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Tsioulos G, Vallianou NG, Skourtis A, Dalamaga M, Kotsi E, Kargioti S, Adamidis N, Karampela I, Mourouzis I, Kounatidis D. Vaccination as a Promising Approach in Cardiovascular Risk Mitigation: Are We Ready to Embrace a Vaccine Strategy? Biomolecules 2024; 14:1637. [PMID: 39766344 PMCID: PMC11727084 DOI: 10.3390/biom14121637] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 12/15/2024] [Accepted: 12/18/2024] [Indexed: 01/12/2025] Open
Abstract
Cardiovascular disease (CVD) remains a leading global health concern, with atherosclerosis being its principal cause. Standard CVD treatments primarily focus on mitigating cardiovascular (CV) risk factors through lifestyle changes and cholesterol-lowering therapies. As atherosclerosis is marked by chronic arterial inflammation, the innate and adaptive immune systems play vital roles in its progression, either exacerbating or alleviating disease development. This intricate interplay positions the immune system as a compelling therapeutic target. Consequently, immunomodulatory strategies have gained increasing attention, though none have yet reached widespread clinical adoption. Safety concerns, particularly the suppression of host immune defenses, remain a significant barrier to the clinical application of anti-inflammatory therapies. Recent decades have revealed the significant role of adaptive immune responses to plaque-associated autoantigens in atherogenesis, opening new perspectives for targeted immunological interventions. Preclinical models indicate that vaccines targeting specific atherosclerosis-related autoantigens can slow disease progression while preserving systemic immune function. In this context, numerous experimental studies have advanced the understanding of vaccine development by exploring diverse targeting pathways. Key strategies include passive immunization using naturally occurring immunoglobulin G (IgG) antibodies and active immunization targeting low-density lipoprotein cholesterol (LDL-C) and apolipoproteins, such as apolipoprotein B100 (ApoB100) and apolipoprotein CIII (ApoCIII). Other approaches involve vaccine formulations aimed at proteins that regulate lipoprotein metabolism, including proprotein convertase subtilisin/kexin type 9 (PCSK9), cholesteryl ester transfer protein (CETP), and angiopoietin-like protein 3 (ANGPTL3). Furthermore, the literature highlights the potential for developing non-lipid-related vaccines, with key targets including heat shock proteins (HSPs), interleukins (ILs), angiotensin III (Ang III), and a disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS-7). However, translating these promising findings into safe and effective clinical therapies presents substantial challenges. This review provides a critical evaluation of current anti-atherosclerotic vaccination strategies, examines their proposed mechanisms of action, and discusses key challenges that need to be overcome to enable clinical translation.
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Affiliation(s)
- Georgios Tsioulos
- Fourth Department of Internal Medicine, Medical School, Attikon General University Hospital, National and Kapodistrian University of Athens, 12462 Athens, Greece;
| | - Natalia G. Vallianou
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (S.K.); (N.A.)
| | - Alexandros Skourtis
- Department of Internal Medicine, Evangelismos General Hospital, 10676 Athens, Greece;
| | - Maria Dalamaga
- Department of Biological Chemistry, National and Kapodistrian University of Athens, 75 Mikras Asias Str., 11527 Athens, Greece;
| | - Evangelia Kotsi
- Second Department of Internal Medicine, Medical School, National and Kapodistrian University of Athens, Hippokratio General Hospital, 11527 Athens, Greece;
| | - Sofia Kargioti
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (S.K.); (N.A.)
| | - Nikolaos Adamidis
- First Department of Internal Medicine, Sismanogleio General Hospital, 15126 Athens, Greece; (S.K.); (N.A.)
| | - Irene Karampela
- Second Department of Critical Care, Medical School, Attikon General University Hospital, University of Athens, 12461 Athens, Greece;
| | - Iordanis Mourouzis
- Department of Pharmacology, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Dimitris Kounatidis
- Diabetes Center, First Department of Propaedeutic Internal Medicine, Medical School, National and Kapodistrian University of Athens, Laiko General Hospital, 11527 Athens, Greece;
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Jeswani BM, Sharma S, Rathore SS, Nazir A, Bhatheja R, Kapoor K. PCSK9 Inhibitors: The Evolving Future. Health Sci Rep 2024; 7:e70174. [PMID: 39479289 PMCID: PMC11522611 DOI: 10.1002/hsr2.70174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 09/14/2024] [Accepted: 10/09/2024] [Indexed: 11/02/2024] Open
Abstract
Introduction PCSK9 inhibitors are a novel class of medications that lower LDL cholesterol (LDL-C) by increasing LDL receptor activity, promoting clearance of LDL-C from the bloodstream. Over the years, PCSK9 inhibitors have been explored as adjunct therapies to statins or as monotherapy in high-risk cardiovascular patients. Aim This review aims to provide an updated perspective on PCSK9 inhibitors, assessing their clinical efficacy, safety, and significance, especially in light of recent clinical trials. Methods The review examines the role of PCSK9 in cholesterol regulation and summarizes the results of major cardiovascular trials, including FOURIER, SPIRE-1, SPIRE-2, and ODYSSEY Outcomes. It also discusses emerging treatments like small interfering RNA (siRNA) therapies and evaluates PCSK9 inhibitor effects on LDL-C and lipoprotein(a) levels. Results Clinical trials have shown PCSK9 inhibitors reduce LDL-C by up to 60%. In the FOURIER trial, evolocumab reduced LDL-C by 59% and major cardiovascular events by 15%-20%. The SPIRE-2 trial, despite early termination, showed a 21% risk reduction in the primary composite endpoint with bococizumab. The ODYSSEY Outcomes trial reported a 57% LDL-C reduction with alirocumab, alongside a 15% reduction in adverse events. Emerging treatments like Inclisiran offer long-term LDL-C control with fewer doses. PCSK9 inhibitors are generally well-tolerated, with the most common side effect being injection site reactions. Conclusion PCSK9 inhibitors significantly lower LDL-C and reduce cardiovascular events, offering promising therapies for high-risk patients, including those with familial hypercholesterolemia (FH) and those who cannot tolerate statins. Future research will focus on optimizing these inhibitors, integrating complementary therapies, and exploring gene-editing technologies to improve patient outcomes.
