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Michalopoulou E, Thymis J, Lampsas S, Pavlidis G, Katogiannis K, Vlachomitros D, Katsanaki E, Kostelli G, Pililis S, Pliouta L, Kountouri A, Papanikolaou IS, Lambadiari V, Ikonomidis I. The Triad of Risk: Linking MASLD, Cardiovascular Disease and Type 2 Diabetes; From Pathophysiology to Treatment. J Clin Med 2025; 14:428. [PMID: 39860434 PMCID: PMC11765821 DOI: 10.3390/jcm14020428] [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: 11/29/2024] [Revised: 12/30/2024] [Accepted: 01/08/2025] [Indexed: 01/27/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is an emerging global health concern, and it is not only the keystone precursor of eventual liver-related morbidity, but it also places patients at considerably higher cardiovascular risk, which is still a leading cause of death in these patients. The most important common underlying pathophysiological mechanisms in these diseases are primarily related to insulin resistance, chronic inflammation and oxidative stress. The presence of MASLD with cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM) elevates the risk for poor outcomes, thus this review highlights a method to the therapeutic approaches. Given the intertwined nature of MASLD, T2DM, and CVD, there is an urgent need for therapeutic strategies that address all three conditions. Although lifestyle changes are important as treatment, medication plays a crucial role in managing hyperglycemia, enhancing liver function and lowering cardiovascular risk. The onset and progression of MASLD should be addressed through a multifaceted therapeutic approach, targeting inflammatory, immune, metabolic, oxidative stress, hormonal and gutaxis pathways, alongside the treatment strategies for T2DM. In this review, we discuss the effects of antidiabetic drugs with an impact on both liver outcomes and cardiovascular risk in patients affected by MASLD, T2DM and CDV.
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Affiliation(s)
- Eleni Michalopoulou
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - John Thymis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Stamatios Lampsas
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - George Pavlidis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Konstantinos Katogiannis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Dimitrios Vlachomitros
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Eleni Katsanaki
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Gavriella Kostelli
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
| | - Sotirios Pililis
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Loukia Pliouta
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Aikaterini Kountouri
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Ioannis S. Papanikolaou
- Hepatogastroenterology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University Hospital, Rimini 1, Chaidari, 12462 Athens, Greece;
| | - Vaia Lambadiari
- Diabetes Center, 2nd Department of Internal Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (S.L.); (S.P.); (L.P.); (A.K.); (V.L.)
| | - Ignatios Ikonomidis
- 2nd Cardiology Department, Attikon University Hospital, National and Kapodistrian University of Athens, Rimini 1, Chaidari, 12462 Athens, Greece; (E.M.); (J.T.); (G.P.); (K.K.); (D.V.); (E.K.); (G.K.)
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Handelsman Y, Anderson JE, Bakris GL, Ballantyne CM, Bhatt DL, Bloomgarden ZT, Bozkurt B, Budoff MJ, Butler J, Cherney DZI, DeFronzo RA, Del Prato S, Eckel RH, Filippatos G, Fonarow GC, Fonseca VA, Garvey WT, Giorgino F, Grant PJ, Green JB, Greene SJ, Groop PH, Grunberger G, Jastreboff AM, Jellinger PS, Khunti K, Klein S, Kosiborod MN, Kushner P, Leiter LA, Lepor NE, Mantzoros CS, Mathieu C, Mende CW, Michos ED, Morales J, Plutzky J, Pratley RE, Ray KK, Rossing P, Sattar N, Schwarz PEH, Standl E, Steg PG, Tokgözoğlu L, Tuomilehto J, Umpierrez GE, Valensi P, Weir MR, Wilding J, Wright EE. DCRM 2.0: Multispecialty practice recommendations for the management of diabetes, cardiorenal, and metabolic diseases. Metabolism 2024; 159:155931. [PMID: 38852020 DOI: 10.1016/j.metabol.2024.155931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 06/10/2024]
Abstract
The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes.
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Affiliation(s)
| | | | | | - Christie M Ballantyne
- Department of Medicine, Baylor College of Medicine, Texas Heart Institute, Houston, TX, USA
| | - Deepak L Bhatt
- Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, NY, New York, USA
| | - Zachary T Bloomgarden
- Department of Internal Medicine, Icahn School of Medicine at Mount Sinai, NY, New York, USA
| | - Biykem Bozkurt
- Department of Medicine, Baylor College of Medicine, Houston, TX, USA
| | | | - Javed Butler
- University of Mississippi Medical Center, Jackson, MS, USA
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Canada
| | | | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Robert H Eckel
- University of Colorado Anschutz Medical Campus, Aurora, CO, USA
| | - Gerasimos Filippatos
- Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece
| | | | | | | | - Francesco Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy
| | | | - Jennifer B Green
- Division of Endocrinology, Metabolism, and Nutrition, Duke University School of Medicine, Durham, NC, USA
| | - Stephen J Greene
- Division of Cardiology, Duke University School of Medicine, Durham, NC, USA
| | - Per-Henrik Groop
- Department of Nephrology, University of Helsinki, Finnish Institute for Health and Helsinki University HospitalWelfare, Folkhälsan Research Center, Helsinki, Finland; Department of Diabetes, Central Clinical School, Monash University, Melbourne, Australia
| | - George Grunberger
- Grunberger Diabetes Institute, Bloomfield Hills, MI, USA; Wayne State University School of Medicine, Detroit, MI, USA; Oakland University William Beaumont School of Medicine, Rochester, MI, USA; Charles University, Prague, Czech Republic
| | | | - Paul S Jellinger
- The Center for Diabetes & Endocrine Care, University of Miami Miller School of Medicine, Hollywood, FL, USA
| | | | - Samuel Klein
- Washington University School of Medicine, Saint Louis, MO, USA
| | - Mikhail N Kosiborod
- Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, MO, USA
| | | | | | - Norman E Lepor
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | | | - Chantal Mathieu
- Department of Endocrinology, Katholieke Universiteit Leuven, Leuven, Belgium
| | - Christian W Mende
- University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Erin D Michos
- Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Javier Morales
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, Advanced Internal Medicine Group, PC, East Hills, NY, USA
| | - Jorge Plutzky
- Harvard Medical School, Brigham and Women's Hospital, Boston, MA, USA
| | | | | | | | | | - Peter E H Schwarz
- Department for Prevention and Care of Diabetes, Faculty of Medicine Carl Gustav Carus at the Technische Universität/TU Dresden, Dresden, Germany
| | - Eberhard Standl
- Munich Diabetes Research Group e.V. at Helmholtz Centre, Munich, Germany
| | - P Gabriel Steg
- Université Paris-Cité, Institut Universitaire de France, AP-HP, Hôpital Bichat, Cardiology, Paris, France
| | | | - Jaakko Tuomilehto
- University of Helsinki, Finnish Institute for Health and Welfare, Helsinki, Finland
| | | | - Paul Valensi
- Polyclinique d'Aubervilliers, Aubervilliers and Paris-Nord University, Paris, France
| | - Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - John Wilding
- University of Liverpool, Liverpool, United Kingdom
| | - Eugene E Wright
- Department of Medicine, Duke University Medical Center, Durham, NC, USA
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Rubio-Ruíz ME, Plata-Corona JC, Soria-Castro E, Díaz-Juárez JA, Sánchez-Aguilar M. Pleiotropic Effects of Peroxisome Proliferator-Activated Receptor Alpha and Gamma Agonists on Myocardial Damage: Molecular Mechanisms and Clinical Evidence-A Narrative Review. Cells 2024; 13:1488. [PMID: 39273057 PMCID: PMC11394383 DOI: 10.3390/cells13171488] [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: 07/17/2024] [Revised: 08/31/2024] [Accepted: 09/02/2024] [Indexed: 09/15/2024] Open
Abstract
Cardiovascular diseases remain the leading cause of death in the world, and that is why finding an effective and multi-functional treatment alternative to combat these diseases has become more important. Fibrates and thiazolidinediones, peroxisome proliferator-activated receptors alpha and gamma are the pharmacological therapies used to treat dyslipidemia and type 2 diabetes, respectively. New mechanisms of action of these drugs have been found, demonstrating their pleiotropic effects, which contribute to preserving the heart by reducing or even preventing myocardial damage. Here, we review the mechanisms underlying the cardioprotective effects of PPAR agonists and regulating morphological and physiological heart alterations (metabolic flexibility, mitochondrial damage, apoptosis, structural remodeling, and inflammation). Moreover, clinical evidence regarding the cardioprotective effect of PPAR agonists is also addressed.
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Affiliation(s)
- María Esther Rubio-Ruíz
- Department of Physiology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
| | - Juan Carlos Plata-Corona
- Department of Interventional Cardiology, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
| | - Elizabeth Soria-Castro
- Department of Cardiovascular Biomedicine, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
| | - Julieta Anabell Díaz-Juárez
- Department of Pharmacology “Dr. Rafael Méndez Martínez”, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
| | - María Sánchez-Aguilar
- Department of Pharmacology “Dr. Rafael Méndez Martínez”, Instituto Nacional de Cardiología Ignacio Chávez, Juan Badiano 1, Sección XVI, Tlalpan, México City 14080, Mexico;
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Ku EJ, Kim B, Han K, Lee SH, Kwon HS. Fenofibrate to prevent amputation and reduce vascular complications in patients with diabetes: FENO-PREVENT. Cardiovasc Diabetol 2024; 23:329. [PMID: 39227923 PMCID: PMC11373174 DOI: 10.1186/s12933-024-02422-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 08/27/2024] [Indexed: 09/05/2024] Open
Abstract
BACKGROUND The potential preventive effect of fenofibrate on lower extremity amputation (LEA) and peripheral arterial disease (PAD) in patients with type 2 diabetes (T2D) is not fully elucidated. METHODS We selected adult patients ≥ 20 years of age with T2D from the Korean National Health Insurance Service Database (2009-2012). The fenofibrate users were matched in a 1:4 ratio with non-users using propensity scores (PS). The outcome variables were a composite of LEA and PAD and the individual components. The risks of outcomes were implemented as hazard ratio (HR) with 95% confidence intervals (CI). For safety issues, the risks of acute kidney injury, rhabdomyolysis and resulting hospitalization were analyzed. RESULTS A total of 114,920 patients was included in the analysis with a median follow-up duration of 7.6 years (22,984 and 91,936 patients for the fenofibrate user and non-user groups, respectively). After PS matching, both groups were well balanced. The fenofibrate group was associated with significantly lower risks of composite outcome of LEA and PAD (HR 0.81; 95% CI 0.70-0.94), LEA (HR 0.76; 95% CI 0.60-0.96), and PAD (HR 0.81; 95% CI 0.68-0.96). The risk of acute kidney injury, rhabdomyolysis, or hospitalization for these events showed no significant difference between the two groups. Subgroup analyses revealed consistent benefits across age groups, genders, and baseline lipid profiles. CONCLUSIONS This nationwide population-based retrospective observational study suggests that fenofibrate can prevent LEA and PAD in patients with T2D who are on statin therapy.
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Affiliation(s)
- Eu Jeong Ku
- Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea
| | - Bongseong Kim
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, South Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, South Korea.
| | - Seung-Hwan Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
- Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, South Korea.
| | - Hyuk-Sang Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
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Shen F, Chu C, Chen J, Kuo C, Hsu C, Lin C, Sheen Y, Su S, Tien K, Lu C, Lee C, Yang Y, Tu S, Chen P, Chen C, Chien M, Li H, Sheu WH, Huang C, Wang C, Ou H. Optimizing lipid control in Taiwanese diabetic patients: A collaborative consensus by the Diabetes Association of the Republic of China (Taiwan) and the Taiwanese Association of Diabetes Educators. J Diabetes Investig 2024; 15:1151-1160. [PMID: 38676417 PMCID: PMC11292399 DOI: 10.1111/jdi.14222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
We present an in-depth analysis of dyslipidemia management strategies for patients with diabetes mellitus in Taiwan. It critically examines the disparity between established guideline recommendations and actual clinical practices, particularly in the context of evolving policies affecting statin prescriptions. The focus is on synthesizing the most recent findings concerning lipid management in patients with diabetes mellitus, with a special emphasis on establishing consensus regarding low-density lipoprotein cholesterol treatment targets. The article culminates in providing comprehensive, evidence-based recommendations tailored to the unique needs of those living with diabetes mellitus in Taiwan. It underscores the criticality of personalized care approaches, which incorporate multifaceted factors, and the integration of novel therapeutic options to enhance cardiovascular health outcomes.
