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1
Alborn, William E., Guoqing Cao, Holly E. Careskey, Yue-Wei Qian, Danise R. Subramaniam, Julian Davies, Elaine M. Conner, and Robert J. Konrad. "Serum Proprotein Convertase Subtilisin Kexin Type 9 Is Correlated Directly with Serum LDL Cholesterol." Clinical Chemistry 53, no. 10 (October 1, 2007): 1814–19. http://dx.doi.org/10.1373/clinchem.2007.091280.
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Abstract Background: Proprotein convertase subtilisin kexin type 9 (PCSK9) is gaining attention as a key regulator of serum LDL-cholesterol (LDLC). This novel serine protease causes the degradation of hepatic LDL receptors by an unknown mechanism. In humans, gain-of-function mutations in the PCSK9 gene cause a form of familial hypercholesterolemia, whereas loss-of-function mutations result in significantly decreased LDLC and decreased cardiovascular risk. Relatively little is known about PCSK9 in human serum. Methods: We used recombinant human PCSK9 protein and 2 different anti-PCSK9 monoclonal antibodies to build a sandwich ELISA. We measured PCSK9 and lipids in 55 human serum samples and correlated the results. We used the anti-PCSK9 antibodies to assay lipoprotein particle fractions separated by sequential flotation ultracentrifugation. Results: Serum concentrations of PCSK9 ranged from 11 to 115 μg/L and were directly correlated with serum concentrations of LDLC (r = 0.45, P = 0.001) and total cholesterol (r = 0.50, P = 0.0003), but not with triglycerides (r = 0.15, P = 0.28) or HDL cholesterol concentrations (r = 0.13, P = 0.36). PCSK9 was not detectable in any lipoprotein particle fraction, including LDL. Conclusions: PCSK9 is present in human serum, likely not associated with specific lipoprotein particles. The circulating concentrations of human PCSK9 are directly correlated with LDL and total cholesterol concentrations.
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Goksøyr, Louise, Magdalena Skrzypczak, Maureen Sampson, Morten A. Nielsen, Ali Salanti, Thor G. Theander, Alan T. Remaley, Willem A. De Jongh, and Adam F. Sander. "A cVLP-Based Vaccine Displaying Full-Length PCSK9 Elicits a Higher Reduction in Plasma PCSK9 Than Similar Peptide-Based cVLP Vaccines." Vaccines 11, no. 1 (December 20, 2022): 2. http://dx.doi.org/10.3390/vaccines11010002.
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Administration of PCSK9-specific monoclonal antibodies, as well as peptide-based PCSK9 vaccines, can lower plasma LDL cholesterol by blocking PCSK9. However, these treatments also cause an increase in plasma PCSK9 levels, presumably due to the formation of immune complexes. Here, we utilize a versatile capsid virus-like particle (cVLP)-based vaccine platform to deliver both full-length (FL) PCSK9 and PCSK9-derived peptide antigens, to investigate whether induction of a broader polyclonal anti-PCSK9 antibody response would mediate more efficient clearance of plasma PCSK9. This head-to-head immunization study reveals a significantly increased capacity of the FL PCSK9 cVLP vaccine to opsonize and clear plasma PCSK9. These findings may have implications for the design of PCSK9 and other vaccines that should effectively mediate opsonization and immune clearance of target antigens.
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Wang, Ellen Q., Jack F. Bukowski, Carla Yunis, Charles L. Shear, Paul M. Ridker, Pamela F. Schwartz, and Daniel Baltrukonis. "Assessing the Potential Risk of Cross-Reactivity Between Anti-Bococizumab Antibodies and Other Anti-PCSK9 Monoclonal Antibodies." BioDrugs 33, no. 5 (September 16, 2019): 571–79. http://dx.doi.org/10.1007/s40259-019-00375-0.
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Momtazi-Borojeni, Amir Abbas, Matteo Pirro, Suowen Xu, and Amirhossein Sahebkar. "PCSK9 Inhibition-Based Therapeutic Approaches: An Immunotherapy Perspective." Current Medicinal Chemistry 29, no. 6 (February 2022): 980–99. http://dx.doi.org/10.2174/0929867328666211027125245.
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Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (PCSK9-I) are novel therapeutic tools to decrease cardiovascular risk. These agents work by lowering the low-density lipoprotein cholesterol (LDL-C) in hypercholesterolemic patients who are statin resistant/intolerant. Current clinically approved and investigational PCSK9- I act generally by blocking PCSK9 activity in the plasma or suppressing its expression or secretion by hepatocytes. The most widely investigated method is the disruption of PCSK9/LDL receptor (LDLR) interaction by fully-humanized monoclonal antibodies (mAbs), evolocumab and alirocumab, which have been approved for the therapy of hypercholesterolemia and atherosclerotic cardiovascular disease (CVD). Besides, a small interfering RNA called inclisiran, which specifically suppresses PCSK9 expression in hepatocytes, is as effective as mAbs but with administration twice a year. Because of the high costs of such therapeutic approaches, several other PCSK9-I have been surveyed, including peptide-based anti-PCSK9 vaccines and small oral anti-PCSK9 molecules, which are under investigation in preclinical and phase I clinical studies. Interestingly, anti-PCSK9 vaccination has been found to serve as a more widely feasible and more cost-effective therapeutic tool over mAb PCSK9-I for managing hypercholesterolemia. The present review will discuss LDL-lowering and cardioprotective effects of PCSK9-I, mainly immunotherapy- based inhibitors including mAbs and vaccines, in preclinical and clinical studies.
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Merćep, Iveta, Nikolina Friščić, Dominik Strikić, and Željko Reiner. "Advantages and Disadvantages of Inclisiran: A Small Interfering Ribonucleic Acid Molecule Targeting PCSK9—A Narrative Review." Cardiovascular Therapeutics 2022 (February 10, 2022): 1–6. http://dx.doi.org/10.1155/2022/8129513.
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As dyslipidemias remain one of the main risk factors for developing cardiovascular disease, the question of maintaining optimal lipid levels with pharmacotherapy remains a subject of interest worldwide. In contrast to conventional pharmacotherapy, human monoclonal antibodies directed against proprotein convertase subtilisin/kexin type 9 (PSCK9) and small interfering RNA- (siRNA-) based drug targeting PCSK9 represent a new strategy for managing lipid disorders and reducing cardiovascular risk. Inclisiran is a long-acting, synthetic siRNA that targets hepatic production of PCSK9 and consequently causes a reduction in LDL-C concentrations by approximately 50% compared to placebo. The structural modification of inclisiran has led to better stability and prolonged biological activity of the drug. The main advantage over conventional pharmacotherapy and anti-PCSK9 monoclonal antibodies is its favorable administration regimen (0–90–180 days), which should lead to much better compliance. Clinical trials conducted so far have confirmed the tolerability and efficacy of inclisiran in long-term PCSK9 and LDL-C level reductions. Moreover, a short-term follow-up on the safety of inclisiran showed a relatively good safety profile of the drug. However, it is still of great importance for ongoing and forthcoming clinical trials to be continued on a larger group of patients in order to assess long-term tolerability, efficacy, and safety of inclisiran.
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Lepor, Norman E., Laurn Contreras, Chirag Desai, and Dean J. Kereiakes. "The Potential Role of Anti-PCSK9 Monoclonal Antibodies in the Management of Hypercholesterolemia." Reviews in Cardiovascular Medicine 15, no. 4 (December 30, 2014): 290–309. http://dx.doi.org/10.3909/ricm0773.
