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Wang Z, Li S, Cai G, Gao Y, Yang H, Li Y, Liang J, Zhang S, Hu J, Zheng J. Mendelian randomization analysis identifies druggable genes and drugs repurposing for chronic obstructive pulmonary disease. Front Cell Infect Microbiol 2024; 14:1386506. [PMID: 38660492 PMCID: PMC11039854 DOI: 10.3389/fcimb.2024.1386506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2024] [Accepted: 03/22/2024] [Indexed: 04/26/2024] Open
Abstract
Background Chronic obstructive pulmonary disease (COPD) is a prevalent condition that significantly impacts public health. Unfortunately, there are few effective treatment options available. Mendelian randomization (MR) has been utilized to repurpose existing drugs and identify new therapeutic targets. The objective of this study is to identify novel therapeutic targets for COPD. Methods Cis-expression quantitative trait loci (cis-eQTL) were extracted for 4,317 identified druggable genes from genomics and proteomics data of whole blood (eQTLGen) and lung tissue (GTEx Consortium). Genome-wide association studies (GWAS) data for doctor-diagnosed COPD, spirometry-defined COPD (Forced Expiratory Volume in one second [FEV1]/Forced Vital Capacity [FVC] <0.7), and FEV1 were obtained from the cohort of FinnGen, UK Biobank and SpiroMeta consortium. We employed Summary-data-based Mendelian Randomization (SMR), HEIDI test, and colocalization analysis to assess the causal effects of druggable gene expression on COPD and lung function. The reliability of these druggable genes was confirmed by eQTL two-sample MR and protein quantitative trait loci (pQTL) SMR, respectively. The potential effects of druggable genes were assessed through the phenome-wide association study (PheWAS). Information on drug repurposing for COPD was collected from multiple databases. Results A total of 31 potential druggable genes associated with doctor-diagnosed COPD, spirometry-defined COPD, and FEV1 were identified through SMR, HEIDI test, and colocalization analysis. Among them, 22 genes (e.g., MMP15, PSMA4, ERBB3, and LMCD1) were further confirmed by eQTL two-sample MR and protein SMR analyses. Gene-level PheWAS revealed that ERBB3 expression might reduce inflammation, while GP9 and MRC2 were associated with other traits. The drugs Montelukast (targeting the MMP15 gene) and MARIZOMIB (targeting the PSMA4 gene) may reduce the risk of spirometry-defined COPD. Additionally, an existing small molecule inhibitor of the APH1A gene has the potential to increase FEV1. Conclusions Our findings identified 22 potential drug targets for COPD and lung function. Prioritizing clinical trials that target these identified druggable genes with existing drugs or novel medications will be beneficial for the development of COPD treatments.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Jinping Zheng
- National Center for Respiratory Medicine, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China
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2
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Olaniyi KS, Areloegbe SE, Areola ED, Sabinari IW, Fafure AA, Agbana RD, Atuma CL, Shah MZUH, Ajadi IO, Olatunji LA. Low-dose spironolactone combats dyslipidemia and hepatic inflammation by modulating PCSK9 in rat model of polycystic ovarian syndrome. Toxicol Appl Pharmacol 2023; 473:116604. [PMID: 37328115 DOI: 10.1016/j.taap.2023.116604] [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: 02/22/2023] [Revised: 05/30/2023] [Accepted: 06/13/2023] [Indexed: 06/18/2023]
Abstract
Polycystic ovarian syndrome (PCOS) is the most common endocrine disorder among women and it is associated with overt metabolic derangement. Circulating lipids are regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9) which blocks low density lipoprotein (LDL) receptors especially in the liver. The liver is highly vulnerable in dyslipidemia as lipid accumulation leads to progression of non-alcoholic fatty liver disease (NAFLD). An array of scientific endeavours hold that low-dose spironolactone (LDS) is beneficial as intervention for PCOS traits, but this claim is yet to be fully elucidated. The aim of this study was to investigate the effect of LDS on dyslipidemia and hepatic inflammation in rats with letrozole (LET)-induced PCOS and to assess the possible involvement of PCSK9 in these effects. Eighteen female Wistar rats were randomly assigned into 3 groups. The control group received vehicle (distilled water; p.o.), LET-treated group received letrozole (1 mg/kg; p.o.), LET+LDS-treated group received LET plus LDS (0.25 mg/kg, p.o.) for 21 days. Exposure to LET increased body and hepatic weights, plasma and hepatic total cholesterol (TC), TC/HDL, LDL, interleukin-6, MDA, PCSK9, ovarian degenerated follicles and hepatic NLRP3 intensity, reduced GSH and normal ovarian follicles. Interestingly, LDS averted dyslipidemia, NLRP3-dependent hepatic inflammation and ovarian PCOS traits. It is evident herein that LDS ameliorates PCOS traits and combats dyslipidemia and hepatic inflammation in PCOS by a PCSK9-dependent mechanism.
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Affiliation(s)
- Kehinde S Olaniyi
- Cardio/Endo-Metabolic and Microbiome Research Unit, Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti 360101, Nigeria.
| | - Stephanie E Areloegbe
- Cardio/Endo-Metabolic and Microbiome Research Unit, Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti 360101, Nigeria
| | - Emmanuel D Areola
- Department of Physiology, College of Health Sciences, University of Ilorin, P.M.B. 1515, Ilorin, Nigeria
| | - Isaiah W Sabinari
- Department of Physiology, College of Health Sciences, University of Ilorin, P.M.B. 1515, Ilorin, Nigeria
| | - Adedamola A Fafure
- Neuroscience Unit, Department of Anatomy, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti 360101, Nigeria
| | - Richard D Agbana
- Department of Community medicine, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti 360101, Nigeria
| | - Chukwubueze L Atuma
- Cardio/Endo-Metabolic and Microbiome Research Unit, Department of Physiology, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti 360101, Nigeria
| | - Mohd Zahoor Ul Haq Shah
- Laboratory of Endocrinology, Department of Bioscience, Barkatullah University Bhopal, Madhya Predesh 462026, India
| | - Isaac O Ajadi
- Department of Physiology, Faculty of Basic Medical Sciences, Ladoke Akintola University of Technology, Ogbomoso, Nigeria
| | - Lawrence A Olatunji
- Department of Physiology, College of Health Sciences, University of Ilorin, P.M.B. 1515, Ilorin, Nigeria
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3
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Zheng YY, Haruehanroengra P, Yadav PK, Irani S, Mao S, Wang T, Hussain MM, Sheng J. Synthesis of Novel MicroRNA-30c Analogs to Reduce Apolipoprotein B Secretion in Human Hepatoma Cells. Bio Protoc 2022; 12:e4574. [PMID: 36618093 PMCID: PMC9797360 DOI: 10.21769/bioprotoc.4574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/30/2022] [Accepted: 11/26/2022] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis, a condition characterized by thickening of the arteries due to lipid deposition, is the major contributor to and hallmark of cardiovascular disease. Although great progress has been made in lowering the lipid plaques in patients, the conventional therapies fail to address the needs of those that are intolerant or non-responsive to the treatment. Therefore, additional novel therapeutic approaches are warranted. We have previously shown that increasing the cellular amounts of microRNA-30c (miR-30c) with the aid of viral vectors or liposomes can successfully reduce plasma cholesterol and atherosclerosis in mice. To avoid the use of viruses and liposomes, we have developed new methods to synthesize novel miR-30c analogs with increasing potency and efficacy, including 2'-O-methyl (2'OMe), 2'-fluoro (2'F), pseudouridine (ᴪ), phosphorothioate (PS), and N-acetylgalactosamine (GalNAc). The discovery of these modifications has profoundly impacted the modern RNA therapeutics, as evidenced by their increased nuclease stability and reduction in immune responses. We show that modifications on the passenger strand of miR-30c not only stabilize the duplex but also aid in a more readily uptake by the cells without the aid of viral vectors or lipid emulsions. After uptake, the analogs with PS linkages and GalNAc-modified ribonucleotides significantly reduce the secretion of apolipoprotein B (ApoB) without affecting apolipoprotein A1 (ApoA1) in human hepatoma Huh-7 cells. We envision an enormous potential for these modified miR-30c analogs in therapeutic intervention for treating cardiovascular diseases. This protocol was validated in: J Biol Chem (2021), DOI: 10.1016/j.jbc.2022.101813.