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Affiliation(s)
- Feng‐Chih Shen
- Division of Endocrinology and Metabolism, Department of Internal MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
- School of Medicine, College of MedicineChang Gung UniversityTaoyuanTaiwan
| | - Chih‐Hsun Chu
- Division of Endocrinology and Metabolism, Department of Internal MedicineKaohsiung Veterans General HospitalKaohsiungTaiwan
| | - Jung‐Fu Chen
- Division of Endocrinology and Metabolism, Department of Internal MedicineKaohsiung Chang Gung Memorial HospitalKaohsiungTaiwan
- School of Medicine, College of MedicineChang Gung UniversityTaoyuanTaiwan
| | - Chin‐Sung Kuo
- Institute of Clinical MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Division of Endocrinology and Metabolism, Department of MedicineTaipei Veterans General HospitalTaipeiTaiwan
| | - Chih‐Yao Hsu
- Department of Internal MedicineTaipei City Hospital, Ren‐Ai BranchTaipeiTaiwan
| | - Ching‐Han Lin
- Department of Internal Medicine, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
| | - Yi‐Jing Sheen
- Division of Endocrinology and Metabolism, Department of Internal MedicineTaichung Veterans General HospitalTaichung CityTaiwan
- School of Medicine, College of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Department of Post‐Baccalaureate Medicine, College of MedicineNational Chung Hsing UniversityTaichungTaiwan
| | - Sheng‐Chiang Su
- Division of Endocrinology and Metabolism, Department of Internal MedicineTri‐Service General Hospital, National Defense Medical CenterTaipeiTaiwan
| | | | - Chieh‐Hua Lu
- Division of Endocrinology and Metabolism, Department of Internal MedicineTri‐Service General Hospital, National Defense Medical CenterTaipeiTaiwan
| | - Chun‐Chuan Lee
- Division of Endocrinology and Metabolism, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMacKay Medical CollegeNew Taipei CityTaiwan
| | - Yi‐Sun Yang
- Division of Endocrinology and Metabolism, Department of Internal MedicineChung Shan Medical University HospitalTaichungTaiwan
- School of MedicineChung Shan Medical UniversityTaichungTaiwan
| | - Shih‐Te Tu
- Division of Endocrinology and Metabolism, Department of MedicineChanghua Christian HospitalChanghuaTaiwan
| | | | - Ching‐Chu Chen
- Division of Endocrinology and Metabolism, Department of Internal MedicineChina Medical University HospitalTaichungTaiwan
- School of Chinese MedicineChina Medical UniversityTaichungTaiwan
| | - Ming‐Nan Chien
- Division of Endocrinology and Metabolism, Department of Internal MedicineMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMacKay Medical CollegeNew Taipei CityTaiwan
| | - Hung‐Yuan Li
- Division of Endocrinology and Metabolism, Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
| | - Wayne Huey‐Herng Sheu
- School of Medicine, College of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Institute of Molecular and Genetic MedicineNational Health Research InstitutesMiaoliTaiwan
| | - Chien‐Ning Huang
- Division of Endocrinology and Metabolism, Department of Internal MedicineChung Shan Medical University HospitalTaichungTaiwan
- School of MedicineChung Shan Medical UniversityTaichungTaiwan
| | - Chih‐Yuan Wang
- Division of Endocrinology and Metabolism, Department of Internal MedicineNational Taiwan University HospitalTaipeiTaiwan
- Department of Internal MedicineNational Taiwan University College of MedicineTaipeiTaiwan
| | - Horng‐Yih Ou
- Department of Internal Medicine, National Cheng Kung University Hospital, College of MedicineNational Cheng Kung UniversityTainanTaiwan
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Shah M, Sharma A, Ayyad M, Swartz E, Jafrani D, Gala D. Targeting Apolipoprotein C-III for the Management of Severe Hypertriglyceridemia: Current Research and Future Directions. Cureus 2024; 16:e67091. [PMID: 39286687 PMCID: PMC11405074 DOI: 10.7759/cureus.67091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2024] [Indexed: 09/19/2024] Open
Abstract
Hypertriglyceridemia is characterized by elevated triglyceride levels in the blood, which increases the risk of cardiovascular disease and pancreatitis. This condition stems from multiple factors including lifestyle choices, genetics, and conditions such as diabetes and metabolic syndrome. Apolipoprotein C-III (APOC3), a protein for lipid metabolism, hinders enzymes necessary for breaking down triglycerides and thus plays a key role in hypertriglyceridemia. Variations in the APOC3 gene are associated with varying triglyceride levels among individuals. Recent genetic studies and clinical trials have shed light on the potential of targeting APOC3 as a potentially promising therapeutic modality of hypertriglyceridemia. Antisense oligonucleotides like volanesorsen have displayed effectiveness in lowering triglyceride levels in individuals with severe hypertriglyceridemia. This review article delves into how APOC3 influences triglyceride control and its potential use in targeting APOC3 to manage severe hypertriglyceridemia.
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Affiliation(s)
- Mili Shah
- Internal Medicine, American University of the Caribbean School of Medicine, Sint Maarten, SXM
| | - Abisheikh Sharma
- Internal Medicine, American University of the Caribbean School of Medicine, Sint Maarten, SXM
| | - Mohammed Ayyad
- Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Ethan Swartz
- Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Danyaal Jafrani
- Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
| | - Dhir Gala
- Internal Medicine, Rutgers University New Jersey Medical School, Newark, USA
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Tokgözoğlu L, Pirillo A, Catapano AL. Disconnect between triglyceride reduction and cardiovascular outcomes: lessons from the PROMINENT and CLEAR Outcomes trials. Eur Heart J 2024; 45:2377-2379. [PMID: 37936268 DOI: 10.1093/eurheartj/ehad485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2023] Open
Affiliation(s)
- Lale Tokgözoğlu
- Department of Cardiology, Hacettepe University Medical Faculty, Sihhiye, 06100, Ankara, Turkey
| | - Angela Pirillo
- Center for the Study of Atherosclerosis, E. Bassini Hospital, via M. Gorki 50, 20092, Cinisello Balsamo, Milan, Italy
- IRCCS MultiMedica, via Milanese 300, 20099, Sesto San Giovanni, Milan, Italy
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Yadav A, Sawant V, Singh Bedi V, Yadav K. Dyslipidemia and peripheral arterial disease. Indian Heart J 2024; 76 Suppl 1:S86-S89. [PMID: 38224837 PMCID: PMC11019313 DOI: 10.1016/j.ihj.2024.01.010] [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: 10/14/2023] [Revised: 12/12/2023] [Accepted: 01/12/2024] [Indexed: 01/17/2024] Open
Abstract
Peripheral arterial disease (PAD) affects 12 % of adult population and is increasing globally and in India. Peripheral arterial disease when associated with atherosclerosis in two or more other arterial beds such as coronary artery disease (CAD), mesenteric/renal artery and cerebrovascular disease (CVD), is known as polyvascular disease. The Reduction of Atherothrombosis for Continued Health (REACH) registry reported that 1 out of 6 patients had multi-vascular bed involvement. Progression of PAD to critical limb ischaemia (CLI) is seen in 1 % of affected patients per year, but patients who progress to CLI may have a 10- to 15-fold increased risk of cardiovascular death. The 2019 ECS/EAS guidelines for the management of dyslipidaemias have suggested that for primary or secondary prevention in very high risk, patients should follow a therapeutic regimen that achieves >50 % LDL-C reduction from baseline and an LDL-C goal of <55 mg/dl. High Intensity Statin is mainstay of treatment but optimal management is inadequate. Statin treatment reduces all-cause mortality by 39 %, CV death by 41 %, CV outcomes by 34 %, ischaemic stroke by 28 %, acute limb ischaemia by 30 % and amputations by 35 %. Ezetimibe when added to statins in IMPROVE-IT trial, showed significant reduction of MACE. PCSK9 inhibitor (FOURIER TRIAL) showed reduction in primary end point in PAD vs Non PAD patients (3.5 % vs 1.6 %). There is a critical need for an Indian multi-disciplinary task force for research on the direct impact of lipid-lowering agents on limb salvage rates and major limb-related events in PAD patients.
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Affiliation(s)
- Ajay Yadav
- Institutions: Sir Ganga Ram Hospital, India.
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Moon JH, Kim Y, Oh TJ, Moon JH, Kwak SH, Park KS, Jang HC, Choi SH, Cho NH. Triglyceride-Glucose Index Predicts Future Atherosclerotic Cardiovascular Diseases: A 16-Year Follow-up in a Prospective, Community-Dwelling Cohort Study. Endocrinol Metab (Seoul) 2023; 38:406-417. [PMID: 37533176 PMCID: PMC10475965 DOI: 10.3803/enm.2023.1703] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 06/12/2023] [Accepted: 06/19/2023] [Indexed: 08/04/2023] Open
Abstract
BACKGRUOUND While the triglyceride-glucose (TyG) index is a measure of insulin resistance, its association with cardiovascular disease (CVD) has not been well elucidated. We evaluated the TyG index for prediction of CVDs in a prospective large communitybased cohort. METHODS Individuals 40 to 70 years old were prospectively followed for a median 15.6 years. The TyG index was calculated as the Ln [fasting triglycerides (mg/dL)×fasting glucose (mg/dL)/2]. CVDs included any acute myocardial infarction, coronary artery disease or cerebrovascular disease. We used a Cox proportional hazards model to estimate CVD risks according to quartiles of the TyG index and plotted the receiver operating characteristics curve for the incident CVD. RESULTS Among 8,511 subjects (age 51.9±8.8 years; 47.5% males), 931 (10.9%) had incident CVDs during the follow-up. After adjustment for age, sex, body mass index, diabetes mellitus, hypertension, total cholesterol, smoking, alcohol, exercise, and C-reactive protein, subjects in the highest TyG quartile had 36% increased risk of incident CVD compared with the lowest TyG quartile (hazard ratio, 1.36; 95% confidence interval, 1.10 to 1.68). Carotid plaque, assessed by ultrasonography was more frequent in subjects in the higher quartile of TyG index (P for trend=0.049 in men and P for trend <0.001 in women). The TyG index had a higher predictive power for CVDs than the homeostasis model assessment of insulin resistance (HOMA-IR) (area under the curve, 0.578 for TyG and 0.543 for HOMA-IR). Adding TyG index on diabetes or hypertension alone gave sounder predictability for CVDs. CONCLUSION The TyG index is independently associated with future CVDs in 16 years of follow-up in large, prospective Korean cohort.
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Affiliation(s)
- Joon Ho Moon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Yongkang Kim
- Institute for Behavioral Genetics, University of Colorado at Boulder, Boulder, CO, USA
| | - Tae Jung Oh
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Jae Hoon Moon
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hak Chul Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Nam H. Cho
- Department of Preventive Medicine, Ajou University School of Medicine, Suwon, Korea
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10
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Abstract
BACKGROUND Diabetic retinopathy (DR) remains a major cause of sight loss worldwide, despite new therapies and improvements in the metabolic control of people living with diabetes. Therefore, DR creates a physical and psychological burden for people, and an economic burden for society. Preventing the development and progression of DR, or avoiding the occurrence of its sight-threatening complications is essential, and must be pursued to save sight. Fenofibrate may be a useful strategy to achieve this goal, by reversing diabetes' effects and reducing inflammation in the retina, as well as improving dyslipidaemia and hypertriglyceridaemia. OBJECTIVES: To investigate the benefits and harms of fenofibrate for preventing the development and progression of diabetic retinopathy in people with type 1 (T1D) or type 2 diabetes (T2D), compared with placebo or observation. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, and three trials registers (February 2022). SELECTION CRITERIA We included randomised controlled trials (RCTs) that included people with T1D or T2D, when these compared fenofibrate with placebo or with observation, and assessed the effect of fenofibrate on the development or progression of DR (or both). DATA COLLECTION AND ANALYSIS We used standard Cochrane methods for data extraction and analysis. Our primary outcome was progression of DR, a composite outcome of 1) incidence of overt retinopathy for participants who did not have DR at baseline, or 2) advancing two or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) severity scale for participants who had any DR at baseline (or both), based on the evaluation of stereoscopic or non-stereoscopic fundus photographs, during the follow-up period. Overt retinopathy was defined as the presence of any DR observed on stereoscopic or non-stereoscopic colour fundus photographs. Secondary outcomes included the incidence of overt retinopathy, reduction in visual acuity of participants with a reduction in visual acuity of 10 ETDRS letters or more, proliferative diabetic retinopathy, and diabetic macular oedema; mean vision-related quality of life, and serious adverse events of fenofibrate. We used GRADE to assess the certainty of evidence. MAIN RESULTS We included two studies and their eye sub-studies (15,313 participants) in people with T2D. The studies were conducted in the US, Canada, Australia, Finland, and New Zealand; follow-up period was four to five years. One was funded by the government, the other by industry. Compared to placebo or observation, fenofibrate likely results in little to no difference in progression of DR (risk ratio (RR) 0.86; 95% confidence interval (CI) 0.60 to 1.25; 1 study, 1012 participants; moderate-certainty evidence) in a population with and without overt retinopathy at baseline. Those without overt retinopathy at baseline showed little or no progression (RR 1.00, 95% CI 0.68 to 1.47; 1 study, 804 participants); those with overt retinopathy at baseline found that their DR progressed slowly (RR 0.21, 95% CI 0.06 to 0.71; 1 study, 208 people; test for interaction P = 0.02). Compared to placebo or observation, fenofibrate likely resulted in little to no difference in either the incidence of overt retinopathy (RR 0.91; 95% CI 0.76 to 1.09; 2 studies, 1631 participants; moderate-certainty evidence); or the incidence of diabetic macular oedema (RR 0.39; 95% CI 0.12 to 1.24; 1 study, 1012 participants; moderate-certainty evidence). The use of fenofibrate increased severe adverse effects (RR 1.55; 95% CI 1.05 to 2.27; 2 studies, 15,313 participants; high-certainty evidence). The studies did not report on incidence of a reduction in visual acuity of 10 ETDRS letters or more, incidence of proliferative diabetic retinopathy, or mean vision-related quality of life. AUTHORS' CONCLUSIONS Current, moderate-certainty evidence suggests that in a mixed group of people with and without overt retinopathy, who live with T2D, fenofibrate likely results in little to no difference in progression of diabetic retinopathy. However, in people with overt retinopathy who live with T2D, fenofibrate likely reduces the progression. Serious adverse events were rare, but the risk of their occurrence was increased by the use of fenofibrate. There is no evidence on the effect of fenofibrate in people with T1D. More studies, with larger sample sizes, and participants with T1D are needed. They should measure outcomes that are important to people with diabetes, e.g. change in vision, reduction in visual acuity of 10 ETDRS letters or more, developing proliferative diabetic retinopathy; and evaluating the requirement of other treatments, e.g. injections of anti-vascular endothelial growth factor therapies, steroids.