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Chaulin, Aleksey M. "Hypolipidemic drugs inhibiting the proprotein convertase of subtilisin/kexin type 9 (PCSK9): monoclonal antibodies, antisense oligonucleotides, small interfering ribonucleic acids." Reviews on Clinical Pharmacology and Drug Therapy 19, no. 1 (May 21, 2021): 37–46. http://dx.doi.org/10.17816/rcf19137-46.
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Hypolipidemic therapy is one of the essential components for the management of patients with cardiovascular diseases (CVD). In this regard, the main task of modern research is to find new targets for creating additional effective groups of hypolipidemic drugs. In 2003, canadian and french research groups led by N. Seidah and M. Abifadel discovered a new enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9), which later turned out to play an important role in lipid metabolism. The main mechanism of action of PCSK9 is to regulate the density of low-density lipoprotein receptors (LDLR) in the cell membrane of hepatocytes. Increased activity of PCSK9 significantly accelerates the degradation of LDL and leads to an increase in the concentration of atherogenic classes of lipoproteins-low-density lipoproteins (LDL). In contrast, reduced PCSK9 activity is accompanied by a decrease in LDL concentrations and a reduced risk of developing atherosclerosis and CVD. The second of the recently discovered and less studied mechanism of PCSK9 protearogenic action is an increase in inflammatory processes in the atherosclerotic plaque. Given this adverse contribution of PCSK9 to the development and progression of atherosclerosis and CVD, the main task of the researchers was to develop drugs that inhibit THIS enzyme. To date, several new groups of drugs have been developed that target the stages of biosynthesis and the function of PCSK9. In this article, we will focus in detail on discussing the mechanisms of action and effectiveness of the following groups of hypolipidemic drugs: anti-PCSK9 monoclonal antibodies (alirocumab, evolocumab), small interfering ribonucleic acids (incliciran), and antisense nucleotides.
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Canclini, L., N. Jabnati, A. M. Malvandi, A. Baragetti, L. Grigore, and A. L. Catapano. "Proprotein convertase subtilisin/kexin type 9 (PCSK9) association to LDL in patients treated with anti-PCSK9 monoclonal antibodies." Atherosclerosis 331 (August 2021): e139. http://dx.doi.org/10.1016/j.atherosclerosis.2021.06.414.
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Bonaventura, Aldo, Alessandra Vecchié, Massimiliano Ruscica, Francesco Grossi, and Francesco Dentali. "PCSK9 as a New Player in Cancer: New Opportunity or Red Herring?" Current Medicinal Chemistry 29, no. 6 (February 2022): 960–69. http://dx.doi.org/10.2174/0929867328666211115122324.
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: Initially described as a factor involved in liver regeneration and neuronal differentiation, proprotein convertase subtilisin/kexin type 9 (PCSK9) has become one of the key regulators of low-density lipoprotein cholesterol. Beside that, a number of studies have suggested PCSK9 may play a role in cancer biology. This is particularly true for gastroenteric (gastric and liver cancers) and lung cancers, where higher PCSK9 levels were associated with the increased ability of the tumor to develop and give metastasis as well as with reduced overall survival. Accordingly, monoclonal antibodies blocking PCSK9 were recently shown to synergize with immunotherapy in different types of cancers to achieve tumor growth suppression through an increased intratumoral infiltration of cytotoxic T cells. Anti-PCSK9 vaccines have been tested in animal models with encouraging results only in colon carcinoma. As most of this evidence is based on pre-clinical studies, this has led to some controversies and inconsistencies, thus suggesting that additional research is needed to clarify the topic. Finally, modulation of intracellular PCSK9 levels by silencing RNA (siRNA) may help understand the physiological and pathological mechanisms of PCSK9.
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Drenina, Yu A., and K. Yu Nikolaev. "PCSK9 in acute coronary syndrome: analysis of associations with clinical and laboratory characteristics." Cardiovascular Therapy and Prevention 19, no. 4 (September 5, 2020): 2484. http://dx.doi.org/10.15829/1728-8800-2020-2484.
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The article discusses a literature review reflecting the importance of identifying novel biomarkers in cardiology for improving conventional methods for diagnosing and stratifying risk in patients with acute coronary syndrome (ACS). Recently, more and more studies have published on such markers, in particular, on the proprotein convertase subtilisin/ kexin type 9 (PCSK9). The aim of this review was to analyze the associations of PCSK9 with clinical and laboratory parameters in patients with ACS. It has been demonstrated that the PCSK9 level in acute myocardial infarction is significantly increased. In patients with ACS, the level of PCSK9 is directly related to the duration of pain, the severity of coronary artery disease, familial hypercholesterolemia and lipid parameters, as well as the severity of coronary atherosclerosis according to the SYNTAX score. It was found that statin therapy before ACS significantly affects the association of PCSK9 with lipid profile. There are conflicting data on the associations of PCSK9 with the parameters of inflammatory response in ACS, as well as isolated evidence of the positive role of anti-IL-6 receptor monoclonal antibodies in ACS patients with dyslipidemia. The impact of PCSK9 on ACS prognosis is currently unstudied.
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Barale, Cristina, Elena Melchionda, Alessandro Morotti, and Isabella Russo. "PCSK9 Biology and Its Role in Atherothrombosis." International Journal of Molecular Sciences 22, no. 11 (May 30, 2021): 5880. http://dx.doi.org/10.3390/ijms22115880.
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It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.
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VG, Athyros. "6th Hellenic Congress in Athens, of the Hellenic Atherosclerosis Society, on the 04-06 December 2014 Novel Pharmacologic Treatments of Familial Hypercholesterolaemia." Open Cardiovascular Medicine Journal 9, no. 1 (October 15, 2015): 73–77. http://dx.doi.org/10.2174/1874192401509010073.
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Familial hypercholesterolaemia (FH) is the most common inherited monogenic lipid disorder. It is caused by mutations of genes related to low density lipoprotein (LDL) receptors, apolipoprotein B or proprotein convertase subtilisin/kexin type 9 (PCSK9). Homozygous FH (HoFH; 1/400,000 births) is treated by LDL apheresis. Recently lomitapide has been used for the treatment of HoFH as a monotherapy or in addition to LDL apheresis. Heterozygous FH (HeFH), 1/250-1/200 births, is associated with an increased cardiovascular disease (CVD) risk. The main treatment for HeFH has been high doses of high intensity statins plus ezetimibe. However, this is not usually enough to attain LDL-C targets, especially in those with overt CVD or equivalents (LDL-C goal of<70 mg/dl). Data from the Atherosclerosis Risk in Communities study showed that loss of function mutations of PCSK9 were associated with a 28% lower LDL-C level and an 88% reduction in the risk of CVD in blacks, while in whites these numbers were 15% and 47%, respectively. This led to the development of technology to block PCSK9 with monoclonal human antibodies (e.g. evolocumab and alirocumab). These antibodies have been shown in phase II and III trials to be safe and to produce reductions in LDL-C levels by around 60% either as monotherapy or on top of optimal therapy with statins and ezetimibe. These antibodies are administered subcutaneously every 2 weeks with an automatic device. Anti-PCSK9 antibodies are expected to be licensed soon (? in 2015) and are considered by many as “the statins of the 21st century”.
