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Daskalakis K, Umekubo N, Indu S, Kawauchi G, Taniguchi T, Monde K, Hayashi Y. Asymmetric Synthesis of Noradamantane Scaffolds via Diphenylprolinol Silyl Ether-Mediated Domino Michael/Epimerization/Michael (or Aldol)/1,2-Addition Reactions. Angew Chem Int Ed Engl 2025; 64:e202500378. [PMID: 40122692 PMCID: PMC12124435 DOI: 10.1002/anie.202500378] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2025] [Revised: 03/17/2025] [Accepted: 03/18/2025] [Indexed: 03/25/2025]
Abstract
Topologically unique chiral noradamantanes are synthesized using a diphenylprolinol silyl ether-mediated domino Michael/epimerization/Michael/1,2-addition or Michael/epimerization/aldol/1,2-addition reaction with excellent enantioselectivity in a single reaction vessel. Three carbon-carbon bonds are formed, and six chiral centers, including one all-carbon quaternary center, are generated, five of which are fully controlled. These functionalized noradamantanes are 3D, cage-like molecules that can serve as valuable chiral building blocks for drug design.
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Affiliation(s)
- Konstantinos Daskalakis
- Department of ChemistryGraduate School of ScienceTohoku University6‐3 Aramaki Aza‐Aoba, Aoba‐kuSendaiMiyagi980–8578Japan
| | - Nariyoshi Umekubo
- Department of ChemistryGraduate School of ScienceTohoku University6‐3 Aramaki Aza‐Aoba, Aoba‐kuSendaiMiyagi980–8578Japan
- Present address:
Graduate School of Pharmaceutical SciencesNagoya UniversityNagoya464–8601Japan
| | - Satrajit Indu
- Department of ChemistryGraduate School of ScienceTohoku University6‐3 Aramaki Aza‐Aoba, Aoba‐kuSendaiMiyagi980–8578Japan
| | - Genki Kawauchi
- Department of ChemistryGraduate School of ScienceTohoku University6‐3 Aramaki Aza‐Aoba, Aoba‐kuSendaiMiyagi980–8578Japan
| | - Tohru Taniguchi
- Frontier Research Center for Advanced Material and Life ScienceFaculty of Advanced Life ScienceHokkaido UniversitySapporo001–0021Japan
| | - Kenji Monde
- Frontier Research Center for Advanced Material and Life ScienceFaculty of Advanced Life ScienceHokkaido UniversitySapporo001–0021Japan
| | - Yujiro Hayashi
- Department of ChemistryGraduate School of ScienceTohoku University6‐3 Aramaki Aza‐Aoba, Aoba‐kuSendaiMiyagi980–8578Japan
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Khan SS, Breathett K, Braun LT, Chow SL, Gupta DK, Lekavich C, Lloyd-Jones DM, Ndumele CE, Rodriguez CJ, Allen LA. Risk-Based Primary Prevention of Heart Failure: A Scientific Statement From the American Heart Association. Circulation 2025; 151:e1006-e1026. [PMID: 40235437 DOI: 10.1161/cir.0000000000001307] [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] [Indexed: 04/17/2025]
Abstract
The growing morbidity, mortality, and health care costs related to heart failure (HF) underscore the urgent need to prioritize its primary prevention. Whereas a risk-based approach for HF prevention remains in its infancy, several key opportunities exist to actualize this paradigm in clinical practice. First, the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America HF guidelines provided recommendations, for the first time, on the clinical utility of multivariable risk equations to estimate risk of incident HF. Second, the American Heart Association recently developed the PREVENT (Predicting Risk of Cardiovascular Disease Events) equations, which not only enable prediction of incident HF separately, but also include HF in the prediction of total cardiovascular disease. Third, the predominant phenotype of HF risk has emerged as the cardiovascular-kidney-metabolic syndrome. Fourth, the emergence of novel therapies that prevent incident HF (eg, sodium-glucose cotransporter-2 inhibitors) and target multiple cardiovascular-kidney-metabolic axes demonstrate growing potential for risk-based interventions. Whereas the concept of risk-based prevention has been established for decades, it has only been operationalized for atherosclerotic cardiovascular disease prevention to date. Translating these opportunities into a conceptual framework of risk-based primary prevention of HF requires implementation of PREVENT-HF (Predicting Risk of Cardiovascular Disease Events-Heart Failure) equations, targeted use of cardiac biomarkers (eg, natriuretic peptides) and echocardiography for risk reclassification and earlier detection of pre-HF, and definition of therapy-specific risk thresholds that incorporate net benefit and cost-effectiveness. This scientific statement reviews the current evidence for accurate risk prediction, defines strategies for equitable prevention, and proposes potential strategies for the successful implementation of risk-based primary prevention of HF.
