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

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.

Figure 1

Relative concentration of apolipoprotein B (ApoB) contained in circulating lipoproteins in normolipidaemic individuals. ApoB content was calculated in nanomoles per litre using 500 000 as the defined molecular mass [i.e. low-density lipoprotein (LDL) 100 mg/dL or 2000 nmol/L, very low-density lipoprotein (VLDL) 5 mg/dL or 100 nmol/L, intermediate density lipoprotein (IDL) remnants 5 mg/dL or 100 nmol/L and lipoprotein(a) 10 nmol/l*]. *Based on population median.

Figure 2

Log-linear association per unit change in low-density lipoprotein cholesterol (LDL-C) and the risk of cardiovascular disease as reported in meta-analyses of Mendelian randomization studies, prospective epidemiologic cohort studies, and randomized trials. The increasingly steeper slope of the log-linear association with increasing length of follow-up time implies that LDL-C has both a causal and a cumulative effect on the risk of cardiovascular disease. The proportional risk reduction (y axis) is calculated as 1−relative risk (as estimated by the odds ratio in Mendelian randomization studies, or the hazard ration in the prospective epidemiologic studies and randomized trials) on the log scale, then exponentiated and converted to a percentage. The included meta-analyses were identified from (i) MEDLINE and EMBASE using the search terms meta-analysis, LDL, and ‘cardiovascular or coronary’; (ii) the reference lists of the identified meta-analyses; (iii) public data from GWAS consortia; and (iv) by discussion with members of the EAS Consensus Panel. We included the most updated meta-analyses available, giving preference to meta-analyses that used individual participant data. Trial acronyms: AF/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ALERT, Assessment of LEscol in Renal Transplantation; ALLHAT-LLT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Lipid Lowering Trial; ALLIANCE, Aggressive Lipid-Lowering Initiation Abates New Cardiac Events; ASPEN, Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in non-insulin-dependent diabetes mellitus; ASCOT LLA, Anglo Scandinavian Cardiac Outcomes Trial Lipid Lowering Arm; AURORA, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events; CARE, Cholesterol and Recurrent Events; CARDS, Collaborative Atorvastatin Diabetes Study; CHGN, Community Health Global Network; 4D Deutsche Diabetes Dialyse Studies; ERFC, Emerging Risk Factors Collaboration; GISSI, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico; HOPE, Heart Outcomes Prevention Evaluation Study; HPS, Heart Protection Study; IDEAL, Incremental Decrease in End Points Through Aggressive Lipid Lowering; IMPROVE-IT, Examining Outcomes in Subjects With Acute Coronary Syndrome: Vytorin (Ezetimibe/Simvastatin) vs Simvastatin; JUPITER, Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial; LIPID,, Long-Term Intervention with Pravastatin in Ischemic Disease; LIPS, Lescol Intervention Prevention Study; MEGA, Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese; POST-CABG, Post Coronary Artery Bypass Graft; PROSPER, Pravastatin in elderly individuals at risk of vascular disease; PROVE-IT, Pravastatin or Atorvastatin Evaluation and Infection Therapy; SHARP, Study of Heart and Renal Protection; TNT, Treating to New Targets; WOSCOPS, West of Scotland Coronary Prevention Study.

Figure 3

Effect of exposure to lower low-density lipoprotein cholesterol (LDL-C) by mechanism of LDL-C lowering. Panel A shows the effect of genetic variants or genetic scores combining multiple variants in the genes that encode for the targets of currently available LDL-C-lowering therapies, adjusted for a standard decrement of 0.35 mmol/L lower LDL-C, in comparison with the effect of lower LDL-C mediated by variants in the LDL receptor gene. Panel B shows the effect of currently available therapies that act to primarily lower LDL-C through the LDL receptor pathway, adjusted per millimole per litre lower LDL-C. Both the naturally randomized genetic data in Panel A and the data from randomized trials in Panel B suggest that the effect of LDL-C on the risk of cardiovascular events is approximately the same per unit change in LDL-C for any mechanism that lowers LDL-C via up-regulation of the LDL receptor where the change in LDL-C (which is used in clinical medicine to estimate the change in LDL particle concentration) is likely to be concordant with changes in LDL particle concentration.

Figure 4

Schematic figure showing that all therapies that act predominantly to lower low-density lipoprotein (LDL) act via the LDL receptor pathway to up-regulate LDL receptors and thus increase LDL clearance.

Figure 5

Linear association between achieved low-density lipoprotein cholesterol (LDL-C) level and absolute coronary heart disease (CHD) event rate or progression of atherosclerosis. Panel A shows absolute cardiovascular event rates in randomized statin trials and Panel B shows progression of atherosclerosis as measured by intravascular ultrasound. In Panel A, achieved LDL-C in primary prevention trials and secondary prevention trials in stable CHD patients was related to the end point of CHD events (fatal plus non-fatal myocardial infarction, sudden CHD death) proportioned to 5 years assuming linear rates with time. Trendlines for primary and secondary prevention associations are virtually superimposable. Key: p, placebo; a, active treatment arm, except for IDEAL, where s, simvastatin and a, atorvastatin; and HOPE-3, where r, rosuvastatin; and TNT where reference is made to atorvastatin 10 and 80 mg dose. Trial acronyms: AFCAPS, Air Force Coronary Atherosclerosis Prevention Study; ASCOT, Anglo Scandinavian Cardiac Outcomes Trial; ASTEROID, A Study To Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden; CARE, Cholesterol and Recurrent Events; CAMELOT, Comparison of Amlodipine vs. Enalapril to Limit Occurrence of Thrombosis; HOPE, Heart Outcomes Prevention Evaluation Study; HPS, Heart Protection Study; IDEAL, Incremental Decrease in End Points Through Aggressive Lipid Lowering; ILLUSTRATE, Investigation of Lipid Level Management Using Coronary Ultrasound To Assess Reduction of Atherosclerosis by CETP Inhibition and HDL Elevation; JUPITER, Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin trial; LIPID, Long-Term Intervention with Pravastatin in Ischemic Disease; PRECISE IVUS, Plaque REgression with Cholesterol absorption Inhibitor or Synthesis inhibitor Evaluated by IntraVascular UltraSound; PROSPER, Pravastatin in elderly individuals at risk of vascular disease; REVERSAL, Reversal of Atherosclerosis With Aggressive Lipid Lowering; 4S Scandinavian Simvastatin Survival Study; SATURN, Study of Coronary Atheroma by Intravascular Ultrasound: Effect of Rosuvastatin vs. Atorvastatin; STRADIVARIUS, Strategy To Reduce Atherosclerosis Development InVolving Administration of Rimonabant—the Intravascular Ultrasound Study; TNT, Treating to New Targets; WOSCOPS, West Of Scotland Coronary Prevention Study.