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Lepor, Norman E., Laurn Contreras, Chirag Desai, and Dean J. Kereiakes. "Correction to “The Potential Role of Anti-PCSK9 Monoclonal Antibodies in the Management of Hypercholesterolemia”." Reviews in Cardiovascular Medicine 16, no. 1 (March 30, 2015): 94. http://dx.doi.org/10.3909/ricm0773corr.
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Ji, Eunhye, and Sahmin Lee. "Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases." International Journal of Molecular Sciences 22, no. 11 (May 28, 2021): 5770. http://dx.doi.org/10.3390/ijms22115770.
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Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.
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Ferri, Nicola, Massimiliano Ruscica, Maria Giovanna Lupo, Marco Vicenzi, Cesare R. Sirtori, and Alberto Corsini. "Pharmacological rationale for the very early treatment of acute coronary syndrome with monoclonal antibodies anti-PCSK9." Pharmacological Research 184 (October 2022): 106439. http://dx.doi.org/10.1016/j.phrs.2022.106439.
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Gouni‐Berthold, Ioanna, Olivier S. Descamps, Uwe Fraass, Elizabeth Hartfield, Kim Allcott, Ricardo Dent, and Winfried März. "Systematic review of published Phase 3 data on anti‐PCSK9 monoclonal antibodies in patients with hypercholesterolaemia." British Journal of Clinical Pharmacology 82, no. 6 (October 4, 2016): 1412–43. http://dx.doi.org/10.1111/bcp.13066.
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Casula, M., E. Olmastroni, M. Boccalari Taddeo, E. Tragni, A. Pirillo, and A. Catapano Luigi. "Safety And Cardiovascular Efficacy Of Anti-Pcsk9 Monoclonal Antibodies: A Meta-Analysis Of Randomised Controlled Trials." Atherosclerosis 287 (August 2019): e39. http://dx.doi.org/10.1016/j.atherosclerosis.2019.06.113.
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Schreml, Julia, and Ioanna Gouni-Berthold. "Role of Anti-PCSK9 Antibodies in the Treatment of Patients with Statin Intolerance." Current Medicinal Chemistry 25, no. 13 (May 7, 2018): 1538–48. http://dx.doi.org/10.2174/0929867324666170616111647.
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Statin intolerance is usually defined as the inability of a patient to tolerate statintreatment due to muscle-related complaints. While randomised trials show that these complaints occure with similar frequency in patients receiving placebo, namely in up to ~5% of the subjects, and data from registries as well as clinical experience indicate a much higher frequency of up to ~30%. The lack of standard definition or of a diagnostic marker of statin intolerance confounds the problem. The diagnosis remains subjective based on the symptoms the patient reports. Therefore, a large number of patients who need a statin are not receiving it, or receiving only very-low and/or intermittent doses unable to achieve a robust decrease in low-density lipoprotein cholesterol (LDL-C), leaving patients at high or very high risk for cardiovascular events requiring an alternative form of lipid-lowering therapy. Until recently, the only available alternatives were niacin, ezetimibe, bile-acid sequestrants and fibrates that decrease LDL-C concentrations by up to 15-20%. Recently the fully human monoclonal antibodies against proprotein convertase subtilisin/kexin 9 (PCSK9), alirocumab (Praluent®) and evolocumab (Repatha®), which have been shown to decrease LDL-C by up to 70% have been approved in Europe for use in patients with primary hypercholesterolemia not at LDL-C target while on maximally tolerated lipid-lowering therapy and specifically for patients with statin intolerance and in the USA for patients with atherosclerotic cardiovascular disease or familial hypercholesterolemia requiring additional LDL-C lowering. Ongoing large clinical trials with cardiovascular endpoints will provide a definitive answer for the role of anti-PCSK9 antibodies in clinical practice.
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Chaulin, A. M. "New groups of hypolipidemic medications based on inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). Part 1." Clinical Medicine (Russian Journal) 98, no. 11-12 (April 18, 2021): 739–44. http://dx.doi.org/10.30629/0023-2149-2020-98-11-12-739-744.
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Hypolipidemic therapy is one of the essential components for the management of patients with cardiovascular diseases (CVD). In this regard, the main task of modern research is to find new targets for creating additional effective groups of hypolipidemic medications. Canadian and French research groups led by N. Seidah and M. Abifadel discovered a new enzyme — proprotein convertase subtilisin-kexin type 9 (PCSK9) in 2003. It turned out to play an important role in lipid metabolism later. The main mechanism of action of PCSK9 is to regulate the density of low-density lipoprotein receptors (LDLR) in the cell membrane of hepatocytes. Increased activity of PCSK9 accelerates the degradation of LDL significantly, and leads to an increase in the concentration of atherogenic classes of lipoproteins — low-density lipoproteins (LDL). In contrast, reduced PCSK9 activity is accompanied by a decrease in LDL concentrations and a reduced risk of developing atherosclerosis and CVD. The second of the recently discovered and less studied mechanism of PCSK9 protearogenic action is an increase in inflammatory processes in the atherosclerotic plaque. Considering this adverse contribution of PCSK9 to the development and progression of atherosclerosis and CVD, the main task of the researchers was to develop medications that inhibit THIS enzyme. Several new groups of medications that target the stages of biosynthesis and the function of PCSK9 have been developed by now. In this article, we will focus on details discussing the mechanisms of action and effectiveness of the following groups of hypolipidemic medications: anti-PCSK9 monoclonal antibodies (alirocumab, evolocumab), small interfering ribonucleic acids (incliciran), and antisense nucleotides.
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Chaulin, Aleksey M., Nikolay A. Svechkov, and Dmitry V. Duplyakov. "New groups of hypolipidemic drugs based on inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). Part 1." Science and Innovations in Medicine 6, no. 1 (March 29, 2021): 54–60. http://dx.doi.org/10.35693/2500-1388-2021-6-1-54-60.
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The hypolipidemic therapy is one of the essential components for the management of patients with cardiovascular diseases (CVD). In this regard, the main task of modern research is to find new targets for creating additional effective groups of lipid-lowering drugs. In 2003, a Canadian and French research team led by N. Seidah and M. Abifadel discovered a new enzyme, proprotein convertase subtilisin-kexin type 9 (PCSK9), which plays an important role in lipid metabolism.
The main mechanism of action of PCSK9 is to regulate the density of low-density lipoprotein receptors (LDLR) in the cell membrane of hepatocytes. The increased activity of PCSK9 significantly accelerates the degradation of LDLR and leads to an increase in the concentration of atherogenic classes of lipoproteins the low-density lipoproteins (LDL). A reduced activity of PCSK9, on the contrary, is accompanied by a decrease in the concentration of LDL and a decrease in the risk of developing atherosclerosis and CVD. The second, recently discovered and less studied, mechanism of the protearogenic action of PCSK9 is the enhancement of inflammatory processes in the atherosclerotic plaque. Given this unfavorable contribution of PCSK9 to the development and progression of atherosclerosis and CVD, the main task of the researchers was to develop drugs that inhibit this enzyme. To date, several new drug groups have been developed that target the biosynthesis steps and the function of PCSK9.
In this article, we will focus in detail on the discussion of the mechanisms of action and effectiveness of the following groups of lipid-lowering drugs: anti-PCSK9 monoclonal antibodies (alirocumab, evolocumab), small interfering ribonucleic acids (incliciran) and antisense nucleotides.