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Affiliation(s)
- Ya Ying Zheng
- Department of Chemistry, and The RNA Institute, University at Albany, SUNY, Albany, NY 12222, USA
| | | | - Pradeep Kumar Yadav
- Department of Foundations of Medicine, NYU Long Island School of Medicine, Mineola, NY 11501, USA
| | - Sarah Irani
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | - Song Mao
- Department of Chemistry, and The RNA Institute, University at Albany, SUNY, Albany, NY 12222, USA
| | - Ting Wang
- Department of Chemistry, and The RNA Institute, University at Albany, SUNY, Albany, NY 12222, USA
| | - Mahmood M. Hussain
- Department of Foundations of Medicine, NYU Long Island School of Medicine, Mineola, NY 11501, USA
,
Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA
,
VA New York Harbor Healthcare System, Brooklyn, NY 11209, USA
,
*For correspondence:
;
| | - Jia Sheng
- Department of Chemistry, and The RNA Institute, University at Albany, SUNY, Albany, NY 12222, USA
,
*For correspondence:
;
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4
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Yadav PK, Haruehanroengra P, Irani S, Wang T, Ansari A, Sheng J, Hussain MM. Novel efficacious microRNA-30c analogs reduce apolipoprotein B secretion in human hepatoma and primary hepatocyte cells. J Biol Chem 2022; 298:101813. [PMID: 35278429 PMCID: PMC8980335 DOI: 10.1016/j.jbc.2022.101813] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2021] [Revised: 03/05/2022] [Accepted: 03/08/2022] [Indexed: 12/18/2022] Open
Abstract
High plasma lipid levels have been demonstrated to increase cardiovascular disease risk. Despite advances in treatments to decrease plasma lipids, additional therapeutics are still needed because many people are intolerant or nonresponsive to these therapies. We previously showed that increasing cellular levels of microRNA-30c (miR-30c) using viral vectors or liposomes reduces plasma lipids and atherosclerosis. In this study, we aimed to synthesize potent miR-30c analogs that can be delivered to hepatoma cells without the aid of viral vectors and lipid emulsions. We hypothesized that modification of the passenger strand of miR-30c would increase the stability of miR-30c and augment its delivery to liver cells. Here, we report the successful synthesis of a series of miR-30c analogs by using different chemically modified nucleosides. In these analogs, we left the active sense strand untouched so that its biological activity remained unaltered, and we modified the passenger strand of miR-30c to enhance the stability and uptake of miR-30c by hepatoma cells through phosphorothiorate linkages and the addition of GalNAc. We show that these analogs significantly reduced apolipoprotein B secretion in Huh-7 human hepatoma cells and human primary hepatocytes without affecting apolipoprotein A1 secretion and cellular lipid levels. Our results provide a proof of concept that the passenger strand of miR-30c can be modified to increase its stability and delivery to cells while retaining the potency of the sense strand. We anticipate these miR-30c analogs will be useful in the development of more efficacious analogs for the treatment of hyperlipidemias and cardiovascular diseases.
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Affiliation(s)
- Pradeep Kumar Yadav
- Department of Foundations of Medicine, NYU Long Island School of Medicine, Mineola, NY 11501, USA
| | | | - Sarah Irani
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY USA
| | - Ting Wang
- Department of Chemistry, The RNA Institute, University at Albany, SUNY, Albany, NY 12222, USA
| | - Abulaish Ansari
- Department of Foundations of Medicine, NYU Long Island School of Medicine, Mineola, NY 11501, USA
| | - Jia Sheng
- Department of Chemistry, The RNA Institute, University at Albany, SUNY, Albany, NY 12222, USA.
| | - M Mahmood Hussain
- Department of Foundations of Medicine, NYU Long Island School of Medicine, Mineola, NY 11501, USA; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY USA; VA New York Harbor Healthcare System, Brooklyn, NY 11209, USA.
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5
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Therapeutic RNA-silencing oligonucleotides in metabolic diseases. Nat Rev Drug Discov 2022; 21:417-439. [PMID: 35210608 DOI: 10.1038/s41573-022-00407-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/19/2022] [Indexed: 12/14/2022]
Abstract
Recent years have seen unprecedented activity in the development of RNA-silencing oligonucleotide therapeutics for metabolic diseases. Improved oligonucleotide design and optimization of synthetic nucleic acid chemistry, in combination with the development of highly selective and efficient conjugate delivery technology platforms, have established and validated oligonucleotides as a new class of drugs. To date, there are five marketed oligonucleotide therapies, with many more in clinical studies, for both rare and common liver-driven metabolic diseases. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in metabolism, review past and current clinical trials, and discuss ongoing challenges and possible future developments.
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Punch E, Klein J, Diaba-Nuhoho P, Morawietz H, Garelnabi M. Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis. J Am Heart Assoc 2022; 11:e023328. [PMID: 35048716 PMCID: PMC9238481 DOI: 10.1161/jaha.121.023328] [Citation(s) in RCA: 46] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Characterized as a chronic inflammatory disease of the large arteries, atherosclerosis is the primary cause of cardiovascular disease, the leading contributor of morbidity and mortality worldwide. Elevated plasma cholesterol levels and chronic inflammation within the arterial plaque are major mediators of plaque initiation, progression, and instability. In 2003, the protein PCSK9 (proprotein convertase subtilisin/kexin 9) was discovered to play a critical role in cholesterol regulation, thus becoming a key player in the mechanisms behind atherosclerotic plaque development. Emerging evidence suggests that PCSK9 could potentially have effects on atherosclerosis that are independent of cholesterol levels. The objective of this review was to discuss the role on PCSK9 in oxidation, inflammation, and atherosclerosis. This function activates proinflammatory cytokine production and affects oxidative modifications within atherosclerotic lesions, revealing its more significant role in atherosclerosis. Although a variety of evidence demonstrates that PCSK9 plays a role in atherosclerotic inflammation, the direct mechanism of involvement is still unknown, driving a gap in knowledge to such a predominant player in cardiovascular disease. Investigation of proteins structurally related to PCSK9 may interestingly be the link in unveiling the mechanistic role of this protein’s involvement in oxidation and inflammation. Importantly, the unique structure of PCSK9 bears structural homology to a one‐of‐a‐kind domain found in the metabolic protein resistin, which is responsible for many of the same inflammatory outcomes as PCSK9. Closing this gap in knowledge of PCSK9`s role in atherosclerotic oxidation and inflammation will provide fundamental information for understanding, preventing, and treating cardiovascular disease.
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Affiliation(s)
- Emily Punch
- Department of Chemistry University of Massachusetts Lowell MA
| | - Justus Klein
- Division of Vascular Endothelium and Microcirculation Department of Medicine III University Hospital and Medical Faculty Carl Gustav CarusTechnische Universität Dresden Germany
| | - Patrick Diaba-Nuhoho
- Division of Vascular Endothelium and Microcirculation Department of Medicine III University Hospital and Medical Faculty Carl Gustav CarusTechnische Universität Dresden Germany
| | - Henning Morawietz
- Division of Vascular Endothelium and Microcirculation Department of Medicine III University Hospital and Medical Faculty Carl Gustav CarusTechnische Universität Dresden Germany
| | - Mahdi Garelnabi
- Biomedical and Nutritional Sciences University of Massachusetts Lowell MA
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7
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Huijgen R, Blom DJ, Hartgers ML, Chemello K, Benito-Vicente A, Uribe KB, Behardien Z, Blackhurst DM, Brice BC, Defesche JC, de Jong AG, Jooste RJ, Solomon GAE, Wolmarans KH, Hovingh GK, Martin C, Lambert G, Marais AD. Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town. Arterioscler Thromb Vasc Biol 2020; 41:934-943. [PMID: 33147992 DOI: 10.1161/atvbaha.120.314482] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
OBJECTIVE Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (<1% of cases). We aimed to evaluate the functional impact of several novel PCSK9 variants in a cohort of patients with FH by genetic cascade screening and in vitro functionality assays. Approach and Results: Patients with clinically diagnosed FH underwent genetic analysis of LDLR, and if negative, sequential testing of APOB and PCSK9. We analyzed cosegregation of hypercholesterolemia with novel PCSK9 variants. Gain of function status was determined by in silico analyses and validated by in vitro functionality assays. Among 1055 persons with clinical FH, we identified nonsynonymous PCSK9 variants in 27 (2.6%) patients and 7 of these carried one of the 4 previously reported gain of function variants. In the remaining 20 patients with FH, we identified 7 novel PCSK9 variants. The G516V variant (c.1547G>T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P<0.001). In vitro studies demonstrated the pathogenicity of the G516V variant. CONCLUSIONS In our study, 1.14% of cases with clinical FH were clearly attributable to pathogenic variants in PCSK9. Pathogenicity is established beyond doubt for the G516V variant.