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Schnell O, Almandoz J, Anderson L, Barnard-Kelly K, Battelino T, Blüher M, Busetto L, Catrinou D, Ceriello A, Cos X, Danne T, Dayan CM, Del Prato S, Fernández-Fernández B, Fioretto P, Forst T, Gavin JR, Giorgino F, Groop PH, Harsch IA, Heerspink HJL, Heinemann L, Ibrahim M, Jadoul M, Jarvis S, Ji L, Kanumilli N, Kosiborod M, Landmesser U, Macieira S, Mankovsky B, Marx N, Mathieu C, McGowan B, Milenkovic T, Moser O, Müller-Wieland D, Papanas N, Patel DC, Pfeiffer AFH, Rahelić D, Rodbard HW, Rydén L, Schaeffner E, Spearman CW, Stirban A, Tacke F, Topsever P, Van Gaal L, Standl E. CVOT summit report 2024: new cardiovascular, kidney, and metabolic outcomes. Cardiovasc Diabetol 2025; 24:187. [PMID: 40316962 PMCID: PMC12048985 DOI: 10.1186/s12933-025-02700-0] [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: 02/18/2025] [Accepted: 03/21/2025] [Indexed: 05/04/2025] Open
Abstract
The 10th Cardiovascular Outcome Trial (CVOT) Summit: Congress on Cardiovascular, Kidney, and Metabolic Outcomes was held virtually on December 5-6, 2024. This year, discussions about cardiovascular (CV) and kidney outcome trials centered on the recent findings from studies involving empagliflozin (EMPACT-MI), semaglutide (STEP-HFpEF-DM and FLOW), tirzepatide (SURMOUNT-OSA and SUMMIT), and finerenone (FINEARTS-HF). These studies represent significant advances in reducing the risk of major adverse cardiovascular events (MACE) and improving metabolic outcomes in heart failure with preserved ejection fraction (HFpEF), chronic kidney disease (CKD), and obstructive sleep apnea (OSA). The congress also comprised sessions on novel and established therapies for managing HFpEF, CKD, and obesity; guidelines for managing CKD and metabolic dysfunction-associated steatotic liver disease (MASLD); organ crosstalk and the development of cardio-kidney-metabolic (CKM) syndrome; precision medicine and person-centered management of diabetes, obesity, cardiovascular disease (CVD) and CKD; early detection of type 1 diabetes (T1D) and strategies to delay its onset; continuous glucose monitoring (CGM) and automated insulin delivery (AID); cardiovascular autonomic neuropathy (CAN) and the diabetic heart; and the role of primary care in the early detection, prevention and management of CKM diseases. The contribution of environmental plastic pollution to CVD risk, the increasing understanding of the efficacy and safety of incretin therapies in the treatment of CKM diseases, and the latest updates on nutrition strategies for CKM management under incretin-based therapies were also topics of interest for a vast audience of endocrinologists, diabetologists, cardiologists, nephrologists and primary care physicians, who actively engaged in online discussions. The 11th CVOT Summit will be held virtually on November 20-21, 2025 ( http://www.cvot.org ).
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Affiliation(s)
- Oliver Schnell
- Forschergruppe Diabetes e. V., Helmholtz Center Munich, Ingolstaedter Landstraße 1, 85764, Neuherberg (Munich), Germany.