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Lupo, Maria, and Nicola Ferri. "Angiopoietin-Like 3 (ANGPTL3) and Atherosclerosis: Lipid and Non-Lipid Related Effects." Journal of Cardiovascular Development and Disease 5, no. 3 (July 14, 2018): 39. http://dx.doi.org/10.3390/jcdd5030039.
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Genetic and clinical studies have demonstrated that loss-of-function variants in the angiopoietin-like 3 (ANGPTL3) gene are associated with decreased plasma levels of triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), which leads to a significant reduction in cardiovascular risk. For this reason, ANGPTL3 is considered an important new pharmacological target for the treatment of cardiovascular diseases (CVDs) together with more conventional lipid lowering therapies, such as statins and anti proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies. Experimental evidence demonstrates that anti-ANGPTL3 therapies have an important anti-atherosclerotic effect. Results from phase I clinical trials with a monoclonal anti-ANGPTL3 antibody (evinacumab) and anti-sense oligonucleotide (ASO) clearly show a significant lipid lowering effect. In addition, from the analysis of the protein structure of ANGPTL3, it has been hypothesized that, beyond its inhibitory activity on lipoprotein and endothelial lipases, this molecule may have a pro-inflammatory, pro-angiogenic effect and a negative effect on cholesterol efflux, implying additional pro-atherosclerotic properties. In the future, data from phase II clinical trials and additional experimental evidence will help to define the efficacy and the additional anti-atherosclerotic properties of anti-ANGPTL3 therapies beyond the already available lipid lowering therapies.
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Verma, Divya Ratan, and Eliot A. Brinton. "Management of Hypercholesterolemia for Prevention of Atherosclerotic Cardiovascular Disease: Focus on the Potential Role of Recombinant Anti-PCSK9 Monoclonal Antibodies." Reviews in Cardiovascular Medicine 15, no. 2 (June 30, 2014): 86–101. http://dx.doi.org/10.3909/ricm0741.
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Pasta, A., A. L. Cremonini, E. Formisano, R. Fresa, S. Bertolini, and L. Pisciotta. "Long-term follow-up of genetically confirmed patients with familial hypercholesterolemia from the treatment with the first-generation statins to monoclonal anti-PCSK9 antibodies." Atherosclerosis 315 (December 2020): e212. http://dx.doi.org/10.1016/j.atherosclerosis.2020.10.662.
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Thiagarajan, D., R. Fiskesund, J. Steen, M. Rahman, S. Lundström, and J. Frostegård. "THU0230 IGG1 ANTIBODIES AGAINST PHOSPHORYLCHOLINE ARE NEGATIVELY ASSOCIATED WITH DISEASE ACTIVITY, DISEASE DAMAGE, CARDIOVASCULAR DISEASE AND ATHEROSCLEROSIS IN SLE: POTENTIAL UNDERLYING MECHANISMS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 342.2–343. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5779.
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Background:Phosphorylcholine (PC) is an important component in cellular membranes and in lipoproteins that is exposed and recognized by the immune system, when cells undergo apoptosis or lipoproteins like LDL undergo oxidation. PC is also exposed in some microorganisms including nematodes and bacteria (non-self). We reported that IgM anti-PC is associated with protection in atherosclerosis, SLE, RA and other chronic inflammatory conditions.1We also reported potential underlying protective mechanisms: 1: increase in clearance of human dead cells,22: inhibition of uptake of oxLDL in macrophages, 3: inhibition of cell death.14: anti-inflammatory; 5: promotion of polarization of T regulatory cells in SLE-patients´ T cells from a low level and also in plaque T cells.3We generated in-house fully human IgG1 anti-PC clones for experimental studies to study anti-PC properties in humans. In contrast to mice, anti-PC are not germ-line encoded with a dominant clone.4Objectives:We here study IgG1 and IgG2 anti-PC, with focus on atherosclerosis and SLE and properties of fully human IgG1 clones, in relation to SLE.Methods:We determined anti-PC by ELISA in 116 SLE-patients and 110 age- and sex-matched controls. For functional studies, we used three in-house generated, fully human monoclonal IgG1 anti-PC (A01, D05, E01). Apoptosis was induced in Jurkat T-cells and pre-incubated with A01, D05, E01 or isotype control IgG1 and effects on efferocytosis by human macrophages studied. Anti-PC peptide/protein characterization was determined using a proteomics de novo sequencing approach.Results:IgG1 but not IgG2 anti-PC levels were higher among SLE patients (p=0.02). IgG1 anti-PC was negatively associated with SLICC and SLEDAI (OR: 2,978 CI: 0.876-10.098, OR: 5.108 CI 1.3 20.067 respectively) and negatively associated with CVD, atherosclerotic plaques and echolucent (potentially vulnerable plaques) but the association for the two former was not significant after controlling for confounders. D05 had maximum effect on macrophage efferocytosis efficiency, followed by A01 and E01. The monoclonal antibodies showed differential binding specificity to PC and PC associated neo-epitopes. Peptide analysis showed difference in the CDR3 region of the three anti-PC IgG1 clones which are crucial for recognition of PC on apoptotic cell surface and other neo-epitopes.Conclusion:Anti-PC IgG1 is negatively associated with disease activity, and disease damage in SLE, but the negative association with CVD is also dependent on confounding risk factors. One potential underlying mechanism could be increased clearance of dead cells.References:[1]Frostegard J. Immunity, atherosclerosis and cardiovascular disease.BMC Med. 2013;11:117.[2]Rahman M, Sing S, Golabkesh Z, Fiskesund R, Gustafsson T, Jogestrand T, Frostegard AG, Hafstrom I, Liu A and Frostegard J. IgM antibodies against malondialdehyde and phosphorylcholine are together strong protection markers for atherosclerosis in systemic lupus erythematosus: Regulation and underlying mechanisms.Clin Immunol. 2016;166-167:27-37.[3]Sun J, Lundstrom SL, Zhang B, Zubarev RA, Steuer J, Gillgren P, Rahman M, Ajeganova S, Liu A and Frostegard J. IgM antibodies against phosphorylcholine promote polarization of T regulatory cells from patients with atherosclerotic plaques, systemic lupus erythematosus and healthy donors.Atherosclerosis. 2018;268:36-48.[4]Fiskesund R, Steen J, Amara K, Murray F, Szwajda A, Liu A, Douagi I, Malmstrom V and Frostegard J. Naturally occurring human phosphorylcholine antibodies are predominantly products of affinity-matured B cells in the adult.J Immunol. 2014;192:4551-9.Disclosure of Interests: :Divya Thiagarajan: None declared, Roland Fiskesund: None declared, Johanna Steen: None declared, Mizanur Rahman: None declared, Susanna Lundström: None declared, Johan Frostegård Grant/research support from: Unconditional competitive grant from Amgen, related only to PCSK9, not the topic of this abstract
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Elis, Avishay, Cheli Melzer Cohen, and Gabriel Chodick. "Real-World Use of Alirocumab: Experience from a Large Healthcare Provider." Journal of Clinical Medicine 12, no. 3 (January 30, 2023): 1084. http://dx.doi.org/10.3390/jcm12031084.