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Affiliation(s)
- Sachiko Y Kataoka
- Department of Health informatics, Kyoto University School of Public Health, Kyoto, Japan
| | - Noemi Lois
- Wellcome-Wolfson Institute for Experimental Medicine, Queen's University Belfast, Belfast, UK
| | | | - Yuki Kataoka
- Department of Internal Medicine, Kyoto Min-Iren Asukai Hospital, Kyoto, Japan
- Section of Clinical Epidemiology, Department of Community Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
- Scientific Research Works Peer Support Group (SRWS-PSG), Osaka, Japan
- Department of Healthcare Epidemiology, Kyoto University Graduate School of Medicine / School of Public Health, Kyoto, Japan
| | - Kana Inoue
- Endocrinology and Metabolism, Ikeda City Hospital, Osaka, Japan
| | - Norio Watanabe
- Department of Psychiatry, Soseikai General Hospital, Kyoto, Japan
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11
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Enea I, Martelli E. Focus on the Prevention of Acute Limb Ischemia: Centrality of the General Practitioner from the Point of View of the Internist. J Clin Med 2023; 12:3652. [PMID: 37297848 PMCID: PMC10254060 DOI: 10.3390/jcm12113652] [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: 04/01/2023] [Revised: 05/01/2023] [Accepted: 05/15/2023] [Indexed: 06/12/2023] Open
Abstract
The thrombotic mechanism, being common to peripheral arterial disease (PAD), acute myocardial infarction (AMI), and stroke, is responsible for the highest number of deaths in the western world. However, while much has been done for the prevention, early diagnosis, therapy of AMI and stroke, the same cannot be said for PAD, which is a negative prognostic indicator for cardiovascular death. Acute limb ischemia (ALI) and chronic limb ischemia (CLI) are the most severe manifestations of PAD. They both are defined by the presence of PAD, rest pain, gangrene, or ulceration and we consider ALI if symptoms last less than 2 weeks and CLI if they last more than 2 weeks. The most frequent causes are certainly atherosclerotic and embolic mechanisms and, to a lesser extent, traumatic or surgical mechanisms. From a pathophysiological point of view, atherosclerotic, thromboembolic, inflammatory mechanisms are implicated. ALI is a medical emergency that puts both limb and the patient's life at risk. In patients over age 80 undergoing surgery, mortality remains high reaching approximately 40% as well as amputation approximately 11%. The purpose of this paper is to summarize the scientific evidence on the possibilities of primary and secondary prevention of ALI and to raise awareness among doctors involved in the management of ALI, in particular by describing the central role of the general practitioner.
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Affiliation(s)
- Iolanda Enea
- Emergency Department, S. Anna and S. Sebastiano Hospital, 81100 Caserta, Italy
| | - Eugenio Martelli
- Division of Vascular Surgery, Department of Cardiovascular Science, S. Anna and S. Sebastiano Hospital, Campania, 81100 Caserta, Italy;
- Department of General and Specialist Surgery Paride Stefanini, Faculty of Pharmacy and Medicine, Sapienza University of Rome, 00161 Rome, Italy
- Medicine and Surgery School of Medicine, Saint Camillus International University of Health Science, 00131 Rome, Italy
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12
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Wang Y, Fang Y, Magliano DJ, Charchar FJ, Sobey CG, Drummond GR, Golledge J. Fasting triglycerides are positively associated with cardiovascular mortality risk in people with diabetes. Cardiovasc Res 2023; 119:826-834. [PMID: 35905014 PMCID: PMC10153411 DOI: 10.1093/cvr/cvac124] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Revised: 06/24/2022] [Accepted: 07/13/2022] [Indexed: 11/12/2022] Open
Abstract
AIMS We investigated the association of fasting triglycerides with cardiovascular disease (CVD) mortality. METHODS AND RESULTS This cohort study included US adults from the National Health and Nutrition Examination Surveys from 1988 to 2014. CVD mortality outcomes were ascertained by linkage to the National Death Index records. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of triglycerides for CVD mortality. The cohort included 26 570 adult participants, among which 3978 had diabetes. People with higher triglycerides had a higher prevalence of diabetes at baseline. The cohort was followed up for a mean of 12.0 years with 1492 CVD deaths recorded. A 1-natural-log-unit higher triglyceride was associated with a 30% higher multivariate-adjusted risk of CVD mortality in participants with diabetes (HR, 1.30; 95% CI, 1.08-1.56) but not in those without diabetes (HR, 0.95; 95% CI, 0.83-1.07). In participants with diabetes, people with high triglycerides (200-499 mg/dL) had a 44% (HR, 1.44; 95% CI, 1.12-1.85) higher multivariate-adjusted risk of CVD mortality compared with those with normal triglycerides (<150 mg/dL). The findings remained significant when diabetes was defined by fasting glucose levels alone, or after further adjustment for the use of lipid-lowering medications, or after the exclusion of those who took lipid-lowering medications. CONCLUSION This study demonstrates that fasting triglycerides of ≥200 mg/dL are associated with an increased risk of CVD mortality in patients with diabetes but not in those without diabetes. Future clinical trials of new treatments to lower triglycerides should focus on patients with diabetes.
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Affiliation(s)
- Yutang Wang
- Discipline of Life Science, School of Science, Psychology and Sport, Federation University Australia, University Drive, Mt Helen, Ballarat, VIC, 3350, Australia
| | - Yan Fang
- Discipline of Life Science, School of Science, Psychology and Sport, Federation University Australia, University Drive, Mt Helen, Ballarat, VIC, 3350, Australia
| | - Dianna J Magliano
- Diabetes and Population Health, Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Fadi J Charchar
- Discipline of Life Science, School of Science, Psychology and Sport, Federation University Australia, University Drive, Mt Helen, Ballarat, VIC, 3350, Australia
| | - Christopher G Sobey
- Centre for Cardiovascular Biology and Disease Research and Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC, Australia
| | - Grant R Drummond
- Centre for Cardiovascular Biology and Disease Research and Department of Microbiology, Anatomy, Physiology and Pharmacology, School of Agriculture, Biomedicine and Environment, La Trobe University, Melbourne, VIC, Australia
| | - Jonathan Golledge
- Queensland Research Centre for Peripheral Vascular Disease, College of Medicine and Dentistry, James Cook University, Townsville, QLD, Australia
- Department of Vascular and Endovascular Surgery, The Townsville University Hospital, Townsville, QLD, Australia
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13
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Thomas MC, Coughlan MT, Cooper ME. The postprandial actions of GLP-1 receptor agonists: The missing link for cardiovascular and kidney protection in type 2 diabetes. Cell Metab 2023; 35:253-273. [PMID: 36754019 DOI: 10.1016/j.cmet.2023.01.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Recent clinical trials in people with type 2 diabetes have demonstrated beneficial actions on heart and kidney outcomes following treatment with GLP-1RAs. In part, these actions are consistent with improved glucose control and significant weight loss. But GLP-1RAs may also have additive benefits by improving postprandial dysmetabolism. In diabetes, dysregulated postprandial nutrient excursions trigger inflammation, oxidative stress, endothelial dysfunction, thrombogenicity, and endotoxemia; alter hormone levels; and modulate cardiac output and regional blood and lymphatic flow. In this perspective, we explore the actions of GLP-1RAs on the postprandial state and their potential role in end-organ benefits observed in recent trials.
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Affiliation(s)
- Merlin C Thomas
- Department of Diabetes, Monash University, Central Clinical School, 99 Commercial Road, Melbourne, Australia; Department of Biochemistry, Monash University, Melbourne, Australia
| | - Melinda T Coughlan
- Department of Diabetes, Monash University, Central Clinical School, 99 Commercial Road, Melbourne, Australia; Drug Discovery Biology, Monash Institute of Pharmaceutical Science, Monash University Parkville Campus, 381 Royal Parade, Parkville, 3052 VIC, Australia
| | - Mark E Cooper
- Department of Diabetes, Monash University, Central Clinical School, 99 Commercial Road, Melbourne, Australia.
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14
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Bonilha I, Luchiari B, Nadruz W, Sposito AC. Very low HDL levels: clinical assessment and management. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2023; 67:3-18. [PMID: 36651718 PMCID: PMC9983789 DOI: 10.20945/2359-3997000000585] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
In individuals with very low high-density lipoprotein (HDL-C) cholesterol, such as Tangier disease, LCAT deficiency, and familial hypoalphalipoproteinemia, there is an increased risk of premature atherosclerosis. However, analyzes based on comparisons of populations with small variations in HDL-C mediated by polygenic alterations do not confirm these findings, suggesting that there is an indirect association or heterogeneity in the pathophysiological mechanisms related to the reduction of HDL-C. Trials that evaluated some of the HDL functions demonstrate a more robust degree of association between the HDL system and atherosclerotic risk, but as they were not designed to modify lipoprotein functionality, there is insufficient data to establish a causal relationship. We currently have randomized clinical trials of therapies that increase HDL-C concentration by various mechanisms, and this HDL-C elevation has not independently demonstrated a reduction in the risk of cardiovascular events. Therefore, this evidence shows that (a) measuring HDL-C as a way of estimating HDL-related atheroprotective system function is insufficient and (b) we still do not know how to increase cardiovascular protection with therapies aimed at modifying HDL metabolism. This leads us to a greater effort to understand the mechanisms of molecular action and cellular interaction of HDL, completely abandoning the traditional view focused on the plasma concentration of HDL-C. In this review, we will detail this new understanding and the new horizon for using the HDL system to mitigate residual atherosclerotic risk.
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Affiliation(s)
- Isabella Bonilha
- Universidade de Campinas (Unicamp), Laboratório de Biologia Vascular e Aterosclerose (AtheroLab), Divisão de Cardiologia, Campinas, SP, Brasil
| | - Beatriz Luchiari
- Universidade de Campinas (Unicamp), Laboratório de Biologia Vascular e Aterosclerose (AtheroLab), Divisão de Cardiologia, Campinas, SP, Brasil
| | - Wilson Nadruz
- Universidade de Campinas (Unicamp), Divisão de Cardiologia, Campinas, SP, Brasil
| | - Andrei C Sposito
- Universidade de Campinas (Unicamp), Laboratório de Biologia Vascular e Aterosclerose (AtheroLab), Divisão de Cardiologia, Campinas, SP, Brasil,
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15
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Khazova EV, Bulashova OV. Residual risk in patients with atherosclerotic cardiovascular disease. КАРДИОВАСКУЛЯРНАЯ ТЕРАПИЯ И ПРОФИЛАКТИКА 2023. [DOI: 10.15829/1728-8800-2023-3382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
Abstract
The residual risk in patients with atherosclerosis, despite the its controversial aspects, remains an urgent problem of modern cardiology. The article presents a review of publications on the prevalence and significance for determining the prognosis of residual risk, which is currently interpreted as the risk of macroand microvascular complications in patients with atherosclerotic cardiovascular disease (ACVD) taking standard therapy, with the achievement of optimal levels of low-density lipoprotein cholesterol, blood pressure and glucose. Based on available publications, we highlighted current views on the factors associated with residual inflammatory and lipid risks in ACVD patients, including those associated with heart failure and diabetes, and the prognostic significance of residual risk in such patients. An attempt was made to rationale the significance of determining the residual risk for secondary prevention of cardiovascular events.