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Affiliation(s)
- Roeland Huijgen
- Department of Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, The Netherlands (R.H., M.L.H., A.G.d.J., G.K.H.).,Spaarne Gasthuis, Haarlem, The Netherlands (R.H.)
| | - Dirk J Blom
- Division of Lipidology, Department of Medicine, Hatter Institute for Cardiovascular Research in Africa (D.J.B., Z.B., D.M.B., D.M.B., B.C.B., R.J.J., K.H.W.), University of Cape Town, South Africa
| | - Merel L Hartgers
- Department of Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, The Netherlands (R.H., M.L.H., A.G.d.J., G.K.H.)
| | - Kévin Chemello
- Laboratoire Inserm UMR1188 DéTROI, Université de La Réunion, Sainte Clotilde, France (K.C., G.L.)
| | - Asier Benito-Vicente
- Biofisika Institute (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain (A.B.-V., K.B.U., C.M.)
| | - Kepa B Uribe
- Biofisika Institute (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain (A.B.-V., K.B.U., C.M.)
| | - Zorena Behardien
- Division of Lipidology, Department of Medicine, Hatter Institute for Cardiovascular Research in Africa (D.J.B., Z.B., D.M.B., D.M.B., B.C.B., R.J.J., K.H.W.), University of Cape Town, South Africa
| | - Dee M Blackhurst
- Division of Lipidology, Department of Medicine, Hatter Institute for Cardiovascular Research in Africa (D.J.B., Z.B., D.M.B., D.M.B., B.C.B., R.J.J., K.H.W.), University of Cape Town, South Africa
| | - Brigitte C Brice
- Division of Lipidology, Department of Medicine, Hatter Institute for Cardiovascular Research in Africa (D.J.B., Z.B., D.M.B., D.M.B., B.C.B., R.J.J., K.H.W.), University of Cape Town, South Africa
| | - Joep C Defesche
- Department of Clinical Genetics, Laboratory of Genome Diagnostics, Amsterdam University Medical Center, The Netherlands (J.C.D.)
| | - Annemiek G de Jong
- Department of Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, The Netherlands (R.H., M.L.H., A.G.d.J., G.K.H.)
| | - Rosemary J Jooste
- Division of Lipidology, Department of Medicine, Hatter Institute for Cardiovascular Research in Africa (D.J.B., Z.B., D.M.B., D.M.B., B.C.B., R.J.J., K.H.W.), University of Cape Town, South Africa
| | - Gabriele A E Solomon
- Division of Chemical Pathology, Department of Pathology (G.A.E.S., A.D.M.), University of Cape Town, South Africa.,Division of Chemical Pathology, Department of Pathology, University of Cape Town, South Africa (G.A.E.S., A.D.M.)
| | - Karen H Wolmarans
- Division of Lipidology, Department of Medicine, Hatter Institute for Cardiovascular Research in Africa (D.J.B., Z.B., D.M.B., D.M.B., B.C.B., R.J.J., K.H.W.), University of Cape Town, South Africa
| | - G Kees Hovingh
- Department of Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, The Netherlands (R.H., M.L.H., A.G.d.J., G.K.H.)
| | - Cesar Martin
- Biofisika Institute (UPV/EHU, CSIC) and Departamento de Bioquímica, Universidad del País Vasco, Bilbao, Spain (A.B.-V., K.B.U., C.M.)
| | - Gilles Lambert
- Laboratoire Inserm UMR1188 DéTROI, Université de La Réunion, Sainte Clotilde, France (K.C., G.L.)
| | - A David Marais
- Division of Chemical Pathology, Department of Pathology (G.A.E.S., A.D.M.), University of Cape Town, South Africa.,Division of Chemical Pathology, Department of Pathology, University of Cape Town, South Africa (G.A.E.S., A.D.M.)
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8
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Langslet G, Zinman B, Wanner C, Hantel S, Espadero RM, Fitchett D, Johansen OE. Cardiovascular outcomes and LDL-cholesterol levels in EMPA-REG OUTCOME ®. Diab Vasc Dis Res 2020; 17:1479164120975256. [PMID: 33307785 PMCID: PMC7919220 DOI: 10.1177/1479164120975256] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
OBJECTIVE It is well established that higher low-density lipoprotein (LDL)-cholesterol levels are associated with increased cardiovascular risk. We analyzed whether effects of empagliflozin on cardiovascular outcomes varied by different LDL-cholesterol levels at baseline in EMPA-REG OUTCOME. METHODS Participants with type 2 diabetes and high cardiovascular risk received empagliflozin (10/25 mg) or placebo in addition to standard of care. We investigated the time to first 3P-MACE, cardiovascular death, hospitalization for heart failure (HHF) and all-cause mortality for empagliflozin versus placebo between baseline LDL-cholesterol categories <1.8, 1.8-<2.2, 2.2- <2.6, 2.6-3.0, and > 3.0 mmol/L, by a Cox regression including the interaction of baseline LDL-cholesterol category and treatment. RESULTS Of the 7020 participants randomized and treated, 81.0% received lipid lowering therapy (77.0% statins). Mean ± SD LDL-cholesterol was 2.2 ± 0.9 mmol/L, and 38%/18%, had LDL-cholesterol <1.8/>3.0 mmol/L. Age, BMI, and HbA1c levels were balanced between the LDL-cholesterol subgroups, but those in the lowest versus highest group, had more coronary artery disease (83.0% vs 59.9%) and statin treatment (88.2% vs 50.9%). Empagliflozin consistently reduced all outcomes across LDL-cholesterol categories (all interaction p-values > 0.05). CONCLUSION The beneficial cardiovascular effects of empagliflozin was consistent across higher and lower LDL-cholesterol levels at baseline.
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Affiliation(s)
- Gisle Langslet
- Lipid Clinic, Oslo University Hospital, Oslo, Norway
- Gisle Langslet, Lipid Clinic, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424, Oslo, Norway.
| | - Bernard Zinman
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
- Division of Endocrinology, University of Toronto, Toronto, Canada
| | - Christoph Wanner
- Department of Medicine, Division of Nephrology, Würzburg University Clinic, Würzburg, Germany
| | - Stefan Hantel
- Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
| | | | - David Fitchett
- St Michael’s Hospital, Division of Cardiology, University of Toronto, Toronto, ON, Canada
| | - Odd Erik Johansen
- Boehringer Ingelheim Norway, TA Cardiometabolism, Asker, Norway
- Nestle Health Science SA, Cardiometabolism & Cx, Vevey, Vaud, Switzerland
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9
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Lorenzatti AJ, Toth PP. New Perspectives on Atherogenic Dyslipidaemia and Cardiovascular Disease. Eur Cardiol 2020; 15:1-9. [PMID: 32180834 PMCID: PMC7066832 DOI: 10.15420/ecr.2019.06] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Accepted: 08/27/2019] [Indexed: 12/12/2022] Open
Abstract
Over the past few decades, atherogenic dyslipidaemia has become one of the most common phenotypic presentations of lipid abnormalities, being strongly and unequivocally associated with an increased risk of cardiovascular (CV) disease. Despite the excellent results achieved from statin and non-statin management of LDL cholesterol and CV events prevention, there still remains a significant residual risk, associated with the prevalence of non-LDL cholesterol lipid patterns characterised by elevated triglyceride levels, low HDL cholesterol, a preponderance of small and dense LDL particles, accumulation of remnant lipoproteins and postprandial hyperlipidaemia. These qualitative and quantitative lipid modifications are largely associated with insulin resistance, type 2 diabetes and obesity, the prevalence of which has grown to epidemic proportions throughout the world. In this review, we analyse the pathophysiology of this particular dyslipidaemia, its relationship with the development of atherosclerotic CV disease and, finally, briefly describe the therapeutic approaches, including changes in lifestyle and current pharmacological interventions to manage these lipid alterations aimed at preventing CV events.