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With the emerging use of anti-PCSK9 monoclonal antibodies for lowering low-density lipoprotein cholesterol (LDL-C) levels, real-world evidence (RWE) is needed to evaluate drug effectiveness. This study aimed to characterize new users of alirocumab and evaluate its effectiveness in achieving LDL-C target levels. Included were patients initiating treatment with alirocumab from 1 August 2016 to 1 May 2020, with blood lipids evaluations during baseline (180 days prior to therapy initiation) and after 120 (±60) days of follow-up. Patients with treatment intensification during the follow-up period were excluded. LDL-C change from baseline and reaching LDL-C target levels, according to 2019 ESC/EAS guidelines, were evaluated. Among 623 included patients, 50.2% were men, the mean age was 65 years (±9 y), 62% were classified as very-high risk, and 76% had statin intolerance. During the follow-up, 65% (n = 407) were treated only with alirocumab. In 90% the initiation dose was 75 mg, and 21% were up-titrated. Alirocumab was associated with a 31.7% reduction in LDL-C, with 20.5% of patients reaching target levels. In this RWE study, alirocumab was used primarily as a single agent for eligible patients. Suboptimal use and adherence to therapy may have led to a lower LDL-C reduction compared to previous RCTs and most reported real-world studies.
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Nestel, Paul J., and Trevor A. Mori. "A Review of Low-Density Lipoprotein-Lowering Diets in the Age of Anti-Sense Technology." Nutrients 15, no. 5 (March 1, 2023): 1249. http://dx.doi.org/10.3390/nu15051249.
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This narrative review discusses an important issue, the primary role of diet in reducing low-density lipoprotein cholesterol (LDLc) concentrations in polygenic hypercholesterolemia. Two effective drugs, statins, and ezetimibe, that lower LDLc > 20% are relatively inexpensive and potential competitors to strict dieting. Biochemical and genomic studies have shown that proprotein convertase subtilisin kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) and lipid metabolism. Clinical trials have demonstrated that inhibitory monoclonal antibodies of PCSK9 dose-dependently lower LDLc up to 60%, with evidence of both regression and stabilization of coronary atherosclerosis and a reduction in cardiovascular risk. Recent approaches using RNA interference to achieve PCSK9 inhibition are currently undergoing clinical evaluation. The latter presents an attractive option of twice-yearly injections. They are, however, currently expensive and unsuitable for moderate hypercholesterolemia, which is largely due to inappropriate patterns of eating. The best dietary approach, the substitution of saturated fatty acids by polyunsaturated fatty acids at 5% energy, yields > 10% lowering of LDLc. Foods such as nuts and brans, especially within a prudent, plant-based diet low in saturates complemented by supplements such as phytosterols, have the potential to reduce LDLc further. A combination of such foods has been shown to lower LDLc by 20%. A nutritional approach requires backing from industry to develop and market LDLc-lowering products before pharmacology replaces the diet option. Energetic support from health professionals is vital.
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Cersosimo, Angelicac, Giuliana Cimino, Ludovica Amore, Andrea Drera, Mara Gavazzoni, and Riccardo Raddino. "170 Evaluation of endothelial function in dyslipidaemic patients treated with anti-PCSK9 monoclonal antibody." European Heart Journal Supplements 23, Supplement_G (December 1, 2021). http://dx.doi.org/10.1093/eurheartj/suab131.010.
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Abstract Aims According to new Guidelines, the use of an anti-PCSK9 monoclonal antibody in combination is recommended in secondary prevention in patients with very high risk who do not reach the target with the maximum tolerated dose of statin and ezetimibe, and in those patients with very high-risk familial hypercholesterolemia. The therapy is always combination, while the single treatment with anti-PCSK9 monoclonal antibody is indicated in patients with statin intolerance. The present study aims to determine the cardiovascular effects that are highlighted in the treatment of dyslipidaemia with the anti-PCSK9 monoclonal antibody, especially as regards the endothelial function (using the non-invasive methods of EndoPAT), the arterial stiffness (using the non-invasive methods of SphygmoCOR) and the effective improvement on the lipid profile (reduction total cholesterol, LDL and triglycerides). Methods The study is a single-centre prospective study enrolling 47 patients in primary and secondary prevention with non-target LDL cholesterol. Patients were evaluated and enrolled from April 2019 to June 2020 (recruitment period). The average follow-up was 12 weeks, from intaking one of anti-PCSK9, Alirocumab 75 or 150 mg and Evolocumab 140 mg. The scheduled evaluations of the enrolled population were before the beginning of the therapy and after a period of 12 weeks. Results After 12 weeks of treatment we demonstrated a statistically significant reduction in total cholesterol (P < 0.001) and LDL (P < 0.001). An important effect on the inflammatory profile was highlighted, resulting in a decrease in Hs-CRP at 12-weeks (P 0.057), associated with an improvement on endothelial function (P 0.003). Reduction of arterial stiffness was no significant (P 0.238). Conclusions Data confirm anti-PCSK9 monoclonal antibodies, associated with statins and/or ezetimibe to reach LDL target, improve significantly lipid profile and endothelial function. Furthermore anti-PCSK9 monoclonal antibodies are safe and practically free of side effects.
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Byun, Jae Hyun, Paul F. Lebeau, Khrystyna Platko, Rachel E. Carlisle, Mahi Faiyaz, Jack Chen, Melissa E. MacDonald, et al. "Inhibitory antibodies against PCSK9 reduce surface CD36 and mitigate diet-induced renal lipotoxicity." Kidney360, April 27, 2022, 10.34067/KID.0007022021. http://dx.doi.org/10.34067/kid.0007022021.
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Background: PCSK9 modulates the uptake of circulating lipids through a range of receptors, including the low-density lipoprotein receptor (LDLR) and CD36. In the kidney, CD36 is known to contribute to renal injury through pro-inflammatory and -fibrotic pathways. In this study, we sought to investigate the role of PCSK9 in modulating renal lipid accumulation and injury through CD36 using a high fat diet (HFD)-induced mouse model. Methods: The effect of PCSK9 on the expression of CD36 and intracellular accumulation of lipid was examined in cultured renal cells and in the kidneys of male C57BL/6J mice. The impact of these findings were subsequently explored in a model of HFD-induced renal injury in Pcsk9-/- and Pcsk9+/+ littermate control mice on a C57BL/6J background. Results: In the absence of PCSK9, we observed heightened CD36 expression levels, which increased free fatty acid (FFA) uptake in cultured renal tubular cells. As a result, PCSK9 deficiency was associated with an increase in long-chain saturated FFA-induced ER stress. Consistent with these observations, Pcsk9-/- mice fed HFD displayed elevated ER stress, inflammation, fibrosis, and renal injury relative to HFD-fed control mice. In contrast to Pcsk9-/- mice, pre-treatment of WT C57BL/6J mice with evolocumab, an anti-PCSK9 monoclonal antibody (mAbs) that binds to and inhibits the function of circulating PCSK9, protected against HFD-induced renal injury in association with reducing cell-surface CD36 expression on renal epithelia. Conclusions: We report that circulating PCSK9 modulates renal lipid uptake in a manner dependent on renal CD36. In the context of increased dietary fat consumption, the absence of circulating PCSK9 may promote renal lipid accumulation and subsequent renal injury. However, while the administration of evolocumab blocks the interaction of PCSK9 with the LDLR, this evolocumab/PCSK9 complex can still bind CD36, thereby protecting against HFD-induced renal lipotoxicity.