| | - Jaime Almandoz
- Division of Endocrinology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Lisa Anderson
- Molecular and Clinical Sciences Research Institute, St. George's University of London, London, UK
- St. George's University Hospitals NHS Foundation Trust, London, UK
| | | | - Tadej Battelino
- University Medical Center, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Matthias Blüher
- Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany
- Medical Department III-Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany
| | - Luca Busetto
- Department of Medicine (DIMED), University of Padova, Padua, Italy
| | - Doina Catrinou
- Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania
| | | | - Xavier Cos
- DAP Cat Research Group, Foundation University Institute for Primary Health Care Research Jordi Gol i Gorina, Barcelona, Spain
| | | | | | - Stefano Del Prato
- Interdisciplinary Research Center "Health Science", Sant'Anna School of Advanced Studies, Pisa, Italy
| | - Beatriz Fernández-Fernández
- Division of Nephrology and Hypertension, University Hospital Fundación Jiménez Díaz, Madrid, Spain
- Faculty of Medicine, Autonomous University of Madrid, Madrid, Spain
| | | | - Thomas Forst
- CRS Clinical Research Services Mannheim GmbH, Mannheim, Germany
| | - James R Gavin
- Emory University School of Medicine, Atlanta, GA, USA
| | - Francesco Giorgino
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, Bari, Italy
| | - Per-Henrik Groop
- Department of Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Folkhälsan Research Center, Biomedicum, Helsinki, Finland
- Department of Diabetes, Central Medical School, Monash University, Melbourne, Australia
- Baker Heart and Diabetes Institute, Melbourne, VIC, Australia
| | - Igor A Harsch
- Division of Endocrinology and Metabolism, Department of Internal Medicine II, Thuringia Clinic Saalfeld "Georgius Agricola", Saalfeld, Germany
| | - Hiddo J L Heerspink
- Department of Clinical Pharmacy and Pharmacology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
| | - Lutz Heinemann
- Science Consulting in Diabetes GmbH, Dusseldorf, Germany
| | | | - Michel Jadoul
- Division of Nephrology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
| | | | - Linong Ji
- Peking University People's Hospital, Xicheng District, Beijing, China
| | | | - Mikhail Kosiborod
- Department of Cardiovascular Disease, Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA
| | - Ulf Landmesser
- Department of Cardiology Angiology and Intensive Care Medicine, Charité Universitätsmedizin Berlin, Berlin, Germany
| | | | - Boris Mankovsky
- Depatment of Diabetology, Shupyk National Healthcare University of Ukraine, Kiev, Ukraine
| | - Nikolaus Marx
- Clinic for Cardiology, Pneumology, Angiology and Internal Intensive Care Medicine (Medical Clinic I), RWTH Aachen University Hospital, Aachen, Germany
| | - Chantal Mathieu
- Department of Endocrinology, Catholic University of Louvain, Louvain, Belgium
| | - Barbara McGowan
- Guy's and St Thomas' Hospital, Kings College London, London, UK
| | - Tatjana Milenkovic
- University Clinic of Endocrinology, Diabetes and Metabolic Diseases, Skopje, North Macedonia
- Faculty of Medicine "St. Cyril and Methodius" University, Skopje, North Macedonia
| | - Othmar Moser
- Institute of Sports Science, University of Bayreuth, Bayreuth, Germany
- Interdisciplinary Metabolic Medicine Trials Unit, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria
| | | | - Nikolaos Papanas
- Diabetes Centre-Diabetic Foot Clinic, Second Department of Internal Medicine, Democritus University of Thrace, Alexandroupolis, Greece
| | - Dipesh C Patel
- Royal Free London, University College London, London, UK
| | - Andreas F H Pfeiffer
- Department of Endocrinology and Metabolic Diseases, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany
- Deutsches Zentrum für Diabetesforschung e.V., Helmholtz Center Munich, Neuherberg, Germany
| | - Dario Rahelić
- Vuk Vrhovac University Clinic for Diabetes, Endocrinology and Metabolic Diseases at Merkur University Hospital, Zagreb, Croatia
| | | | - Lars Rydén
- Department of Medicine K2, Karolinska Institute, Stockholm, Sweden
| | - Elke Schaeffner
- Institute of Public Health, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - C Wendy Spearman
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Alin Stirban
- Asklepios Klinik Birkenwerder, Birkenwerder, Germany
| | - Frank Tacke
- Department of Hepatology and Gastroenterology, Charité - Universitätsmedizin Berlin, Campus Virchow-Klinikum and Campus Charité Mitte, Berlin, Germany
| | - Pinar Topsever
- Department of Family Medicine, Acıbadem Mehmet Ali Aydınlar University School of Medicine, Istanbul, Turkey
| | - Luc Van Gaal
- Department of Endocrinology-Diabetology and Metabolism, Antwerp University Hospital, Antwerp, Belgium
| | - Eberhard Standl
- Forschergruppe Diabetes e. V., Helmholtz Center Munich, Ingolstaedter Landstraße 1, 85764, Neuherberg (Munich), Germany
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Iacovoni A, Navazio A, De Luca L, Gori M, Corda M, Milli M, Iacoviello M, Di Lenarda A, Di Tano G, Marini M, Iorio A, Mortara A, Mureddu GF, Zilio F, Chimenti C, Cipriani MG, Senni M, Bilato C, Di Marco M, Geraci G, Pascale V, Riccio C, Scicchitano P, Tizzani E, Gulizia MM, Nardi F, Gabrielli D, Colivicchi F, Grimaldi M, Oliva F. ANMCO position paper: diagnosis and treatment of heart failure with preserved systolic function. Eur Heart J Suppl 2025; 27:v216-v246. [PMID: 40385467 PMCID: PMC12078774 DOI: 10.1093/eurheartjsupp/suaf070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
Heart failure is the leading cardiovascular cause of hospitalization with an increasing prevalence, especially in older patients. About 50% of patients with heart failure have preserved ventricular function, a form of heart failure that, until a few years ago, was orphaned by pharmacological treatments effective in reducing hospitalization and mortality. New trials, which have tested the use of gliflozins in patients with heart failure with preserved ejection fraction (HFpEF), have for the first time demonstrated their effectiveness in changing the natural history of this insidious and frequent form of heart failure. Therefore, diagnosing those patients early is crucial to provide the best treatment. Moreover, the diagnosis is influenced by the patient's comorbidities, and some HFpEF patients have symptoms common to other rare diseases that, if unrecognized, develop an unfavourable prognosis. This position paper aims to provide the clinician with a useful tool for diagnosing and treating patients with HFpEF, guiding the clinician towards the most appropriate diagnostic and therapeutic pathway.