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Affiliation(s)
- Alberto J Lorenzatti
- DAMIC Medical Institute, Rusculleda Foundation for Research, Cordoba, Argentina.,Department of Cardiology, Cordoba Hospital, Cordoba, Argentina
| | - Peter P Toth
- CGH Medical Center, Sterling, IL, US.,Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, US
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Iqbal Z, Dhage S, Mohamad JB, Abdel-Razik A, Donn R, Malik R, Ho JH, Liu Y, Adam S, Isa B, Stefanutti C, Soran H. Efficacy and safety of PCSK9 monoclonal antibodies. Expert Opin Drug Saf 2019; 18:1191-1201. [DOI: 10.1080/14740338.2019.1681395] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Zohaib Iqbal
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | - Shaishav Dhage
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | | | - Alaa Abdel-Razik
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | - Rachelle Donn
- Cardiovascular Research Group, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Rayaz Malik
- Department of Medicine, Weill Cornell Medical College, Doha, Qatar
| | - Jan Hoong Ho
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | - Yifen Liu
- Cardiovascular Research Group, School of Medical Sciences, University of Manchester, Manchester, UK
| | - Safwaan Adam
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
| | - Basil Isa
- Department of Endocrinology and Diabetes, Wythenshawe Hospital, Manchester, UK
| | - Claudia Stefanutti
- Department of Molecular Medicine, Sapienza’ University of Rome, Rome, Italy
| | - Handrean Soran
- Cardiovascular Trials Unit, The Old St Mary’s Hospital, Central Manchester University Hospitals, Manchester, UK
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11
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Du H, Li X, Su N, Li L, Hao X, Gao H, Kwong JSW, Vandvik PO, Yang X, Nemeth I, Mordi IR, Li Q, Zhang L, Rao L, Lang CC, Li J, Tian H, Li S. Proprotein convertase subtilisin/kexin 9 inhibitors in reducing cardiovascular outcomes: a systematic review and meta-analysis. Heart 2019; 105:1149-1159. [PMID: 30842207 DOI: 10.1136/heartjnl-2019-314763] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 01/28/2019] [Accepted: 01/30/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND To evaluate the effects of proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors on major adverse cardiovascular events (MACE). METHODS Our systematic review included randomised controlled trials if they studied PCSK9 inhibitors in patients for primary and/or secondary prevention of cardiovascular diseases or with hypercholesterolaemia/hyperlipidaemia. Dichotomous variables from individual studies were pooled by relative risks (RR) and their 95% CIs using the random-effect model. Risk difference (RD) in the 10-year frame was also estimated using the pooled RR and the estimated baseline risk using the control group. Grading of Recommendation Assessment, Development and Evaluation was used to assess the quality of evidence. RESULTS We included 54 trials with 97 910 patients in the analysis. Compared with controls, PCSK9 inhibitors significantly reduced the risk of MACE by 16% (RR, 0.84; 95% CI 0.79 to 0.89; RD: 47 fewer per 1000 vs 286 as the baseline risk; 95% CI 32 to 59 fewer), non-fatal myocardial infarction (MI) by 17% (RR, 0.83; 95% CI 0.74 to 0.93; RD, 35 fewer per 1000 vs 207 as the baseline; 95% CI 13 to 53 fewer) and any stroke by 25% (RR, 0.75; 95% CI 0.65 to 0.85; RD, 16 fewer per 1000 vs 61 as the baseline; 95% CI 9 to 21 fewer) with moderate quality evidence. No significant differences were found between PCSK9 inhibitors and control groups in all-cause mortality, cardiovascular death, heart failure or unstable angina with low-quality evidence. CONCLUSIONS This study demonstrated that PCSK9 inhibitors could significantly reduce the risk of MACE, non-fatal MI and stroke. TRIAL REGISTRATION PROSPERO; CRD42017073904.
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Affiliation(s)
- Heyue Du
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Xiaodan Li
- Department of Gastroenterology, West China Hospital, Sichuan University, Chengdu, China
| | - Na Su
- Department of Pharmacy, West China Hospital, Sichuan University, Chengdu, China
| | - Ling Li
- Chinese Evidence-based Medicine Center and CREAT group, West China Hospital, Sichuan University, Chengdu, China
| | - Xiaoting Hao
- Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Haihui Gao
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- Department of Rheumatology and Clinical Immunology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Joey Sum-Wing Kwong
- Jockey Club School of Public Health andPrimary Care, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, Hong Kong, China
| | - Per Olav Vandvik
- Norwegian Institute of Public Health, Oslo, Norway
- Department of Medicine, Innlandet Hospital Trust, Gjøvik, Norway
| | - Xueli Yang
- Departmentof Epidemiology, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Imola Nemeth
- Division of Population Health & Genomics, Ninewells Hospital, University of Dundee, Dundee, UK
| | - Ify R Mordi
- Division of Molecular & Clinical Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
| | - Qianrui Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- Institute of Health Informatics, University College London, London, UK
- Health Data Research UK London, University College London, London, UK
| | - Longhao Zhang
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Li Rao
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China
| | - Chim C Lang
- Division of Molecular & Clinical Medicine, Ninewells Hospital, University of Dundee, Dundee, UK
| | - Jianshu Li
- Department of Biomedical Polymer and Artificial Organs, College of Polymer Science and Engineering, Sichuan University, Chengdu, China
| | - Haoming Tian
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
| | - Sheyu Li
- Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu, China
- Division of Population Health & Genomics, Ninewells Hospital, University of Dundee, Dundee, UK
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12
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Jellinger PS, Handelsman Y, Rosenblit PD, Bloomgarden ZT, Fonseca VA, Garber AJ, Grunberger G, Guerin CK, Bell DSH, Mechanick JI, Pessah-Pollack R, Wyne K, Smith D, Brinton EA, Fazio S, Davidson M. AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS AND AMERICAN COLLEGE OF ENDOCRINOLOGY GUIDELINES FOR MANAGEMENT OF DYSLIPIDEMIA AND PREVENTION OF CARDIOVASCULAR DISEASE. Endocr Pract 2019; 23:1-87. [PMID: 28437620 DOI: 10.4158/ep171764.appgl] [Citation(s) in RCA: 667] [Impact Index Per Article: 111.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
OBJECTIVE The development of these guidelines is mandated by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). METHODS Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. RESULTS The Executive Summary of this document contains 87 recommendations of which 45 are Grade A (51.7%), 18 are Grade B (20.7%), 15 are Grade C (17.2%), and 9 (10.3%) are Grade D. These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world medical care. The evidence base presented in the subsequent Appendix provides relevant supporting information for Executive Summary Recommendations. This update contains 695 citations of which 203 (29.2 %) are EL 1 (strong), 137 (19.7%) are EL 2 (intermediate), 119 (17.1%) are EL 3 (weak), and 236 (34.0%) are EL 4 (no clinical evidence). CONCLUSION This CPG is a practical tool that endocrinologists, other health care professionals, health-related organizations, and regulatory bodies can use to reduce the risks and consequences of dyslipidemia. It provides guidance on screening, risk assessment, and treatment recommendations for a range of individuals with various lipid disorders. The recommendations emphasize the importance of treating low-density lipoprotein cholesterol (LDL-C) in some individuals to lower goals than previously endorsed and support the measurement of coronary artery calcium scores and inflammatory markers to help stratify risk. Special consideration is given to individuals with diabetes, familial hypercholesterolemia, women, and youth with dyslipidemia. Both clinical and cost-effectiveness data are provided to support treatment decisions. ABBREVIATIONS 4S = Scandinavian Simvastatin Survival Study A1C = glycated hemoglobin AACE = American Association of Clinical Endocrinologists AAP = American Academy of Pediatrics ACC = American College of Cardiology ACE = American College of Endocrinology ACS = acute coronary syndrome ADMIT = Arterial Disease Multiple Intervention Trial ADVENT = Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial AFCAPS/TexCAPS = Air Force/Texas Coronary Atherosclerosis Prevention Study AHA = American Heart Association AHRQ = Agency for Healthcare Research and Quality AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides trial ASCVD = atherosclerotic cardiovascular disease ATP = Adult Treatment Panel apo = apolipoprotein BEL = best evidence level BIP = Bezafibrate Infarction Prevention trial BMI = body mass index CABG = coronary artery bypass graft CAC = coronary artery calcification CARDS = Collaborative Atorvastatin Diabetes Study CDP = Coronary Drug Project trial CI = confidence interval CIMT = carotid intimal media thickness CKD = chronic kidney disease CPG(s) = clinical practice guideline(s) CRP = C-reactive protein CTT = Cholesterol Treatment Trialists CV = cerebrovascular CVA = cerebrovascular accident EL = evidence level FH = familial hypercholesterolemia FIELD = Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes trial FOURIER = Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects With Elevated Risk trial HATS = HDL-Atherosclerosis Treatment Study HDL-C = high-density lipoprotein cholesterol HeFH = heterozygous familial hypercholesterolemia HHS = Helsinki Heart Study HIV = human immunodeficiency virus HoFH = homozygous familial hypercholesterolemia HPS = Heart Protection Study HPS2-THRIVE = Treatment of HDL to Reduce the Incidence of Vascular Events trial HR = hazard ratio HRT = hormone replacement therapy hsCRP = high-sensitivity CRP IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial IRAS = Insulin Resistance Atherosclerosis Study JUPITER = Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin LDL-C = low-density lipoprotein cholesterol Lp-PLA2 = lipoprotein-associated phospholipase A2 MACE = major cardiovascular events MESA = Multi-Ethnic Study of Atherosclerosis MetS = metabolic syndrome MI = myocardial infarction MRFIT = Multiple Risk Factor Intervention Trial NCEP = National Cholesterol Education Program NHLBI = National Heart, Lung, and Blood Institute PCOS = polycystic ovary syndrome PCSK9 = proprotein convertase subtilisin/kexin type 9 Post CABG = Post Coronary Artery Bypass Graft trial PROSPER = Prospective Study of Pravastatin in the Elderly at Risk trial QALY = quality-adjusted life-year ROC = receiver-operator characteristic SOC = standard of care SHARP = Study of Heart and Renal Protection T1DM = type 1 diabetes mellitus T2DM = type 2 diabetes mellitus TG = triglycerides TNT = Treating to New Targets trial VA-HIT = Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial VLDL-C = very low-density lipoprotein cholesterol WHI = Women's Health Initiative.