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Neele, Annette E., Sophie J. Bernelot Moens, Jeffrey Kroon, Fleur M. van der Valk, Jan Van den Bossche, Marten A. Hoeksema, Renate M. Hoogeveen, et al. "Abstract 401: Hypercholesterolemia Induces Pro-Inflammatory Changes in Monocytes Which Are Reversed by PCSK9 Antibody Treatment." Arteriosclerosis, Thrombosis, and Vascular Biology 37, suppl_1 (May 2017). http://dx.doi.org/10.1161/atvb.37.suppl_1.401.
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Aims: Migration of monocytes into the arterial wall contributes to arterial inflammation and atherosclerosis progression. Since elevated LDL levels have been associated with activation of monocytes, intensive LDL lowering may reverse these pro-inflammatory changes. Subjects with elevated LDL levels are currently treated with statins, which are also described to have pleiotropic effects. Using proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies which selectively reduce LDL we studied the impact of LDL lowering on monocyte phenotype and function in patients with familial hypercholesterolemia (FH). Methods and Results: We assessed monocyte phenotype and function using flow cytometry for a broad range of monocyte-relevant markers and a trans-endothelial migration assay in FH patients (n=22: LDL-C 6.8±1.9mmol/L) and healthy controls (n=18, LDL-C 2.9±0.8mmol/L). Interestingly, monocyte chemokine receptor (CCR) 2 expression was approximately 3-fold increased in FH patients compared with controls (ΔMFI 605±214 vs 236±155 P <0.001). CCR2 expression correlated significantly with plasma LDL-C levels (r=0.709) and positively associated with intracellular lipid accumulation. Monocytes from FH patients also displayed enhanced migratory capacity ex vivo. After 24 weeks of PCSK9 monoclonal antibody treatment (n=17), plasma LDL-C was reduced by 49% (from 6.7±1.3 mmol/L to 3.4±1.3 mmol/L P <0.001), which coincided with reduced monocyte intracellular lipid accumulation and suppressed CCR2 expression (ΔMFI: baseline 607±209, post PCSK9 mAbs: 207±180, P <0.001). Functional relevance was substantiated by the reversal of enhanced migratory capacity of monocytes following PCSK9 monoclonal antibody therapy. All changes were comparable in subjects who were treated with statins (n=14: LDL-C 2.8±0.6mmol/L) indicating that the anti-inflammatory effects were mainly mediated through LDL lowering. Conclusions: Elevated LDL levels in FH induce pro-inflammatory changes in monocytes, which is dampened by PCSK9 monoclonal antibody therapy. LDL lowering was paralleled by reduced intracellular lipid accumulation, suggesting that LDL lowering itself is associated with anti-inflammatory effects on circulating monocytes.
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Arnold, Natalie, and Wolfgang Koenig. "PCSK9 Inhibitor Wars: How Does Inclisiran Fit in with Current Monoclonal Antibody Inhibitor Therapy? Considerations for Patient Selection." Current Cardiology Reports, September 10, 2022. http://dx.doi.org/10.1007/s11886-022-01782-6.
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Abstract Purpose of Review Treatment of dyslipidemia represents one of the most crucial strategies to reduce risk of atherosclerotic cardiovascular (CV) disease (ASCVD). In this review, we critically summarize our knowledge on emerging cholesterol-lowering therapy, targeting PCSK9, paying particular attention on treatment allocation of two drug groups, currently available for clinical use, namely, anti-PCSK9 monoclonal antibodies (mAbs) and inclisiran, a first-in-class small interfering RNA against PCSK9. Recent Findings Although both drug classes show a pronounced, but fairly similar reduction in LDL-cholesterol, their long-term safety is still unknown. Compared to mAbs, inclisiran has a more favorable dosing regimen with biannual application that might improve therapeutic adherence significantly. However, a CV outcome trial (CVOT) for inclisiran is still missing. Summary If inclisiran will be safe and effective in ongoing/future CVOTs, it has a huge potential to overcome medication non-compliance, thereby providing a powerful therapeutic option to decrease the burden of ASCVD.
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Mazura, Alexander D., Anke Ohler, Steffen E. Storck, Magdalena Kurtyka, Franka Scharfenberg, Sascha Weggen, Christoph Becker-Pauly, and Claus U. Pietrzik. "PCSK9 acts as a key regulator of Aβ clearance across the blood–brain barrier." Cellular and Molecular Life Sciences 79, no. 4 (March 27, 2022). http://dx.doi.org/10.1007/s00018-022-04237-x.
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AbstractDespite the neurodegenerative disorder Alzheimer’s disease (AD) is the most common form of dementia in late adult life, there is currently no therapy available to prevent the onset or slow down the progression of AD. The progressive cognitive decline in AD correlates with a successive accumulation of cerebral amyloid-β (Aβ) due to impaired clearance mechanisms. A significant percentage is removed by low-density lipoprotein receptor-related protein 1 (LRP1)-mediated transport across the blood–brain barrier (BBB) into the periphery. Circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) binds to members of the low-density lipoprotein receptor protein family at the cell surface and targets them for lysosomal degradation, which reduces the number of functional receptors. However, the adverse impact of PCSK9 on LRP1-mediated brain Aβ clearance remains elusive. By using an established BBB model, we identified reduced LRP1-mediated brain-to-blood Aβ clearance due to PCSK9 across different endothelial monolayer in vitro. Consequently, the repetitive application of FDA-approved monoclonal anti-PCSK9 antibodies into 5xFAD mice decreased the cerebral Aβ burden across variants and aggregation state, which was not reproducible in brain endothelial-specific LRP1−/− 5xFAD mice. The peripheral PCSK9 inhibition reduced Aβ pathology in prefrontal cortex and hippocampus–brain areas critically involved in memory processing—and prevented disease-related impairment in hippocampus-dependent memory formation. Our data suggest that peripheral inhibition of PCSK9 by already available therapeutic antibodies may be a novel and easily applicable potential AD treatment.
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"114. Production of Anti-PCSK9 Monoclonal Antibodies by Using E1/E2b/E3-Deleted Adenovirus Vector." Molecular Therapy 17 (May 2009): S45. http://dx.doi.org/10.1016/s1525-0016(16)38472-6.
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Ma, I., D. Angoulvant, N. Azzopardi, D. Ternant, F. Ivanes, G. Paintaud, and T. Bejan-Angoulvant. "LDL-cholesterol decrease by anti-PCSK9 monoclonal antibodies: systematic review, meta-analysis and meta-regression of randomized controlled trials." European Heart Journal 41, Supplement_2 (November 1, 2020). http://dx.doi.org/10.1093/ehjci/ehaa946.3334.