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Affiliation(s)
- Bijay Mukesh Jeswani
- Department of MedicineGCS Medical College, Hospital & Research CentreAhmedabadIndia
| | | | | | - Abubakar Nazir
- Department of MedicineKing Edward Medical UniversityLahorePakistan
- Department of MedicineOli Health Magazine Organization, Research, and EducationKigaliRwanda
| | | | - Kapil Kapoor
- Cardiology, AdventHealth OrlandoOrlandoFloridaUSA
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Ahmad P, Alvi SS, Waiz M, Khan MS, Ahmad S, Khan MS. Naturally occurring organosulfur compounds effectively inhibits PCSK-9 activity and restrict PCSK-9-LDL-receptor interaction via in-silico and in-vitro approach. Nat Prod Res 2024; 38:3924-3933. [PMID: 37842787 DOI: 10.1080/14786419.2023.2269465] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 09/20/2023] [Accepted: 10/01/2023] [Indexed: 10/17/2023]
Abstract
The present study intended to divulge the potential role of garlic-derived organosulfur compounds (OSCs) in targeting PCSK-9 and averting its interaction with the EGF-A portion of LDL-R via in-vitro and in-silico analysis. Our in-silico screening data showed that 3-(Propylsulfinyl)-L-alanine (PSA), S-Ethyl-L-cysteine (SEC), alliin, and S-Allyl-L-cysteine (SAC) exhibited higher binding energy (-7.05, -7.00, -6.65, and -6.31 Kcal/mol, respectively) against PCSK-9, among other selected OSCs. Further, the protein-protein interaction study of PCSK-9-OSCs-complex with EGF-A demonstrated a similar binding pattern with E-total values ranging from -430.01 to -405.6 Kcal/mol. These results were further validated via in-vitro analysis which showed that SEC, SAC, and diallyl trisulphide (DAT) exhibited the lowest IC50 values of 4.70, 5.26, and 5.29 µg/mL, respectively. In conclusion, the presented data illustrated that SEC, SAC, and DAT were the best inhibitors of PCSK-9 activity and may have the potential to improve the LDL-R function and lower the circulatory LDL-C level.
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Affiliation(s)
- Parvej Ahmad
- IIRC-5, Clinical Biochemistry and Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Sahir S Alvi
- Department of Immunology and Microbiology, South TX Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
| | - Mohd Waiz
- IIRC-5, Clinical Biochemistry and Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Mohd Shahnawaz Khan
- Department of Biochemistry, College of Science, King Saud University, Kingdom of Saudi Arabia
| | - Saheem Ahmad
- Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Hail, Hail, Saudi Arabia
| | - M Salman Khan
- IIRC-5, Clinical Biochemistry and Natural Product Research Lab, Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
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Bao X, Liang Y, Chang H, Cai T, Feng B, Gordon K, Zhu Y, Shi H, He Y, Xie L. Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside. Signal Transduct Target Ther 2024; 9:13. [PMID: 38185721 PMCID: PMC10772138 DOI: 10.1038/s41392-023-01690-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 28.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 09/27/2023] [Accepted: 10/27/2023] [Indexed: 01/09/2024] Open
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.
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Affiliation(s)
- Xuhui Bao
- Institute of Therapeutic Cancer Vaccines, Fudan University Pudong Medical Center, Shanghai, China.
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China.
- Center for Clinical Research, Fudan University Pudong Medical Center, Shanghai, China.
- Clinical Research Center for Cell-based Immunotherapy, Fudan University, Shanghai, China.
- Department of Pathology, Duke University Medical Center, Durham, NC, USA.
| | - Yongjun Liang
- Center for Medical Research and Innovation, Fudan University Pudong Medical Center, Shanghai, China
| | - Hanman Chang
- Institute for Food Safety and Health, Illinois Institute of Technology, Chicago, IL, USA
| | - Tianji Cai
- Department of Sociology, University of Macau, Taipa, Macau, China
| | - Baijie Feng
- Department of Oncology, Fudan University Pudong Medical Center, Shanghai, China
| | - Konstantin Gordon
- Medical Institute, Peoples' Friendship University of Russia, Moscow, Russia
- A. Tsyb Medical Radiological Research Center, Obninsk, Russia
| | - Yuekun Zhu
- Department of Colorectal Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Zhangjiang Hi-tech Park, Shanghai, China
| | - Yundong He
- Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, China.
| | - Liyi Xie
- Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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Ai JY, Zhao PC, Zhang W, Rao GW. Research Progress in the Clinical Treatment of Familial Hypercholesterolemia. Curr Med Chem 2024; 31:1082-1106. [PMID: 36733200 DOI: 10.2174/0929867330666230202111849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 11/30/2022] [Accepted: 12/15/2022] [Indexed: 02/04/2023]
Abstract
Familial hypercholesterolemia (FH) is an autosomal dominant inheritable disease with severe disorders of lipid metabolism. It is mainly marked by increasing levels of plasma total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), xanthoma, corneal arch, and early-onset coronary heart disease (CHD). The prevalence of FH is high, and it is dangerous and clinically underdiagnosed. The clinical treatment for FH includes both pharmacological and non-pharmacological treatment, of which non-pharmacological treatment mainly includes therapeutic lifestyle change and dietary therapy, LDL apheresis, liver transplantation and gene therapy. In recent years, many novel drugs have been developed to treat FH more effectively. In addition, the continuous maturity of non-pharmacological treatment techniques has also brought more hope for the treatment of FH. This paper analyzes the pathogenic mechanism and the progress in clinical treatment of FH. Furthermore, it also summarizes the mechanism and structure-activity relationship of FH therapeutic drugs that have been marketed. In a word, this article provides a reference value for the research and development of FH therapeutic drugs.
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Affiliation(s)
- Jing-Yan Ai
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P.R. China
| | - Peng-Cheng Zhao
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P.R. China
| | - Wen Zhang
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P.R. China
| | - Guo-Wu Rao
- College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, P.R. China
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Gao S, Wang L, Bai F, Xu S. In silico discovery of food-derived phytochemicals against asialoglycoprotein receptor 1 for treatment of hypercholesterolemia: Pharmacophore modeling, molecular docking and molecular dynamics simulation approach. J Mol Graph Model 2023; 125:108614. [PMID: 37651861 DOI: 10.1016/j.jmgm.2023.108614] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 08/22/2023] [Accepted: 08/23/2023] [Indexed: 09/02/2023]
Abstract
Hypercholesterolemia is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD). Successful management of cholesterol metabolism disorders can prevent these ASCVD effectively. Asialoglycoprotein receptor 1 (ASGR1) is the main subtype of sialoglycoprotein receptor, which is specifically expressed in the liver and mediates the endocytosis of blood asialoglycoprotein to lysosome degradation. Recently, ASGR1 has been reported as a new therapeutic target for the treatment of hypercholesterolemia. In this study, the main aim was to identify natural ASGR1 inhibitors from plant food chemicals library through pharmacophore and docking based virtual screening. Total 14 phytochemicals of potential ASGR1 inhibitors were identified, which presented docking affinity higher than control compound through docking based virtual screening. The docking pose showed the top three hits interacted residues were located at active pocket of ASGR1 with hydrogen bonds, hydrophobic interactions and electrostatic interactions. The top three hits (ZINC85664954, ZINC169372863, and ZINC195764535) were then subjected to 200 ns molecular dynamics simulation to evaluate the stability of docked complexes. These results showed that selected phytochemicals bound to ASGR1 with higher stability than control compound. Binding free energy of each docked complex was calculated by the Molecular Mechanics Poisson-Boltzmann Surface Area (MM/PBSA) method. The binding free energy of ZINC85664954, ZINC169372863, ZINC195764535, and control-ASGR1 docked complexes were -18.359, -13.303, -14.389, and -6.229 kcal/mol, respectively. This indicated that selected hits bound to ASGR1 with higher affinity than control compound. Network pharmacology analysis shows that these phytochemicals have obvious multiple-effects and can regulate various biochemical pathways related to hypercholesterolemia. Besides, selected phytochemicals have suitable pharmacokinetics properties, suggesting that these compounds may be potential drug candidates. This study may be contributed to rational design of novel ASGR1 inhibitors for treatment of hypercholesterolemia.