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Helper-dependent adenovirus-mediated gene transfer of a secreted LDL receptor/transferrin chimeric protein reduces aortic atherosclerosis in LDL receptor-deficient mice. Gene Ther 2019; 26:121-130. [PMID: 30700805 DOI: 10.1038/s41434-019-0061-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2018] [Revised: 11/02/2018] [Accepted: 11/23/2018] [Indexed: 01/05/2023]
Abstract
Familial hypercholesterolemia (FH) is a genetic hyperlipidemia characterized by elevated concentrations of plasma LDL cholesterol. Statins are not always effective for the treatment of FH patients; unresponsive patients have poor prognosis and rely on LDL apheresis. In the past, we developed safe and effective gene therapy strategies for the expression of anti-atherogenic proteins using PEGylated helper-dependent adenoviral (HD-Ad) vectors. We recently developed a HD-Ad vector for the expression of the soluble form of the extracellular portion of the human LDL receptor (LDLR) fused with a rabbit transferrin dimer (LDLR-TF). We evaluated the efficacy of the LDLR-TF chimeric protein in CHOLDLA7, a cell line lacking LDLR expression, restoring the ability to uptake LDL. Subsequently, we administered intravenously 1 × 10E13 vp/kg of this vector in LDLR-deficient mice and observed amelioration of lipid profile and reduction of aortic atherosclerosis. Finally, we studied LDL distribution after HD-Ad vector-mediated expression of LDLR-TF in LDLR-deficient mice and found LDL accumulation in liver, and in heart and intestine. These results support the possibility of lowering LDL-C levels and reducing aortic atherosclerosis using a secreted therapeutic transgene; the present strategy potentially can be modified and adapted to non-systemic gene transfer with expression of the secreted chimeric protein in muscle or other tissues. Intramuscular or local administration strategies could improve the safety profile of this strategy and facilitate applicability.
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Patti AM, Giglio RV, Papanas N, Rizzo M, Rizvi AA. Future perspectives of the pharmacological management of diabetic dyslipidemia. Expert Rev Clin Pharmacol 2019; 12:129-143. [PMID: 30644763 DOI: 10.1080/17512433.2019.1567328] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
INTRODUCTION Diabetic dyslipidemia is frequent among patients with type 2 diabetes mellitus (T2DM) and is characterized by an increase in triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and small-dense (atherogenic) particles, and by a decrease in low high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 that are strongly related to insulin resistance. The increased flux of free fatty acids from adipose tissue to the liver aggravates hepatic insulin resistance and promotes all of aspects of the dyslipidemic state. Areas covered: Statins are the first-line agents for treatment while other lipid-lowering drugs (ezetimibe, fibrate and proprotein convertase subtilisin/kexin type 9) or novel anti-diabetic agents (dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon like peptide-1 receptor agonist (GLP-1RA), sodium/glucose cotransporter 2 inhibitors (SGLT2is)) or nutraceuticals (berberine, omega 3 fatty acid, red yeast rice) can be used alone or in combination. Expert commentary: In patients with T2DM, lipid abnormalities should be identified and treated as part of the overall diabetic treatment, in order to prevent cardiovascular disease. The choice of drugs to be used is mainly based on the lipid profile and on the characteristic lipoprotein abnormalities; the use of new drugs for the treatment of hyperglycemia and lipids alteration in these patients can improve diabetic dyslipidemia.
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Affiliation(s)
- Angelo Maria Patti
- a Biomedical Department of Internal Medicine and Medical Specialties , University of Palermo , Palermo , Italy
| | - Rosaria Vincenza Giglio
- a Biomedical Department of Internal Medicine and Medical Specialties , University of Palermo , Palermo , Italy
| | - Nikolaos Papanas
- b Diabetes Centre, Second Department of Internal Medicine , Democritus University of Thrace, University Hospital of Alexandroupolis , Alexandroupolis , Greece
| | - Manfredi Rizzo
- a Biomedical Department of Internal Medicine and Medical Specialties , University of Palermo , Palermo , Italy.,c Division of Endocrinology , Diabetes and Metabolism University of South Carolina School of Medicine Columbia , South Carolina , SC , USA
| | - Ali A Rizvi
- c Division of Endocrinology , Diabetes and Metabolism University of South Carolina School of Medicine Columbia , South Carolina , SC , USA
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15
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The effect of chronic kidney disease on lipid metabolism. Int Urol Nephrol 2018; 51:265-277. [DOI: 10.1007/s11255-018-2047-y] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2018] [Accepted: 11/27/2018] [Indexed: 12/26/2022]
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Toth PP, Patti AM, Giglio RV, Nikolic D, Castellino G, Rizzo M, Banach M. Management of Statin Intolerance in 2018: Still More Questions Than Answers. Am J Cardiovasc Drugs 2018; 18:157-173. [PMID: 29318532 PMCID: PMC5960491 DOI: 10.1007/s40256-017-0259-7] [Citation(s) in RCA: 109] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Statin therapy is generally well tolerated and very effective in the prevention and treatment of cardiovascular disease, regardless of cholesterol levels; however, it can be associated with various adverse events (myalgia, myopathy, rhabdomyolysis, and diabetes mellitus, among others). Patients frequently discontinue statin therapy without medical advice because of perceived side effects and consequently increase their risk for cardiovascular events. In patients with statin intolerance, it may be advisable to change the dose, switch to a different statin, or try an alternate-day regimen. If intolerance is associated with all statins-even at the lowest dose-non-statin drugs and certain nutraceuticals can be considered. This review focuses on the definition of statin intolerance and on the development of clinical and therapeutic strategies for its management, including emerging alternative therapies.
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Affiliation(s)
- Peter P Toth
- CGH Medical Center, Sterling, IL, USA
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Angelo Maria Patti
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Rosaria Vincenza Giglio
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Dragana Nikolic
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Giuseppa Castellino
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Manfredi Rizzo
- Biomedical Department of Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy
| | - Maciej Banach
- Chair of Nephrology and Hypertension, Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549, Lodz, Poland.
- Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
- Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland.
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Serhiyenko VA, Serhiyenko AA. Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment. World J Diabetes 2018; 9:1-24. [PMID: 29359025 PMCID: PMC5763036 DOI: 10.4239/wjd.v9.i1.1] [Citation(s) in RCA: 124] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2017] [Revised: 12/09/2017] [Accepted: 12/29/2017] [Indexed: 02/06/2023] Open
Abstract
Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus (DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate (HR) to development of "silent" myocardial infarction. Clinical correlates or risk markers for CAN are age, DM duration, glycemic control, hypertension, and dyslipidemia (DLP), development of other microvascular complications. Established risk factors for CAN are poor glycemic control in type 1 DM and a combination of hypertension, DLP, obesity, and unsatisfactory glycemic control in type 2 DM. Symptomatic manifestations of CAN include sinus tachycardia, exercise intolerance, orthostatic hypotension (OH), abnormal blood pressure (BP) regulation, dizziness, presyncope and syncope, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction. Methods of CAN assessment in clinical practice include assessment of symptoms and signs, cardiovascular reflex tests based on HR and BP, short-term electrocardiography (ECG), QT interval prolongation, HR variability (24 h, classic 24 h Holter ECG), ambulatory BP monitoring, HR turbulence, baroreflex sensitivity, muscle sympathetic nerve activity, catecholamine assessment and cardiovascular sympathetic tests, heart sympathetic imaging. Although it is common complication, the significance of CAN has not been fully appreciated and there are no unified treatment algorithms for today. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Pathogenetic treatment of CAN includes: Balanced diet and physical activity; optimization of glycemic control; treatment of DLP; antioxidants, first of all α-lipoic acid (ALA), aldose reductase inhibitors, acetyl-L-carnitine; vitamins, first of all fat-soluble vitamin B1; correction of vascular endothelial dysfunction; prevention and treatment of thrombosis; in severe cases-treatment of OH. The promising methods include prescription of prostacyclin analogues, thromboxane A2 blockers and drugs that contribute into strengthening and/or normalization of Na+, K+-ATPase (phosphodiesterase inhibitor), ALA, dihomo-γ-linolenic acid (DGLA), ω-3 polyunsaturated fatty acids (ω-3 PUFAs), and the simultaneous prescription of ALA, ω-3 PUFAs and DGLA, but the future investigations are needed. Development of OH is associated with severe or advanced CAN and prescription of nonpharmacological and pharmacological, in the foreground midodrine and fludrocortisone acetate, treatment methods are necessary.
