Supporting evidence
In 1913, Anitschow demonstrated the relationship between cholesterol consumption and the formation of atheroma plaques by feeding mice a high cholesterol diet, reproducing the disease in an experimental model and evidencing the causal role of cholesterol in the pathogenesis of the atherosclerotic phenomenon (5). Later in 1939, Müller described the association between high levels of circulating cholesterol in families and the increased risk of ASCVD (6). The presence of cholesterol in experimentally induced atherosclerotic plaques in herbivores supports and reinforces the biological-experimental evidence of the cholesterol-atherosclerosis relationship (7). Furthermore, the description of populations with extremely high levels of LDL-C such as cases of Familial Hypercholesterolemia (FH), both heterozygous and homozygous, and its high prevalence of ASCVD provides clear pathophysiological evidence of this causal relationship (8).
The evidence derived from prospective epidemiological studies demonstrates a linear relationship between LDL-C levels and the risk of ASCVD. Two large meta-analyses summarize this evidence; the Collaboration Prospective Study and the Emerging Risk Factor Collaborations. The former reported data from 892,337 participants without evidence of ASCVD from 61 prospective cohort studies with a follow-up of 12 million individual-years; as a result, a direct association between plasma cholesterol levels and the risk of mortality from ischemic heart disease (IHD) was demonstrated. The latter collected data from 302,430 people without baseline ASCVD from 68 prospective studies, with a follow-up of 2.7 million individuals-years; as a result, a linear association was described between the levels of LDL-C and fatal and nonfatal myocardial infarction (MI) (9-10).
Mendelian randomization (MR) studies demonstrate evidence of causality, avoiding confounding factors, biases and reverse causation, potential characteristics of epidemiologic studies. MR studies also allow observational anticipation of the results of randomized and controlled studies. These genetic studies have unequivocally determined the association of more than 50 genes related to low levels of LDL-C and decreased risk of ASCVD. Randomized studies (average 5 years of follow up) with statins have shown a relative risk reduction (RRR) of 22% per 38.67 mg/dL (1mmol/L) of decrease in LDL-C (11). MR studies (lifetime effect) showed that with the same LDL-C decrease levels, an RRR of 55% is achieved. This evidences the deleterious cumulative effect of the deposit of LDL-C, emphasizing the need for early treatment strategies (12-13). On the other hand, MR studies have shown that the beneficial effect of the decrease in LDL-C is independent of the mechanism that produces this effect; these types of studies have also provided important information regarding the safety of low levels of LDL-C as well as potential pharmacological targets for the development of new therapeutic strategies (14).
Evidence derived from RCTs provides an unequivocal causality relationship between LDL-C levels and the atherosclerotic phenomenon. Studies using cholestyramine (15), and one study performing partial ileal bypass (16), have shown that decreasing LDL-C levels result in reduced risk of cardiovascular events. The Cholesterol Treatment Trialists’ (CTT) Collaboration analyzed 26 studies with statins that included almost 170,000 patients, demonstrating an RRR of cardiovascular events greater than 22% for every 38.6 mg/dL (1 mm/L) of decrease in LDL-C. This effect was independent from the baseline value of LDL-C and from ​​the existence of previous ASCVD, evidenced in the different subgroups analyzed (11, 17).
The IMPROVE-IT trial demonstrated that adding ezetimibe to statins resulted in a reduction of major cardiovascular events through a different mechanism than the inhibition of cholesterol synthesis. The magnitude of the risk reduction in cardiovascular events was consistent with the decrease in levels of LDL-C, agreeing with the evidence in the studies with statins (18).
The use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in the trials Further Cardiovascular Outcomes Research with PCSK9 Inhibition in study participants with Elevated Risk (FOURIER -27,564 patients-) (19) and (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) (ODYSSEY Outcomes -18,924 patients-) (20) achieve low levels of LDL-C never seen before, evidencing a reduction in the risk of cardiovascular events proportional to the decrease in circulating levels of LDL-C. It should be noted that there were no safety concerns when reaching such low levels of LDL-C (15-20 mg/dL). In addition, the benefit was continuous as the LDL-C values decreased, implying that there is no J-curve effect with a lower limit for LDL-C (21-22). Finally, GLAGOV trial with evolocumab, showed statistically significant regression of the atherosclerotic plaque measured by intravascular ultrasound when reaching an average level of 37 mg/dL of LDL-C (22).