. https://doi.org/10.1016/S0140-6736(05)67394-1.

CAS  Article  PubMed  Google Scholar 

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–22. https://doi.org/10.1056/NEJMoa1615664.

CAS  Article  PubMed  Google Scholar 

Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–107. https://doi.org/10.1056/NEJMoa1801174.

CAS  Article  PubMed  Google Scholar 

Karagiannis AD, Mehta A, Dhindsa DS, et al. How low is safe? The frontier of very low (<30 mg/dL) LDL cholesterol. Eur Heart J. 2021;42(22):2154–69. https://doi.org/10.1093/eurheartj/ehaa1080.

CAS  Article  PubMed  Google Scholar 

Michos ED, Ferdinand KC. Lipid-lowering for the prevention of cardiovascular disease in the new era: A practical approach to combination therapy. Eur Ath J. 2022;1(1):30–6. https://doi.org/10.56095/eaj.v1i1.9.

Article  Google Scholar 

Masana L, Ibarretxe D, Andreychuk N, Royuela M, Rodriguez-Borjabad C, Plana N. Combination therapy in the guidelines: from high-intensity statins to high-intensity lipid-lowering therapies. Eur Ath J. 2022;1(1):25–9. https://doi.org/10.56095/eaj.v1i1.10.

Article  Google Scholar 

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(1):111–88. https://doi.org/10.1093/eurheartj/ehz455.

Article  PubMed  Google Scholar 

Seidah NG, Prat A, Pirillo A, Catapano AL, Norata GD. Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. Cardiovasc Res. 2019;115(3):510–8. https://doi.org/10.1093/cvr/cvz003.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Norata GD, Tibolla G, Catapano AL. Targeting PCSK9 for hypercholesterolemia. Annu Rev Pharmacol Toxicol. 2014;54:273–93. https://doi.org/10.1146/annurev-pharmtox-011613-140025.

CAS  Article  PubMed  Google Scholar 

Catapano AL, Pirillo A, Norata GD. New pharmacological approaches to target PCSK9. Curr Atheroscler Rep. 2020;22(7):24. https://doi.org/10.1007/s11883-020-00847-7.

CAS  Article  PubMed  Google Scholar 

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(12):1264–72. https://doi.org/10.1056/NEJMoa054013.

CAS  Article  PubMed  Google Scholar 

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(4):e001632. https://doi.org/10.1161/CIRCGENETICS.116.001632.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Cariou B, Ouguerram K, Zair Y, et al. PCSK9 dominant negative mutant results in increased LDL catabolic rate and familial hypobetalipoproteinemia. Arterioscler Thromb Vasc Biol. 2009;29(12):2191–7. https://doi.org/10.1161/ATVBAHA.109.194191.

CAS  Article  PubMed  Google Scholar 

Mayne J, Dewpura T, Raymond A, et al. 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. Clin Chem. 2011;57(10):1415–23. https://doi.org/10.1373/clinchem.2011.165191.

CAS  Article  PubMed  Google Scholar 

Slimani A, Jelassi A, Jguirim I, et al. Effect of mutations in LDLR and PCSK9 genes on phenotypic variability in Tunisian familial hypercholesterolemia patients. Atherosclerosis. 2012;222(1):158–66. https://doi.org/10.1016/j.atherosclerosis.2012.02.018.

CAS  Article  PubMed  Google Scholar 

Lee CJ, Lee Y, Park S, et al. Rare and common variants of APOB and PCSK9 in Korean patients with extremely low low-density lipoprotein-cholesterol levels. PLoS One. 2017;12(10):e0186446. https://doi.org/10.1371/journal.pone.0186446.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Abifadel M, Guerin M, Benjannet S, et al. Identification and characterization of new gain-of-function mutations in the PCSK9 gene responsible for autosomal dominant hypercholesterolemia. Atherosclerosis. 2012;223(2):394–400. https://doi.org/10.1016/j.atherosclerosis.2012.04.006.

CAS  Article  PubMed  Google Scholar 

Ohta N, Hori M, Takahashi A, et al. Proprotein convertase subtilisin/kexin 9 V4I variant with LDLR mutations modifies the phenotype of familial hypercholesterolemia. J Clin Lipidol. 2016;10(3):547-555.e545. https://doi.org/10.1016/j.jacl.2015.12.024.

Article  PubMed  Google Scholar 

Di Taranto MD, Benito-Vicente A, Giacobbe C, et al. Identification and in vitro characterization of two new PCSK9 gain of function variants found in patients with familial hypercholesterolemia. Sci Rep. 2017;7(1):15282. https://doi.org/10.1038/s41598-017-15543-x.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Elbitar S, Susan-Resiga D, Ghaleb Y, et al. New sequencing technologies help revealing unexpected mutations in autosomal dominant hypercholesterolemia. Sci Rep. 2018;8(1):1943. https://doi.org/10.1038/s41598-018-20281-9.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Mabuchi H, Nohara A, Noguchi T, et al. Genotypic and phenotypic features in homozygous familial hypercholesterolemia caused by proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutation. Atherosclerosis. 2014;236(1):54–61. https://doi.org/10.1016/j.atherosclerosis.2014.06.005.

CAS  Article  PubMed  Google Scholar 

Guedeney P, Giustino G, Sorrentino S, et al. Efficacy and safety of alirocumab and evolocumab: a systematic review and meta-analysis of randomized controlled trials. Eur Heart J. 2019. https://doi.org/10.1093/eurheartj/ehz430.

Article  PubMed  Google Scholar 

Guedeney P, Sorrentino S, Giustino G, et al. Indirect comparison of the efficacy and safety of alirocumab and evolocumab: a systematic review and network meta-analysis. Eur Heart J Cardiovasc Pharmacother. 2021;7(3):225–35. https://doi.org/10.1093/ehjcvp/pvaa024.

Article  PubMed  Google Scholar 

Mu G, Xiang Q, Zhou S, et al. Efficacy and safety of PCSK9 monoclonal antibodies in patients at high cardiovascular risk: an updated systematic review and meta-analysis of 32 randomized controlled trials. Adv Ther. 2020;37(4):1496–521. https://doi.org/10.1007/s12325-020-01259-4.

CAS  Article  PubMed  Google Scholar 

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(22):2144–53. https://doi.org/10.1056/NEJMoa1604304.

CAS  Article  PubMed  Google Scholar 

Baragetti A, Balzarotti G, Grigore L, et al. PCSK9 deficiency results in increased ectopic fat accumulation in experimental models and in humans. Eur J Prev Cardiol. 2017;24(17):1870–7. https://doi.org/10.1177/2047487317724342.

Article  PubMed  Google Scholar 

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(4):357–68. https://doi.org/10.1093/eurheartj/ehy357.

CAS  Article  PubMed  Google Scholar 

Da Dalt L, Castiglioni L, Baragetti A, et al. PCSK9 deficiency rewires heart metabolism and drives heart failure with preserved ejection fraction. Eur Heart J. 2021;42(32):3078–90. https://doi.org/10.1093/eurheartj/ehab431.

CAS  Article  PubMed  PubMed Central  Google Scholar 

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(33):11915–20. https://doi.org/10.1073/pnas.0805434105.

Article  PubMed  PubMed Central  Google Scholar 

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(9911):60–8. https://doi.org/10.1016/S0140-6736(13)61914-5.

CAS  Article  PubMed  Google Scholar 

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(15):1430–40. https://doi.org/10.1056/NEJMoa1615758.

CAS  Article  PubMed  Google Scholar 

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(11):1067–75. https://doi.org/10.1001/jamacardio.2019.3502.

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