Hypercholesterolemia represents a leading cause in the development of
atherosclerotic plaques, increasing the risk for ACVS. It actually counts as a major cause of
cardiovascular disease etiopathogenesis. The causes of
hypercholesterolemia are multifactorial, spanning from genetic constitution, age, sex, to sedentary lifestyle and diets rich in
sugars and
lipids. Although
dietary restriction in saturated
fats, increased exercise, and other modification in lifestyle represent a first-line approach to treat very initial stages in
hypercholesterolemia, most patients will require the addition of pharmacological agents. Pharmacological approaches include inhibition of
cholesterol synthesis, decreased fat absorption from the GI tract, and increased degradation of FA. These strategies present a series of side effects, low therapeutic efficiency in some patients, and reduced tolerability. One of the major goals in treatment for
hypercholesterolemia is to decrease the levels of
low density lipoproteins (
LDL), while maintaining those of
high density lipoproteins (HDL).
LDL particles contain about 80% of
lipids, most of it
cholesterol and
cholesteryl esters, and 20% of the
ApoB-100 protein.
LDL carries
cholesterol to the tissues, to be incorporated to biological membranes, or to be transformed to
steroids. Excess of
LDL translates into increased levels of circulating
cholesterol particles and accumulation in certain tissues, especially vascular tissue, initiating a fatty streak, which may evolve to an
atheroma, causing a series of cardiovascular problems, including impaired circulation,
high blood pressure, increased cardiac workload, and
coronary artery disease. It is essential to prevent
LDL accumulation into the bloodstream to avoid the formation of these fatty streaks and the initiation of a cascade that will lead to the development of
atherosclerosis. In healthy individuals. Under physiological conditions,
LDL is effectively removed from circulation through receptor-mediated endocytosis.
LDL clearance involves binding to its receptor, LDLR, which enables the internalization of the
LDL particle and drives its degradation in lysosomes. Once the
LDL particle is degraded, the free receptor recycles to the plasma membrane, and captures new
LDL particles. Adequate levels of LDLR are essential to remove the excess of
cholesterol-laden
LDL.
Proprotein convertase, subtilysin kexin type 9 (PCSK-9), expressed in liver and intestine, binds to LDLR, and internalized. Once inside the cell, PCSK-9 catalyzes the proteolysis of LDLR, preventing its recycling to the cell surface, and effectively decreasing the number of LDLR, notoriously decreasing the ability to clear
LDL from circulation. Levels of PCSK-9 varies with age, gender, and levels of
insulin,
glucose, and
triglycerides. Loss-of-function mutations in PCSK-9 gene invariably translates into lower levels of
LDL, and decreased risk of developing
coronary artery disease. Conversely, increased activity or expression of this
enzyme leads to
hypercholesterolemia. Inhibition of PCSK9 has proven to be successful in decreasing
LDL levels and risk of the development of
hypercholesterolemia with its associated higher risk for ASCVD. Patient with gain-of-function mutations in the PCSK9 undoubtedly benefit from
therapies based on PCSK-9 inhibitors. However, millions of patients show
statin intolerance, or cannot be efficiently controlled by
statins alone- the most prevalent
therapy for hypeprcholesterolemia. This commentary will evaluate the possibilities, caveats and future directions in the treatment of
hypercholesterolemia, and
therapies with combination of drugs.