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Affiliation(s)
- Shengyun Gao
- Chest Pain Center, Department of Cardiovascular Medicine, Gansu Wuwei Tumor Hospital, Wuwei, Gansu, 733000, China
| | - Lei Wang
- Chest Pain Center, Department of Cardiovascular Medicine, Gansu Wuwei Tumor Hospital, Wuwei, Gansu, 733000, China
| | - Feng Bai
- Drug Clinical Trial Center, Gansu Wuwei Tumor Hospital, Wuwei, Gansu, 733000, China
| | - Shaohua Xu
- Drug Clinical Trial Center, Gansu Wuwei Tumor Hospital, Wuwei, Gansu, 733000, China.
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Lv F, Cai X, Lin C, Yang W, Hu S, Ji L. Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors and the Risk of Fracture: A Systematic Review and Meta-analysis of Randomized Controlled Trials. Calcif Tissue Int 2023:10.1007/s00223-023-01085-0. [PMID: 37099141 DOI: 10.1007/s00223-023-01085-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 04/13/2023] [Indexed: 04/27/2023]
Abstract
Osteoporosis and hyperlipidemia are closely correlated and statins might be associated with a decreased risk of fracture. We aimed to investigate the association between proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) therapy and the risk of fracture. The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to October 22, 2022. Randomized clinical trials (RCTs) that addressed to fracture events of participants using alirocumab, evolocumab, bococizumab or inclisiran, with a follow-up of ≥ 24 weeks were included. Meta-analyses were conducted to calculate the odds ratio (OR) with 95% confidence intervals (CIs) for major osteoporotic fracture, hip fracture, osteoporotic non-vertebral fracture, and total fracture. 30 trials assessing PCSK9i among 95, 911 adults were included. There were no significant associations between PCSK9i therapy and the risk of major osteoporotic fracture [OR 1.08 (95% Cl 0.87-1.34), p = 0.49], hip fracture [OR 1.05 (95% Cl 0.73-1.53), p = 0.79], osteoporotic non-vertebral fracture [OR 1.03 (95% Cl 0.80-1.32), p = 0.83], and total fracture [OR 1.03 (95% Cl 0.88-1.19), p = 0.74] over a period of 6-64 months. No significant associations were detected in any of the sensitivity analyses and subgroup analyses stratified by the type of PCSK9i, follow-up duration, age, sex, sample size, and patient profile. Pooled results of our meta-analysis showed that exposure to PCSK9i was not associated with reduced risks of fracture in the short term.
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Affiliation(s)
- Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
| | - Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Suiyuan Hu
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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May L, Bartolo B, Harrison D, Guzik T, Drummond G, Figtree G, Ritchie R, Rye KA, de Haan J. Translating atherosclerosis research from bench to bedside: navigating the barriers for effective preclinical drug discovery. Clin Sci (Lond) 2022; 136:1731-1758. [PMID: 36459456 PMCID: PMC9727216 DOI: 10.1042/cs20210862] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 10/21/2022] [Accepted: 11/04/2022] [Indexed: 08/10/2023]
Abstract
Cardiovascular disease (CVD) remains the leading cause of death worldwide. An ongoing challenge remains the development of novel pharmacotherapies to treat CVD, particularly atherosclerosis. Effective mechanism-informed development and translation of new drugs requires a deep understanding of the known and currently unknown biological mechanisms underpinning atherosclerosis, accompanied by optimization of traditional drug discovery approaches. Current animal models do not precisely recapitulate the pathobiology underpinning human CVD. Accordingly, a fundamental limitation in early-stage drug discovery has been the lack of consensus regarding an appropriate experimental in vivo model that can mimic human atherosclerosis. However, when coupled with a clear understanding of the specific advantages and limitations of the model employed, preclinical animal models remain a crucial component for evaluating pharmacological interventions. Within this perspective, we will provide an overview of the mechanisms and modalities of atherosclerotic drugs, including those in the preclinical and early clinical development stage. Additionally, we highlight recent preclinical models that have improved our understanding of atherosclerosis and associated clinical consequences and propose model adaptations to facilitate the development of new and effective treatments.
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Affiliation(s)
- Lauren T. May
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia
| | | | - David G. Harrison
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville TN, U.S.A
| | - Tomasz Guzik
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, U.K
- Department of Medicine, Jagiellonian University Medical College, Krakow, Poland
| | - Grant R. Drummond
- Centre for Cardiovascular Biology and Disease Research, Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Melbourne, Victoria, Australia
| | - Gemma A. Figtree
- Kolling Research Institute, University of Sydney, Sydney, Australia
- Imaging and Phenotyping Laboratory, Charles Perkins Centre and Faculty of Medicine and Health, University of Sydney, Sydney, Australia
| | - Rebecca H. Ritchie
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Kerry-Anne Rye
- Lipid Research Group, School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney 2052, Australia
| | - Judy B. de Haan
- Cardiovascular Inflammation and Redox Biology Lab, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia
- Department of Chemistry and Biotechnology, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia
- Department Cardiometabolic Health, University of Melbourne, Parkville, Victoria 3010, Australia
- Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Victoria 3086, Australia
- Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, Victoria 3004, Australia
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Crocetin exerts hypocholesterolemic effect by inducing LDLR and inhibiting PCSK9 and Sortilin in HepG2 cells. Nutr Res 2022; 98:41-49. [DOI: 10.1016/j.nutres.2021.08.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2021] [Revised: 08/30/2021] [Accepted: 08/30/2021] [Indexed: 12/23/2022]
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Farmaki P, Damaskos C, Garmpis N, Garmpi A, Savvanis S, Diamantis E. PCSK9 Inhibitors and Cardiovascular Disease: Impact on Cardiovascular Outcomes. Curr Drug Discov Technol 2021; 17:138-146. [PMID: 30526464 DOI: 10.2174/1570163816666181211112358] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 10/21/2018] [Accepted: 11/09/2018] [Indexed: 12/20/2022]
Abstract
Cardiovascular Disease (CVD) remains the leading cause of morbidity and mortality in the western world. Hypolipidemic drugs have long been used for the primary and secondary prevention of heart disease. However, the high frequency of recurrent events in patients despite hypolipidemic therapy has increased the need for new more targeted therapeutic approaches. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are monoclonal antibodies to the PCSK9 gene and represent a new class of drugs that have been shown to further decrease LDL-C when administered as a monotherapy or in combination with statins. In addition to LDL reduction, PCSK9 inhibitors are shown to decrease apolipoprotein B and lipoprotein (a) levels without major adverse effects. Whether or not PCSK9 inhibitors can actually reduce the incidence of cardiovascular events and ameliorate CVD prognosis is yet to be clarified. This review summarizes recent literature on the safety and efficacy of PCSK9 inhibitors on CVD outcome and its potential role in the management of patients with high-risk cardiovascular disease.
