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cholesterol . Additionally, activation of these nuclear recep- Pelacarsen, olpasiran, and SLN360
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tors leads to increased production of Apo A-I and A-II, resul-
ting in desirable elevation of HDL cholesterol levels. Pelacarsen is an antisense oligonucleotide that binds to
Apo mRNA, forming a complex that prevents the synthesis
The results of a meta-analysis that combined several of Lp(a) in hepatocytes, thereby reducing its production and
studies have shown that fibrates reduce the incidence of consequently the level of Lp(a) in the serum . Moreover,
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cardiovascular events by approximately 10% . Fibrates can these are the only drugs capable of modulating the level of
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be safely combined with statins in patients where secon- Lp(a) for which there has been no therapeutic option until
dary causes of hypertriglyceridemia are excluded and who, now. Pelacarsen has a significant impact on reducing total
despite dietary management, maintain high levels of trigly- cholesterol, LDL-C, and triglycerides, and it is administered
cerides . subcutaneously once a month. Currently, this drug is in Pha-
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se III of the HORIZON clinical trial, which aims to investigate
the protective effect of pelacarsen on adverse cardiovascu-
ANGPTL3 inhibitors lar events. Similar mechanisms of action are also exhibited
by olpasiran and SLN360, which are also in clinical trial pha-
ANGPLT3 (Angiopoietin-like protein 3) is a polypeptide ses 44, 45 .
that plays a significant role in lipid metabolism by inhibi-
ting lipoprotein and endothelial lipase, thereby increasing
levels of triglycerides and LDL cholesterol . Therefore, by Mipomersen
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inhibiting ANGPTL3, there is a reduction in triglycerides and
LDL cholesterol, which is the mechanism of action of this Mipomersen inhibits the production of Apo B found in
group of drugs that is independent of LDL receptors . Evi- LDL-C, VLDL, and Lp(a) . It significantly lowers LDL-C, non-
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nacumab is a monoclonal antibody from the group of AN- HDL-C, Lp(a), triglycerides, and Apo B. In the United States,
GPTL3 inhibitors approved for the treatment of homozygo- its subcutaneous administration at a dose of 200 mg was
us familial hypercholesterolemia (HoFH) with a significant approved in 2012 for patients with HoFH. However, due to
effect on lowering LDL cholesterol . The administration of serious adverse effects such as hepatotoxicity and liver ste-
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evinacumab is intravenous at a dose of 15 mg/kg every four atosis, the drug was withdrawn from the market in 2019 .
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weeks. In the third phase of clinical trials, the efficacy of
evinacumab was confirmed with a reduction in LDL chole-
sterol levels by 47.1% compared to placebo . Good results Lomitapide
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have been achieved with the use of evinacumab in mixed
dyslipidemia by lowering triglyceride levels. This could im- Lomitapide is an inhibitor of microsomal triglyceride
ply successful future applications for these patients. Adver- transfer protein (MTP), which is localized in the endoplasmic
se effects associated with the use of evinacumab include reticulum of hepatocytes. The role of MTP is to transport tri-
“flu-like“ symptoms, mild elevation in creatine kinase, and glycerides, phospholipids, and cholesterol esters to Apo B,
liver enzymes . and its inhibition reduces hepatic production of VLDL, con-
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sequently lowering levels of total cholesterol, serum LDL-C,
non-HDL-C, and Apo B. Lomitapide is approved for use in
Volanesorsen and olezarsen patients with HoFH, either alone or in combination with ot-
her lipid-lowering drugs, and it is administered orally once
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Volanesorsen and olezarsen inhibit the production of daily at a dose of 5-10 mg .
Apo C-III in the liver and small intestine, which is found in
triglyceride-rich lipoproteins. Volanesorsen, when admini-
stered to patients with familial hypertriglyceridemia, has a Lerodalcibep
favorable effect on reducing triglyceride levels, thereby re-
ducing the incidence of acute pancreatitis . A meta-analysis Lerodalcibep inhibits PCSK9 via CRISPR-Cas9 (Clustered
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has shown that treatment with volanesorsen leads to a re- Regularly Interspaced Short Palindromic Repeat-Cas9) te-
duction in triglycerides by approximately 72%, VLDL by 74%, chnology. Cas9 is a double-stranded DNA nuclease directed
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Apo B-48 by 60%, Apo C-III by 80%, with an increase in HDL to its target using guide RNA (CRISPR RNA, crRNA) . Lero-
by 46% and LDL by around 67% . dalcibep is a recombinant fusion protein consisting of the
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PCSK9-binding domain and human serum albumin. Results
Volanesorsen is administered subcutaneously at a dose from the third phase of clinical trials indicate that lerodalci-
of 285 mg once weekly for the first three months, and la- bep, administered subcutaneously once monthly at a dose
ter every two weeks. Olezarsen has a more favorable safety of 300 mg in patients with HeFH, on maximum tolerable do-
profile in terms of a lower risk of thrombocytopenia . In the ses of statins and ezetimibe, after 24 weeks of follow-up,
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early phase of clinical trials, ARO-APOC31001 siRNA, which showed effective reduction of LDL-C by approximately 60%,
degrades Messenger Ribonucleic Acid (mRNA) for Apo C-III, with about 70% of patients achieving LDL-C reduction ≥ 50%
is also being investigated . and recommended target values according to the 2019 ESC/
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EAS guidelines compared to placebo .
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REVIEW PAPER Galenika Medical Journal, 2024; 3(9):26-34. 31