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Affiliation(s)
- Victoria A Serhiyenko
- Department of Endocrinology, Lviv National Medical University Named by Danylo Halitsky, Lviv 79010, Ukraine
| | - Alexandr A Serhiyenko
- Department of Endocrinology, Lviv National Medical University Named by Danylo Halitsky, Lviv 79010, Ukraine
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Lipid lowering agents of natural origin: An account of some promising chemotypes. Eur J Med Chem 2017; 140:331-348. [DOI: 10.1016/j.ejmech.2017.09.020] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2017] [Revised: 04/07/2017] [Accepted: 09/12/2017] [Indexed: 12/22/2022]
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El Khoury P, Elbitar S, Ghaleb Y, Khalil YA, Varret M, Boileau C, Abifadel M. PCSK9 Mutations in Familial Hypercholesterolemia: from a Groundbreaking Discovery to Anti-PCSK9 Therapies. Curr Atheroscler Rep 2017; 19:49. [PMID: 29038906 DOI: 10.1007/s11883-017-0684-8] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW In 2003, Abifadel et al. (Nat. Genet. 34:154-156, 2003) identified PCSK9, encoding proprotein convertase subtilisin/kexin type 9, as the third causal gene for autosomal dominant hypercholesterolemia. This review focuses on the main steps from this major breakthrough in familial hypercholesterolemia (FH) to the latest clinical trials with the anti-PCSK9 antibodies. RECENT FINDINGS The year 2015 was remarkable in cardiovascular disease through the field of cholesterol. Nearly 30 years after the discovery of statins, a new class of effective lipid-lowering drugs has emerged: the anti-PCSK9 antibodies. The discovery of the first gain-of-function mutations of PCSK9 in FH rapidly became the center of interest of researchers worldwide. Preclinical and clinical studies launched by pharmaceutical companies led to the first three anti-PCSK9 antibodies, two of which (evolocumab and alirocumab) reduce LDL cholesterol levels by 50-60% and received FDA and European Medicines Agency approvals in 2015 on top of statin therapy. Recently, results of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, the outcome trial of evolocumab over 2.2 years, showed a reduction of 15-20% in the risk of major cardiovascular outcomes in high-risk patients receiving statin therapy. Results of ODYSSEY OUTCOMES trial, evaluating the effect of alirocumab in 18,000 patients with established CVD are also eagerly awaited in 2018. The evolution of research on PCSK9, starting from the discovery of the first set of mutations in PCSK9 in FH in 2003, is an amazing example of successful translational research. It shows how rigorous and powered genetic analyses can lead to the discovery of a new class of lipid-lowering drugs that give hope in fighting high cholesterol levels and their cardiovascular complications.
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Affiliation(s)
- Petra El Khoury
- LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France.,Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie Santé, Saint Joseph University, Beirut, Lebanon
| | - Sandy Elbitar
- LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France.,Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie Santé, Saint Joseph University, Beirut, Lebanon
| | - Youmna Ghaleb
- LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France.,Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie Santé, Saint Joseph University, Beirut, Lebanon
| | - Yara Abou Khalil
- LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France.,Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie Santé, Saint Joseph University, Beirut, Lebanon
| | - Mathilde Varret
- LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France.,Faculté de Médecine Paris 7, Université Denis Diderot, Paris, France
| | - Catherine Boileau
- LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France. .,Faculté de Médecine Paris 7, Université Denis Diderot, Paris, France. .,Département de Génétique, AP-HP, CHU Xavier Bichat, Paris, France.
| | - Marianne Abifadel
- LVTS, INSERM U1148, Hôpital Xavier-Bichat, Paris Cedex 18, France.,Laboratory of Biochemistry and Molecular Therapeutics, Faculty of Pharmacy, Pôle Technologie Santé, Saint Joseph University, Beirut, Lebanon
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Maggi P, Di Biagio A, Rusconi S, Cicalini S, D'Abbraccio M, d'Ettorre G, Martinelli C, Nunnari G, Sighinolfi L, Spagnuolo V, Squillace N. Cardiovascular risk and dyslipidemia among persons living with HIV: a review. BMC Infect Dis 2017; 17:551. [PMID: 28793863 PMCID: PMC5550957 DOI: 10.1186/s12879-017-2626-z] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2017] [Accepted: 07/20/2017] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Aim of this review is to focus the attention on people living with HIV infection at risk of developing a cardiovascular event. What is or what would be the most suitable antiretroviral therapy? Which statin or fibrate to reduce the risk? How to influence behavior and lifestyles? DISCUSSION Prevention of cardiovascular disease (CVD) risk remains the first and essential step in a medical intervention on these patients. The lifestyle modification, including smoking cessation, increased physical activity, weight reduction, and the education on healthy dietary practices are the main instruments. Statins are the cornerstone for the treatment of hypercholesterolemia. They have been shown to slow the progression or promote regression of coronary plaque, and could also exert an anti-inflammatory and immunomodulatory effect. However the current guidelines for the use of these drugs in general population are dissimilar, with important differences between American and European ones. The debate between American and European guidelines is still open and, also considering the independent risk factor represented by HIV, specific guidelines are warranted. Ezetimibe reduces the intestinal absorption of cholesterol. It is effective alone or in combination with rosuvastatin. It does not modify plasmatic concentrations of antiretrovirals. A number of experimental new classes of drugs for the treatment of hypercholesterolemia are being studied. Fibrates represent the first choice for treatment of hypertriglyceridemia, however, the renal toxicity of fibrates and statins should be considered. Omega 3 fatty acids have a good safety profile, but their efficacy is limited. Another concern is the high dose needed. Other drugs are acipimox and tesamorelin. Current antiretroviral therapies are less toxic and more effective than regimens used in the early years. Lipodistrophy and dyslipidemia are the main causes of long-term toxicities. Not all antiretrovirals have similar toxicities. Protease Inhibitors may cause dyslipidemia and lipodystrophy, while integrase inhibitors have a minimal impact on lipids profile, and no evidence of lipodystrophy. There is still much to be written with the introduction of new drugs in clinical practice. CONCLUSIONS Cardiovascular risk among HIV infected patients, interventions on behavior and lifestyles, use of drugs to reduce the risk, and switch in antiretroviral therapy, remain nowadays major issues in the management of HIV-infected patients.
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Affiliation(s)
- Paolo Maggi
- Clinica Malattie Infettive Policlinico, Bari, Italy.
| | - Antonio Di Biagio
- Clinica Malattie Infettive, Policlinico Ospedale S. Martino, Genoa, Italy
| | - Stefano Rusconi
- Divisione Clinicizzata di Malattie Infettive, DIBIC L. Sacco, Università degli Studi di Milano, Milan, Italy
| | | | - Maurizio D'Abbraccio
- UOC. di Immunodeficienze e Malattie Infettive di Genere, P.O. "D. Cotugno", AORN Dei Colli, Naples, Italy
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Gupta S. Development of proprotein convertase subtilisin/kexin type 9 inhibitors and the clinical potential of monoclonal antibodies in the management of lipid disorders. Vasc Health Risk Manag 2016; 12:421-433. [PMID: 27877050 PMCID: PMC5108562 DOI: 10.2147/vhrm.s83719] [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: 12/11/2022] Open
Abstract
The aim of this manuscript is to review available data to evaluate the present status of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors in the treatment of hypercholesterolemia. Relevant literature since 2003 is reviewed. The effectiveness of PCSK9 inhibitors in lowering low-density lipoprotein cholesterol and other atherogenic lipid fractions was studied in various Phase 2 and Phase 3 trials of Alirocumab, Evolocumab, and Bococizumab. The results of published long-term ODYSSEY and OSLER studies are summarized. There have been three excellent meta-analysis studies on PCSK9 inhibitors which are outlined. The complex problem of cost-effectiveness was carefully evaluated by the Institute for Clinical and Economic Review (ICER). The draft report (ICER-2015) is summarized herewith. The cardiovascular outcome trials with Evolocumab (FOURIER), Alirocumab (ODYSSEY OUTCOME) and Bococizumab (SPIRE-1 and SPIRE-2) are the ongoing clinical trials, and their results are expected in 2017-2018. The search for new cost-effective analogs of PCSK9 inhibitors is ongoing.