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Affiliation(s)
- Paraskevi Farmaki
- First Department of Pediatrics, Aghia Sophia Children's Hospital, Athens, Greece
| | - Christos Damaskos
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Nikolaos Garmpis
- Second Department of Propedeutic Surgery, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna Garmpi
- Internal Medicine Department, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Spyridon Savvanis
- Department of Internal Medicine, General Hospital of Athens "Elpis", Athens, Greece
| | - Evangelos Diamantis
- Department of Endocrinology, Diabetes and Metabolism, Evangelismos Hospital, Athens, Greece
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Rogula S, Błażejowska E, Gąsecka A, Szarpak Ł, Jaguszewski MJ, Mazurek T, Filipiak KJ. Inclisiran-Silencing the Cholesterol, Speaking up the Prognosis. J Clin Med 2021; 10:2467. [PMID: 34199468 PMCID: PMC8199585 DOI: 10.3390/jcm10112467] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/29/2021] [Accepted: 05/31/2021] [Indexed: 12/15/2022] Open
Abstract
The reduction of circulating low-density lipoprotein-cholesterol (LDL-C) is a primary target in cardiovascular risk reduction due to its well-established benefits in terms of decreased mortality. Despite the use of statin therapy, 10%-20% of high- and very-high-risk patients do not reach their LDL-C targets. There is an urgent need for improved strategies to manage dyslipidemia, especially among patients with homozygous familial hypercholesterolemia, but also in patients with established cardiovascular disease who fail to achieve LDL goals despite combined statin, ezetimibe, and PCSK9 inhibitor (PCSK9i) therapy. Inclisiran is a disruptive, first-in-class small interfering RNA (siRNA)-based therapeutic developed for the treatment of hypercholesterolemia that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) synthesis, thereby upregulating the number of LDL receptors on the hepatocytes, thus lowering the plasma LDL-C concentration. Inclisiran decreases the LDL-C levels by over 50% with one dose every 6 months, making it a simple and well-tolerated treatment strategy. In this review, we summarize the general information regarding (i) the role of LDL-C in atherosclerotic cardiovascular disease, (ii) data regarding the role of PCSK9 in cholesterol metabolism, (iii) pleiotropic effects of PCSK9, and (iv) the effects of PCSK9 silencing. In addition, we focus on inclisiran, in terms of its (i) mechanism of action, (ii) biological efficacy and safety, (iii) results from the ORION trials, (iv) benefits of its combination with statins, and (v) its potential future role in atherosclerotic cardiovascular disease.
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Affiliation(s)
- Sylwester Rogula
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland; (S.R.); (E.B.); (T.M.); (K.J.F.)
| | - Ewelina Błażejowska
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland; (S.R.); (E.B.); (T.M.); (K.J.F.)
| | - Aleksandra Gąsecka
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland; (S.R.); (E.B.); (T.M.); (K.J.F.)
| | - Łukasz Szarpak
- Maria Sklodowska-Curie Białystok Oncology Centre, Ogrodowa 12, 15-027 Białystok, Poland;
- Maria Sklodowska-Curie Medical Academy in Warsaw, Solidarności 12, 03-411 Warsaw, Poland
| | - Milosz J. Jaguszewski
- 1st Department of Cardiology, Medical University of Gdańsk, Dębinki 7, 80-211 Gdańsk, Poland;
| | - Tomasz Mazurek
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland; (S.R.); (E.B.); (T.M.); (K.J.F.)
| | - Krzysztof J. Filipiak
- 1st Chair and Department of Cardiology, Medical University of Warsaw, Banacha 1a, 02-097 Warsaw, Poland; (S.R.); (E.B.); (T.M.); (K.J.F.)
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Kalra S, Bhattacharya S, Rawal P. Hepatocrinology. Med Sci (Basel) 2021; 9:medsci9020039. [PMID: 34205986 PMCID: PMC8293374 DOI: 10.3390/medsci9020039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/10/2021] [Accepted: 05/24/2021] [Indexed: 11/17/2022] Open
Abstract
Hepatocrinology is defined as a bidirectional, complex relationship between hepatic physiology and endocrine function, hepatic disease and endocrine dysfunction, hepatotropic drugs and endocrine function, and endocrine drugs and hepatic health. The scope of hepatocrinology includes conditions of varied etiology (metabolic, infectious, autoimmune, and invasive) that we term as hepato-endocrine syndromes. This perspective shares the definition, concept, and scope of hepatocrinology and shares insight related to this aspect of medicine. It is hoped that this communication will encourage further attention and research in this critical field.
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Affiliation(s)
- Sanjay Kalra
- Department of Endocrinology, Bharti Hospital, Karnal 132001, India
- Correspondence: ; Tel.: +09-(19)-896048555
| | | | - Pawan Rawal
- Department of Gastroenterology, Artemis Hospital, Gurgaon 122002, India;
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Abstract
PURPOSE OF REVIEW To collect evidence on statin pharmacogenomics, and review what is known in this field for familial hypercholesterolemia (FH) patients. RECENT FINDINGS There are well-known associations between specific single nucleotide polymorphisms involved in statin transport and metabolism and either adverse effects or altered lipid-lowering efficacy. However, the applicability of this knowledge is uncertain, especially in high-risk populations. There are alternative approaches to study plasma concentrations of statins and new insights on why some association studies fail to be replicated. SUMMARY Statin therapy recommendations are not always followed in primary and secondary prevention and, even when followed, patients often fail to reach therapeutic target values. Considering the stringent 2019 European Atherosclerosis Society and European Society of Cardiology recommended target lipid levels, as well as the persistently high cost for alternative lipid-lowering therapies such as PCSK9 inhibitors, the variability in low-density lipoprotein cholesterol reductions on statin therapy is still an important factor that needs to be addressed to ensure better cardiovascular disease risk management, especially for FH patients, who have not been well studied historically in this context.
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Affiliation(s)
- Joana Rita Chora
- Instituto Nacional de Saúde Doutor Ricardo Jorge
- Biosystems and Integrative Sciences Institute, Lisbon, Portugal
| | - Mafalda Bourbon
- Instituto Nacional de Saúde Doutor Ricardo Jorge
- Biosystems and Integrative Sciences Institute, Lisbon, Portugal
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Shafiq M, Walmann T, Nutalapati V, Gibson C, Zafar Y. Effects of proprotein convertase subtilisin/kexin type-9 inhibitors on fatty liver. World J Hepatol 2020; 12:1258-1167. [PMID: 33442452 PMCID: PMC7772734 DOI: 10.4254/wjh.v12.i12.1258] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 10/07/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Many studies have investigated the progression of nonalcoholic fatty liver disease (NAFLD) and its predisposing risk factors, but the conclusions from these studies have been conflicting. More challenging is the fact that no effective treatment is currently available for NAFLD.
AIM To determine the effects of proprotein convertase subtilisin/kexin type-9 (PCSK9) inhibitors on fatty infiltration of the liver.
METHODS This retrospective, chart review-based study was conducted on patients, 18-year-old and above, who were currently on PCSK9 inhibitor drug therapy. Patients were excluded from the study according to missing pre- or post-treatment imaging or laboratory values, presence of cirrhosis or rhabdomyolysis, or development of acute liver injury during the PCSK9 inhibitor treatment period; the latter being due to false elevation of liver function markers, alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Radiographic improvement was assessed by a single radiologist, who read both the pre- and post-treatment images to minimize reading bias. Fatty infiltration of the liver was also assessed by changes in ALT and AST, with pre- and post-treatment levels compared by paired t-test (alpha criterion: 0.05).
