Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement fromthe European Atherosclerosis Society Consensus Panel

TY - JOUR

T1 - Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement fromthe European Atherosclerosis Society Consensus Panel

AU - Ference, Brian A.

AU - Ginsberg, Henry N.

AU - Graham, Ian

AU - Ray, Kausik K.

AU - Packard, Chris J.

AU - Bruckert, Eric

AU - Hegele, Robert A.

AU - Krauss, Ronald M.

AU - Raal, Frederick J.

AU - Schunkert, Heribert

AU - Watt, Gerald F.

AU - Borén, Jan

AU - Fazio, Sergio

AU - Horton, Jay D.

AU - Masana, Luis

AU - Nicholls, Stephen J.

AU - Nordestgaard, Børge G.

AU - Van De Sluis, Bart

AU - Taskinen, Marja Riitta

AU - Tokgözoǧlu, Lale

AU - Landmesser, Ulf

AU - Laufs, Ulrich

AU - Wiklund, Olov

AU - Stock, Jane K.

AU - Chapman, M. John

AU - Catapano, Alberico L.

PY - 2017/8/21

Y1 - 2017/8/21

N2 - 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.

AB - 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.

KW - Atherosclerosis

KW - Cardiovascular disease

KW - Causality

KW - Clinical trials

KW - Ezetimibe

KW - Low-density lipoprotein

KW - Mendelian randomization

KW - PCSK9

KW - Recommendations

KW - Statin

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UR - http://www.scopus.com/inward/citedby.url?scp=85027715986&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehx144

DO - 10.1093/eurheartj/ehx144

M3 - Article

C2 - 28444290

AN - SCOPUS:85027715986

VL - 38

SP - 2459

EP - 2472

JO - European Heart Journal

JF - European Heart Journal

SN - 0195-668X

IS - 32

ER -