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PCSK9 inhibitors

Kévin Ly, Rachid Essalmani, Roxane Desjardins, Nabil G Seidah, Robert Day
The mechanism of LDL receptor (LDLR) degradation mediated by the proprotein convertase subtilisin/kexin type 9 (PCSK9) has been extensively studied, however many steps within this process remain unclear and still require characterization. Recent studies have shown that PCSK9 lacking its Cys/His-rich domain can still promote LDLR internalization, but the complex does not reach the lysosome suggesting the presence of an additional interaction partner(s). In the present study we carried out an unbiased screening approach to identify PCSK9 interacting proteins in the HepG2 cells' secretome using co-immunoprecipitation combined with mass spectrometry analyses...
October 7, 2016: Journal of Biological Chemistry
Michel Farnier
PURPOSE OF REVIEW: After the approval of alirocumab and evolocumab, the first two monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin kexin type 9 (PCSK9), this review provides an update on recent PCSK9 inhibitors data and describes recommendations for the use before the results of the ongoing cardiovascular endpoint trials. RECENT FINDINGS: New studies and complementary analysis of phase III trials have consistently shown that alirocumab and evolocumab are highly effective in reducing LDL-cholesterol and to some extent lipoprotein (a)...
October 17, 2016: Current Opinion in Lipidology
Bernd Hohenstein
As a major event in the field of therapeutic apheresis, lipidology and immune-modulating extracorporeal treatments, Dresden hosted the 4(th) International Symposium on Therapeutic Apheresis 17-19 March 2016. In conjunction with the newly founded European Group - International Society for Apheresis, this meeting attracted more than 300 clinicians and scientists from more than a dozen European countries and further developed into an important event for participants, industry and nursing staff. Due to the relevant role of lipoprotein apheresis in Germany and the recent launch of PCSK9 inhibitors corresponding sessions, the symposium reflected all aspects of this new lipidological therapy in a number of sessions...
October 2016: Therapeutic Apheresis and Dialysis
Zachary R Noel, Craig J Beavers
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors serve as a valuable addition to the armamentarium of lipid lowering agents and have promising potential. By inhibiting the PCSK9 enzyme, this novel molecule leads to increase low density lipoprotiein (LDL) receptor density and decreased circulation of LDL. The fact the agent is a monoclonal antibody has led to limited drug interactions and minimized adverse drug events. It is critical for all providers to have a basic understanding of these novel therapies with their introduction and use for treatment...
October 14, 2016: American Journal of Medicine
Donna N Petersen, Julie Hawkins, Wanida Ruangsiriluk, Kimberly A Stevens, Bruce A Maguire, Thomas N O'Connell, Benjamin N Rocke, Markus Boehm, Roger B Ruggeri, Tim Rolph, David Hepworth, Paula M Loria, Philip A Carpino
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin...
October 13, 2016: Cell Chemical Biology
Luiz Sérgio F de Carvalho, Hiroshi Yoshida
No abstract text is available yet for this article.
October 13, 2016: Atherosclerosis
Terry McCormack, Ricardo Dent, Mark Blagden
BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in Europe and increased low-density lipoprotein cholesterol (LDL-C) is a major contributor to CVD risk. Extensive evidence from clinical studies of statins has demonstrated a linear relationship between LDL-C levels and CVD risk. It has been proposed that lower LDL-C levels than those currently recommended may provide additional clinical benefit to patients. AIM: This review summarises the genetic and clinical evidence on the efficacy and safety of achieving very low LDL-C levels...
October 14, 2016: International Journal of Clinical Practice
L Bonanni, A Cutolo, M Dalla Vestra
Familial hypercholesterolemia (FH) is an autosomal disorder characterized by increased levels of total cholesterol and low density lipoprotein (LDL) cholesterol.The extent of underdiagnosis and undertreatment of individuals with FH is largely unknown.The LDL-lowering capacity of statins in combination with other lipid-lowering drugs is maximally around 50-60%. FH patients have a strongly elevated LDL-C and in most cases maximal current treatment is not sufficient to reach the desired LDL targets.Therefore, FH patients have a large residual cardiovascular risk despite the use of statins and there is a medical need for new additional drugs to further lower LDL-C in patients with FH to improve their prognosis...
October 6, 2016: Experimental and Clinical Endocrinology & Diabetes
Matthew Peach, Ren Xu, Dan Fitzpatrick, Lisa Hamilton, Ransi Somaratne, Rob Scott, Scott M Wasserman, C Stephen Djedjos
The effects of cholesterol-lowering drugs, including those that reduce cholesterol synthesis (statins) and those that reduce cholesterol absorption (ezetimibe), on cholesterol absorption and synthesis are well understood. PCSK9 inhibitors are a novel class of cholesterol-lowering drugs that robustly reduce LDL-C, but little is known about their effects on cholesterol absorption and synthesis. We evaluated how treatment with evolocumab, a fully human monoclonal IgG2 antibody to PCSK9, affects markers of cholesterol synthesis and absorption by measuring these markers in patients from an evolocumab clinical trial...