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Affiliation(s)
- Attilio Iacovoni
- S.S.D. Chirurgia dei Trapianti e del Trattamento Chirurgico dello Scompenso, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Piazza OMS 1, Bergamo 24127, Italy
| | - Alessandro Navazio
- S.O.C. Cardiologia Ospedaliera, Presidio Ospedaliero Arcispedale Santa Maria Nuova, Azienda USL di Reggio Emilia—IRCCS, Reggio Emilia, Italy
| | - Leonardo De Luca
- S.C. Cardiologia, Dipartimento Cardio-Toraco-Vascolare, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Mauro Gori
- U.O.C. Cardiologia 1, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Bergamo, Italy
| | - Marco Corda
- S.C. Cardiologia, Azienda di Rilievo Nazionale e Alta Specializzazione ‘G. Brotzu’, Cagliari, Italy
| | - Massimo Milli
- Cardiologia Firenze 1 (Ospedali S. Maria Nuova e Nuovo San Giovanni di Dio), Azienda USL Toscana Centro, Florence, Italy
| | | | - Andrea Di Lenarda
- S.C. Patologie Cardiovascolari, Dipartimento Specialistico Territoriale, Azienda Sanitaria Universitaria Giuliano-Isontina (ASUGI), Trieste, Italy
| | - Giuseppe Di Tano
- U.O. CARDIOLOGIA - UCC, Ospedale Cernusco sul Naviglio, Cernusco sul Naviglio, MI, Italy
| | - Marco Marini
- S.O.S. Terapia Intensiva Cardiologica, S.O.D. Cardiologia-UTIC, Dipartimento di Scienze Cardiovascolari, AOU delle Marche, Ancona, Italy
| | - Annamaria Iorio
- S.S.D. Chirurgia dei Trapianti e del Trattamento Chirurgico dello Scompenso, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Piazza OMS 1, Bergamo 24127, Italy
| | - Andrea Mortara
- Dipartimento di Cardiologia Clinica, Policlinico di Monza, Monza, Italy
| | - Gian Francesco Mureddu
- U.O.S.D. Cardiologia Riabilitativa, Azienda Ospedaliera San Giovanni Addolorata, Rome, Italy
| | - Filippo Zilio
- U.O. Cardiologia, Ospedale Santa Chiara, Trento, Italy
| | - Cristina Chimenti
- Dipartimento di Scienze Cliniche, Internistiche, Anestesiologiche e Cardiovascolari, Azienda Ospedaliera Policlinico Umberto I, Sapienza Università di Roma, Rome, Italy
| | - Manlio Gianni Cipriani
- Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione (ISMETT)-IRCCS, Palermo, Italy
| | - Michele Senni
- S.S.D. Chirurgia dei Trapianti e del Trattamento Chirurgico dello Scompenso, Dipartimento Cardiovascolare, ASST Papa Giovanni XXIII, Piazza OMS 1, Bergamo 24127, Italy
| | - Claudio Bilato
- U.O.C. Cardiologia, Ospedali dell’Ovest Vicentino, Azienda ULSS 8 Berica, Vicenza, Italy
| | | | - Giovanna Geraci
- U.O.C. Cardiologia, Presidio Ospedaliero Sant’Antonio Abate, ASP Trapani, Erice, TP, Italy
| | - Vittorio Pascale
- UTIC-Emodinamica e Cardiologia Interventistica, Ospedale Civile Pugliese, Catanzaro, Italy
| | - Carmine Riccio
- U.O.S.D. Follow-up del Paziente Post-Acuto, Dipartimento Cardio-Vascolare, AORN Sant’Anna e San Sebastiano, Caserta, Italy
| | | | - Emanuele Tizzani
- Dipartimento di Cardiologia, Ospedale degli Infermi, Rivoli, TO, Italy
| | - Michele Massimo Gulizia
- U.O.C. Cardiologia, Ospedale Garibaldi-Nesima, Azienda di Rilievo Nazionale e Alta Specializzazione ‘Garibaldi’, Catania, Italy
| | - Federico Nardi
- Dipartimento di Cardiologia, Ospedale Santo Spirito, Casale Monferrato, AL, Italy
| | - Domenico Gabrielli
