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

AimsTo appraise the clinical and genetic evidence that low-density lipoproteins (LDLs) cause atherosclerotic cardiovascular disease (ASCVD).Methods and resultsWe 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.ConclusionConsistent evidence from numerous and multiple different types of clinical and genetic studies unequivocally establishes that LDL causes ASCVD.

Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*

“…Compared to CTTC data, treatment with evolocumab has very similar effects on the risk of major CVD events [16]. In light of the current body of evidence, the European Atherosclerosis Society (EAS) deems PCSK9 inhibitors as equivalent to statins in terms of their effects on the risk of CV events per unit decrease in LDL-C [44]. …”

A Critical Review of the Consensus Statement from the European Atherosclerosis Society Consensus Panel 2017

“…Data reproduced with permission from Figure 2 in Ference et al [13]. The y-axis is calculated as 1-relative risk (as estimated by the hazard ratio) on a log scale, then exponentiated and converted to a percentage.…”

“…However, statin-associated risks have gradually become recognized in the field of evidence-based medicine. Therefore, the Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 (hereafter, the EAS Consensus Statement 2017) with its conclusion that “LDL is the cause of atherosclerotic CVD (ASCVD)” [13] was unexpected.…”

High Intensity Hypolipidemic Therapy and Decreased Level of Low Density Lipoproteides Cholesterol: Is the Approach Justified? Point of View

“…Исследования с "менделевской рандоми-зацией" подтвердили клиническую пользу от сниже-ния уровня ХС ЛНП независимо от гипохолестерине-мического механизма действия лекарства [1,2]. На каждый ммоль/л снижения концентрации ХС ЛНП в крови можно ожидать уменьшение относительного риска (ОР) развития ИБС при лечении статинами на 21% (ОР=0,79; 95% доверительный интервал (ДИ): 0,77-0,81), на терапии эзетимибом на 19% (ОР=0,81; 95% ДИ: 0,73-0,89), при приеме ингибиторов про-протеин-конвертазы субтилизин/кексин типа 9 (PCSK9) -на 24% (ОР=0,76; 95% ДИ: 0,65-0,87), а в целом на гиполипидемической терапии -на 21% (ОР=0,79; 95% ДИ: 0,76-0,81) [1].…”