RESULTS Of the 29 patients included in the study, 8 were male (27.6%) and 21 were female (72.4%). Essential hypertension was present in 25 (86.2%) of the patients, diabetes mellitus in 18 (62.1%) and obesity in 15 (51.7%). In all, patients were on PCSK9 inhibitors for a mean duration of 23.69 ± 11.18 mo until the most recent ALT and AST measures were obtained. Of the 11 patients who received the radiologic diagnosis of hepatic steatosis, 8 (72.73%) achieved complete radiologic resolution upon use of PCSK9 inhibitors (mean duration of 17.6 mo). On average, the ALT level (IU/L) decreased from 21.83 ± 11.89 at pretreatment to 17.69 ± 8.00 at post-treatment (2-tailed P = 0.042) and AST level (IU/L) decreased from 22.48 ± 9.00 pretreatment to 20.59 ± 5.47 post-treatment (2-tailed P = 0.201).
CONCLUSION PCSK9 inhibitors can slow down or even completely resolve NAFLD.
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Affiliation(s)
- Muhammad Shafiq
- General and Geriatric Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Timothy Walmann
- Department of Diagnostic Radiology, University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Venkat Nutalapati
- Department of Gastroenterology, University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Cheryl Gibson
- General and Geriatric Medicine, University of Kansas Medical Center, Kansas City, KS 66160, United States
| | - Yousaf Zafar
- Internal Medicine, NCH Health Care System, Naples, FL 34102, United States
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Insights into pharmacological mechanisms of polydatin in targeting risk factors-mediated atherosclerosis. Life Sci 2020; 254:117756. [DOI: 10.1016/j.lfs.2020.117756] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 04/30/2020] [Accepted: 05/04/2020] [Indexed: 12/20/2022]
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Barale C, Bonomo K, Frascaroli C, Morotti A, Guerrasio A, Cavalot F, Russo I. Platelet function and activation markers in primary hypercholesterolemia treated with anti-PCSK9 monoclonal antibody: A 12-month follow-up. Nutr Metab Cardiovasc Dis 2020; 30:282-291. [PMID: 31653513 DOI: 10.1016/j.numecd.2019.09.012] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 08/14/2019] [Accepted: 09/09/2019] [Indexed: 10/26/2022]
Abstract
BACKGROUND AND AIMS In the association between hypercholesterolemia (HC) and thrombotic risk platelet hyper-reactivity plays an important role. The inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) to reduce plasma LDL-cholesterol merges as effective therapeutic strategy to prevent cardiovascular (CV) events. Aim of this study was to verify whether a treatment up to 12 months with the monoclonal antibodies (mAbs) anti-PCSK9 influences platelet function in primary HC. METHODS AND RESULTS In patients affected by primary HC (n = 24), all on background of statin and 17 on acetyl salicylic acid (ASA), platelet function parameters were evaluated at baseline up to 12 months of treatment with the mAb anti-PCSK9 alirocumab or evolocumab. From baseline, the treatment with anti-PCSK9 mAbs: i) in ASA HC patients, significantly decreased platelet aggregation detected in platelet-rich plasma by light transmission aggregometry and in whole blood Platelet Function Analyzer-100 assay; ii) in all HC patients, significantly decreased platelet membrane expression of CD62P and plasma levels of the in vivo platelet activation markers soluble CD40 Ligand, Platelet Factor-4, and soluble P-Selectin. Furthermore, CD62P expression, and sP-Selectin, PF-4, sCD40L levels significantly correlated with serum PCSK9. CONCLUSION Besides markedly lowering LDL-c levels, our results suggest that HC patients benefit from anti-PCSK9 mAb treatment also for reducing platelet reactivity and increasing platelet sensitivity to the inhibitory effects of aspirin. These effects on platelets could play a role in the reduction of CV event incidence in patients treated with PCSK9 inhibitors.
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Affiliation(s)
- Cristina Barale
- Department of Clinical and Biological Sciences of Turin University, Orbassano, Turin, Italy
| | - Katia Bonomo
- Metabolic Disease and Diabetes Unit, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy
| | - Chiara Frascaroli
- Metabolic Disease and Diabetes Unit, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy
| | - Alessandro Morotti
- Department of Clinical and Biological Sciences of Turin University, Orbassano, Turin, Italy
| | - Angelo Guerrasio
- Department of Clinical and Biological Sciences of Turin University, Orbassano, Turin, Italy
| | - Franco Cavalot
- Metabolic Disease and Diabetes Unit, San Luigi Gonzaga Hospital, Orbassano, Turin, Italy
| | - Isabella Russo
- Department of Clinical and Biological Sciences of Turin University, Orbassano, Turin, Italy.
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Abstract
PURPOSE OF REVIEW We comment on the role of dyslipidaemia in cardiovascular disease (CVD) in HIV-infected patients. We have discussed various risk factors, including traditional CVD risk factors, HIV-related risk factors and antiretroviral therapy (ART)-induced dyslipidaemia. RECENT FINDINGS HIV-infected individuals are prone to lipid and lipoprotein abnormalities as a result of the infection itself and the effect of ART. The older drugs used for the treatment of HIV were associated with an increased risk of these abnormalities. New therapies used to treat HIV are lipid friendly. Calculating CVD risk in the HIV population is complex due to the infection itself and the ART-related factors. The advancement in ART has helped to increase the life expectancy of HIV patients. As a result, a growing number of patients die of non-HIV related complications such as CVD, hepatic and renal disease. Outcome studies with intervention for dyslipidaemia in HIV are underway. SUMMARY The implications of the above findings suggest that all patients with HIV should undergo a CVD risk assessment before starting ART. Appropriate lipid-friendly ART regimen should be initiated along with intervention for associated CVD risk factors (e.g. lipids, hypertension and smoking).
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Emerging Lipid-Lowering Therapies in Secondary Prevention. CURRENT CARDIOVASCULAR RISK REPORTS 2019. [DOI: 10.1007/s12170-019-0607-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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Martinez JM, Brunet A, Hurbin F, DiCioccio AT, Rauch C, Fabre D. Population Pharmacokinetic Analysis of Alirocumab in Healthy Volunteers or Hypercholesterolemic Subjects Using a Michaelis-Menten Approximation of a Target-Mediated Drug Disposition Model-Support for a Biologics License Application Submission: Part I. Clin Pharmacokinet 2019; 58:101-113. [PMID: 29725996 PMCID: PMC6325993 DOI: 10.1007/s40262-018-0669-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Alirocumab, a human monoclonal antibody, inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) to significantly reduce low-density lipoprotein cholesterol levels; pharmacokinetics (PK) are governed by non-linear, target-mediated drug disposition (TMDD). OBJECTIVES We aimed to develop and qualify a population PK (PopPK) model to characterize the PK profile of alirocumab, evaluate the impact of covariates on alirocumab PK and on individual patient exposures, and estimate individual predicted concentrations for a subsequent PK/pharmacodynamic (PD) analysis. METHODS Data from 13 phase I-III trials of 2799 healthy volunteers or patients with hypercholesterolemia treated with intravenous or subcutaneous alirocumab (13,717 alirocumab concentrations) were included; a Michaelis-Menten approximation of the TMDD model was used to estimate PK parameters and exposures. The final model comprised two compartments with first-order absorption. Elimination from the central compartment was described by linear (CLL) and non-linear Michaelis-Menten clearance (Vm and Km). The model was validated using visual predictive check and bootstrap methods. Patient exposures to alirocumab were computed using individual PK parameters. RESULTS The PopPK model was well-qualified, with the majority of observed alirocumab concentrations in the 2.5th-97.5th predicted percentiles. Covariates responsible for interindividual variability were identified. Body weight and concomitant statin administration impacted CLL, whereas time-varying free PCSK9 concentrations and age affected Km and peripheral distribution volume (V3), respectively. No covariates were clinically meaningful, therefore no dose adjustments were needed. CONCLUSIONS The model explained the between-subject variability, quantified the impact of covariates, and, finally, predicted alirocumab concentrations (subsequently used in a PopPK/PD model, see Part II) and individual exposures.