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Abstract Background PCSK9 antibodies are novel potent and expansive lipid lowering agents that demonstrated clinical benefit in high risk patients. We hypothesized that optimization of dose and administration schedule, ideally adapted to the target population, could reduce costs while maintaining the clinical benefit. Objective To explore the relationship between LDL-Cholesterol (LDL-C) decrease by anti-PCSK9 monoclonal antibodies and several covariates such as drug dose, administration schedule, baseline LDL-C, population and statins. Methods We performed systematic review, meta-analysis and meta-regression of randomized controlled trials that compared alirocumab or evolocumab to placebo or no treatment and reported LDL-C decrease, with a minimum follow-up of 12 weeks and with a sample size of 30 patients or more. Electronic searches of MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov from inception to March 2019. We evaluated the quality of included studies and extracted aggregate data. We used random effect models and multivariate multilevel meta-regression to explore factors influencing LDL-C decrease. All analyses were performed with R. Results From 1479 references identified and screened on title/abstract, the full texts of 72 articles were screened. We included 32 studies (31 references.) Anti-PCSK9 mAbs decreased LDL-C by 53%, 95% CI (−56% to −50%), with no significant difference between the two drugs (p=0.07). In univariate meta-regressions, higher baseline LDL-C level, monthly administration, higher percentage of patients with high-dose statins were associated with a lower LDL-C decrease (p<0.0001, p=0.02 and p=0.006 respectively). Drug dose and population did not influence LDL-C decrease in univariate analysis, but with a significant statistical interaction between drug dose and administration schedule (p=0.03). In multivariate meta-regression, LDL-C decrease remained significantly and negatively influenced by baseline LDL-C level (p<0.0001) and the percentage of patients with high-dose statins (p=0.0009), and was significantly and positively influenced by drug dose (p<0.0001). Conclusion Alirocumab and evolocumab showed substantial LDL-C reductions in clinical trials, without significant differences in their biological efficacies. A higher baseline LDL-C, higher intensity of statin co-treatment and a lower dose seemed to negatively influence LDL-C decrease. Funding Acknowledgement Type of funding source: None
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Tsouka, A. N., E. N. Liberopoulos, C. V. Rizos, E. C. Christopoulou, M. S. Elisaf, and A. D. Tselepis. "2980The effect of monoclonal antibodies against PCSK9 on circulating CD34+ progenitor cells interactions with platelets in patients with familial hypercholesterolemia." European Heart Journal 40, Supplement_1 (October 1, 2019). http://dx.doi.org/10.1093/eurheartj/ehz745.0001.
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Abstract Introduction Platelets interact with circulating CD34+ progenitor cells inducing their differentiation into endothelial progenitor cells (EPCs) and further promoting EPC maturation into endothelial cells, an important step for endothelial regeneration and angiogenesis. PSCK9 is a serine protease that may not only play a crucial role in binding to the low density lipoprotein receptor (LDL-R) increasing its endosomal and lysosomal degradation thus inhibiting its recycling to the cell surface, leading to increasing LDL-cholesterol levels in plasma, but may also exhibit several, independent on LDL-R, activities on a plethora of cell types, including platelets. Purpose We investigated whether monoclonal antibodies (mabs) against PCSK9 could affect platelet interaction with CD34+ cells as well as their differentiation into EPCs, in patients with Familial Hypercholestorelemia (FH). Patients and methods Patients with FH (n=11, 8 men and 3 women, mean age 53±10 years) being under statin/ezetimibe therapy (40mg statin/ 10mg ezetimibe) participated in the study. Patients exhibited resisting high LDL-cholesterol levels, therefore following the existing guidelines, they received mab against PCSK9 (7 evolocumab, 140mg/ml and 4 alirocumab, 150mg/ml) every two weeks. Blood samples were drawn before and after 4 doses of the antibody i.e. after two months (Follow-up). In addition to the patients' serum lipid profile, the endothelial phenotype of CD34+ (membrane expression levels of KDR which is a receptor for VEGF and an endothelial phenotype marker) on CD34+ cells (CD34+-KDR+ cells) and the formation of platelet-CD34+ (CD61+-CD34+) and platelet-KDR+ (CD61+-KDR+) conjugates were also determined by flow cytometry on whole blood after dual labelling with anti-VEGFR-R2/KDR-PE, anti-CD61-PerCP and anti-CD34-FITC. The results were expressed as the %gated of CD34+-KDR+ cells, as well as CD61+-CD34+ and CD61+-KDR+ conjugates. Results The baseline LDL-cholesterol levels were significantly reduced from 172±43 mg/dl to 51±17 at follow-up, p=0.0001. Importantly, the formation of CD61+-CD34+ and CD61+-KDR+ conjugates were increased from baseline to follow-up (from 1.39±1.3 to 2.23±2.8, p=0.037) and (from 2.91±4.2 to 5.92±6.01, p=0.014), respectively. The membrane expression of KDR on CD34+ cells was also increased from 0.79±0.9 to 1.36±0.90, p=0.042, which reflects the increase in the CD34+ endothelial phenotype. Conclusion We show for the first time that the mabs against PCSK9, significantly increase the CD34+ endothelial phenotype in FH patients, which may at least partially attributed to the increase in the platelet interaction with CD34+ cells (platelet-CD34+ conjugates). The underlying mechanisms as well as the consequences of this effect at the clinical level for these patients are under investigation.
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Wang, Hong-Fei, Yu-Cheng Mao, Xin-Yi Xu, Si-Yu Zhao, Dan-Dan Han, Shi-Yao Ge, Kai Song, Chang Geng, and Qing-Bao Tian. "Effect of alirocumab and evolocumab on all-cause mortality and major cardiovascular events: A meta-analysis focusing on the number needed to treat." Frontiers in Cardiovascular Medicine 9 (December 2, 2022). http://dx.doi.org/10.3389/fcvm.2022.1016802.
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AimsThe efficacy of anti-proprotein convertase subtilisin/Kexin type 9 (PCSK9) monoclonal antibodies in patients with atherosclerotic cardiovascular disease (ASCVD) remains unclear. Therefore, this study aims to assess the effect of PCSK9 inhibitors (alirocumab and evolocumab) on ASCVD patients considering the number needed to treat (NNT).MethodsWe reviewed randomized controlled trials (RCTs) which compared the effects of alirocumab or evolocumab and placebo or standards of care. All articles were published in English up to May 2022. Using random effect models, we estimated risk ratios (RRs), NNT, and 95% confidence intervals (CI).ResultsWe incorporated 12 RCTs with 53 486 patients total, of which 27 674 received PCSK9 inhibitors and 25 812 received placebos. The mean follow-up duration was 1.56 years. The effect of PCSK9 inhibitors on major adverse cardiovascular events (MACE) was statistically significant, and the corresponding mean NNT was 36. Alirocumab reduced the risk of MACE, stroke, and coronary revascularization; the corresponding mean NNT were 37, 319, and 107, respectively. Evolocumab positively affected MACE, myocardial infarction, stroke, and coronary revascularization; the corresponding mean NNT were 32, 78, 267, and 65, respectively. The effects of alirocumab or evolocumab on all-cause mortality and cardiovascular mortality were not statistically significant.ConclusionThis study suggests that preventing one patient from MACE needed to treat 36 patients with ASCVD with PCSK9 inhibitors for 1.56 years. Both alirocumab and evolocumab reduced MACE, stroke, and coronary revascularization. Evolocumab had a positive effect on myocardial infarction, but no effects were noted for alirocumab. In addition, alirocumab may not be as effective as evolocumab. NNT visualizes the magnitude of efficacy to assist in clinical decisions.Systematic review registration[https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=344908], identifier [CRD42022344908].
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Zhou, Yufei, and Chen Chen. "From Bench to Bedside: Current Developments in RNA-Based Therapies for Treatment of Hyperlipidemia." International Journal of Drug Discovery and Pharmacology, December 21, 2022, 7. http://dx.doi.org/10.53941/ijddp.v1i1.141.
