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PCSK9 inhibitors Inclisiran
Proprotein convertase subtilisin/kexin type 9 (PCSK9) Inclisiran is a small interfering ribonucleic acid (siRNA)
is an enzyme predominantly produced in the liver. Its fun- that blocks the synthesis of PCSK9 in hepatocytes 26, 29 . As a
ction involves the degradation of LDL receptors (LDL-R) in result, there is an up-regulation of LDL receptors (LDL-R) and
hepatocytes, reducing the recycling of these receptors,and better uptake of LDL cholesterol from circulation, leading
down-regulating them. Consequently, this leads to an in- to significant lowering of LDL cholesterol levels. Inclisiran
crease in serum LDL cholesterol levels (reducing available is approved for the treatment of patients with heterozygo-
LDL-R for LDL clearance from circulation). Therefore, by in- us familial hypercholesterolemia (HeFH), familial combined
hibiting PCSK9 with monoclonal antibodies, the number of hyperlipidemia, and confirmed atherosclerotic cardiovas-
available LDL receptors is increased (up-regulation of recep- cular disease (CVD). It is administered as a subcutaneous
tors), leading to enhanced clearance of LDL cholesterol and injection at a dose of 284 mg. After the initial administration
significant reduction in its circulation . PCSK9 inhibitors of the drug, the second dose is given after three months,
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are injectable agents (monoclonal antibodies) administered and each subsequent dose is administered every six mon-
subcutaneously once or twice a month, with an extremely ths . The main advantage of inclisiran compared to PCSK9
29
low number of adverse effects. However, a limiting factor monoclonal antibodies is the dosing regimen and the lon-
for their wider use is their high cost . The most common ger-lasting effect, which ensures better compliance .
25
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adverse effects associated with direct use of PCSK9 inhibi-
tors are lower levels of vitamin E. The efficacy and safety of the drug were investigated in
the ORION studies involving patients receiving maximum
Evolocumab and alirocumab are monoclonal antibodies tolerated doses of statins and other lipid-lowering medicati-
that inhibit PCSK9 and are approved for clinical use as mo- ons. Results from one year of follow-up indicated that incli-
notherapy or in combination with statins and ezetimibe. siran lowers LDL cholesterol by 50% compared to placebo .
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Evolocumab reduces plasma LDL cholesterol levels by 53% Additionally, inclisiran has favorable effects on lowering
to 75%, depending on whether it is used as monotherapy or total cholesterol, triglycerides, non-HDL cholesterol, Lp(a),
in combination with statins, in patients with heterozygous and increasing HDL cholesterol . Currently, studies such
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familial hypercholesterolemia (HeFH). However, in patients as ORION-4, VICTORION-2, and PREVENT are underway to
with homozygous FH (HoFH) with defective LDL receptors, analyze the effects of inclisiran on the occurrence of new
this percentage is lower, around 31%. Alirocumab reduces cardiovascular disease (CVD) in patients with confirmed
plasma LDL cholesterol levels by 39% to 58% in patients with atherosclerotic CVD who were previously on statin therapy
HeFH and by 11.9% to 34.3% in patients with HoFH, depen- compared to placebo.
ding on whether it is used as monotherapy or in combinati-
on with statins .
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Omega-3 fatty acids
Results from two large randomized controlled clinical
trials (FOURIER and ODYSSEY) have shown that the use of Omega-3 fatty acids, such as eicosapentaenoic acid
evolocumab and alirocumab in patients with high cardiovas- (EPA) and docosahexaenoic acid (DHA), can reduce the risk
cular risk who were previously on statin therapy reduces the of new cardiovascular events through various mechanisms,
risk of new cardiovascular events by 15% . The mentioned including lowering triglyceride levels and exerting antit-
27
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studies have shown that the use of evolocumab leads to a hrombotic, anti-inflammatory, or antiarrhythmic effects .
reduction in total cholesterol, triglycerides, non-HDL chole- The results of a meta-analysis that included randomized
sterol, Apo B, and a mild increase in HDL cholesterol. Unlike clinical trials have shown the superiority of EPA monothera-
statins, the use of PCSK9 inhibitors unequivocally lowers se- py over EPA + DHA in reducing cardiovascular mortality, the
rum concentrations of Lp(a). Additionally, it has been shown frequency of non-fatal myocardial infarction, new cardiovas-
that the use of alirocumab has favorable effects on redu- cular events, and revascularization. However, a high dose of
cing oxidative stress, decreasing the production of inflam- the drug (2-4 grams of EPA per day) is necessary .
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matory cytokines, and reducing the activity of metallopro-
teinase 2, osteopontin, and osteoprotegerin, which are key
pathophysiological processes underlying atherosclerosis . Fibrates
28
Current guidelines recommend the use of PCSK9 inhibitors
in patients with high and very high cardiovascular risk who, The mechanism of action of fibrates involves the acti-
despite being on maximum tolerated doses of statins and vation of peroxisome proliferator-activated receptor-alpha
ezetimibe therapy, do not achieve the recommended target (PPAR-α), which, upon activation, stimulates lipolysis and
LDL cholesterol levels 9, 26 . the elimination of atherogenic particles rich in triglycerides
from the plasma by activating lipoprotein lipase. Activati-
on of PPAR-α induces a reduction in the production of Apo
C-III in the liver, leading to a decrease in the lipid fraction
contained in very low-density lipoprotein (VLDL) and LDL

30 DOI: 10.5937/Galmed2409031L