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16
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Tejera C, Porca C, Rodriguez-Carnero G, Andújar P, Casanueva FF, Bellido D, Crujeiras AB. Reducing Metabolic Syndrome through a Group Educational Intervention Program in Adults with Obesity: IGOBE Program. Nutrients 2022; 14:1066. [PMID: 35268040 PMCID: PMC8912562 DOI: 10.3390/nu14051066] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 02/23/2022] [Accepted: 03/01/2022] [Indexed: 02/01/2023] Open
Abstract
Metabolic syndrome (MetS) increases the risk of cardiovascular disease, type 2 diabetes mellitus, and cancer. Despite the higher prevalence of MetS in obese adults, little is known about the effectiveness of intensive and group interventions in improving MetS prevalence. This study aimed to investigate the effectiveness of an intensive lifestyle program in reducing the prevalence of MetS in adults with obesity. Patients with obesity (n = 456, 48.8 ± 12.8 years, 18.5% male) were randomized in two groups as indicated in a prospective interventional real-life study: a control group (CG), in which patients received usual care, and an interventional group (IG), in which the patients participate in a healthy lifestyle habits program in six weekly sessions, IGOBE program. Anthropometric, body composition, medications, and MetS features data were analyzed in both groups at the pre-intervention and post-intervention stages using a completer’s analysis. At 12 months of follow-up, the IG showed a relative reduction of 13.4% in the prevalence of MetS from baseline, while the CG showed a reduction of 2.1% (p < 0.001). A significant reduction was also observed in four of five MetS features. In this trial, implementation of the IGOBE program resulted in a significant reduction in MetS prevalence and better control of MetS features compared with the standard of care.
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Affiliation(s)
- Cristina Tejera
- Division of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Ferrol (CHUF/ SERGAS), 15405 Ferrol, Spain; (C.P.); (D.B.)
- Epigenomics in Endocrinology and Nutrition Group, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Univeristario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain; (G.R.-C.); (A.B.C.)
| | - Cristina Porca
- Division of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Ferrol (CHUF/ SERGAS), 15405 Ferrol, Spain; (C.P.); (D.B.)
- Epigenomics in Endocrinology and Nutrition Group, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Univeristario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain; (G.R.-C.); (A.B.C.)
| | - Gemma Rodriguez-Carnero
- Epigenomics in Endocrinology and Nutrition Group, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Univeristario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain; (G.R.-C.); (A.B.C.)
- Division of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain;
| | - Paula Andújar
- Division of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain;
| | - Felipe F. Casanueva
- Molecular Endocrinology Group, Instituto de Investigacion Sanitaria de Santiago (IDIS), Complejo Hospitalario Universitario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain;
- Centro de Investigacion Biomedica en Red Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain
| | - Diego Bellido
- Division of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Ferrol (CHUF/ SERGAS), 15405 Ferrol, Spain; (C.P.); (D.B.)
- Epigenomics in Endocrinology and Nutrition Group, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Univeristario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain; (G.R.-C.); (A.B.C.)
| | - Ana B. Crujeiras
- Epigenomics in Endocrinology and Nutrition Group, Instituto de Investigación Sanitaria de Santiago (IDIS), Complejo Hospitalario Univeristario de Santiago de Compostela (CHUS/SERGAS), 15706 Santiago de Compostela, Spain; (G.R.-C.); (A.B.C.)
- Centro de Investigacion Biomedica en Red Fisiopatologia de la Obesidad y Nutricion (CIBERobn), 28029 Madrid, Spain
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Handelsman Y, Anderson JE, Bakris GL, Ballantyne CM, Beckman JA, Bhatt DL, Bloomgarden ZT, Bozkurt B, Budoff MJ, Butler J, Dagogo-Jack S, de Boer IH, DeFronzo RA, Eckel RH, Einhorn D, Fonseca VA, Green JB, Grunberger G, Guerin C, Inzucchi SE, Jellinger PS, Kosiborod MN, Kushner P, Lepor N, Mende CW, Michos ED, Plutzky J, Taub PR, Umpierrez GE, Vaduganathan M, Weir MR. DCRM Multispecialty Practice Recommendations for the management of diabetes, cardiorenal, and metabolic diseases. J Diabetes Complications 2022; 36:108101. [PMID: 34922811 PMCID: PMC9803322 DOI: 10.1016/j.jdiacomp.2021.108101] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2021] [Accepted: 11/27/2021] [Indexed: 02/06/2023]
Abstract
Type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF)-along with their associated risk factors-have overlapping etiologies, and two or more of these conditions frequently occur in the same patient. Many recent cardiovascular outcome trials (CVOTs) have demonstrated the benefits of agents originally developed to control T2D, ASCVD, or CKD risk factors, and these agents have transcended their primary indications to confer benefits across a range of conditions. This evolution in CVOT evidence calls for practice recommendations that are not constrained by a single discipline to help clinicians manage patients with complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. The ultimate goal for these recommendations is to be comprehensive yet succinct and easy to follow by the nonexpert-whether a specialist or a primary care clinician. To meet this need, we formed a volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM Practice Recommendations, a multispecialty consensus on the comprehensive management of the patient with complicated metabolic disease. The task force recommendations are based on strong evidence and incorporate practical guidance that is clinically relevant and simple to implement, with the aim of improving outcomes in patients with DCRM. The recommendations are presented as 18 separate graphics covering lifestyle therapy, patient self-management education, technology for DCRM management, prediabetes, cognitive dysfunction, vaccinations, clinical tests, lipids, hypertension, anticoagulation and antiplatelet therapy, antihyperglycemic therapy, hypoglycemia, nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), ASCVD, HF, CKD, and comorbid HF and CKD, as well as a graphical summary of medications used for DCRM.
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Affiliation(s)
| | | | | | | | | | - Deepak L Bhatt
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | | | | | | | - Javed Butler
- University of Mississippi Medical Center, Jackson, MS, USA
| | | | | | | | - Robert H Eckel
- University of Colorado Anschutz Medical Campus, Denver, CO, USA
| | - Daniel Einhorn
- Scripps Whittier Institute for Diabetes, San Diego, CA, USA
| | | | | | - George Grunberger
- Grunberger Diabetes Institute, Bloomfield Hills, MI, USA, Wayne State University School of Medicine, Detroit, MI, USA, Oakland University William Beaumont School of Medicine, Rochester, MI, USA, Charles University, Prague, Czech Republic
| | - Chris Guerin
- University of California San Diego School of Medicine, San Diego, CA, USA
| | | | - Paul S Jellinger
- The Center for Diabetes & Endocrine Care, University of Miami Miller School of Medicine, Hollywood, FL, USA
| | - Mikhail N Kosiborod
- Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City, MO, USA
| | | | - Norman Lepor
- David Geffen School of Medicine, UCLA, Los Angeles, CA, USA
| | - Christian W Mende
- University of California San Diego School of Medicine, San Diego, CA, USA
| | - Erin D Michos
- Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jorge Plutzky
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Pam R Taub
- University of California San Diego School of Medicine, San Diego, CA, USA
| | | | | | - Matthew R Weir
- University of Maryland School of Medicine, Baltimore, MD, USA
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18
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Therapeutic Effects of Fenofibrate Nano-Emulsion Eye Drops on Retinal Vascular Leakage and Neovascularization. BIOLOGY 2021; 10:biology10121328. [PMID: 34943243 PMCID: PMC8698460 DOI: 10.3390/biology10121328] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 12/07/2021] [Accepted: 12/10/2021] [Indexed: 01/08/2023]
Abstract
Macular edema caused by retinal vascular leakage and ocular neovascularization are the leading causes of severe vision loss in diabetic retinopathy (DR) and age-related macular degeneration (AMD) patients. Oral administration of fenofibrate, a PPARα agonist, has shown therapeutic effects on macular edema and retinal neovascularization in diabetic patients. To improve the drug delivery to the retina and its efficacy, we have developed a nano-emulsion-based fenofibrate eye drop formulation that delivered significantly higher amounts of the drug to the retina compared to the systemic administration, as measured by liquid chromatography-mass spectrometer (LC-MS). The fenofibrate eye drop decreased leukocytes adherent to retinal vasculature and attenuated overexpression of multiple inflammatory factors in the retina of very low-density lipoprotein receptor knockout (Vldlr-/-) mice, a model manifesting AMD phenotypes, and streptozotocin-induced diabetic rats. The fenofibrate eye drop also reduced retinal vascular leakage in these models. The laser-induced choroidal neovascularization was also alleviated by the fenofibrate eye drop. There were no detectable ocular toxicities associated with the fenofibrate eye drop treatment. These findings suggest that fenofibrate can be delivered efficiently to the retina through topical administration of the nano-emulsion eye drop, which has therapeutic potential for macular edema and neovascularization.
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Al Sayed N, Almahmeed W, Alnouri F, Al Waili K, Sabbour H, Sulaiman K, Zubaid M, Ray KK, Al-Rasadi K. Consensus clinical recommendations for the management of plasma lipid disorders in the Middle East – 2021 update. Atherosclerosis 2021; 343:28-50. [DOI: 10.1016/j.atherosclerosis.2021.11.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 11/20/2021] [Accepted: 11/23/2021] [Indexed: 12/14/2022]
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A new phenotypic classification system for dyslipidemias based on the standard lipid panel. Lipids Health Dis 2021; 20:170. [PMID: 34838008 PMCID: PMC8627634 DOI: 10.1186/s12944-021-01585-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2021] [Accepted: 10/22/2021] [Indexed: 02/07/2023] Open
Abstract
Background Dyslipoproteinemias can be classified by their distinct lipoprotein patterns, which helps determine atherosclerotic cardiovascular disease (ASCVD) risk and directs lipid management but this has required advanced laboratory testing. Objective To develop a new algorithm for classifying lipoprotein disorders that only relies on the standard lipid panel. Methods Lipid thresholds for defining the different lipoprotein phenotypes were derived for Non-High-Density Lipoprotein-Cholesterol (NonHDL-C) and Triglycerides (TG) to be concordant when possible with the current US Multi-Society guidelines for blood cholesterol management. Results The new classification method categorizes patients into all the classical Fredrickson-like phenotypes except for Type III dysbetalipoproteinemia. In addition, a new hypolipidemic phenotype (Type VI) due to genetic mutations in apoB-metabolism is described. The validity of the new algorithm was confirmed by lipid analysis by NMR (N = 11,365) and by concordance with classification by agarose gel electrophoresis/beta-quantification (N = 5504). Furthermore, based on the Atherosclerosis Risk in Communities (ARIC) cohort (N = 14,742), the lipoprotein phenotypes differ in their association with ASCVD (TypeV>IIb > IVb > IIa > IVa > normolipidemic) and can be used prognostically as risk enhancer conditions in the management of patients. Conclusions We describe a clinically useful lipoprotein phenotyping system that is only dependent upon the standard lipid panel. It, therefore, can be easily implemented for increasing compliance with current guidelines and for improving the care of patients at risk for ASCVD. Supplementary Information The online version contains supplementary material available at 10.1186/s12944-021-01585-8. A new algorithm is described for categorizing dyslipidemic patients into Fredrickson-like lipoprotein phenotypes except for Type III. The new lipoprotein phenotypes were validated by NMR-lipoprotein analysis and by agarose gel electrophoresis/beta-quantification in a large number of subjects. The new lipoprotein phenotyping system identifies high-risk cardiovascular patients and helps direct clinical management. A major advance is that the new lipoprotein phenotypes are based on just the standard lipid panel, and thus can be automatically calculated by the clinical laboratory and widely implemented.
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Abstract
Plasma HDL-cholesterol concentrations correlate negatively with the risk of atherosclerotic cardiovascular disease (ASCVD). According to a widely cited model, HDL elicits its atheroprotective effect through its role in reverse cholesterol transport, which comprises the efflux of cholesterol from macrophages to early forms of HDL, followed by the conversion of free cholesterol (FCh) contained in HDL into cholesteryl esters, which are hepatically extracted from the plasma by HDL receptors and transferred to the bile for intestinal excretion. Given that increasing plasma HDL-cholesterol levels by genetic approaches does not reduce the risk of ASCVD, the focus of research has shifted to HDL function, especially in the context of macrophage cholesterol efflux. In support of the reverse cholesterol transport model, several large studies have revealed an inverse correlation between macrophage cholesterol efflux to plasma HDL and ASCVD. However, other studies have cast doubt on the underlying reverse cholesterol transport mechanism: in mice and humans, the FCh contained in HDL is rapidly cleared from the plasma (within minutes), independently of esterification and HDL holoparticle uptake by the liver. Moreover, the reversibility of FCh transfer between macrophages and HDL has implicated the reverse process - that is, the transfer of FCh from HDL to macrophages - in the aetiology of increased ASCVD under conditions of very high plasma HDL-FCh concentrations.