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Review From Bench to Bedside: Current Developments in RNA-Based Therapies for Treatment of Hyperlipidemia Yufei Zhou and Chen Chen * Division of Cardiology and Hubei Key Laboratory of Genetics and Molecular Mechanisms of Cardiological Disorders, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. * Correspondence: chenchen@tjh.tjmu.edu.cn; Tel. & Fax: 86-27-6937-8422. Received: 7 October 2022 Accepted: 1 November 2022 Published: 21 December 2022 Abstract: Hyperlipidemia is one of the conditions that constitute metabolic disorder and it is a common public health problem. The condition is characterized by increased levels of cholesterol, triglycerides and/or lipoproteins; it is a recognized as a risk factor for the onset of many diseases such as type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. Up to now, the primary drugs for treating hyperlipidemia are statins and monoclonal antibody drugs against proprotein convertase subtilisin/kexin type 9 (PCSK9). The main limitation of statins for long-term use is intolerable side effects. Evolocumab and Alirocumab, two monoclonal antibodies against PCSK9, can effectively decrease the level of low-density lipoprotein cholesterol (LDL-C) in patients with statin intolerance and familial hypercholesterolemia, while causing fewer side effects. However, due to its short half-life and high costs, these monoclonal antibody treatments might result in patients’ non-compliance with medication and considerable economic burden on patients. Given that RNA plays a key role in gene regulation, RNA-based therapeutics have become powerful blueprints for designing new anti-hyperlipidemia drugs. Here, we summarized RNA-based therapeutic strategies and the current clinical trials for RNA drugs in hyperlipidemia treatment.
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Sun, J., N. E. Lepor, G. Canton, L. Contreras, D. S. Hippe, D. A. Isquith, N. Balu, et al. "Effects of alirocumab on carotid plaque lipid content and inflammation: a time course study using serial vessel wall imaging." European Heart Journal 41, Supplement_2 (November 1, 2020). http://dx.doi.org/10.1093/ehjci/ehaa946.0204.
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Abstract Background PCSK9 inhibition has emerged as a potent pharmaceutical approach to lowering LDL cholesterol (LDL-C). Monoclonal anti-PCSK9 antibodies have been shown in recent clinical trials to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease, but the underlying mechanisms are not fully understood. Meanwhile, circulatory inflammation markers were not reduced with PCSK9 inhibitors, thus their effects on plaque inflammation remain elusive. Vessel wall imaging with magnetic resonance (VW-MRI) has enabled serial monitoring of changes in carotid plaque lipid content and inflammation noninvasively that correlates with coronary and carotid vascular events. Purpose Using serial VW-MRI, we studied the effects and time course of PCSK9 inhibition with alirocumab on carotid plaque lipid content and inflammation. Methods Patients with LDL-C ≥70 mg/dl on ≤70 mg per week atorvastatin or an equivalent (due to statin intolerance or treating-physician discretion) and soft carotid plaque(s) identified on ultrasound underwent carotid VW-MRI. Those with confirmed lipid-rich plaque(s) on VW-MRI received alirocumab (150 mg subcutaneously every other week) and were re-scanned at 3, 6, and 12 months after treatment. Carotid VW-MRI included pre- and post-contrast images for measuring percent lipid-rich necrotic core volume (%LRNC) and dynamic contrast-enhanced images for measuring the extravasation rate of gadolinium contrast (Ktrans, reflecting tissue blood flow, endothelial surface area, and microvessel permeability), a marker of plaque inflammation. The co-primary endpoints were changes in %LRNC and Ktrans at 12 months from baseline. Results Of 31 patients enrolled, 27 completed the study (mean age: 69±9; male: 67%; on statins and/or ezetimibe: 41%; median LDL-C: 120 mg/dl [interquartile range: 99, 158]). Alirocumab induced a 59% reduction in LDL-C (p<0.001) on average at 3 months to a median of 54 mg/dl (interquartile range: 29, 69), which was maintained at later time points. From 9.8% at baseline, %LRNC was progressively reduced to 8.4% at 3 months, 7.5% at 6 months, and 7.2% at 12 months, representing a rapid 14% reduction (p=0.032) at 3 months and a total reduction of 20% (p=0.019) at 12 months. From 0.07±0.02 min-1 at baseline, Ktrans was not reduced at 3 or 6 months but was significantly reduced by 17% (p=0.029) at 12 months to 0.06±0.02 min-1. No significant changes in lumen or wall area were observed during the study period. Conclusions Serial VW-MRI documented plaque-stabilizing effects of PCSK9 inhibition with alirocumab, including plaque delipidation and attenuation of plaque inflammation. The reduction in plaque lipid content was apparent as early as 3 months. The reduction in Ktrans was not seen until 12 months of treatment and may indicate a later effect on microvascular structure and/or function. This observation represents the earliest time course of plaque morphology modification by non-statin therapy reported to date. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): The study was funded by an investigator-initiated grant from Regeneron and Sanofi.
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Morales-Villegas, Enrique. "The Cardio Diabetology Era. A Concise and Illustrated Review: Four Phenotypes and Three New Evidence-Based and Practical Therapeutic Algorithms." Medical Research Archives 10, no. 10 (2022). http://dx.doi.org/10.18103/mra.v10i10.3207.
Full textAbstract:
Type 2 diabetes mellitus (T2DM) has undergone therapeutic approaches evolving from glucocentricity towards holism, in which it is currently considered a microvascular and macrovascular risk condition determined by multiple variables beyond glucose. These include visceral adiposity, metaflammation, insulin resistance with its hemodynamic (endothelial dysfunction and hypertension) and metabolic (mixed dyslipidemia) surrogates; together with other metabolic regulation system dysfunction such as the incretin system, sodium, and glucose cotransporters at the intestinal and renal level, and the intestinal microbiota, among the most studied. Therefore, the current treatment of this risk condition called T2DM, includes the control of all its determining factors: adiposity through a healthy diet, aerobic physical activity, and/or drugs such as glucagon-like peptide-1 receptor agonists (GLP1-RA) or bariatric surgical procedures. Inflammation remains a therapeutic target under investigation, although it has not yet been transferred to clinical practice guidelines. Insulin resistance and its hemodynamic and metabolic subrogates are the therapeutic targets of multiple pharmacological interventions, essentially insulin sensitizers, inhibitors of the renin-angiotensin-aldosterone system, facilitators of the transformation and elimination of lipoproteins with apo-B100 as omega-3 ultra-purified fatty acids, fibrates, antisense oligonucleotides (ASO) against apoC3, ASO and monoclonal antibodies (mAbs) anti-ANGPTL3, statins, ezetimibe, mAbs and small interfering RNA (siRNA) anti-PCSK9, among others. In the last 14 years, drugs such as the dipeptidyl peptidase 4 (DPP-4) inhibitors, GLP1-RA, and, more recently, the dual GIP-GLP-1 analogs, have been incorporated to correct the dysfunction of the incretin system, as well as many others that inhibit the intestinal and renal reabsorption of sodium and glucose as sodium–glucose co-transporter-2 and 1 (SGLT2/1) inhibitors. Surprisingly, new drugs have emerged between the GLP1-RA and the SGLT2/1 inhibitors that, beyond their essential therapeutic effect (glucose control), have shown brain, cardiac, and renal protection of variable magnitude. Finally, manipulating the intestinal microbiota is a strategy under extensive investigation and incipient clinical application. From this summary, it is clear that the current therapeutic landscape in T2DM has expanded dramatically, from a “gluco-panorama” focused on glucose control with insulin, sulfonylureas, metformin, and glitazones, to a “holo-panorama” incorporating five new therapeutic classes and at least eighteen new "anti-diabetic" drugs, in addition to a similar number of medications for hypertension and dyslipidemia control.