- U.O.C. Cardiologia, Dipartimento Cardio-Toraco-Vascolare, Azienda Ospedaliera San Camillo Forlanini, Rome, Italy
- Fondazione per il Tuo cuore—Heart Care Foundation, Florence, Italy
| | - Furio Colivicchi
- U.O.C. Cardiologia Clinica e Riabilitativa, Presidio Ospedaliero San Filippo Neri—ASL Roma 1, Rome, Italy
| | - Massimo Grimaldi
- U.O.C. Cardiologia-UTIC, Ospedale Miulli, Acquaviva delle Fonti, BA, Italy
| | - Fabrizio Oliva
- Fondazione per il Tuo cuore—Heart Care Foundation, Florence, Italy
- Cardiologia 1-Emodinamica, Dipartimento Cardiotoracovascolare ‘A. De Gasperis’, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Associazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Florence, Italy
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Muir KC, Harris DD, Stone C, Kanuparthy M, Broadwin M, Hamze J, Abid MR, Sellke FW. Linagliptin Modulation of Inflammation in Chronic Coronary Artery Disease. J Surg Res 2025; 309:146-155. [PMID: 40253935 DOI: 10.1016/j.jss.2025.03.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2024] [Revised: 03/04/2025] [Accepted: 03/22/2025] [Indexed: 04/22/2025]
Abstract
INTRODUCTION Coronary artery disease (CAD) confers a continued challenge to healthcare necessitating innovative therapies. Linagliptin, a dipeptidyl peptidase 4 inhibitor, has been shown in preclinical and clinical studies to have cardioprotective effects independent of its glycemic control. An important pathway by which linagliptin has been described to induce these effects is due to its immune regulation. This study aims to evaluate the immune modulation by linagliptin treatment in a porcine model of chronic myocardial ischemia. METHODS Yorkshire swine underwent ameroid constrictor placement to the left circumflex artery, which induced chronic myocardial ischemia. Two wk later, swine either received no drug (n = 8) or 2.5 mg linagliptin daily (n = 8). Five weeks later, swine were sacrificed and left ventricular tissue was harvested. Protein expression and immune cell count was measured with immunoblotting and immunofluorescence, respectively. Data were statistically analyzed via Wilcoxon rank-sum test. RESULTS Linagliptin treatment was associated with decreased expression of inflammatory markers interleukin (IL)-1β (P = 0.0012), IL-6 (P = 0.0073), nuclear factor kappa B (NFκB) (P = 0.0106), transforming growth factor beta (P = 0.001), and IL-4 (P = 0.0419) in chronically ischemic myocardium. There was increased expression of phosphorylated NFκB at Ser536 (p=<0.0001) and nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor alpha (P = 0.0167). Interestingly, there was increased expression of cluster of differentiation (CD) 11c (P = 0.0002) and increased cell count of CD11c dendritic cells (P = 0.014). CONCLUSIONS Linagliptin treatment was associated with a reduction of proinflammatory cytokines in the setting of chronically ischemic myocardium, with identified modulation of the NFκB pathway. Following treatment, there was found to be an increase in CD11c expression, demonstrating an increase in dendritic cells as a possible immune modulating cell population within the ischemic myocardium.
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Affiliation(s)
- Kelsey C Muir
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island.