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The Glitazars Paradox: Cardiotoxicity of the Metabolically Beneficial Dual PPARα and PPARγ Activation. J Cardiovasc Pharmacol 2021; 76:514-526. [PMID: 33165133 DOI: 10.1097/fjc.0000000000000891] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The most common complications in patients with type-2 diabetes are hyperglycemia and hyperlipidemia that can lead to cardiovascular disease. Alleviation of these complications constitutes the major therapeutic approach for the treatment of diabetes mellitus. Agonists of peroxisome proliferator-activated receptor (PPAR) alpha and PPARγ are used for the treatment of hyperlipidemia and hyperglycemia, respectively. PPARs belong to the nuclear receptors superfamily and regulate fatty acid metabolism. PPARα ligands, such as fibrates, reduce circulating triglyceride levels, and PPARγ agonists, such as thiazolidinediones, improve insulin sensitivity. Dual-PPARα/γ agonists (glitazars) were developed to combine the beneficial effects of PPARα and PPARγ agonism. Although they improved metabolic parameters, they paradoxically aggravated congestive heart failure in patients with type-2 diabetes via mechanisms that remain elusive. Many of the glitazars, such as muraglitazar, tesaglitazar, and aleglitazar, were abandoned in phase-III clinical trials. The objective of this review article pertains to the understanding of how combined PPARα and PPARγ activation, which successfully targets the major complications of diabetes, causes cardiac dysfunction. Furthermore, it aims to suggest interventions that will maintain the beneficial effects of dual PPARα/γ agonism and alleviate adverse cardiac outcomes in diabetes.
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Shaya GE, Leucker TM, Jones SR, Martin SS, Toth PP. Coronary heart disease risk: Low-density lipoprotein and beyond. Trends Cardiovasc Med 2021; 32:181-194. [PMID: 33872757 DOI: 10.1016/j.tcm.2021.04.002] [Citation(s) in RCA: 106] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Revised: 03/30/2021] [Accepted: 04/05/2021] [Indexed: 01/06/2023]
Abstract
Coronary heart disease (CHD) is the leading cause of morbidity and mortality world-wide and has been characterized as a chronic immunoinflammatory, fibroproliferative disease fueled by lipids. Great advances have been made in elucidating the complex mechanistic interactions among risk factors associated with CHD, yielding abundant success towards preventive measures and the development of pharmaceuticals to prevent and treat CHD via attenuation of lipoprotein-mediated risk. However, significant residual risk remains. Several potentially modifiable CHD risk factors ostensibly contributing to this residual risk have since come to the fore, including systemic inflammation, diabetes mellitus, high-density lipoprotein, plasma triglycerides (TG) and remnant lipoproteins (RLP), lipoprotein(a) (Lp[a]), and vascular endothelial dysfunction (ED). Herein, we summarize the body of evidence implicating each of these risk factors in residual CHD risk.
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Affiliation(s)
- Gabriel E Shaya
- Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, MD, USA
| | - Thorsten M Leucker
- Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, MD, USA
| | - Steven R Jones
- Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, MD, USA
| | - Seth S Martin
- Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, MD, USA
| | - Peter P Toth
- Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Baltimore, MD, USA; Community Hospital General Medical Center, Sterling, IL, USA.
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Zhang X, Wang K, Zhu L, Wang Q. Reverse Cholesterol Transport Pathway and Cholesterol Efflux in Diabetic Retinopathy. J Diabetes Res 2021; 2021:8746114. [PMID: 34746320 PMCID: PMC8564209 DOI: 10.1155/2021/8746114] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 09/16/2021] [Accepted: 10/01/2021] [Indexed: 11/21/2022] Open
Abstract
Cholesterol esters, synthesized from cholesterol with long-chain fatty acids, are essential components of plasma lipoproteins and cell membranes that participate in various metabolic processes in the body. Cholesterol can be excreted through the cholesterol reverse transport (RCT) pathway when excessive cholesterol is produced in the extrahepatic cells, which is regulated by the liver X receptor (LXR) and its downstream regulators ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1) genes. Abnormal cholesterol metabolism is closely associated with the development of diabetic retinopathy (DR). However, the precise underlying mechanism of the RCT pathway in the pathogenesis of DR is still not fully understood. This review focused on cholesterol metabolism, with a particular emphasis on the RCT pathway and its correlation with the development of DR. Particular attention has been paid to the key regulators of the RCT pathway: LXR, ABCA1, and ABCG1 genes and their potential therapeutic targets in the management of DR.
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Affiliation(s)
- Xinyuan Zhang
- Beijing Institute of Ophthalmology, Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, China
- Beijing Retinal and Choroidal Vascular Study Group, China
| | - Kaiyue Wang
- Beijing Institute of Ophthalmology, Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, China
| | - Ling Zhu
- Save Sight Institute, University of Sydney, Australia
| | - Qiyun Wang
- Beijing Institute of Ophthalmology, Department of Ophthalmology, Beijing Tongren Hospital, Capital Medical University, China
- Beijing Retinal and Choroidal Vascular Study Group, China
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Saeed A, Virani SS, Mulukutla S, Chow CK. Dyslipidemia and Cardiovascular Disease Prevention in South Asians: A Review and Discussion of Causes, Challenges and Management Strategies. Curr Diabetes Rev 2021; 17:e011221190238. [PMID: 33438542 DOI: 10.2174/1573399817999210112192419] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 09/29/2020] [Accepted: 10/03/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND South Asians are at a significantly increased risk of atherosclerotic cardiovascular disease (ASCVD). For a major portion of the South Asian population, the cardiovascular disease events occur at a relatively younger age, are associated with worse outcomes, and have potentially more severe socioeconomic implications compared to their western counterparts. METHODS The term "South Asian" typically constitutes individuals from India, Pakistan, Nepal, Bhutan, Bangladesh, Sri Lanka, and Maldives, including expatriates as well as their families from these countries. Based on this, South Asians form approximately 25% of the world's population, with a high ASCVD burden in this group. In this review, we discuss the pathophysiological factors underlying ASCVD in South Asians, the dyslipidemia types and management, and discuss approaches to improve the overall ASCVD prevention efforts in this large subset population of the world. Although the pathophysiological mechanisms underlying the excess risk of cardiovascular disease in South Asians are multifactorial, dyslipidemia is a primary risk factor for the incidence and prevalence of this disease. The traditional "South Asian" dyslipidemia pattern includes levels of low-density lipoprotein cholesterol (LDL-C) in the normal range with a high concentration of LDL particles, elevated triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) with dysfunctional HDL particles, and high levels of lipoprotein(a). CONCLUSION While combined efforts to study the expatriate South Asians in western countries have been able to identify South Asian specific dyslipidemias, causal associations and optimal management remain relatively less explored. Larger scale studies are needed to better quantify the relationship of each lipid parameter with ASCVD risk among South Asians as well as optimal lipid targets and management strategies to reduce morbidity and mortality in this high-risk group.
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Affiliation(s)
- Anum Saeed
- Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Salim S Virani
- Department of Health Policy, Quality and Informatics Program, Michael E. DeBakey Veterans Affairs Medical Center Health Services Research and Development Center for Innovations, Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, TX, United States
| | - Suresh Mulukutla
- Heart and Vascular Institute, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States
| | - Clara K Chow
- Westmead Applied Research Centre, Faculty of Medicine and Health, University of Sydney, Department of Cardiology, Westmead Hospital, The George Institute, Sydney, Australia
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Patoulias D, Stavropoulos K, Imprialos K, Athyros V, Doumas M, Karagiannis A. Pharmacological Management of Cardiac Disease in Patients with Type 2 Diabetes: Insights into Clinical Practice. Curr Vasc Pharmacol 2020; 18:125-138. [PMID: 32013815 DOI: 10.2174/1570161117666190426162746] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/18/2018] [Accepted: 10/26/2018] [Indexed: 01/16/2023]
Abstract
BACKGROUND Type 2 Diabetes Mellitus (T2DM) has emerged as a growing pandemic. Cardiovascular disease (CVD) constitutes another major health problem, with coronary heart disease being the leading cause of cardiovascular death. Patients with T2DM require a multilevel therapeutic approach, both for primary and secondary prevention of CVD. OBJECTIVE To present and summarize the most recent, highest level evidence retrieved from literature, relevant to the pharmaceutical management of CVD in T2DM. METHODS We conducted a comprehensive search of the literature on MEDLINE from its inception till today, primarily for relevant systematic reviews, meta-analyses and randomized controlled trials. RESULTS There is a trend towards more intensified therapeutic interventions in T2DM, concerning glycemic, lipid and blood pressure control. New drugs, such as sodium-glucose co-transporter 2 (SGLT-2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and proprotein convertase subtilisin/ kexin type 9 (PCSK9) inhibitors might evolve as key players in the management of diabetes and its complications within the next years. Classic drugs, such as those targeting the renin-angiotensinaldosterone system, statins and aspirin remain first-line treatment options, both for primary and secondary prevention of CVD. Lifestyle interventions should always be integrated into a complete therapeutic strategy in diabetic patients. Novel drugs, such as finerenone and LCZ696 have provided significant results in cardiovascular outcome studies; however, their role in T2DM has to be further elucidated. CONCLUSION Pharmaceutical approach of CVD in T2DM is multilevel and complex. Drug classes featuring pleiotropic effects may boost our armamentarium in the fight against CVD.
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Affiliation(s)
- Dimitrios Patoulias
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Stavropoulos
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Konstantinos Imprialos
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vasilios Athyros
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Michael Doumas
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece.,VA Medical Center, and George Washington University, Washington, DC, United States
| | - Asterios Karagiannis
- Second Propedeutic Department of Internal Medicine, General Hospital "Hippokration", Aristotle University of Thessaloniki, Thessaloniki, Greece
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Gamdzyk M, Lenahan C, Tang J, Zhang JH. Role of peroxisome proliferator-activated receptors in stroke prevention and therapy-The best is yet to come? J Neurosci Res 2020; 98:2275-2289. [PMID: 32772463 DOI: 10.1002/jnr.24709] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/08/2020] [Accepted: 07/20/2020] [Indexed: 12/25/2022]
Abstract
Role of peroxisome proliferator-activated receptors (PPARs) in the pathophysiology of stroke and protective effects of PPAR ligands have been widely investigated in the last 20 years. Activation of all three PPAR isoforms, but especially PPAR-γ, was documented to limit postischemic injury in the numerous in vivo, as well as in in vitro studies. PPARs have been demonstrated to act on multiple mechanisms and were shown to activate multiple protective pathways related to inflammation, apoptosis, BBB protection, neurogenesis, and oxidative stress. The aim of this review was to summarize two decades of PPAR research in stroke with emphasis on in vivo animal studies. We focus on each PPAR receptor separately and detail their implication in stroke. This review also discusses recent clinical efforts in the field and the epidemiological data with regard to role of PPAR polymorphisms in susceptibility to stroke, and tries to draw conclusions and describe future perspectives.
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Affiliation(s)
- Marcin Gamdzyk
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Cameron Lenahan
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - Jiping Tang
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA
| | - John H Zhang
- Department of Physiology and Pharmacology, Basic Sciences, School of Medicine, Loma Linda University, Loma Linda, CA, USA.,Department of Anesthesiology, Neurosurgery and Neurology, Loma Linda University School of Medicine, Loma Linda, CA, USA
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Yokote K, Niwa K, Hakoda T, Oh F, Kajimoto Y, Fukui T, Kim H, Noda Y, Lundström T, Yajima T. Short-Term Efficacy (at 12 Weeks) and Long-Term Safety (up to 52 Weeks) of Omega-3 Free Fatty Acids (AZD0585) for the Treatment of Japanese Patients With Dyslipidemia - A Randomized, Double-Blind, Placebo-Controlled, Phase III Study. Circ J 2020; 84:994-1003. [PMID: 32281579 DOI: 10.1253/circj.cj-19-0358] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND This study is the first to evaluate the short-term efficacy and long-term safety of AZD0585, a mixture of omega-3 free fatty acids, in Japanese patients with dyslipidemia. METHODS AND RESULTS In this randomized double-blind placebo-controlled Phase III study, 383 patients were randomized to 2 g AZD0585, 4 g AZD0585, or placebo once daily for 52 weeks. Eligible patients had low-density lipoprotein cholesterol (LDL-C) levels controlled regardless of statin use, and triglyceride levels between 150 and 499 mg/dL. The least-squares (LS) mean percentage changes in triglyceride concentrations from baseline to the 12-week endpoint (mean of measurements at Weeks 10 and 12) in the 2 and 4 g AZD0585 and placebo groups were -15.57%, -21.75%, and 11.15% respectively (P<0.0001 for both AZD0585 doses vs. placebo). No clinically significant changes from baseline to the 12-week endpoint in total cholesterol, LDL-C, and LDL-C/apolipoprotein (Apo) B were found with AZD0585. High-density lipoprotein cholesterol (HDL-C) was slightly increased and very low-density lipoprotein cholesterol, non-HDL-C, ApoC-II, and ApoC-III were decreased with AZD0585 compared with placebo at the 12-week endpoint. Lipid profiles up to Week 52 were consistent with those up to the 12-week endpoint. No clinically important safety concerns were raised. CONCLUSIONS AZD0585 significantly decreased serum triglyceride levels compared with placebo at the 12-week endpoint and was generally safe and well tolerated in Japanese patients with dyslipidemia.
