Angiopoietin-like proteins inhibitors: New horizons in the treatment of atherogenic dyslipidemia and familial hypercholesterolemia

Surma, Stanisław; Romańczyk, Monika; Filipiak‬, Krzysztof J.

doi:10.5603/cj.a2021.0006

Cited by 14 publications

(23 citation statements)

References 45 publications

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“…The previously-mentioned angiopoietin-like protein-3 (ANGPTL3) inhibitors (evinacumab) recently introduced in familial hypercholesterolemia follow the same development route as PCSK9 modulators [115]. Evinacumab-the monoclonal antibody (like alirocumab/evolocumab)-was introduced as the first of its kind, but newer drugs based on RNA therapeutics technology, e.g., antisense oligonucleotides targeting mRNAs for ANGPTL3, are under investigation and some of them might be administered twice a year (like inclisiran).…”

Section: Potential Future Role Of Inclisiran In Hyperlipidemiamentioning

confidence: 99%

Inclisiran—Silencing the Cholesterol, Speaking up the Prognosis

Rogula

Błażejowska

Szarpak

et al. 2021

JCM

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The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%–20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.

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Section: Potential Future Role Of Inclisiran In Hyperlipidemiamentioning

confidence: 99%

Inclisiran—Silencing the Cholesterol, Speaking up the Prognosis

Rogula

Błażejowska

Szarpak

et al. 2021

JCM

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“…ANGPTL3, ANGPTL4 and ANGPTL8 play an important role in terms of cardiovascular physiology and lipid metabolism. These proteins regulate the metabolism of triglyceride-rich lipoproteins [1,2]. The main source of ANGPTL3 is liver, ANGPTL4 is liver, adipose tissue, skeletal muscle, gut, heart and brain, and ANGPTL8 is liver and adipose tissue.…”

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confidence: 99%

“…The main source of ANGPTL3 is liver, ANGPTL4 is liver, adipose tissue, skeletal muscle, gut, heart and brain, and ANGPTL8 is liver and adipose tissue. These proteins form a ANGPTL3-4-8 system that controls the availability of triglycerides depending on the current nutritional status of the body, temperature and physical activity (Figure 1) [1,2].…”

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confidence: 99%

“…In the heart, skeletal muscle and brown adipose tissue, the activity of LPL after a meal is reduced by ANGPTL3 and ANGPTL8 (after a meal, the expression of ANGPTL8 is particularly increased, while the expression of ANGPTL3 is not dependent on the nutritional status) forming a heterodimer (ANGPTL8 is an activator of ANGPTL3 (Figure 1). Thus, the ANGPTL3-4-8 system plays an important role in regulating triglyceride metabolism [1][2][3]. In a study by Dewey et al it was found that persons carrying the LOF mutation (loss of function) of the Angptl3 gene were characterized by decreased plasma concentrations of the four major lipid fractions, which translated into a 39% reduction in the risk of ischemic heart disease in these patients [4].…”

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confidence: 99%

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Evinacumab - a new drug in the treatment of homozygous familial hypercholesterolaemia

Surma¹,

Romańczyk²,

Filipiak‬³

2021

Integr Cancer Sci Therap

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Evinacumab, being a fully humanized anti-ANGPTL3 monoclonal antibody, February, 11th, 2021, as Evkeeza® preparation, has been registered by the U.S. Food & Drug Administration for the treatment of homozygous familial hypercholesterolaemia (HoHF).Angiopoietin-like proteins (ANGPTL) include the compounds ANGPTL1 through ANGPTL8 and belong to the vascular endothelial growth factor (VEGF) family. ANGPTL3, ANGPTL4 and ANGPTL8 play an important role in terms of cardiovascular physiology and lipid metabolism. These proteins regulate the metabolism of triglyceride-rich lipoproteins [1,2]. The main source of ANGPTL3 is liver, ANGPTL4 is liver, adipose tissue, skeletal muscle, gut, heart and brain, and ANGPTL8 is liver and adipose tissue. These proteins form a ANGPTL3-4-8 system that controls the availability of triglycerides depending on the current nutritional status of the body, temperature and physical activity (Figure 1) [1,2].

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“…Several compounds are currently in the late phases of clinical trials, e.g. inclisiran -a small interfering RNA against PCSK9, and vupanorsen -an antisense oligonucleotide against angiopoietin-like 3 (ANGPTL3) protein, or evinacumab -a monoclonal antibody against ANGPTL3 [13]. All of these compounds may become useful in the treatment of HeFH.…”

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confidence: 99%