| | - Dwight D Harris
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Christopher Stone
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Meghamsh Kanuparthy
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Mark Broadwin
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Jad Hamze
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - M Ruhul Abid
- Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
| | - Frank W Sellke
- Department of Surgery, Division of Cardiothoracic Surgery, Warren Alpert Medical School, Brown University, Providence, Rhode Island; Cardiovascular Research Center, Rhode Island Hospital, Providence, Rhode Island
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Yu N, Xu W, Guo X, Xu M, Zhang W, Yan C, Pang S, Shu X, Zhang W, Peng W, Zhang Y, Li G, Zhang X, Zhou D. Fotagliptin add-on therapy to metformin in patients with uncontrolled type 2 diabetes: A randomised, multicentre, double-blind, placebo-controlled, phase 3 trial. Diabetes Obes Metab 2025. [PMID: 40302627 DOI: 10.1111/dom.16427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Revised: 04/15/2025] [Accepted: 04/15/2025] [Indexed: 05/02/2025]
Abstract
AIM Fotagliptin is a novel dipeptidyl peptidase-4 inhibitor for glycaemic control in patients with type 2 diabetes (T2D). This trial aimed to assess the efficacy and safety of fotagliptin add-on to metformin in patients with T2D. MATERIALS AND METHODS In this phase 3 randomised, double-blind, placebo-controlled study, patients with T2D who had inadequate glycaemic control using metformin alone were randomly allocated to fotagliptin or placebo at a 2:1 ratio for 24-week double-blind treatment period, followed by an open-label treatment with fotagliptin for all patients, making up a total of 52 weeks. All eligible patients were treated with a stable dose of metformin (≥1500 mg per day). The primary endpoint was the change in HbA1c level from baseline to week 24. Safety was assessed in all patients who received at least one dose of the study drug. RESULTS After 24 weeks, LS mean change of HbA1c from baseline was -0.81% with fotagliptin versus -0.28% with placebo. Estimated treatment difference for fotagliptin versus placebo of HbA1c was -0.53% (95% confidence interval [CI] -0.68% to -0.39%; p < 0.001). Significantly more patients on fotagliptin than on placebo achieved HbA1c < 7.0% after 24 weeks (38.7% vs. 16.9%; p < 0.001). The incidence of adverse events was similar between the two groups. No severe hypoglycaemia events were reported in patients treated with fotagliptin and metformin combined therapy. CONCLUSIONS In patients with T2D who experienced inadequate glycaemic control with metformin, fotagliptin achieved a superior and clinically meaningful improvement in glycaemic control compared with placebo.
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Affiliation(s)
- Nan Yu
- Peking University First Hospital, Beijing, China
| | - Wenjie Xu
- Shenzhen Salubris Pharmaceuticals Co., Ltd, Shenzhen, China
| | - Xiaohui Guo
- Peking University First Hospital, Beijing, China
| | - Mingtong Xu
- Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wei Zhang
- The First Hospital of Qiqihar, Qiqihar, China
| | - Chaoli Yan
- The Affiliated Hospital of Inner Mongolia Medical University, Huhehaote, China
| | - Shuguang Pang
- Certer Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Xiuhai Shu
- Cangzhou Hospital of Integrated TCM-WM Heibei, Cangzhou, China
| | - Wei Zhang
- Puyang Oilfield General Hospital, Puyang, China
| | | | - Yawei Zhang
- Pingxiang People's Hospital, Pingxiang, China
| | - Gaixian Li
- General Hospital of Huabei Petroleum Administration Bureau, Cangzhou, China
| | - Xin Zhang
- Genertec Liaoyou Gem Flowe Hospital, Panjin, China
| | - Dongmei Zhou
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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7
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Liu F, Cai H. Diabetes and calcific aortic valve disease: implications of glucose-lowering medication as potential therapy. Front Pharmacol 2025; 16:1583267. [PMID: 40356984 PMCID: PMC12066769 DOI: 10.3389/fphar.2025.1583267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2025] [Accepted: 04/15/2025] [Indexed: 05/15/2025] Open
Abstract
Calcific aortic valve disease (CAVD) is a progressive disease, of which the 2-year mortality is >50% for symptomatic disease. However, there are currently no pharmacotherapies to prevent the progression of CAVD unless transcatheter or surgical aortic valve replacement is performed. The prevalence of diabetes among CAVD has increased rapidly in recent decades, especially among those undergoing aortic valve replacement. Diabetes and its comorbidities, such as hypertension, hyperlipidemia, chronic kidney disease and ageing, participated jointly in the initiation and progression of CAVD, which increased the management complexity in patients with CAVD. Except from hyperglycemia, the molecular links between diabetes and CAVD included inflammation, oxidative stress and endothelial dysfunction. Traditional cardiovascular drugs like lipid-lowering agents and renin-angiotensin system blocking drugs have proven to be unsuccessful in retarding the progression of CAVD in clinical trials. In recent years, almost all kinds of glucose-lowering medications have been specifically assessed for decelerating the development of CAVD. Based on the efficacy for atherosclerotic cardiovascular disease and CAVD, this review summarized current knowledge about glucose-lowering medications as promising treatment options with the potential to retard CAVD.