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Affiliation(s)
- Jean-Marie Martinez
- TMED/PKDM Department, Sanofi, 371 Rue du Professeur Joseph Blayac, 34184, Montpellier Cedex 04, France.
| | - Aurélie Brunet
- TMED/PKDM Department, Sanofi, 371 Rue du Professeur Joseph Blayac, 34184, Montpellier Cedex 04, France
| | - Fabrice Hurbin
- TMED/PKDM Department, Sanofi, 371 Rue du Professeur Joseph Blayac, 34184, Montpellier Cedex 04, France
| | | | - Clémence Rauch
- TMED/PKDM Department, Sanofi, 371 Rue du Professeur Joseph Blayac, 34184, Montpellier Cedex 04, France
| | - David Fabre
- TMED/PKDM Department, Sanofi, 371 Rue du Professeur Joseph Blayac, 34184, Montpellier Cedex 04, France
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Wu Q, Wang Q, Fu J, Ren R. Polysaccharides derived from natural sources regulate triglyceride and cholesterol metabolism: a review of the mechanisms. Food Funct 2019; 10:2330-2339. [DOI: 10.1039/c8fo02375a] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
This paper presents a comprehensive review of hypolipidemic mechanism of polysaccharides from natural sources.
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Affiliation(s)
- Qingqian Wu
- Department of Pathology and Pathophysiology
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province
- First Affiliated Hospital
- School of Medicine
- Zhejiang University
| | - Qintao Wang
- Department of Pathology and Pathophysiology
- Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province
- First Affiliated Hospital
- School of Medicine
- Zhejiang University
| | - Junfen Fu
- Children's Hospital
- School of Medicine
- Zhejiang University
- Hangzhou
- China
| | - Rendong Ren
- School of Public Health
- Fujian Medical University
- Fuzhou
- China
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Li L, Shen C, Huang YX, Li YN, Liu XF, Liu XM, Liu JH. A New Strategy for Rapidly Screening Natural Inhibitors Targeting the PCSK9/LDLR Interaction In Vitro. Molecules 2018; 23:molecules23092397. [PMID: 30235833 PMCID: PMC6225438 DOI: 10.3390/molecules23092397] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 09/13/2018] [Accepted: 09/17/2018] [Indexed: 01/14/2023] Open
Abstract
The interaction between proprotein convertase subtilisin/kexin type 9 (PCSK9) and the low-density lipoprotein receptor (LDLR) is a promising target for the treatment of hyperc-holesterolemia. In this study, a new method based on competitive affinity and tag detection was developed, which aimed to evaluate potent natural inhibitors preventing the interaction of PCSK9/LDLR directly. Herein, natural compounds with efficacy in the treatment of hypercholesterolemia were chosen to investigate their inhibitory activities on the PCSK9/LDLR interaction. Two of them, polydatin (1) and tetrahydroxydiphenylethylene-2-O-glucoside (2), were identified as potential inhibitors for the PCSK9/LDLR interaction and were proven to prevent PCSK9-mediated LDLR degradation in HepG2 cells. The results suggested that this strategy could be applied for evaluating potential bioactive compounds inhibiting the interaction of PCSK9/LDLR and this strategy could accelerate the discovery of new drug candidates for the treatment of PCSK9-mediated hypercholesterolemia.
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Affiliation(s)
- Li Li
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Chen Shen
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Ya-Xuan Huang
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Ya-Nan Li
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Xiu-Feng Liu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
| | - Xu-Ming Liu
- School of Life Science and Technology, China Pharmaceutical University, Nanjing 211198, China.
| | - Ji-Hua Liu
- Jiangsu Key Laboratory of TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 211198, China.
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China.
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Afroz R, Cao Y, Rostam MA, Ta H, Xu S, Zheng W, Osman N, Kamato D, Little PJ. Signalling pathways regulating galactosaminoglycan synthesis and structure in vascular smooth muscle: Implications for lipoprotein binding and atherosclerosis. Pharmacol Ther 2018; 187:88-97. [DOI: 10.1016/j.pharmthera.2018.02.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Song KH, Kim YH, Im AR, Kim YH. Black Raspberry Extract Enhances LDL Uptake in HepG2 Cells by Suppressing PCSK9 Expression to Upregulate LDLR Expression. J Med Food 2018; 21:560-567. [DOI: 10.1089/jmf.2017.4069] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Affiliation(s)
- Kwang Hoon Song
- Mibyeong Research Center, Korea Institute of Oriental Medicine, Yuseong-gu, Daejeon, Korea
- University of Science and Technology, Yuseong-gu, Daejeon, Korea
| | - Young Hwa Kim
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Yuseong-gu, Daejeon, Korea
| | - A-Rang Im
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Yuseong-gu, Daejeon, Korea
| | - Yun Hee Kim
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Yuseong-gu, Daejeon, Korea
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Nhoek P, Chae HS, Masagalli JN, Mailar K, Pel P, Kim YM, Choi WJ, Chin YW. Discovery of Flavonoids from Scutellaria baicalensis with Inhibitory Activity Against PCSK 9 Expression: Isolation, Synthesis and Their Biological Evaluation. Molecules 2018; 23:E504. [PMID: 29495284 PMCID: PMC6100156 DOI: 10.3390/molecules23020504] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 02/22/2018] [Accepted: 02/22/2018] [Indexed: 12/21/2022] Open
Abstract
Nine flavonoids were isolated and identified from a chloroform-soluble fraction of the roots of Scutellaria baicalensis through a bioactivity-guided fractionation using a proprotein convertase subtilisin/kexin type 9 (PCSK9) monitoring assay in HepG2 cells. All structures were established by interpreting the corresponding spectroscopic data and comparing measured values from those in the literature. All compounds were assessed for their ability to inhibit PCSK9 mRNA expression; compounds 1 (3,7,2'-trihydroxy-5-methoxy-flavanone) and 4 (skullcapflavone II) were found to suppress PCSK9 mRNA via SREBP-1. Furthermore, compound 1 was found to increase low-density lipoprotein receptor protein expression. Also, synthesis of compound 1 as a racemic mixture form (1a) was completed for the first time. Natural compound 1 and synthetic racemic 1a were evaluated for their inhibitory activities against PCSK9 mRNA expression and the results confirmed the stereochemistry of 1 was important.
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Affiliation(s)
| | | | - Jagadeesh Nagarajappa Masagalli
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Korea.
| | - Karabasappa Mailar
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Korea.
| | - Pisey Pel
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Korea.
| | - Young-Mi Kim
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Korea.
| | - Won Jun Choi
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Korea.
| | - Young-Won Chin
- College of Pharmacy and Integrated Research Institute for Drug Development, Dongguk University-Seoul, 32 Dongguk-lo, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Korea.