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Affiliation(s)
- Sanjiv Gupta
- Department of Interventional Cardiology, Santokba Durlabhji Memorial Hospital Cum Medical Research Institute, Jaipur, India
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22
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Al Sayed N, Al Waili K, Alawadi F, Al-Ghamdi S, Al Mahmeed W, Al-Nouri F, Al Rukhaimi M, Al-Rasadi K, Awan Z, Farghaly M, Hassanein M, Sabbour H, Zubaid M, Barter P. Consensus clinical recommendations for the management of plasma lipid disorders in the Middle East. Int J Cardiol 2016; 225:268-283. [PMID: 27741487 DOI: 10.1016/j.ijcard.2016.09.081] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 09/22/2016] [Accepted: 09/23/2016] [Indexed: 12/22/2022]
Abstract
BACKGROUND Plasma lipid disorders are key risk factors for the development of atherosclerotic cardiovascular disease (ASCVD) and are prevalent in the Middle East, with rates increasing in recent decades. Despite this, no region-specific guidelines for managing plasma lipids exist and there is a lack of use of guidelines developed in other regions. METHODS A multidisciplinary panel of regional experts was convened to develop consensus clinical recommendations for the management of plasma lipids in the Middle East. The panel considered existing international guidelines and regional clinical experience to develop recommendations. RESULTS The panel's recommendations include plasma lipid screening, ASCVD risk calculation and treatment considerations. The panel recommend that plasma lipid levels should be measured in all at-risk patients and at regular intervals in all adults from the age of 20years. A scoring system should be used to calculate ASCVD risk that includes known lipid and non-lipid risk factors. Primary treatment targets include low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol. Lifestyle modifications should be first-line treatment for all patients; the first-line pharmacological treatment targeting plasma lipids in patients at moderate-to-high risk of ASCVD is statin therapy, with a number of adjunctive or second-line agents available. Guidance is also provided on the management of underlying conditions and special populations; of particular pertinence in the region are familial hypercholesterolaemia, diabetes and metabolic dyslipidaemia. CONCLUSIONS These consensus clinical recommendations provide practicing clinicians with comprehensive, region-specific guidance to improve the detection and management of plasma lipid disorders in patients in the Middle East.
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Affiliation(s)
- Nasreen Al Sayed
- Gulf Diabetes Specialist Center, P.O. Box 21686, Manama, Bahrain.
| | - Khalid Al Waili
- Department of Clinical Biochemistry, Sultan Qaboos University Hospital, Al-Khod, P.O. Box 38, postal code 123, Muscat, Oman.
| | - Fatheya Alawadi
- Endocrine Department, Dubai Hospital, Dubai Health Authority, Dubai, United Arab Emirates.
| | - Saeed Al-Ghamdi
- Department of Medicine, King Abdulaziz University Hospital, P.O. Box 80215, Jeddah 21589, Saudi Arabia.
| | - Wael Al Mahmeed
- Heart and Vascular Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates.
| | - Fahad Al-Nouri
- Cardiovascular Prevention Unit, Prince Sultan Cardiac Center, Riyadh, Saudi Arabia.
| | - Mona Al Rukhaimi
- Dubai Medical College, P.O. Box 22331, Dubai, United Arab Emirates.
| | - Khalid Al-Rasadi
- Department of Biochemistry, Sultan Qaboos University Hospital, Al-Khod, P.O. Box 38, postal code 123, Muscat, Oman.
| | - Zuhier Awan
- King Abdulaziz University, Jeddah 22254, Saudi Arabia.
| | | | | | - Hani Sabbour
- Shaikh Khalifa Medical City, Cardiac Sciences Institute, Abu Dhabi, United Arab Emirates.
| | - Mohammad Zubaid
- Department of Medicine, Faculty of Medicine, Kuwait University, Kuwait.
| | - Philip Barter
- School of Medical Sciences, University of New South Wales, Sydney, NSW 2052, Australia.
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Banach M, Stulc T, Dent R, Toth PP. Statin non-adherence and residual cardiovascular risk: There is need for substantial improvement. Int J Cardiol 2016; 225:184-196. [PMID: 27728862 DOI: 10.1016/j.ijcard.2016.09.075] [Citation(s) in RCA: 142] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/24/2016] [Accepted: 09/23/2016] [Indexed: 12/18/2022]
Abstract
Although statin therapy has proven to be the cornerstone for prevention and treatment of cardiovascular disease (CVD), there are many patients for whom long-term therapy remains suboptimal. The aims of this article are to review the current complex issues associated with statin use and to explore when novel treatment approaches should be considered. Statin discontinuation as well as adherence to statin therapy remain two of the greatest challenges for lipidologists. Evidence suggests that between 40 and 75% of patients discontinue their statin therapy within one year after initiation. Furthermore, whilst the reasons for persistence with statin therapy are complex, evidence shows that low-adherence to statins negatively impacts clinical outcomes and residual CV risk remains a major concern. Non-adherence or lack of persistence with long-term statin therapy in real-life may be the main cause of inadequate low density lipoprotein cholesterol lowering with statins. There is a large need for the improvement of the use of statins, which have good safety profiles and are inexpensive. On the other hand, in a non-cost-constrained environment, proprotein convertase subtilisin/kexin type 9 inhibitors should arguably be used more often in those patients in whom treatment with statins remains unsatisfactory.
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Affiliation(s)
- Maciej Banach
- Department of Hypertension, Chair of Nephrology and Hypertension, Medical University of Lodz, Lodz, Poland; Healthy Aging Research Centre, Medical University of Lodz, Lodz, Poland; Polish Mother's Memorial Hospital Research Institute, Lodz, Poland.
| | - Tomas Stulc
- 3rd Department of Internal Medicine, 1st University of Medicine, Prague, Czech Republic
| | | | - Peter P Toth
- CGH Medical Center, Sterling, IL, USA; Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD, USA
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24
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Irani S, Pan X, Peck BCE, Iqbal J, Sethupathy P, Hussain MM. MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice. J Biol Chem 2016; 291:18397-409. [PMID: 27365390 PMCID: PMC5000085 DOI: 10.1074/jbc.m116.728451] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Revised: 05/28/2016] [Indexed: 02/01/2023] Open
Abstract
High plasma cholesterol levels are a major risk factor for atherosclerosis. Plasma cholesterol can be reduced by inhibiting lipoprotein production; however, this is associated with steatosis. Previously we showed that lentivirally mediated hepatic expression of microRNA-30c (miR-30c) reduced hyperlipidemia and atherosclerosis in mice without causing hepatosteatosis. Because viral therapy would be formidable, we examined whether a miR-30c mimic can be used to mitigate hyperlipidemia and atherosclerosis without inducing steatosis. Delivery of a miR-30c mimic to the liver diminished diet-induced hypercholesterolemia in C57BL/6J mice. Reductions in plasma cholesterol levels were significantly correlated with increases in hepatic miR-30c levels. Long term dose escalation studies showed that miR-30c mimic caused sustained reductions in plasma cholesterol with no obvious side effects. Furthermore, miR-30c mimic significantly reduced hypercholesterolemia and atherosclerosis in Apoe(-/-) mice. Mechanistic studies showed that miR-30c mimic had no effect on LDL clearance but reduced lipoprotein production by down-regulating microsomal triglyceride transfer protein expression. MiR-30c had no effect on fatty acid oxidation but reduced lipid synthesis. Additionally, whole transcriptome analysis revealed that miR-30c mimic significantly down-regulated hepatic lipid synthesis pathways. Therefore, miR-30c lowers plasma cholesterol and mitigates atherosclerosis by reducing microsomal triglyceride transfer protein expression and lipoprotein production and avoids steatosis by diminishing lipid syntheses. It mitigates atherosclerosis most likely by reducing lipoprotein production and plasma cholesterol. These findings establish that increasing hepatic miR-30c levels is a viable treatment option for reducing hypercholesterolemia and atherosclerosis.