October 5, 2016: Journal of Lipid Research
Thomas Knickelbine, Matthew Lui, Ross Garberich, Michael D Miedema, Craig Strauss, Jeffrey J VanWormer
BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease resulting in elevated serum low-density lipoprotein cholesterol (LDL-C) levels. Patients with FH have a very high lifetime risk of cardiovascular disease, but FH often goes unrecognized in clinical care. New treatments including PCSK9 inhibitors are now available for this population, and the use of the electronic record may be able to help identify potential patients for therapy. OBJECTIVES: The goal of this study was to determine the period prevalence of FH in a large ambulatory care population, including the homozygous form...
September 2016: Journal of Clinical Lipidology
Dave L Dixon, Cory Trankle, Leo Buckley, Eric Parod, Salvatore Carbone, Benjamin W Van Tassell, Antonio Abbate
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an integral role in the degradation of low-density lipoprotein receptors (LDL-R), making it an intriguing target for emerging pharmacotherapy. Two PCSK9 inhibitors, alirocumab and evolocumab, have been approved and are available in the United States and European Union. However, much of the PCSK9 story remains to be told. The pipeline for additional pharmacotherapy options is rich with several compounds under development, using alternative strategies for inhibiting PCSK9...
September 2016: Journal of Clinical Lipidology
Loretta Fala
No abstract text is available yet for this article.
March 2016: American Health & Drug Benefits
Lisa A Raedler
No abstract text is available yet for this article.
March 2016: American Health & Drug Benefits
Ying Du, Sha Li, Chuan-Jue Cui, Yan Zhang, Sheng-Hua Yang, Jian-Jun Li
BACKGROUND: Previous studies have suggested that people with obesity showed elevated serum levels of leptin as well as lipid dysfunction and proprotein convertase subtilisin/kexin type 9 (PCSK9) played an important role in the regulation of lipid metabolism recently. The aim of this study was to determine if leptin participated in regulating the uptake of low-density lipoproteins (LDL) in hepatocytes via PCSK9. METHODS: HepG2 cells were treated with human recombinant leptin...
2016: Journal of Translational Medicine
Alon Eisen, Robert P Giugliano
PURPOSE OF REVIEW: Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors are promising therapies that inhibit the degradation of low-density lipoprotein (LDL) receptors in the hepatocyte and thus increase LDL cholesterol (LDL-C) uptake from the blood. This review summarizes main findings in the field of PCSK9 inhibitors, from basic mechanism to clinical studies, and aims to provide a contemporary and practical overview of the clinical implication and future directions with PCSK9 inhibitors...
November 2016: Current Opinion in Cardiology
Alessandro Colletti, Giuseppe Derosa, Arrigo Fg Cicero
Hypercholesterolemia is one of the main risk factors for atherosclerosis and cardiovascular diseases. The treatment is based on the modification of the diet and lifestyle and if necessary on a pharmacological therapy. The most widely used drugs are the inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase (statins); nevertheless, many patients do not reach optimal levels of low-density lipoprotein-cholesterol (LDL-C) even with maximal dosage of statins (eventually associated to ezetimibe) or present side effects, which do not allow them to continue the treatment...
2016: Therapeutics and Clinical Risk Management
Manuel Anguita Sánchez, Almudena Castro Conde, Alberto Cordero Fort, Xavier García-Moll Marimón, Juan José Gómez Doblas, José R González-Juanatey, Rosa María Lidón Corbi, José Luis López-Sendón, José Mostaza Prieto, Luis Rodríguez Padial
Lipid-lowering therapy is one of the cornerstones of cardiovascular prevention and is one of the most effective strategies in the secondary prevention of ischemic heart disease. Nevertheless, the current treatment of lipid disorders, together with lifestyle changes, fails to achieve the targets recommended in clinical guidelines in a substantial proportion of patients. PCSK9 inhibitors have demonstrated safety and efficacy in the treatment of dyslipidemia. Due to their ability to reduce low-density lipoprotein cholesterol levels, these drugs have recently been approved for clinical use by Spanish regulatory agencies, with the aim of reducing cardiovascular risk in selected patient groups...
September 16, 2016: Revista Española de Cardiología
Chuan-Jue Cui, Sha Li, Cheng-Gang Zhu, Jing Sun, Ying Du, Yan Zhang, Na-Qiong Wu, Yuan-Lin Guo, Rui-Xia Xu, Ying Gao, Jian-Jun Li
Plasma C-reactive protein (CRP) concentration is associated positively with cardiovascular risk, including dyslipidemia. We suggested a regulating role of CRP on pro-protein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein (LDL) metabolism, and demonstrated the PCSK9 as a pathway linking CRP and LDL regulation. Firstly, experiments were carried out in the presence of human CRP on the protein and mRNA expression of PCSK9 and LDL receptor (LDLR) in human hepatoma cell line HepG2 cells...
September 15, 2016: Journal of Cellular and Molecular Medicine
Gregory B Lim
No abstract text is available yet for this article.
November 2016: Nature Reviews. Cardiology
Michal Vrablík
UNLABELLED: Dyslipidemia in type 2 diabetics represents a complex change of lipoprotein metabolism that is highly proatherogenic. It originates on a genetic background in the context of insulin resistance and affects lipoprotein metabolism at multiple levels (e.g. hepatocyte, enterocyte, intravascular processing) mainly in the postprandial phase. The treatment of diabetic (atherogenic) dyslipidemia is an effective option to lower the risk of both macro- and microvascular complications of diabetes...
2016: Vnitr̆ní Lékar̆ství
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