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

Brian A Ference; Henry N Ginsberg; Ian Graham; Kausik K Ray; Chris J Packard; Eric Bruckert; Robert A Hegele; Ronald M Krauss; Frederick J Raal; Heribert Schunkert; Gerald F Watts; Jan Borén; Sergio Fazio; Jay D Horton; Luis Masana; Stephen J Nicholls; Børge G Nordestgaard; Bart van de Sluis; Marja-Riitta Taskinen; Lale Tokgözoglu; Ulf Landmesser; Ulrich Laufs; Olov Wiklund; Jane K Stock; M John Chapman; Alberico L Catapano

doi:10.1093/eurheartj/ehx144

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 Aug 21;38(32):2459-2472. doi: 10.1093/eurheartj/ehx144.

Authors

Brian A Ference¹, Henry N Ginsberg², Ian Graham³, Kausik K Ray⁴, Chris J Packard⁵, Eric Bruckert⁶, Robert A Hegele⁷, Ronald M Krauss⁸, Frederick J Raal⁹, Heribert Schunkert^{10

11}, Gerald F Watts¹², Jan Borén¹³, Sergio Fazio¹⁴, Jay D Horton^{15

16}, Luis Masana¹⁷, Stephen J Nicholls¹⁸, Børge G Nordestgaard^{19

20

21}, Bart van de Sluis²², Marja-Riitta Taskinen²³, Lale Tokgözoglu²⁴, Ulf Landmesser^{2

6

25}, Ulrich Laufs²⁶, Olov Wiklund^{27

28}, Jane K Stock²⁹, M John Chapman³⁰, Alberico L Catapano³¹

Affiliations

¹ Division of Translational Research and Clinical Epidemiology, Division of Cardiovascular Medicine, Wayne State University School of Medicine, Detroit, MI 48202, USA.
² Irving Institute for Clinical and Translational Research, Columbia University, New York, NY, USA.
³ Trinity College Dublin, Ireland.
⁴ Department of Primary Care and Public Health, Imperial Centre for Cardiovascular Disease Prevention, Imperial College, London, UK.
⁵ College of Medical, Veterinary, and Life Sciences, University of Glasgow, Glasgow, UK.
⁶ INSERM UMRS1166, Department of Endocrinology-Metabolism, ICAN - Institute of CardioMetabolism and Nutrition, AP-HP, Hôpital de la Pitié, Paris, France.
⁷ Department of Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada.
⁸ Department of Atherosclerosis Research, Children's Hospital Oakland Research Institute, Oakland, CA 94609, USA.
⁹ Faculty of Health Sciences, University of Witwatersrand, Johannesburg, South Africa.
¹⁰ Deutsches Herzzentrum München, Technische Universität München, Munich 80636, Germany.
¹¹ Deutsches Zentrum für Herz und Kreislauferkrankungen (DZHK), Partner Site Munich Heart Alliance, Munich 81377, Germany.
¹² Lipid Disorders Clinic, Centre for Cardiovascular Medicine, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Perth, Western Australia, Australia.
¹³ Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg, Sweden.
¹⁴ Department of Medicine, Center for Preventive Cardiology of the Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR, USA.
¹⁵ Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁶ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
¹⁷ Research Unit of Lipids and Atherosclerosis, University Rovira i Virgili, C. Sant Llorenç 21, Reus 43201, Spain.
¹⁸ South Australian Health and Medical Research Institute, University of Adelaide, Adelaide, Australia.
¹⁹ Department of Clinical Biochemistry and The Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark.
²⁰ Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
²¹ The Copenhagen City Heart Study, Frederiksberg Hospital, Copenhagen University Hospital, Denmark.
²² Department of Pediatrics, Molecular Genetics Section, University of Groningen, University Medical Center Groningen, Antonius Deusinglaan 1, Groningen AV 9713, The Netherlands.
²³ Helsinki University Central Hospital and Research Programs' Unit, Diabetes and Obesity, Heart and Lung Centre, University of Helsinki, Helsinki, Finland.
²⁴ Hacettepe University, Ankara, Turkey.
²⁵ Department of Cardiology, Charité-Universitätsmedizin Berlin (CBF), Hindenburgdamm 30, Berlin 12203, Germany.
²⁶ Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg, Saar, Germany.
²⁷ Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden.
²⁸ Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden.
²⁹ European Atherosclerosis Society, Gothenburg, Sweden.
³⁰ INSERM, Dyslipidemia and Atherosclerosis Research, and University of Pierre and Marie Curie, Pitié-Sâlpetrière University Hospital, Paris, France.
³¹ Department of Pharmacological and Biomolecular Sciences, University of Milan and IRCCS Multimedica, Milan, Italy.

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.

Publication types

Review

MeSH terms

Anticholesteremic Agents / therapeutic use
Atherosclerosis / etiology*
Atherosclerosis / prevention & control
Cholesterol, HDL / metabolism
Cholesterol, LDL / metabolism
Consensus
Epidemiologic Methods
Ezetimibe / therapeutic use
Genetic Predisposition to Disease / genetics
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
Hyperlipidemias / prevention & control
Lipoproteins, LDL / physiology*
PCSK9 Inhibitors

Substances

Anticholesteremic Agents
Cholesterol, HDL
Cholesterol, LDL
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lipoproteins, LDL
PCSK9 Inhibitors
PCSK9 protein, human
Ezetimibe