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

Abstract

Background: The Consensus Statement from the European Atherosclerosis Society (EAS) Consensus Panel 2017 concludes on the basis of 3 different types of clinical studies that low-density lipoprotein (LDL) causes atherosclerotic cardiovascular disease (ASCVD). In Mendelian randomization studies, rare genetic mutations affecting LDL receptor function were found to cause higher or lower LDL-C levels, which are associated with correspondingly altered ASCVD risk. In prospective cohort studies and randomized controlled trials (RCTs) of statins, a remarkably consistent log-linear association was demonstrated between the absolute magnitude of LDL-C exposure and ASCVD risk. The EAS Statement proposes that any mechanism of lowering plasma LDL 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. However, as we explain, we do not find this conclusion acceptable. Summary: Our review points out that different interpretations are possible for the results of Mendelian randomization studies. As for prospective cohort studies, many inconsistent reports on the association of LDL-C and ASCVD were disregarded when drafting the Statement, reports with and without genetic factors related to LDL receptor function should be analyzed separately, and the term ASCVD in the Statement is used inappropriately because myocardial infarction and cerebral infarction differ in their association with LDL-C. As for RCTs, clinical reports on statins published before and after the implementation of new regulations affecting clinical trials (2004/2005) should not both be included in meta-analyses because the evaluated efficacy of statins changed markedly, and the irreversible adverse effects of statins need to be evaluated more rigorously now that their mechanisms have been elucidated. Key Messages: Apart from the EAS hypothesis that LDL causes ASCVD, recent pharmacological/biochemical studies, as summarized in this review and elsewhere, have revealed that atherosclerosis is caused by statins taken to lower LDL-C, as well as by warfarin and some types of vegetable fats and oils, in the absence of significantly elevated LDL-C levels. Thus, the promotion of statin treatment by the Statement is rather risky and we do not feel that the conclusions are justified for the prevention of ASCVD.

LDL-C does not cause cardiovascular disease: a comprehensive review of the current literature

“…This is correct, but association is not the same as causation. Few authors have adjusted for other CVD-promoting factors such as mental stress, coagulation factors, inflammation, infections, and endothelial sensitivity, all of which are closely related to LDL receptor abnormalities [105]. For instance, mental stress can raise TC [17,18] possibly because cholesterol is necessary for the production of cortisol and other steroid stress hormones, and mental stress may cause CVD by an increased production of epinephrine and norepinephrine, which contribute to hypertension and hypercoagulation.…”

Conceptualization of Heterogeneity of Chronic Diseases and Atherosclerosis as a Pathway to Precision Medicine: Endophenotype, Endotype, and Residual Cardiovascular Risk

“…Currently, various variants of genetic mutations that cause an increase in LDL and the development of atherosclerosis and related cardiovascular diseases are known: LDLR, PCSK9, APOE, APOB-100, SORT1, ANGPTL3, CELSR2, PSRC1, HMGCR, etc. [42][43][44]. In studies using the multiomics approach, the causal effects of the genetic variants SORT1 and HMGCR have been established [45,46].…”

Statins in primary prevention: is the enthusiasm justified?

“… 14 , 25 However, the total events and mortality in women on placebo were almost consistently lower than in men on statins, 25 whereas adverse effects (AE) were higher in women, who were more likely to develop muscle pains, hepatic dysfunction and diabetes. 8 , 14 , 18 , 22 , 24 , 25 , 26 …”