Confluence of Mendelian Randomization with Clinical Trials as To Very Low Levels of LDL Cholesterol

Abstract

Atherosclerotic disease and its clinical manifestations, including acute myocardial infarction and ischemic stroke, are the leading cause of morbidity and mortality worldwide. Among the atherogenic risk factors, the most well-documented and the one that determines a causal relationship with atherosclerotic disease is low-density lipoprotein cholesterol (LDL-C) values. It is essential to identify LDL-C as a therapeutic target to reduce cardiovascular risk, especially after the emergence of new drugs that further reduce LDL-C levels, with additional risk reduction. Our objective is to demonstrate that LDL-C is an important atherogenic risk factor and that any mechanism of reduction of plasma LDL-C concentrations reduces the risk of events proportional to the absolute reduction of LDL-C and the cumulative time of exposure to it. Mendelian randomization studies: even though the association between LDL-C and cardiovascular risk is well demonstrated and reproducible in meta-analyses of prospective cohort studies, such studies are not randomized and therefore susceptible to biases such as reverse causality and confounders. Mendelian randomization is used especially when randomized controlled trials to examine causality are not feasible. This method will assess the causal relationship between a modifiable exposure, or risk factor, and a clinically relevant outcome. The confluence of the results of both Mendelian randomization and clinical trials leads to the same proposition: the lower the LDL-C, the better for the prevention of atherosclerotic lesions.