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Affiliation(s)
- Sara Irani
- From the Molecular and Cell Biology Program, School of Graduate Studies and Departments of Cell Biology and Pediatrics, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York 11203
| | - Xiaoyue Pan
- Departments of Cell Biology and Pediatrics, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York 11203
| | - Bailey C E Peck
- Curriculum in Genetics and Molecular Biology, Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599
| | - Jahangir Iqbal
- Departments of Cell Biology and Pediatrics, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York 11203
| | - Praveen Sethupathy
- Curriculum in Genetics and Molecular Biology, Department of Genetics, University of North Carolina, Chapel Hill, North Carolina 27599
| | - M Mahmood Hussain
- Departments of Cell Biology and Pediatrics, State University of New York (SUNY) Downstate Medical Center, Brooklyn, New York 11203, Veterans Affairs New York Harbor Healthcare System, Brooklyn, New York 11422, and Winthrop University Hospital, Mineola, New York 11501
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25
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Peng W, Qiang F, Peng W, Qian Z, Ke Z, Yi L, Jian Z, Chongrong Q. Therapeutic efficacy of PCSK9 monoclonal antibodies in statin-nonresponsive patients with hypercholesterolemia and dyslipidemia: A systematic review and meta-analysis. Int J Cardiol 2016; 222:119-129. [PMID: 27494723 DOI: 10.1016/j.ijcard.2016.07.239] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2016] [Revised: 06/01/2016] [Accepted: 07/29/2016] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVE Heterozygous familial hypercholesterolemia and dyslipidemia are the predominant causes for cardiovascular disease (CVD). Clinical guidelines for lowering CVD risk have advocated that low density lipoprotein-cholesterol (LDL-C) must be reduced. The primary choice of therapy for controlling lipidemia has been statins, which are not completely effective. Proprotein convertase subtilisin/kexin type-9 (PCSK9), which interferes with LDL clearance from circulation, inversely relates to the LDL-C levels. The loss of statin efficacy is likely due to increased circulating PCSK9 and antibody therapy against PCSK9 has been found to be efficacious in lowering LDL-C. In this study, we evaluated the efficacy of PCSK9-mAbs for lowering LDL-C, in statin non-responsive hypercholesterolemia patients. STUDY DESIGN AND METHODS PubMed, EMBASE, Scholar, Web of Science and Scopus databases were searched to identify randomized controlled trials of PCSK9 antibody-statin combination vs statin, published till 2015. Two reviewers independently screened the articles, and a collective decision was reached about the included studies in the metaanalysis. Parameters analyzed: change from baseline in LDL-C, high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC); ApoB and ApoA1 levels. RESULTS A total of 12 studies with 4909 patients were selected. Overall, add-on therapy with PCSK9-mAb to the ongoing statin therapy was found to achieve greater reduction in LDL-C, ApoB, TC, compared to statin therapy. There were no major treatment emergent adverse effects due to PCSK9-mAb therapy. CONCLUSIONS In adult patients with heterozygous familial hypercholesterolemia and dyslipidemia, PCSK9-mAb therapy in combination with statins was able to achieve the goal of lowering LDL-C.
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Affiliation(s)
- Wan Peng
- Department of Cardiology, Xuzhou Hospital Affiliated East South University School of Medicine, Xuzhou Cardiovascular Disease Institute, 199 Jiefang Road, Xuzhou 221009, PR China
| | - Fu Qiang
- Department of Cardiology, Xuzhou Hospital Affiliated East South University School of Medicine, Xuzhou Cardiovascular Disease Institute, 199 Jiefang Road, Xuzhou 221009, PR China.
| | - Wei Peng
- Department of Cardiology, Xuzhou Hospital Affiliated East South University School of Medicine, Xuzhou Cardiovascular Disease Institute, 199 Jiefang Road, Xuzhou 221009, PR China
| | - Zhang Qian
- Department of Cardiology, Xuzhou Hospital Affiliated East South University School of Medicine, Xuzhou Cardiovascular Disease Institute, 199 Jiefang Road, Xuzhou 221009, PR China
| | - Zhu Ke
- Department of Cardiology, Xuzhou Hospital Affiliated East South University School of Medicine, Xuzhou Cardiovascular Disease Institute, 199 Jiefang Road, Xuzhou 221009, PR China
| | - Lu Yi
- Department of Cardiology, Xuzhou Hospital Affiliated East South University School of Medicine, Xuzhou Cardiovascular Disease Institute, 199 Jiefang Road, Xuzhou 221009, PR China
| | - Zhong Jian
- Department of Cardiology, Xuzhou Hospital Affiliated East South University School of Medicine, Xuzhou Cardiovascular Disease Institute, 199 Jiefang Road, Xuzhou 221009, PR China
| | - Qiu Chongrong
- Department of Cardiology, Xuzhou Hospital Affiliated East South University School of Medicine, Xuzhou Cardiovascular Disease Institute, 199 Jiefang Road, Xuzhou 221009, PR China
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26
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Langslet G. Replacing statins with PCSK9-inhibitors and delaying treatment until 18 years of age in patients with familial hypercholesterolaemia is not a good idea. Eur Heart J 2016; 37:1357-9. [PMID: 27026748 DOI: 10.1093/eurheartj/ehw098] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2015] [Accepted: 02/22/2016] [Indexed: 11/13/2022] Open
Affiliation(s)
- Gisle Langslet
- Lipid Clinic, Oslo University Hospital, Forskningsveien 2 B, Postboks 4950 Nydalen, Oslo 0424, Norway
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27
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Zhou L, Irani S, Sirwi A, Hussain MM. MicroRNAs regulating apolipoprotein B-containing lipoprotein production. Biochim Biophys Acta Mol Cell Biol Lipids 2016; 1861:2062-2068. [PMID: 26923435 DOI: 10.1016/j.bbalip.2016.02.020] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Revised: 02/18/2016] [Accepted: 02/22/2016] [Indexed: 02/07/2023]
Abstract
MicroRNAs (miRs) are small, non-coding RNAs that regulate gene expression and have been implicated in many pathological conditions. Significant progress has been made to unveil their role in lipid metabolism. This review aims at summarizing the role of different miRs that regulate hepatic assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins. Overproduction and/or impaired clearance of these lipoproteins from circulation increase plasma concentrations of lipids enhancing risk for cardiovascular disease. So far, three miRs, miR-122, miR-34a, and miR-30c have been shown to modulate hepatic production of apoB-containing low density lipoproteins. In this review, we will first provide a brief overview of lipid metabolism and apoB-containing lipoprotein assembly to orient readers to different steps that have been shown to be regulated by miRs. Then, we will discuss the role of each miR on plasma lipids and atherosclerotic burden. Furthermore, we will summarize mechanistic studies explaining how these miRs regulate hepatic lipid synthesis, fatty acid oxidation, and lipoprotein secretion. Finally, we will briefly highlight the potential use of each miR as a therapeutic drug for treating cardiovascular diseases. This article is part of a Special Issue entitled: MicroRNAs and lipid/energy metabolism and related diseases edited by Carlos Fernández-Hernando and Yajaira Suárez.
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Affiliation(s)
- Liye Zhou
- School of Graduate Studies, Molecular and Cell Biology Program, USA; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | - Sara Irani
- School of Graduate Studies, Molecular and Cell Biology Program, USA; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | - Alaa Sirwi
- School of Graduate Studies, Molecular and Cell Biology Program, USA; Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY, USA
| | - M Mahmood Hussain
- Department of Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY, USA; Department of Pediatrics, SUNY Downstate Medical Center, Brooklyn, NY, USA; VA New York Harbor Healthcare System, Brooklyn, NY, USA.
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28
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Vuorio A, Watts GF, Kovanen PT. Initiation of PCSK9 inhibition in patients with heterozygous familial hypercholesterolaemia entering adulthood: a new design for living with a high-risk condition? Eur Heart J 2016; 37:1353-6. [PMID: 26851704 DOI: 10.1093/eurheartj/ehw010] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2015] [Accepted: 01/11/2016] [Indexed: 01/12/2023] Open
Affiliation(s)
- Alpo Vuorio
- Mehiläinen Airport Health Center, Lentäjäntie 1 E, Vantaa 00150, Finland
| | - Gerald F Watts
- Lipid Disorders Clinic, Department of Cardiology, Royal Perth Hospital, School of Medicine and Pharmacology, University of Western Australia, Crawley, Australia
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29
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Abstract
Cardiovascular disease (CVD) is the most important cause of premature death and disability globally. Much is known of the main aetiological risk factors, including elevated blood pressure, dyslipidaemia and smoking, with a raft of additional risks of increasing prevalence, such as obesity and diabetes. Furthermore, some of the most secure evidence-based management strategies in healthcare relate to interventions that modify risk. Yet major gaps remain in the implementation of such evidence, summarized in international guideline recommendations. Some of this gap relates to knowledge deficits amongst clinicians, but also to continued uncertainties over interpretation of the evidence base and areas where data are less available. This article collection in BMC Medicine seeks to offer reflections in each of these areas of uncertainty, spanning issues of better diagnosis, areas of controversy and glimpses of potentially potent future interventions in the prevention of CVD.
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Affiliation(s)
- F D Richard Hobbs
- Nuffield Department of Primary Care Health Sciences, University of Oxford, New Radcliffe House, Radcliffe Observatory Quarter, Walton Street, Oxford, OX2 6GG, UK. .,Harris Manchester College, University of Oxford, Mansfield Road, Oxford, OX1 3TD, UK.
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