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Katsiki N, Kolovou G, Perez-Martinez P, Mikhailidis DP. Dyslipidaemia in the elderly: to treat or not to treat? Expert Rev Clin Pharmacol 2018; 11:259-278. [PMID: 29303009 DOI: 10.1080/17512433.2018.1425138] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION The elderly population (i.e. aged ≥ 65 years) is increasing worldwide. Ageing is associated with a higher incidence and prevalence of cardiovascular disease (CVD). Areas covered: The prevalence of CVD risk factors including type 2 diabetes mellitus, hypertension and dyslipidaemia also increases with advancing age, contributing to the higher absolute CVD risk observed in the elderly. The present narrative review comments on the associations of dyslipidaemia with CVD as well as the effects of lifestyle measures and lipid-lowering drugs on lipids and CVD risk with a special focus on the elderly population. Individual treatment goals and therapeutic options according to current guidelines are also reviewed. Finally, we discuss special characteristics of the elderly that may influence the efficacy and safety of drug therapy and should be considered before selection of hypolipidaemic pharmacotherapy. Expert commentary: There may be a greater CVD benefit in older patients following drug therapy compared with younger ones. Treatment goals and therapeutic options should be individualized according to current guidelines. Specific characteristics that may influence the efficacy and safety of drug therapy in the elderly should be considered in relation to dyslipidaemia treatment.
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Affiliation(s)
- Niki Katsiki
- a Second Propedeutic Department of Internal Medicine, Medical School , Aristotle University of Thessaloniki, Hippocration Hospital , Thessaloniki , Greece
| | - Genovefa Kolovou
- b Cardiology Department and LDL-Apheresis Unit , Onassis Cardiac Surgery Center , Athens , Greece
| | - Pablo Perez-Martinez
- c Lipid and Atherosclerosis Unit , IMIBIC/Reina Sofia University Hospital/University of Cordoba, and CIBER Fisiopatologia Obesidad y Nutricion (CIBEROBN), Instituto de Salud Carlos III , Spain
| | - Dimitri P Mikhailidis
- d Department of Clinical Biochemistry , Royal Free Hospital Campus, University College London Medical School, University College London (UCL) , London , UK
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Shafik NM, Baalash A, Ebeid AM. Synergistic Cardioprotective Effects of Combined Chromium Picolinate and Atorvastatin Treatment in Triton X-100-Induced Hyperlipidemia in Rats: Impact on Some Biochemical Markers. Biol Trace Elem Res 2017; 180:255-264. [PMID: 28409410 DOI: 10.1007/s12011-017-1010-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2017] [Accepted: 03/31/2017] [Indexed: 11/26/2022]
Abstract
Hyperlipidemia is one of the major risk factors for atherosclerosis and ischemic heart disease. Chromium (Cr) mineral is playing a crucial role in glucose and lipid homeostasis. The aim of this study was to evaluate the protective effects of combined chromium picolinate (CrPic) and atorvastatin treatment against hyperlipidemia-induced cardiac injury. Seventy-five male albino rats were divided into five groups (15 rats each). Hyperlipidemia was induced by intraperitoneal injection of a single dose of Triton X-100 (300 mg/kg body weight (b.w) (group ІІ). Treatment of hyperlipidemic rats was induced by daily administration of CrPic at a dose of 200 μg/kg b.w/day (group ІІІ), atorvastatin at a dose of 10 mg/kg/day (group IV), and combined treatment with both (group V) by gavage for 7 days. At the end of experiment, serum and heart tissues were obtained. Hyperlipidemia was confirmed by histopathology of heart tissues, marked serum dyslipidemia, increased atherogenic indices, and values of ischemia-modified albumin. In addition to increased values of proprotein convertase subtilisin/kexin type 9, activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase enzyme and high relative expression levels of pentraxin-3 were observed. However, paraoxonase-1 activity was markedly decreased in the hyperlipidemic group. Significant improvement in all assessed parameters was observed in the rat group treated with both CrPic and atorvastatin. It can be concluded that combined CrPic and atorvastatin treatments had synergistic cardioprotective effects against hyperlipidemia which may be through modulating atherosclerosis as well as cardiac and aortic damage and/or activation of anti-inflammatory and anti-oxidant pathways, thus reversing endothelial dysfunction.
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Affiliation(s)
- Noha M Shafik
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Tanta University, Tanta, 31111, Egypt.
| | - Amal Baalash
- Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Tanta University, Tanta, 31111, Egypt
| | - Abla M Ebeid
- Department of Clinical Pharmacy, Faculty of Pharmacy, Al-Delta University, Gamasa, Egypt
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Campo R. Estudios clínicos con inhibidores de la PCSK9. REVISTA COLOMBIANA DE CARDIOLOGÍA 2017. [DOI: 10.1016/j.rccar.2017.08.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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29
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Sultan Alvi S, Ansari IA, Khan I, Iqbal J, Khan MS. Potential role of lycopene in targeting proprotein convertase subtilisin/kexin type-9 to combat hypercholesterolemia. Free Radic Biol Med 2017; 108:394-403. [PMID: 28412198 DOI: 10.1016/j.freeradbiomed.2017.04.012] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Revised: 03/18/2017] [Accepted: 04/12/2017] [Indexed: 11/23/2022]
Abstract
Proprotein convertase subtilisin/kexin type 9 (PCSK-9) is a serine protease of the proprotien convertase (PC) family that has profound effects on plasma low density lipoprotein cholesterol (LDL-C) levels, the major risk factor for coronary heart disease (CHD), through its ability to mediate LDL receptor (LDL-R) protein degradation and reduced recycling to the surface of hepatocytes. Thus, the current study was premeditated not only to evaluate the role of lycopene in targeting the inhibition of PCSK-9 via modulation of genes involved in cholesterol homeostasis in HFD rats but also to examine a correlation between HFD induced inflammatory cascades and subsequent regulation of PCSK-9 expression. Besides the effect of lycopene on hepatic PCSK-9 gene expression, PPI studies for PCSK-9-Lycopene complex and EGF-A of LDL-R were also performed via molecular informatics approach to assess the dual mode of action of lycopene in LDL-R recycling and increased removal of circulatory LDL-C. We for the first time deciphered that lycopene treatment significantly down-regulates the expression of hepatic PCSK-9 and HMGR, whereas, hepatic LDL-R expression was significantly up-regulated. Furthermore, lycopene ameliorated inflammation stimulated expression of PCSK-9 via suppressing the expression of inflammatory markers. The results from our molecular informatics studies confirmed that lycopene, while occupying the active site of PCSK-9 crystal structure, reduces the affinity of PCSK-9 to complex with EGF-A of LDL-R, whereas, atorvastatin makes PCSK-9-EGF-A complex formation more feasible than both of PCSK-9-EGF-A alone and Lycopene-PCSK-9-EGF-A complex. Based on above results, it can be concluded that lycopene exhibits potent hypolipidemic activities via molecular mechanisms that are either identical (HMGR inhibition) or distinct from that of statins (down-regulation of PCSK-9 mRNA synthesis). To the best of our knowledge, this is the first report that lycopene has this specific biological property. Being a natural, safer and alternative therapeutic agent, lycopene could be used as a complete regulator of cholesterol homeostasis and ASCVD.
