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: