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PCSK9 inhibitors

Guglielmo Maulucci, Francesco Cipriani, Dolores Russo, Grazia Casavecchia, Carlo Di Staso, Luigi Di Martino, Antonio Ruggiero, Matteo Di Biase, Natale Daniele Brunetti
BACKGROUND: The reduction of cholesterol levels with cholesterol-lowering therapy may improve endothelial function. Lipid-lowering therapy has been greatly enhanced by the introduction of proprotein convertase subtilisin/kexin type 9 (PCSK9) antibodies. Less is known of the effect of PCSK9 inhibitors on endothelial function of subjects with hypercholesterolemia. OBJECTIVE: To assess whether treatment with PCSK9 inhibitors may improve endothelial function evaluated by brachial artery vasoreactivity test...
February 14, 2018: Journal of Clinical Lipidology
Vesa M Olkkonen, Juha Sinisalo, Matti Jauhiainen
Remarkably good results have been achieved in the treatment of atherosclerotic cardiovascular diseases (CVD) by using statin, ezetimibe, antihypertensive, antithrombotic, and PCSK9 inhibitor therapies and their proper combinations. However, despite this success, the remaining CVD risk is still high. To target this residual risk and to treat patients who are statin-intolerant or have an exceptionally high CVD risk for instance due to familial hypercholesterolemia (FH), new therapies are intensively sought. One pathway of drug development is targeting the circulating triglyceride-rich lipoproteins (TRL) and their lipolytic remnants, which, according to the current view, confer a major CVD risk...
March 8, 2018: Atherosclerosis
Bernardo Cortese, Gaetano Di Palma, Corrado Lettieri, Giuseppe Musumeci
No abstract text is available yet for this article.
February 2018: Giornale Italiano di Cardiologia
Erin A Bohula, Robert P Giugliano, Lawrence A Leiter, Subodh Verma, Jeong-Gun Park, Peter S Sever, Armando Lira Pineda, Narimon Honarpour, Huei Wang, Sabina A Murphy, Anthony Keech, Terje R Pedersen, Marc S Sabatine
BACKGROUND : In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. It is not known whether the efficacy of evolocumab is modified by baseline inflammatory risk. We explored the efficacy of evolocumab stratified by baseline high-sensitivity C-reactive protein (hsCRP). We also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL-C concentrations...
March 12, 2018: Circulation
Angelos D Karagiannis, Martin Liu, Peter P Toth, Shijia Zhao, Devendra K Agrawal, Peter Libby, Yiannis S Chatzizisis
PURPOSE OF REVIEW: Clinical trials with PCSK9 inhibitors have shown a robust decrease in plasma LDL levels and a significant reduction in the incidence of cardiovascular atherosclerotic events. However, the role of PCSK9 in atherosclerosis is not well investigated and it remains unclear whether PCSK9 inhibition has direct, LDL-independent, anti-atherosclerotic effects. This review outlines the molecular pathways and targets of PCSK9 in atherosclerosis and summarizes the experimental and clinical data supporting the anti-atherosclerotic (pleiotropic) actions of PCSK9 inhibitors...
March 10, 2018: Current Atherosclerosis Reports
Cori Russell, Samip Sheth, Douglas Jacoby
PURPOSE OF REVIEW: We provide an overview of our current understanding of combination lipid-lowering therapies intended for dyslipidemia treatment and cardiovascular disease prevention. First, we analyze recent statin and non-statin combination therapy guidelines and clinical studies since the publication of 2013 American College of Cardiology Cholesterol Guidelines. Second, we examine the clinical utility of non-statin agents alone and in combination in terms of LDL-C lowering and ASCVD risk reduction...
March 7, 2018: Current Atherosclerosis Reports
Seth J Baum, Christopher P Cannon
Low-density lipoprotein cholesterol (LDL-C) has been extensively evaluated. Prospective cohort studies, randomized controlled trials, biology, pathophysiology, genetics, and Mendelian randomization studies, have clearly taught us that LDL-C causes atherosclerotic cardiovascular disease. The newest class of drugs to lower LDL-C, the proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, have been found to safely reduce LDL-C approximately 60% when added to high-intensity statin therapy...
March 7, 2018: Clinical Cardiology
Barbara S Wiggins, Jeffrey Senfield, Helina Kassahun, Armando Lira, Ransi Somaratne
PURPOSE OF REVIEW: To review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. RECENT FINDINGS: PCSK9 inhibitors are a class of lipid-lowering agents that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia. Evolocumab is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia...
March 6, 2018: Current Atherosclerosis Reports
Kyoung Im Cho, Ichiro Sakuma, Il Suk Sohn, Toshio Hayashi, Kazunori Shimada, Kwang Kon Koh
Statins are important for preventing adverse cardiovascular events in patients with both high and low risk of vascular disease, by reducing the levels of low-density lipoprotein cholesterol (LDL-C). However, statins dose-dependently increase adverse effects and increase the risk of type 2 diabetes. Previously, it was hypothesized this was caused by to off-target effects, but recent studies demonstrate it is caused by on-target effects. Nonetheless, the American guidelines recommend the use of high-intensity statin therapy, and extend its use to most people at risk of vascular diseases, particularly older people...
March 2, 2018: Circulation Journal: Official Journal of the Japanese Circulation Society
Vladimír Bláha, Milan Bláha, Miriam Lánská, Eduard Havel, Pavel Vyroubal, Zdeněk Zadák, Pavel Žák
PCSK9-inhibitors belong to the new class of hypolipidemic agents. They enhance catabolism of low density lipoprotein cholesterol (LDL-C) through inhibiting activity of proprotein convertase subtilisin/kexin type 9 (PCSK9). They are monoclonal antibodies (alirocumab, evolocumab etc). Under clinical development are also other types of PCSK9-inhibitors which act at a subcellular level. The treatment with PCSK9-inhibitors can be beneficially combined with lipoprotein apheresis (LA). If such treatment using PCSK9-inhibitors is possible with regard to an individual patients genotype, the combination of LA and PCSK9-inhibitors leads to slowing the space of LDL-C increase between individual procedures of apheresis and enables attaining of the lowest possible values of LDL-cholesterolemia for the longest possible period of time...
2018: Vnitr̆ní Lékar̆ství
Chuantao Jiang, Hersharan Nischal, Hua Sun, Li Li, Ying Cao, Peng Wei, Jui-Yoa Chang, Ba-Bie Teng
PCSK9 (Proprotein convertase subtilisin/kexin type 9) increases plasma cholesterol levels by promoting LDL receptor degradation. Current antibody inhibitors block the interaction between PCSK9 and LDL receptors, significantly decrease plasma cholesterol levels, and provide beneficial clinical outcomes. To reduce the action of PCSK9 in plasma, a novel strategy that will produce a panel of non-native, conformationally-altered isomers of PCSK9 (X-PCSK9) to develop active immunotherapy targeting of native PCSK9 and inhibiting/blocking the interaction of PCSK9 with LDL receptor, thus decreasing plasma cholesterol levels is proposed...
February 24, 2018: International Journal of Molecular Sciences
Baris Gencer, David Nanchen, Tinh-Hai Collet, Nicolas Rodondi, François Mach
PCSK9 (proprotein convertase subtilisin kexin 9) monoclonal antibodies (mAb) are new therapeutic agents to lower efficiently LDL-cholesterol levels. New data from large clinical trials suggest that the addition of PCSK9 mAb to statins can reduce the incidence of major adverse cardiovascular events in very high risk patients. Alirocumab and evolocumab are two agents available in Switzerland with specific limitations for reimbursement. PCSK9 mAb should be considered in patients with clinical atherosclerotic cardiovascular disease (ASCVD), as well as in patients with familial hypercholesterolemia without ASCVD who have substantially high LDL-cholesterol levels despite the use of statin at maximally tolerated dose with or without ezetimibe, or intolerance to appropriate doses of several statins...
February 28, 2018: Revue Médicale Suisse
Toshiyuki Nishikido, Kausik K Ray
Dyslipidemia is one of the most important risk factors for cardiovascular disease. Insufficient reduction in LDL-C from existing therapies in patients at high risk of atherogenic cardiovascular disease is an unmet clinical need. Circulating PCSK9 causes hypercholesterolemia by reducing LDL receptors in hepatocytes. Areas covered: PCSK9 inhibition has emerged as a promising new therapeutic strategy to reduce LDL-C. Inclisiran, a novel, synthetic, siRNA molecule, inhibits PCSK9 synthesis in hepatocytes. Inclisiran targets intracellular PCSK9 synthesis specifically, resulting in a dose-dependent, long-term, significant reduction in LDL-C...
March 2018: Expert Opinion on Investigational Drugs
Theodosios D Filippatos, Angelos Liontos, Eliza C Christopoulou, Moses S Elisaf
Over the last 3 decades, hypolipidaemic treatment has significantly reduced both cardiovascular (CV) risk and events, with statins being the cornerstone of this achievement. Nevertheless, residual CV risk and unmet goals in hypolipidaemic treatment make novel options necessary. Recently marketed monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) have shown the way towards innovation, while other ways of PCSK9 inhibition like small interfering RNA (Inclisiran) are already being tested...
February 8, 2018: Current Vascular Pharmacology
Niki Katsiki, Athanasios D Giannoukas, Vasilios G Athyros, Dimitri P Mikhailidis
Peripheral artery disease (PAD) is characterized by increased cardiovascular (CV) risk, limb morbidity and all-cause mortality. According to the current guidelines (2016) of the American Heart Association/American College of Cardiology on the management of PAD patients, statin therapy is recommended for PAD patients in order to treat dyslipidemia and reduce CV risk. The present narrative review discusses the use of statins and other lipid-lowering drugs such as ezetimibe, fibrates, niacin, anacetrapib and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in PAD patients in terms of both CV and limb outcomes...
January 31, 2018: Current Opinion in Pharmacology
Katrin Gebauer, Holger Reinecke
Low-density lipoprotein cholesterol (LDL-C) has been proven to be a causal factor of atherosclerosis and, along with other triggers like inflammation, the most frequent reason for peripheral arterial disease. Moreover, a linear correlation between LDL-C concentration and cardiovascular outcome in high-risk patients could be established during the past century. After the development of statins, numerous randomized trials have shown the superiority for LDL-C reduction and hence the decrease in cardiovascular outcomes including mortality...
February 7, 2018: VASA. Zeitschrift Für Gefässkrankheiten
Gregory S Pokrywka
Elevated low-density lipoprotein cholesterol (LDL-C) plays a major role in the development of atherosclerotic cardiovascular disease. Statins are the first-line treatment to lower LDL-C in patients with hypercholesterolemia; however, some high cardiovascular risk patients may have inadequate responses to statin therapy or are intolerant to statins, and may need additional and/or alternative non-statin therapies to further reduce their LDL-C levels. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of circulating LDL-C levels, have received considerable attention as promising non-statin therapeutic options for the management of hypercholesterolemia...
February 23, 2018: Postgraduate Medicine
Theodosios D Filippatos, Thalia Panagiotopoulou, Eleftheria Tzavella, Moses S Elisaf
Clinical trials and meta-analyses have shown that statins can dose dependently increase the incidence of new-onset diabetes mellitus (DM) especially in patients with underlying abnormalities of carbohydrate homeostasis. Mendelian randomization studies support these findings since genetic variants in the gene encoding the target of statins, the enzyme 3-hydroxy-3-methylglutaryl coenzyme A reductase, are associated with increased incidence of new-onset DM, suggesting that the so-called diabetogenic effect of statins is an "on-target effect" possibly related to their main mechanism of action, that is the increased low-density lipoprotein (LDL) receptor expression...
January 1, 2018: Journal of Cardiovascular Pharmacology and Therapeutics
Michael Zimmer, Pradeep Bista, Ericka L Benson, Diana Y Lee, Feng Liu, Dominic Picarella, Rick B Vega, Chi B Vu, Maisy Yeager, Min Ding, Guosheng Liang, Jay D Horton, Robert Kleemann, Teake Kooistra, Martine C Morrison, Peter Y Wielinga, Jill C Milne, Michael R Jirousek, Andrew J Nichols
CAT-2003 is a novel conjugate of eicosapentaenoic acid (EPA) and niacin designed to be hydrolyzed by fatty acid amide hydrolase to release EPA inside cells at the endoplasmic reticulum. In cultured liver cells, CAT-2003 blocked the maturation of sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 proteins and decreased the expression of multiple SREBP target genes, including HMGCR and PCSK9 . Consistent with proprotein convertase subtilisin/kexin type 9 (PCSK9) reduction, both low-density lipoprotein receptor protein at the cell surface and low-density lipoprotein particle uptake were increased...
June 2017: Hepatology communications
Knut Tore Lappegård, Christian Abendstein Kjellmo, Stefan Ljunggren, Karin Cederbrant, Maritha Marcusson-Ståhl, Monica Mathisen, Helen Karlsson, Anders Hovland
Lipoprotein apheresis and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are last therapeutic resorts in patients with familial hypercholesterolemia (FH). We explored changes in lipoprotein subclasses and high-density lipoprotein (HDL) function when changing treatment from lipoprotein apheresis to PCSK9 inhibition. We measured the levels of low-density lipoprotein (LDL) and HDL particle subclasses, serum amyloid A1 (SAA1), paraoxonase-1 (PON1) activity and cholesterol efflux capacity (CEC) in three heterozygous FH patients...
January 4, 2018: Transfusion and Apheresis Science
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