@article{b82c45321533455e97a9b5b445abd6b3,
title = "Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement fromthe European Atherosclerosis Society Consensus Panel",
abstract = "Aims To appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD). Methods and results We assessed whether the association between LDL and ASCVD fulfils the criteria for causality by evaluating the totality of evidence from genetic studies, prospective epidemiologic cohort studies, Mendelian randomization studies, and randomized trials of LDL-lowering therapies. In clinical studies, plasma LDL burden is usually estimated by determination of plasma LDL cholesterol level (LDL-C). Rare genetic mutations that cause reduced LDL receptor function lead to markedly higher LDL-C and a dose-dependent increase in the risk of ASCVD, whereas rare variants leading to lower LDL-C are associated with a correspondingly lower risk of ASCVD. Separate meta-analyses of over 200 prospective cohort studies, Mendelian randomization studies, and randomized trials including more than 2 million participants with over 20 million person-years of follow-up and over 150 000 cardiovascular events demonstrate a remarkably consistent dose-dependent log-linear association between the absolute magnitude of exposure of the vasculature to LDL-C and the risk of ASCVD; and this effect appears to increase with increasing duration of exposure to LDL-C. Both the naturally randomized genetic studies and the randomized intervention trials consistently demonstrate that any mechanism of lowering plasma LDL particle concentration should reduce the risk of ASCVD events proportional to the absolute reduction in LDL-C and the cumulative duration of exposure to lower LDL-C, provided that the achieved reduction in LDL-C is concordant with the reduction in LDL particle number and that there are no competing deleterious off-target effects. Conclusion Consistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.",
keywords = "Atherosclerosis, Cardiovascular disease, Causality, Clinical trials, Ezetimibe, Low-density lipoprotein, Mendelian randomization, PCSK9, Recommendations, Statin",
author = "Ference, {Brian A.} and Ginsberg, {Henry N.} and Ian Graham and Ray, {Kausik K.} and Packard, {Chris J.} and Eric Bruckert and Hegele, {Robert A.} and Krauss, {Ronald M.} and Raal, {Frederick J.} and Heribert Schunkert and Watt, {Gerald F.} and Jan Bor{\'e}n and Sergio Fazio and Horton, {Jay D.} and Luis Masana and Nicholls, {Stephen J.} and Nordestgaard, {B{\o}rge G.} and {Van De Sluis}, Bart and Taskinen, {Marja Riitta} and Lale Tokg{\"o}zoǧlu and Ulf Landmesser and Ulrich Laufs and Olov Wiklund and Stock, {Jane K.} and Chapman, {M. John} and Catapano, {Alberico L.}",
note = "Funding Information: Travel and meeting logistics were supported by unrestricted educational grants from MSD and Amgen to the European Atherosclerosis Society. These companies were not present at the Consensus Panel meetings, had no role in the design or content of the manuscript, and had no right to approve or disapprove the final document. Funding to pay the Open Access publication charges for this article was provided by the European Atherosclerosis Society. Funding Information: Conflict of interest: J.B. has received research grants from Amgen, AstraZeneca, NovoNordisk, Pfizer and Regeneron/Sanofi and honoraria for consultancy and lectures from Amgen, AstraZeneca, Eli Lilly, Merck, Novo-Nordisk, Pfizer, and Regeneron/Sanofi. E.B. has received honoraria from AstraZeneca, Amgen, Genfit, MSD, Sanofi-Regeneron, Unilever, Danone, Aegerion, Chiesi, Rottapharm, Lilly and research grants from Amgen, Danone and Aegerion. A.L.C. has received research grants to his institution from Amgen, Astra-Zeneca, Merck, Regeneron/Sanofi, and Sigma Tau, and honoraria for advisory boards, consultancy or speaker bureau from Abbot, Aegerion, Amgen, AstraZeneca, Eli Lilly, Genzyme, Merck/MSD,Mylan, Pfizer, Rottapharm