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Affiliation(s)
- Koutaro Yokote
- Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine
- Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital
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Jun JE, Jeong IK, Yu JM, Kim SR, Lee IK, Han KA, Choi SH, Kim SK, Park HK, Mok JO, Lee YH, Kwon HS, Kim SH, Kang HC, Lee SA, Lee CB, Choi KM, Her SH, Shin WY, Shin MS, Ahn HS, Kang SH, Cho JM, Jo SH, Cha TJ, Kim SY, Won KH, Kim DB, Lee JH, Lee MK. Efficacy and Safety of Omega-3 Fatty Acids in Patients Treated with Statins for Residual Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Diabetes Metab J 2020; 44:78-90. [PMID: 31237134 PMCID: PMC7043989 DOI: 10.4093/dmj.2018.0265] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2018] [Accepted: 02/28/2019] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Cardiovascular risk remains increased despite optimal low density lipoprotein cholesterol (LDL-C) level induced by intensive statin therapy. Therefore, recent guidelines recommend non-high density lipoprotein cholesterol (non-HDL-C) as a secondary target for preventing cardiovascular events. The aim of this study was to assess the efficacy and tolerability of omega-3 fatty acids (OM3-FAs) in combination with atorvastatin compared to atorvastatin alone in patients with mixed dyslipidemia. METHODS This randomized, double-blind, placebo-controlled, parallel-group, and phase III multicenter study included adults with fasting triglyceride (TG) levels ≥200 and <500 mg/dL and LDL-C levels <110 mg/dL. Eligible subjects were randomized to ATOMEGA (OM3-FAs 4,000 mg plus atorvastatin calcium 20 mg) or atorvastatin 20 mg plus placebo groups. The primary efficacy endpoints were the percent changes in TG and non-HDL-C levels from baseline at the end of treatment. RESULTS After 8 weeks of treatment, the percent changes from baseline in TG (-29.8% vs. 3.6%, P<0.001) and non-HDL-C (-10.1% vs. 4.9%, P<0.001) levels were significantly greater in the ATOMEGA group (n=97) than in the atorvastatin group (n=103). Moreover, the proportion of total subjects reaching TG target of <200 mg/dL in the ATOMEGA group was significantly higher than that in the atorvastatin group (62.9% vs. 22.3%, P<0.001). The incidence of adverse events did not differ between the two groups. CONCLUSION The addition of OM3-FAs to atorvastatin improved TG and non-HDL-C levels to a significant extent compared to atorvastatin alone in subjects with residual hypertriglyceridemia.
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Affiliation(s)
- Ji Eun Jun
- Department of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea
| | - In Kyung Jeong
- Department of Endocrinology and Metabolism, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea
| | - Jae Myung Yu
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Hallym University Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
| | - Sung Rae Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Bucheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Bucheon, Korea
| | - In Kye Lee
- Department of Endocrinology and Metabolism of Internal Medicine, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Kyung Ah Han
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Sung Hee Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea
| | - Soo Kyung Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Hyeong Kyu Park
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea
| | - Ji Oh Mok
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soonchunhyang University College of Medicine, Bucheon, Korea
| | - Yong Ho Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Hyuk Sang Kwon
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Yeouido St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - So Hun Kim
- Division of Endocrinology and Metabolism Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea
| | - Ho Cheol Kang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Korea
| | - Sang Ah Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Jeju National University School of Medicine, Jeju, Korea
| | - Chang Beom Lee
- Department of Endocrinology and Metabolism, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea
| | - Kyung Mook Choi
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Sung Ho Her
- Division of Cardiology, Department of Internal Medicine, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, Korea
| | - Won Yong Shin
- Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Soonchunhyang University College of Medicine, Cheonan, Korea
| | - Mi Seung Shin
- Division of Cardiology, Department of Internal Medicine, Gachon University Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Hyo Suk Ahn
- Division of Cardiology, Department of Internal Medicine, Uijeongbu St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Uijeongbu, Korea
| | - Seung Ho Kang
- Division of Cardiology, Department of Internal Medicine, Cheju Halla General Hospital, Jeju, Korea
| | - Jin Man Cho
- Division of Cardiology, Department of Internal Medicine, Kyung Hee University Hospital at Gangdong, Kyung Hee University School of Medicine, Seoul, Korea
| | - Sang Ho Jo
- Division of Cardiology, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea
| | - Tae Joon Cha
- Division of Cardiology, Department of Internal Medicine, Kosin University Gospel Hospital, Kosin University College of Medicine, Busan, Korea
| | - Seok Yeon Kim
- Division of Cardiology, Department of Internal Medicine, Seoul Medical Center, Seoul, Korea
| | - Kyung Heon Won
- Division of Cardiology, Department of Internal Medicine, Seoul Medical Center, Seoul, Korea
| | - Dong Bin Kim
- Division of Cardiology, Department of Internal Medicine, St. Paul's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jae Hyuk Lee
- Division of Endocrinology, Department of Internal Medicine, Myongji Hospital, Goyang, Korea
| | - Moon Kyu Lee
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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Van Wyngene L, Vanderhaeghen T, Timmermans S, Vandewalle J, Van Looveren K, Souffriau J, Wallaeys C, Eggermont M, Ernst S, Van Hamme E, Gonçalves A, Eelen G, Remmerie A, Scott CL, Rombouts C, Vanhaecke L, De Bus L, Decruyenaere J, Carmeliet P, Libert C. Hepatic PPARα function and lipid metabolic pathways are dysregulated in polymicrobial sepsis. EMBO Mol Med 2020; 12:e11319. [PMID: 31916705 PMCID: PMC7005534 DOI: 10.15252/emmm.201911319] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 11/28/2019] [Accepted: 11/29/2019] [Indexed: 12/14/2022] Open
Abstract
Despite intensive research and constant medical progress, sepsis remains one of the most urgent unmet medical needs of today. Most studies have been focused on the inflammatory component of the disease; however, recent advances support the notion that sepsis is accompanied by extensive metabolic perturbations. During times of limited caloric intake and high energy needs, the liver acts as the central metabolic hub in which PPARα is crucial to coordinate the breakdown of fatty acids. The role of hepatic PPARα in liver dysfunction during sepsis has hardly been explored. We demonstrate that sepsis leads to a starvation response that is hindered by the rapid decline of hepatic PPARα levels, causing excess free fatty acids, leading to lipotoxicity, and glycerol. In addition, treatment of mice with the PPARα agonist pemafibrate protects against bacterial sepsis by improving hepatic PPARα function, reducing lipotoxicity and tissue damage. Since lipolysis is also increased in sepsis patients and pemafibrate protects after the onset of sepsis, these findings may point toward new therapeutic leads in sepsis.
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Affiliation(s)
- Lise Van Wyngene
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Tineke Vanderhaeghen
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Steven Timmermans
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Jolien Vandewalle
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Kelly Van Looveren
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Jolien Souffriau
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Charlotte Wallaeys
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Melanie Eggermont
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Sam Ernst
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Evelien Van Hamme
- Bio Imaging Core, VIB Center for Inflammation Research, Ghent, Belgium
| | - Amanda Gonçalves
- Bio Imaging Core, VIB Center for Inflammation Research, Ghent, Belgium
| | - Guy Eelen
- Laboratory of Angiogenesis and Vascular Biology, VIB Center for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Anneleen Remmerie
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Charlotte L Scott
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
| | - Caroline Rombouts
- Faculty of Veterinary Medicine, Department of Veterinary Public Health and Food Safety, Laboratory of Chemical Analysis, Ghent University, Ghent, Belgium
| | - Lynn Vanhaecke
- Faculty of Veterinary Medicine, Department of Veterinary Public Health and Food Safety, Laboratory of Chemical Analysis, Ghent University, Ghent, Belgium
| | - Liesbet De Bus
- Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
| | - Johan Decruyenaere
- Department of Critical Care Medicine, Ghent University Hospital, Ghent, Belgium
| | - Peter Carmeliet
- Laboratory of Angiogenesis and Vascular Biology, VIB Center for Cancer Biology, VIB, Leuven, Belgium.,Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology and Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
| | - Claude Libert
- Center for Inflammation Research, VIB, Ghent, Belgium.,Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium
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Stahel P, Xiao C, Nahmias A, Lewis GF. Role of the Gut in Diabetic Dyslipidemia. Front Endocrinol (Lausanne) 2020; 11:116. [PMID: 32231641 PMCID: PMC7083132 DOI: 10.3389/fendo.2020.00116] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 02/21/2020] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and impaired clearance of liver-derived very-low-density lipoproteins and gut-derived chylomicrons (CMs) contribute to hypertriglyceridemia and elevated atherogenic remnant lipoproteins. Although ingested fat is the major stimulus of CM secretion, intestinal lipid handling and ultimately CM secretory rate is determined by numerous additional regulatory inputs including nutrients, hormones and neural signals that fine tune CM secretion during fasted and fed states. Insulin resistance and T2D represent perturbed metabolic states in which intestinal sensitivity to key regulatory hormones such as insulin, leptin and glucagon-like peptide-1 (GLP-1) may be altered, contributing to increased CM secretion. In this review, we describe the evidence from human and animal models demonstrating increased CM secretion in insulin resistance and T2D and discuss the molecular mechanisms underlying these effects. Several novel compounds are in various stages of preclinical and clinical investigation to modulate intestinal CM synthesis and secretion. Their efficacy, safety and therapeutic utility are discussed. Similarly, the effects of currently approved lipid modulating therapies such as statins, ezetimibe, fibrates, and PCSK9 inhibitors on intestinal CM production are discussed. The intricacies of intestinal CM production are an active area of research that may yield novel therapies to prevent atherosclerotic CVD in insulin resistance and T2D.
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Ray KK, Del Prato S, Müller-Wieland D, Cariou B, Colhoun HM, Tinahones FJ, Domenger C, Letierce A, Mandel J, Samuel R, Bujas-Bobanovic M, Leiter LA. Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies. Cardiovasc Diabetol 2019; 18:149. [PMID: 31706300 PMCID: PMC6842201 DOI: 10.1186/s12933-019-0951-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2019] [Accepted: 10/24/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Individuals with diabetes often have high levels of atherogenic lipoproteins and cholesterol reflected by elevated low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (ApoB), and LDL particle number (LDL-PN). The presence of atherosclerotic cardiovascular disease (ASCVD) increases the risk of future cardiovascular events. We evaluated the efficacy and safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, alirocumab, among individuals with type 2 diabetes (T2DM), high LDL-C or non-HDL-C, and established ASCVD receiving maximally tolerated statin in ODYSSEY DM-DYSLIPIDEMIA (NCT02642159) and DM-INSULIN (NCT02585778). METHODS In DM-DYSLIPIDEMIA, individuals with T2DM and mixed dyslipidemia (non-HDL-C ≥ 100 mg/dL; n = 413) were randomized to open-label alirocumab 75 mg every 2 weeks (Q2W) or usual care (UC) for 24 weeks, with UC options selected before stratified randomization. In DM-INSULIN, insulin-treated individuals with T2DM (LDL-C ≥ 70 mg/dL; n = 441) were randomized in a double-blind fashion to alirocumab 75 mg Q2W or placebo for 24 weeks. Study participants also had a glycated hemoglobin < 9% (DM-DYSLIPIDEMIA) or < 10% (DM-INSULIN). Alirocumab dose was increased to 150 mg Q2W at week 12 if week 8 LDL-C was ≥ 70 mg/dL (DM-INSULIN) or non-HDL-C was ≥ 100 mg/dL (DM-DYSLIPIDEMIA). Lipid reductions and safety were assessed in patients with ASCVD from these studies. RESULTS This analysis included 142 DM-DYSLIPIDEMIA and 177 DM-INSULIN participants with ASCVD, including 95.1% and 86.4% with coronary heart disease, and 32.4% and 49.7% with microvascular diabetes complications, respectively. At week 24, alirocumab significantly reduced LDL-C, non-HDL-C, ApoB, and LDL-PN from baseline versus control. This translated into a greater proportion of individuals achieving non-HDL-C < 100 mg/dL (64.6% alirocumab/23.8% UC [DM-DYSLIPIDEMIA]; 65.4% alirocumab/14.9% placebo [DM-INSULIN]) and ApoB < 80 mg/dL (75.1% alirocumab/35.4% UC and 76.8% alirocumab/24.8% placebo, respectively) versus control at week 24 (all P < 0.0001). In pooling these studies, 66.4% (alirocumab) and 67.0% (control) of individuals reported treatment-emergent adverse events. The adverse event pattern was similar with alirocumab versus controls. CONCLUSIONS Among individuals with T2DM and ASCVD who had high non-HDL-C/LDL-C levels despite maximally tolerated statin, alirocumab significantly reduced atherogenic cholesterol and LDL-PN versus control. Alirocumab was generally well tolerated. Trial registration Clinicaltrials.gov. NCT02642159. Registered 30 December 2015 and Clinicaltrials.gov. NCT02585778. Registered 23 October 2015.