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Affiliation(s)
| | - Haipeng Cai
- Department of Cardiology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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8
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Duan X, Zhang X, Sun B. The landscape of novel antidiabetic drugs in diabetic HFpEF: relevant mechanisms and clinical implications. Cardiovasc Diabetol 2025; 24:186. [PMID: 40295996 PMCID: PMC12038999 DOI: 10.1186/s12933-025-02750-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 04/19/2025] [Indexed: 04/30/2025] Open
Abstract
As a heterogeneous syndrome, heart failure with preserved ejection fraction (HFpEF) has become the leading form of heart failure worldwide. Increasing evidence has identified that diabetes mellitus (DM) increases the risk of HFpEF. Worse still, the coexistence of both diseases poses a great threat to human health by further worsening the cardiovascular system and accelerating the progression of diabetes. Although several studies have indicated that the novel antidiabetic drugs, including sodium glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase 4 inhibitors (DPP4i) provide the cardiovascular benefits in T2DM patients with HFpEF, the elaborated roles and mechanisms are not fully understood. In this review, we summarize the state-of-the-art evidence regarding the epidemiology and pathophysiology of diabetic HFpEF, and the landscape of the novel antidiabetic drugs in the treatment of diabetic HFpEF, as well as discuss the relevant mechanisms, aiming to broaden the understanding of diabetic HFpEF and gain new insight into the treatment of this disease.
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Affiliation(s)
- Xiangling Duan
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, No. 139, People's Middle Street, Changsha, 410011, China
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China
| | - Xiaomeng Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 102488, China
| | - Bao Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, No. 139, People's Middle Street, Changsha, 410011, China.
- National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, 410011, China.
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9
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Elemary T, Nicola M, Abdelrahim MEA, Zaafar D. The impact of DPP-4 inhibitors on cardiovascular disease treatment: a comprehensive review of current therapeutic strategies and future directions. Mol Biol Rep 2025; 52:400. [PMID: 40244362 DOI: 10.1007/s11033-025-10458-7] [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: 10/01/2024] [Accepted: 03/20/2025] [Indexed: 04/18/2025]
Abstract
Patients diagnosed with type 2 diabetes have an increased risk of developing cardiovascular complications. The researchers are currently working on understanding how to prevent these progressions from occurring. Since 2006, dipeptidyl-peptidase-4 inhibitors have been made available to patients as a relatively new treatment for diabetes. These substances inhibit the enzyme known as dipeptidyl peptidase-4 (DPP-4), which in turn increases the levels of the glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). This results in an increase in the effectiveness of insulin release after meals, which in turn has a positive impact on glycemic control. Regarding the safety of this category of medication in the treatment of cardiovascular disorders, there have been a great deal of debates. Emerging research suggests that DPP-4 inhibitors could be useful in the treatment of a variety of cardiovascular conditions, including coronary atherosclerosis, heart failure, and hypertension, among others. In order to investigate the possibility of using dipeptidyl-peptidase-4 inhibitors as a treatment option for cardiovascular disease, the molecular pathways that are thought to be responsible for their cardioprotective effect will be clarifies throughout the course of this review.
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Affiliation(s)
- Toka Elemary
- Clinical Pharmacy Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt.
| | - Mina Nicola
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Mohamed E A Abdelrahim
- Clinical Pharmacy Department, Faculty of Pharmacy, Beni-Suef University, Beni-Suef, Egypt
| | - Dalia Zaafar
- Pharmacology and Toxicology Department, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt
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10
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Berger M, Marx N, Marx-Schütt K. Cardiovascular Risk Reduction in Patients with Type 2 Diabetes: What Does the Cardiologist Need to Know? Eur Cardiol 2025; 20:e09. [PMID: 40309220 PMCID: PMC12042294 DOI: 10.15420/ecr.2024.29] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 11/29/2024] [Indexed: 05/02/2025] Open
Abstract
Patients with diabetes are at an increased risk of cardiovascular disease (CVD), including atherosclerotic CVD and heart failure. In addition, diabetes is associated with a higher risk of developing chronic kidney disease, which is considered to be one of the strongest risk factors for CVD and mortality. To address the increased cardiovascular risk of patients with diabetes, dedicated screening strategies for CVD are necessary; conversely, screening for diabetes needs to be performed in all patients with CVD to allow timely identification. Once diabetes is diagnosed, rapid implementation of treatment with therapies to reduce cardiovascular risk on top of standard of care is necessary. This review gives an overview of contemporary therapeutic strategies to reduce cardiovascular risk in patients with type 2 diabetes.