and Sanofi-Regeneron. M.J.C. has received research grants from MSD, Kowa, Pfizer, and Randox and honoraria for consultancy/speaker activities from Amgen, Kowa, Merck, Sanofi, Servier, Unilever, and Regeneron. S.F. has the following disclosures for the last 12 months: Compensated consultant and advisory activities with Merck, Kowa, Sanofi, Amgen, Amarin, and Aegerion. B.A.F. has received research grants from Merck, Amgen and Esperion Therapeutics and received honoraria for lectures, consulting and/or advisory board membership from Merck, Amgen, Esperion, Ionis, and the American College of Cardiology. I.G. has received speaker fees from MSD and Pfizer relating to cardiovascular risk estimation and lipid guidelines, and consultancy/ speaker fee from Amgen. H.N.G. has received research grants from Merck, Sanofi-Regeneron, and Amgen. He consults for Merck, Sanofi, Regeneron, Lilly, Kowa, Resverlogix, Boehringer Ingelheim. R.A.H. has received research grants from Aegerion, Amgen, The Medicines Company, Pfizer, and Sanofi. He consults for Amgen, Aegerion, Boston Heart Diagnostics, Gemphire, Lilly, and Sanofi. J.D.H reports honoraria/ research grants from Aegerion, Alnylam, Catabasis, Lilly, Merck, Pfizer, Novartis, Regeneron, Sanofi. R.M.K is a Member, Merck Global Atherosclerosis Advisory Board. U.L. has received honoraria for lectures and/or consulting from Amgen, Medicines Company, Astra Zeneca, MSD, Berlin Chemie, Bayer, Abbott, and Sanofi. U.L. aufs has received honoraria for board membership, consultancy, and lectures from Amgen, MSD, Sanofi, and Servier. L.M. has received honoraria for consultancy and lectures from Amgen, Danone, Kowa, Merck, and Sanofi-Regeneron. S.J.N. has received research support from Amgen, AstraZeneca, Anthera, Cerenis, Novartis, Eli Lilly, Esperion, Resverlogix, Sanofi-Regeneron, InfraReDx. and LipoScience and is a consultant for Amgen, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly, Merck, Takeda, Pfizer, Roche, Sanofi-Regeneron, Kowa. and Novartis. B.G.N. reports consultancies and honoraria for lectures from AstraZeneca, Sanofi, Regeneron, Aegerion, Fresenius, B Braun, Kaneka, Amgen. C.J.P. has received research support from Roche, MSD and honoraria from MSD, Sanofi/Regeneron, Amgen and Pfizer. F.J.R. has received grants/research support from Amgen and Sanofi and has received speaker fees or honoraria for consultation from AstraZeneca, Merck, Amgen, and Sanofi. K.K.R. has received research grants from Amgen, Sanofi-Regeneron and Pfizer and honoraria for lectures, advisory boards or as a steering committee member from Aegerion, Amgen, Sanofi-Regeneron, Pfizer, AstraZeneca, Cerenis, ISIS Pharma, Medco, Resverlogix, Kowa, Novartis, Cipla, Lilly, Algorithm, Takeda, Boehringer Ingelheim, MSD. Esperion, and AbbieVie. H.S. has received research grants from AstraZeneca, MSD, Bayer Vital, sanofi-aventis, and Pfizer and honoraria for speaker fees from AstraZeneca, MSD, Genzyme, sanofi-aventis, and Synlab. He has consulted for MSD and AstraZeneca. M.R.T. has received speaker fees from Amgen, Astra Zeneca, Chiesi Pharma and Eli Lilly and speaker fees and research support from Amgen, Sanofi Aventis and Novo Nordisk. She has consulted for AstraZeneca. L.T. has received research funding and/or honoraria for advisory boards, consultancy or speaker bureau from Abbott Mylan, Actelion, Aegerion, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi-Sankyo, GlaxoSmithKline, Menarini, Merck, Novartis, Pfizer, Sanofi-Regeneron, Servier and Synageva. G.F.W. has received research support from Amgen and Sanofi-Regeneron. O.W. has received honoraria for lectures or consultancy from Sanofi, Amgen, MSD, and Astra-Zeneca. B.v.S, and J.K.S. report no disclosures.",
year = "2017",
month = aug,
day = "21",
doi = "10.1093/eurheartj/ehx144",
language = "English (US)",
volume = "38",
pages = "2459--2472",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "32",
}