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).