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MESH Headings
- Antibodies, Monoclonal, Humanized/adverse effects
- Antibodies, Monoclonal, Humanized/therapeutic use
- Anticholesteremic Agents/adverse effects
- Anticholesteremic Agents/therapeutic use
- Atherosclerosis/blood
- Atherosclerosis/diagnosis
- Atherosclerosis/drug therapy
- Atherosclerosis/epidemiology
- Biomarkers/blood
- Cholesterol, HDL/blood
- Cholesterol, LDL/blood
- Clinical Trials, Phase III as Topic
- Clinical Trials, Phase IV as Topic
- Coronary Disease/blood
- Coronary Disease/diagnosis
- Coronary Disease/drug therapy
- Coronary Disease/epidemiology
- Diabetes Mellitus, Type 2/blood
- Diabetes Mellitus, Type 2/diagnosis
- Diabetes Mellitus, Type 2/drug therapy
- Diabetes Mellitus, Type 2/epidemiology
- Drug Therapy, Combination
- Dyslipidemias/blood
- Dyslipidemias/diagnosis
- Dyslipidemias/drug therapy
- Dyslipidemias/epidemiology
- Humans
- Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use
- Multicenter Studies as Topic
- PCSK9 Inhibitors
- Randomized Controlled Trials as Topic
- Risk Factors
- Serine Proteinase Inhibitors/adverse effects
- Serine Proteinase Inhibitors/therapeutic use
- Time Factors
- Treatment Outcome
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Affiliation(s)
- Kausik K Ray
- Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College, Kensington, London, SW7 2AZ, UK.
| | - Stefano Del Prato
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Dirk Müller-Wieland
- Department of Internal Medicine I, University Hospital Aachen, Aachen, Germany
| | - Bertrand Cariou
- l'institut du thorax, Department of Endocrinology, CHU Nantes, INSERM, 1413, Nantes, France
| | | | - Francisco J Tinahones
- Department of Clinical Endocrinology and Nutrition (IBIMA), Hospital Virgen de la Victoria, University of Málaga, CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III, Málaga, Spain
| | | | - Alexia Letierce
- Biostatistics and Programming Department, Sanofi, Chilly-Mazarin, France
| | | | - Rita Samuel
- Regeneron Pharmaceuticals, Inc., Tarrytown, New York, NY, USA
| | | | - Lawrence A Leiter
- Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
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Ma S, Liu S, Wang Q, Chen L, Yang P, Sun H. Fenofibrate-induced hepatotoxicity: A case with a special feature that is different from those in the LiverTox database. J Clin Pharm Ther 2019; 45:204-207. [PMID: 31518450 PMCID: PMC6973072 DOI: 10.1111/jcpt.13042] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/13/2019] [Accepted: 08/08/2019] [Indexed: 12/17/2022]
Abstract
What is known and objective We report a special case of fenofibrate‐induced acute severe DILI with sudden onset and rapid recovery, which is different from those in the LiverTox database. Case summary description The acute severe DILI occurred within only 4 days after fenofibrate initial treatment for hypertriglyceridemia. Liver enzyme levels eventually declined to normal within two weeks after the discontinuation of fenofibrate. What is new and Conclusion Early detection of elevated hepatic enzymes after fenofibrate initial treatment helps physicians to avoid delayed diagnosis and subsequent treatment.
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Affiliation(s)
- Shizhan Ma
- Department of Endocrinology and Metabolism, Shandong Provincial Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China
| | - Shudong Liu
- Department of Endocrinology, Shandong Rongjun General Hospital, Jinan, Shandong, China
| | - Qi Wang
- Department of Pharmacy, The Fifth People's Hospital of Jinan, Jinan, Shandong, China
| | - Lijuan Chen
- Department of Endocrinology, Shandong Rongjun General Hospital, Jinan, Shandong, China
| | - Ping Yang
- Department of Endocrinology, Shandong Rongjun General Hospital, Jinan, Shandong, China
| | - Huihuan Sun
- Department of Endocrinology, Shandong Rongjun General Hospital, Jinan, Shandong, China
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34
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Mello e Silva A, Aguiar C, Sequeira Duarte J, Couto L, Teixeira Veríssimo M, Marques da Silva P. CODAP: um consenso multidisciplinar sobre a definição, diagnóstico e tratamento da dislipidemia aterogénica em Portugal. Rev Port Cardiol 2019; 38:531-542. [DOI: 10.1016/j.repc.2019.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 03/11/2019] [Accepted: 03/24/2019] [Indexed: 10/26/2022] Open
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35
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Mello e Silva A, Aguiar C, Duarte JS, Couto L, Veríssimo MT, da Silva PM. CODAP: A multidisciplinary consensus among Portuguese experts on the definition, detection and management of atherogenic dyslipidemia. REVISTA PORTUGUESA DE CARDIOLOGIA (ENGLISH EDITION) 2019. [DOI: 10.1016/j.repce.2019.03.010] [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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36
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Case BC, Bress AP, Kolm P, Philip S, Herrick JS, Granowitz CB, Toth PP, Fan W, Wong ND, Hull M, Weintraub WS. The economic burden of hypertriglyceridemia among US adults with diabetes or atherosclerotic cardiovascular disease on statin therapy. J Clin Lipidol 2019; 13:754-761. [PMID: 31427271 DOI: 10.1016/j.jacl.2019.07.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Revised: 07/03/2019] [Accepted: 07/15/2019] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hypertriglyceridemia (HTG) is associated with increased cardiovascular disease (CVD) risk. However, the cost burden of HTG-related CVD in high-risk US adults on statins has not been well characterized. OBJECTIVE We estimated the HTG-related health care cost burden among US adults with CVD or diabetes taking statin therapy. METHODS We estimated population sizes and annual health care costs among US adults aged ≥45 years with diabetes or CVD taking statin therapy with normal triglycerides (TGs) defined as TG < 150 mg/dL compared with those with HTG defined as TG ≥ 150 mg/dL. Population sizes were estimated from the 2007-2014 National Health and Nutrition Examination Surveys. Adjusted mean total annual health care costs in 2015 US dollars were estimated using the Optum Research Database. The annual total health care cost burden was estimated by multiplying the population size by the mean annual total incremental health care costs overall and within subgroups. RESULTS There were 6.2 (95% confidence interval [CI], 5.4 - 7.1) million and 12.0 (95% CI, 11.1 - 12.9) million US adults aged ≥45 years with diabetes and/or CVD on statin therapy with TG ≥ 150 mg/dL and TG < 150 mg/dL, respectively. The mean adjusted incremental total one-year health care costs in adults with TG ≥ 150 mg/dL compared with those with TG < 150 mg/dL was $1730 (95% CI, $1160 - $2320). This leads to a projected annual incremental cost burden associated with HTG in patients with diabetes or CVD on statins of $10.7 billion (95% CI, $6.8 B - $14.6 B). CONCLUSION In US adults on statins and at high risk for CVD, the health care costs associated with HTG are substantial.
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Affiliation(s)
- Brian C Case
- MedStar Heart & Vascular Institute, MedStar Washington Hospital Center, Washington, DC
| | - Adam P Bress
- Division of Health System Innovation and Research, Department of Population Health Sciences, University of Utah School of Medicine, Salt Lake City, UT
| | - Paul Kolm
- MedStar Heart & Vascular Institute, MedStar Washington Hospital Center, Washington, DC
| | - Sephy Philip
- Medical Affairs, Amarin Pharma, Inc, Bedminster, NJ
| | - Jennifer S Herrick
- Division of Epidemiology, Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City, UT
| | | | - Peter P Toth
- Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Wenjun Fan
- Department of Medicine, School of Medicine University of California, Irvine, CA
| | - Nathan D Wong
- Department of Medicine, School of Medicine University of California, Irvine, CA
| | - Michael Hull
- Health Economics and Outcomes Research, Optum Research Database, Eden Prairie, MN
| | - William S Weintraub
- MedStar Heart & Vascular Institute, MedStar Washington Hospital Center, Washington, DC.
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HDL Triglycerides: A New Marker of Metabolic and Cardiovascular Risk. Int J Mol Sci 2019; 20:ijms20133151. [PMID: 31252694 PMCID: PMC6651243 DOI: 10.3390/ijms20133151] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 06/25/2019] [Accepted: 06/26/2019] [Indexed: 01/10/2023] Open
Abstract
While cholesterol content in high-density lipoproteins (HDLs) is a well-established inverse marker of cardiovascular risk, the importance of HDL–triglyceride (HDL-TG) concentration is not well known. We aim to examine plasma HDL-TG concentrations, assessed by 1H-NMR, in patients with metabolic diseases and their association with classical biomarkers. In this cross-sectional study, we included 502 patients with type 2 diabetes or metabolic syndrome attending the lipid unit of our University Hospital. The presence of arteriosclerotic plaques was assessed by ultrasonography. A complete lipoprotein profile was performed by 1H-NMR (Liposcale test). HDL-TG was strongly positively correlated with total triglycerides, glycerol, and fatty liver index, while a strong negative correlation was observed with HDL-cholesterol (HDL-C) and HDL-particle number (HDL-P). HDL-TG was associated with all triglyceride-rich lipoprotein parameters and had an opposite association with HDL-C and HDL-P. It was also significantly correlated with circulating cholesterol ester transfer protein (CETP). HDL-TG concentrations were higher as metabolic syndrome components increased. HDL-TG was also higher with worsening glucose metabolism. Patients with carotid plaques also showed higher HDL-TG. In contrast to HDL-C, HDL-TG is directly associated with metabolism and arteriosclerotic vascular alterations. HDL-TG should be considered a biomarker of metabolic and cardiovascular risk and could be a marker of HDL dysfunction.
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Park JE, Miller M. Triglycerides: Mendelian Randomization Studies Suggest Causal Role, but How to Treat in 2019? CURRENT CARDIOVASCULAR RISK REPORTS 2019. [DOI: 10.1007/s12170-019-0603-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Cavallari I, Delli Veneri A, Maddaloni E, Melfi R, Patti G, Napoli N, Pozzilli P, Di Sciascio G. Comparison of Lipid-Lowering Medications and Risk for Cardiovascular Disease in Diabetes. Curr Diab Rep 2018; 18:138. [PMID: 30370486 DOI: 10.1007/s11892-018-1117-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF THE REVIEW To summarize available evidence regarding lipid-lowering interventions for the prevention of cardiovascular disease in patients with diabetes. RECENT FINDINGS Statins and non-statin therapies that act through upregulation of LDL receptor expression are associated with similar cardiovascular risk reduction per decrease in LDL cholesterol. In subjects with diabetes, with or without established cardiovascular disease, each 39 mg/dl reduction in LDL cholesterol observed with statins is associated with a 21% relative reduction in the risk of major coronary events at 5 years. Statins remain the first-line lipid-lowering agents for the management of dyslipidemia in individuals with diabetes; however, the addition of non-statin therapies to lower LDL cholesterol, such as ezetimibe and PCSK-9 inhibitors, to maximally tolerated statin therapy is recommended in patients with atherosclerotic cardiovascular disease and baseline LDL cholesterol over 70 mg/dl. Recent data support even lower LDL cholesterol targets (< 55 mg/dl) to further reduce the risk of cardiovascular events especially in subjects with diabetes and documented cardiovascular disease.