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Affiliation(s)
- Sahir Sultan Alvi
- Clinical Biochemistry & Natural Product Research Lab., Department of Biosciences, Integral University, Lucknow 226026, India
| | - Irfan A Ansari
- Clinical Biochemistry & Natural Product Research Lab., Department of Biosciences, Integral University, Lucknow 226026, India
| | - Imran Khan
- Clinical Biochemistry & Natural Product Research Lab., Department of Biosciences, Integral University, Lucknow 226026, India
| | - Johar Iqbal
- Department of Biochemistry, Faculty of Medicine, Jazan University, Jazan, Kingdom of Saudi Arabia
| | - M Salman Khan
- Clinical Biochemistry & Natural Product Research Lab., Department of Biosciences, Integral University, Lucknow 226026, India.
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Preventing cardiovascular heart disease: Promising nutraceutical and non-nutraceutical treatments for cholesterol management. Pharmacol Res 2017; 120:219-225. [PMID: 28408313 DOI: 10.1016/j.phrs.2017.04.008] [Citation(s) in RCA: 76] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 03/20/2017] [Accepted: 04/07/2017] [Indexed: 11/24/2022]
Abstract
Hypercholesterolemia is one of the major risk factors for the development of cardiovascular disease. Atherosclerosis resulting from hypercholesterolemia causes many serious cardiovascular diseases. Statins are generally accepted as a treatment of choice for lowering low-density lipoprotein (LDL) cholesterol, which reduces coronary heart disease morbidity and mortality. Since statin use can be associated with muscle problems and other adverse symptoms, non-adherence and discontinuation of statin therapy often leads to inadequate control of plasma cholesterol levels and increased cardiovascular risk. Moreover, there is compelling evidence on the presence of still considerable residual cardiovascular risk in statin-treated patients. Ezetimibe improves cholesterol-lowering efficacy and provides mild additional cardiovascular protection when combined with statin treatment. Despite a favorable safety profile compared to statins, ezetimibe-induced cholesterol-lowering is modest when used alone. Hence, there is a critical need to identity additional effective hypolipidemic agents that can be used either in combination with statins, or alone, if statins are not tolerated. Thus, hypolipidemic agents such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, apolipoprotein B-100 antisense oligonucleotides, cholesteryl ester transfer protein (CETP) inhibitors, and microsomal triglyceride transfer protein (MTTP) inhibitors, as well as yeast polysaccharides (beta-glucans and mannans) and compounds derived from natural sources (nutraceuticals) such as glucomannans, plant sterols, berberine, and red yeast rice are being used. In this review, we will discuss hypercholesterolemia, its impact on the development of cardiovascular disease (CVD), and the use of yeast polysaccharides, various nutraceuticals, and several therapeutic agents not derived from 'natural' sources, to treat hypercholesterolemia.
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Li S, Guo YL, Zhao X, Zhang Y, Zhu CG, Wu NQ, Xu RX, Qing P, Gao Y, Li XL, Sun J, Liu G, Dong Q, Li JJ. Novel and traditional lipid-related biomarkers and their combinations in predicting coronary severity. Sci Rep 2017; 7:360. [PMID: 28336922 PMCID: PMC5428477 DOI: 10.1038/s41598-017-00499-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 03/02/2017] [Indexed: 12/19/2022] Open
Abstract
We investigated simultaneously traditional and novel lipid indices, alone or in combination, in predicting coronary severity assessed by Gensini score (GS) in 1605 non-lipid-lowering-drug-treated patients undergoing coronary angiography. Firstly, levels of triglycerides (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), non high density lipoprotein cholesterol (non-HDL-C), apolipoprotein (apo) B, lipoprotein (a) [Lp(a)], proprotein convertase subtilisin/kexin type 9 (PCSK9), apoC3, small dense LDL (sdLDL) and large HDL were increased, while HDL-C and apoA1 levels were decreased as GS status (all p for trend <0.05). However, gender stratification analyses showed similar associations between lipids and GS in men but not in women. Secondly, multiple logistic regression analyses indicated that the 12 indices were predictive for high GS (≥24) but not for low GS (1–23) compared with normal coronary (GS = 0) except for TG (neither) and apoB (both). Finally, we found that interactions between two indices with mutually exclusive composition were positively associated with GS status except for couples of TC + apoC3, apoB/PCSK9/apoC3 + sdLDL-C. Concordant elevations in the two showed the highest predictive values for high GS (all p for trend <0.05). Therefore, lipid biomarkers were associated with coronary severity and their adverse changes in combination emerged greater risks in men but not in women.
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Affiliation(s)
- Sha Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Yuan-Lin Guo
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Xi Zhao
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Yan Zhang
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Cheng-Gang Zhu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Na-Qiong Wu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Rui-Xia Xu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Ping Qing
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Ying Gao
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Xiao-Lin Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Jing Sun
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Geng Liu
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Qian Dong
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China
| | - Jian-Jun Li
- Division of Dyslipidemia, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, BeiLiShi Road 167, Beijing, 100037, China.
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Tonstad S. Statinintoleranse. TIDSSKRIFT FOR DEN NORSKE LEGEFORENING 2017; 137:36-38. [DOI: 10.4045/tidsskr.16.0646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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Colletti A, Derosa G, Cicero AF. Retargeting the management of hypercholesterolemia - focus on evolocumab. Ther Clin Risk Manag 2016; 12:1365-76. [PMID: 27660454 PMCID: PMC5019477 DOI: 10.2147/tcrm.s116679] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
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. Inhibitors of PCSK9 represent a new therapeutic approach for lowering LDL-C. Evolocumab and alirocumab are human monoclonal antibodies, which bind to extracellular PCSK9 and thus interfere with the degradation of low-density lipoprotein receptor. Evolocumab use is approved for the treatment of patients with heterozygous familial hypercholesterolemia (FH) and homozygous FH as an adjunct to diet and maximally tolerated statin therapy or for subjects with clinical atherosclerotic cardiovascular disease who require additional lowering of LDL-C. Phase III clinical trials have demonstrated the effectiveness of evolocumab (140 mg/every 2 weeks or 420 mg/month, via subcutaneous injection) in monotherapy and in combination with statins, in the treatment of patients intolerant to statins or with FH. In monotherapy, it reduces LDL-C by 55%, and its association with statins leads to a reduction of LDL-C by up to 63%–75%. Evolocumab has been demonstrated to be safe and well tolerated. Ongoing clinical trials are assessing the long-term effects of evolocumab on the incidence of cardiovascular risk, safety, and tolerability. This review resumes the available clinical evidence on the efficacy and safety of evolocumab, for which a relatively large amount of clinical data are currently available, and discusses the retargeting of cholesterol-lowering therapy in clinical practice.
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Affiliation(s)
| | - Giuseppe Derosa
- Department of Internal Medicine and Therapeutics, University of Pavia and Policlinico San Matteo Foundation, Pavia, Italy
| | - Arrigo Fg Cicero
- Department of Medical and Surgical Sciences, University of Bologna, Bologna
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