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Affiliation(s)
- Ilaria Cavallari
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy.
| | - Alessia Delli Veneri
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy
| | - Ernesto Maddaloni
- Department of Medicine, Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy
| | - Rosetta Melfi
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy
| | - Giuseppe Patti
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy
| | - Nicola Napoli
- Department of Medicine, Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy
| | - Paolo Pozzilli
- Department of Medicine, Unit of Endocrinology and Diabetes, Campus Bio-Medico University, Rome, Italy
| | - Germano Di Sciascio
- Department of Cardiovascular Science, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 200, 00128, Rome, Italy
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Cardiovascular Risk Assessment in Patients with Hypertriglyceridemia. Curr Cardiol Rep 2018; 20:71. [DOI: 10.1007/s11886-018-1013-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Bahtiyar G, Pujals-Kury J, Sacerdote A. Cardiovascular Effects of Different GLP-1 Receptor Agonists in Patients with Type 2 Diabetes. Curr Diab Rep 2018; 18:92. [PMID: 30171481 DOI: 10.1007/s11892-018-1043-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
PURPOSE OF REVIEW Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have positive effects on weight loss, blood pressure, hyperlipidemia, and glycemic control. They exhibit a broad range of effects on the cardiovascular system that are independent of changes in blood glucose. Cardiovascular outcome trials have demonstrated safety of GLP-1 RAs but results for cardiovascular efficacy were varied. The aim of the present review is the assessment of the effects of GLP-1 RAs on cardiovascular risk factors, and major cardiovascular events. RECENT FINDINGS Use of GLP-1 RAs was associated with relative risk reduction in cardiovascular mortality and all-cause mortality with no significant differences for the incidence of severe hypoglycemia, pancreatitis, pancreatic cancer, or medullary thyroid cancer when compared to placebo. Although there are differences between individual medications with respect to their effects on cardiovascular events, GLP-1 RAs offer a favorable risk-benefit profile. The present review confirms the cardiovascular safety and efficacy vs placebo of GLP-1 RAs in patients with type 2 diabetes at moderate-to-high atherosclerotic cardiovascular risk without significant side effects. Although professional guidelines recommend metformin as the sole first-line agent, GLP-1 RAs can be used as first-line therapy in individuals with type 2 diabetes who either are intolerant to metformin or have high cardiovascular risk factors.
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Affiliation(s)
- Gül Bahtiyar
- Division of Endocrinology, State University of New York Health Science Center, Brooklyn, NY, USA
- Department of Medicine, Woodhull Medical & Mental Health Center, Brooklyn, NY, USA
- Department of Internal Medicine, Division of Endocrinology, Woodhull Medical & Mental Health Center, New York University School of Medicine, 760 Broadway, Brooklyn, NY, 11206, USA
| | - Jean Pujals-Kury
- Division of Endocrinology, State University of New York Health Science Center, Brooklyn, NY, USA
| | - Alan Sacerdote
- Division of Endocrinology, State University of New York Health Science Center, Brooklyn, NY, USA.
- Department of Medicine, Woodhull Medical & Mental Health Center, Brooklyn, NY, USA.
- Department of Internal Medicine, Division of Endocrinology, Woodhull Medical & Mental Health Center, New York University School of Medicine, 760 Broadway, Brooklyn, NY, 11206, USA.
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DOUBLE MONITORING INDICES OF ARTERIAL PRESSURE AND THE LIPID PROFILE STATUS IN PATIENTS WITH DIABETES MELLITUS 1 AND 2 TYPE DEPENDING ON THE GLOMERULAR FILTRATION RATE. WORLD OF MEDICINE AND BIOLOGY 2018. [DOI: 10.26724/2079-8334-2018-3-65-103-110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
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Wiesner P, Watson KE. Triglycerides: A reappraisal. Trends Cardiovasc Med 2017; 27:428-432. [DOI: 10.1016/j.tcm.2017.03.004] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 03/13/2017] [Accepted: 03/13/2017] [Indexed: 12/22/2022]
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Diabetes-Related Dyslipidemia and Cardiovascular Events. Am J Med Sci 2017; 354:103-104. [DOI: 10.1016/j.amjms.2017.06.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2017] [Accepted: 06/16/2017] [Indexed: 11/21/2022]
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Grundy SM. Metabolic syndrome update. Trends Cardiovasc Med 2015; 26:364-73. [PMID: 26654259 DOI: 10.1016/j.tcm.2015.10.004] [Citation(s) in RCA: 565] [Impact Index Per Article: 56.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 10/16/2015] [Accepted: 10/16/2015] [Indexed: 11/25/2022]
Abstract
The metabolic syndrome is a multiplex risk factor for atherosclerotic cardiovascular disease and type 2 diabetes. It is composed of atherogenic dyslipidemia, elevated blood pressure, insulin resistance and elevated glucose, a pro-thrombotic state, and a pro-inflammatory state. Excess energy intake and concomitant obesity are the major drivers of the syndrome. Lifestyle intervention can reverse metabolic risk factors, but at times, drug therapies or bariatric surgery may be required to control more overt risk factors.
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Affiliation(s)
- Scott M Grundy
- Department of Internal Medicine and Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX; Veterans Affairs Medical Center, Dallas, TX.
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Pang J, Chan DC, Watts GF. Origin and therapy for hypertriglyceridaemia in type 2 diabetes. World J Diabetes 2014; 5:165-75. [PMID: 24748930 PMCID: PMC3990315 DOI: 10.4239/wjd.v5.i2.165] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2013] [Revised: 03/08/2014] [Accepted: 03/17/2014] [Indexed: 02/05/2023] Open
Abstract
Hypertriglyceridaemia (HTG) is a risk factor for cardiovascular disease (CVD) in type 2 diabetes and is caused by the interaction of genes and non-genetic factors, specifically poor glycaemic control and obesity. In spite of statin treatment, residual risk of CVD remains high in type 2 diabetes, and this may relate to HTG and atherogenic dyslipidemia. Treatment of HTG emphasises correcting secondary factors and adverse lifestyles, in particular, diet and exercise. Pharmacotherapy is also required in most type 2 diabetic patients. Statins are the first-line therapy to achieve recommended therapeutic targets of plasma low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol. Fibrates, ezetimibe and n-3 fatty acids are adjunctive treatment options for residual and persistent HTG. Evidence for the use of niacin has been challenged by non-significant CVD outcomes in two recent large clinical trials. Further investigation is required to clarify the use of incretin-based therapies for HTG in type 2 diabetes. Extreme HTG, with risk of pancreatitis, may require insulin infusion therapy or apheresis. New therapies targeting HTG in diabetes need to be tested in clinical endpoint trials. The purpose of this review is to examine the current evidence and provide practical guidance on the management of HTG in type 2 diabetes.
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Reiner Z. Managing the residual cardiovascular disease risk associated with HDL-cholesterol and triglycerides in statin-treated patients: a clinical update. Nutr Metab Cardiovasc Dis 2013; 23:799-807. [PMID: 23932901 DOI: 10.1016/j.numecd.2013.05.002] [Citation(s) in RCA: 101] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Revised: 04/16/2013] [Accepted: 05/09/2013] [Indexed: 01/23/2023]
Abstract
Cardiovascular disease (CVD) is a significant cause of death in Europe. In addition to patients with proven CVD, those with type 2 diabetes (T2D) are at a particularly high-risk of CVD and associated mortality. Treatment for dyslipidaemia, a principal risk factor for CVD, remains a healthcare priority; evidence supports the reduction of low-density lipoprotein cholesterol (LDL-C) as the primary objective of dyslipidaemia management. While statins are the treatment of choice for lowering LDL-C in the majority of patients, including those with T2D, many patients retain a high CVD risk despite achieving the recommended LDL-C targets with statins. This 'residual risk' is mainly due to elevated triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Following statin therapy optimisation additional pharmacotherapy should be considered as part of a multifaceted approach to risk reduction. Fibrates (especially fenofibrate) are the principal agents recommended for add-on therapy to treat elevated TG or low HDL-C levels. Currently, the strongest evidence of benefit is for the addition of fenofibrate to statin treatment in high-risk patients with T2D and dyslipidaemia. An alternative approach is the addition of agents to reduce LDL-C beyond the levels attainable with statin monotherapy. Here, addition of fibrates and niacin to statin therapy is discussed, and novel approaches being developed for HDL-C and TG management, including cholesteryl ester transfer protein inhibitors, Apo A-1 analogues, mipomersen, lomitapide and monoclonal antibodies against PCSK9, are reviewed.
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Affiliation(s)
- Z Reiner
- Department of Internal Medicine, University Hospital Center Zagreb, School of Medicine, University of Zagreb, Kispaticeva 12, 10 000 Zagreb, Croatia.
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Jacobson TA. Opening a new lipid "apo-thecary": incorporating apolipoproteins as potential risk factors and treatment targets to reduce cardiovascular risk. Mayo Clin Proc 2011; 86:762-80. [PMID: 21803958 PMCID: PMC3146376 DOI: 10.4065/mcp.2011.0128] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Statins (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors) represent the cornerstone of drug therapy to reduce low-density lipoprotein (LDL) cholesterol and cardiovascular risk. However, even optimal statin management of LDL cholesterol leaves many patients with residual cardiovascular risk, in part because statins are more effective in reducing LDL cholesterol than apolipoprotein B (Apo B). Apo B may be a better marker of atherogenic risk than LDL cholesterol because Apo B measures the total number of all atherogenic particles (total atherosclerotic burden), including LDL, very low-density lipoprotein, intermediate-density lipoprotein, remnant lipoproteins, and lipoprotein(a). To determine whether Apo B is a better indicator of baseline cardiovascular risk and residual risk after lipid therapy compared with LDL cholesterol, a MEDLINE search of the literature published in English from January 1, 1975, through December 1, 2010, was conducted. On the basis of data from most population studies, elevated Apo B was more strongly associated with incident coronary heart disease than similarly elevated LDL cholesterol. Apo B was also a superior benchmark (vs LDL cholesterol) of statins' cardioprotective efficacy in both primary-prevention and secondary-prevention trials. To minimize cardiovascular risk among persons with hypercholesterolemia or dyslipidemia, the best available evidence suggests that intensive therapy with statins should be initiated to achieve the lowest possible Apo B level (with adequate drug toleration) and then other therapies (eg, niacin, bile acid resins, ezetimibe) added to potentiate these Apo B-lowering effects. In future consensus lipid-lowering treatment guidelines, Apo B should be considered as an index of residual risk, a potential parameter of treatment efficacy, and a treatment target to minimize risk of coronary heart disease.
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Affiliation(s)
- Terry A Jacobson
- Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University, Atlanta, GA 30303, USA.
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Keating GM. Fenofibrate: a review of its lipid-modifying effects in dyslipidemia and its vascular effects in type 2 diabetes mellitus. Am J Cardiovasc Drugs 2011; 11:227-247. [PMID: 21675801 DOI: 10.2165/11207690-000000000-00000] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
Fenofibrate is a fibric acid derivative with lipid-modifying effects that are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has a number of nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein, and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes. The beneficial effects of fenofibrate on the lipid profile have been shown in a number of randomized controlled trials. In primary dyslipidemia, fenofibrate monotherapy consistently decreased triglyceride (TG) levels to a significantly greater extent than placebo; significantly greater increases in high-density lipoprotein cholesterol (HDL-C) levels and significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were also seen in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil. Fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent than statin monotherapy in primary dyslipidemia, whereas statin monotherapy decreased LDL-C and TC levels to a significantly greater extent than fenofibrate monotherapy. Fenofibrate also had a beneficial effect on atherogenic dyslipidemia in patients with the metabolic syndrome or type 2 diabetes mellitus, reducing TG levels, tending to increase HDL-C levels, and promoting a shift to larger low-density lipoprotein particles. In terms of cardiovascular outcomes, fenofibrate did not reduce the risk of coronary heart disease (CHD) events to a greater extent than placebo in patients with type 2 diabetes in the FIELD trial. However, the risk of some nonfatal macrovascular events (e.g. nonfatal myocardial infarction, revascularization) and certain microvascular outcomes (e.g. amputation, first laser therapy for diabetic retinopathy, progression of albuminuria) was reduced to a significantly greater extent with fenofibrate than with placebo. Subgroup analysis revealed a significant reduction in the cardiovascular disease (CVD) event rate among fenofibrate recipients in the subgroup of patients with marked hypertriglyceridemia or marked dyslipidemia at baseline. In the ACCORD Lipid trial, there were no significant differences between patients with type 2 diabetes and a high risk of CVD events who received fenofibrate plus simvastatin and those who received placebo plus simvastatin for any of the primary or secondary cardiovascular outcomes. However, fenofibrate plus simvastatin was of benefit in patients who had markedly high TG levels and markedly low HDL-C levels at baseline. In addition, fenofibrate plus simvastatin slowed the progression of diabetic retinopathy. Fenofibrate is generally well tolerated. Common adverse events included increases in transaminase levels that were usually transient, minor, and asymptomatic, and gastrointestinal signs and symptoms. In conclusion, monotherapy with fenofibrate remains a useful option in patients with dyslipidemia, particularly in atherogenic dyslipidemia characterized by high TG and low HDL-C levels.
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