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Affiliation(s)
- Martin Berger
- Department of Internal Medicine I, University Hospital Aachen Aachen, Germany
| | - Nikolaus Marx
- Department of Internal Medicine I, University Hospital Aachen Aachen, Germany
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11
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Colagiuri S, Ceriello A. 6. Cardio-renal protection in type 2 diabetes. Diabetes Res Clin Pract 2025:112150. [PMID: 40209900 DOI: 10.1016/j.diabres.2025.112150] [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: 04/12/2025]
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12
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Song M, Dai H, Zhou Q, Meng X. The immunology of diabetic cardiomyopathy. Front Endocrinol (Lausanne) 2025; 16:1542208. [PMID: 40260277 PMCID: PMC12009709 DOI: 10.3389/fendo.2025.1542208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 03/18/2025] [Indexed: 04/23/2025] Open
Abstract
Diabetic cardiomyopathy is a notable microvascular complication of diabetes, characterized primarily by myocardial fibrosis and functional abnormalities. Long-term hyperglycemia induces excessive activation and recruitment of immune cells and triggers the cascade of inflammatory responses, resulting in systemic and local cardiac inflammation. Emerging evidence highlights the significant roles of immunology in modulating the pathology of diabetic cardiomyopathy. As the primary effectors of inflammatory reactions, immune cells are consistently present in cardiac tissue and can be recruited under pathological hyperglycemia circumstances. A disproportionate favor to proinflammatory types of immune cells and the increased proinflammatory cytokine levels mediate fibroblast proliferation, phenotypic transformation, and collagen synthesis and ultimately rise to cardiac fibrosis and hypertrophy. Meanwhile, the severity of cardiac fibrosis is also strongly associated with the diverse phenotypes and phenotypic alterations of the immune cells, including macrophages, dendritic cells, mast cells, neutrophils, and natural killer cells in innate immunity and CD4+ T lymphocytes, CD8+ T lymphocytes, and B lymphocytes in adaptive immunity. In this review, we synthesized the current analysis of the critical role played by the immune system and its components in the progression of diabetic cardiomyopathy. Finally, we highlight preclinical and clinical immune targeting strategies and translational implications.
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Affiliation(s)
| | | | | | - Xiao Meng
- State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, China
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13
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Ruggeri RM, Grossrubatscher EM, Ciocca E, Hasballa I, Jaafar S, Oldani M, Rubino M, Russo F, Isidori AM, Colao A, Faggiano A. Incretins and SGLT-2 inhibitors in diabetic patients with neuroendocrine tumors: current updates and future directions. Rev Endocr Metab Disord 2025:10.1007/s11154-025-09958-5. [PMID: 40175622 DOI: 10.1007/s11154-025-09958-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/17/2025] [Indexed: 04/04/2025]
Abstract
Neuroendocrine tumors (NET) are frequently associated with glycemic disorders, such as prediabetes or diabetes, which may result from either surgical or medical treatments or hormonal hypersecretion by the tumor itself. Moreover, pre-existing diabetes is a known risk factor for NET development, with metabolic control and antidiabetic therapies potentially influencing tumor progression. The complex interplay between diabetes and NET, which share several molecular pathways, has spurred interest in the anti-cancer effects of antidiabetic medications. This is particularly relevant as new antidiabetic drugs continue to emerge, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin-based therapies, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor (GLP-1R) agonists and dual GIP/GLP- 1 R agonists. This review explores the impact of these novel pharmacological options on NET development and progression through a comprehensive analysis of pre-clinical and clinical studies, with the purpose to evaluate safety and feasibility of introducing these drugs in the treatment of NETs patients. We conducted a comprehensive search of online databases, including PubMed, ISI Web of Science, and Scopus, for studies assessing the therapeutic effects and potential mechanisms of action of incretins and SGLT2 inhibitors in patients with NET. These novel antidiabetic drugs exhibit promising anticancer properties, potentially inhibiting tumor cell proliferation and inducing apoptosis, though concerns about certain cancer risks remain. Based on current evidence, the benefits of incretin-based therapies outweigh any potential cancer risks, leading to the proposal of tailored management algorithms for diabetes in NET patients, factoring in the diabetes aetiology, comorbidities, and life expectancy.
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Affiliation(s)
- Rosaria M Ruggeri
- Endocrinology, Department of Human Pathology of Adulthood and Childhood DETEV, University of Messina, Messina, Italy
| | | | - Eleonora Ciocca
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Iderina Hasballa
- Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DIMI), University of Genoa, 16132, Genoa, Italy
| | - Simona Jaafar
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy
- Endocrinology, Diabetology and Andrology Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Monica Oldani
- Laboratory of Geriatric and Oncologic Neuroendocrinology Research, IRCCS, Istituto Auxologico Italiano, Milan, Italy
| | - Manila Rubino
- Onco-Endocrinology Unit, European Institute of Oncology, Milan, Italy
| | - Flaminia Russo
- Endocrinology Unit, Department of Clinical and Molecular Medicine, European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy
| | - Andrea M Isidori
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Annamaria Colao
- Endocrinology, Diabetology and Andrology Unit, Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
- UNESCO Chair "Education for Health and Sustainable Development", Federico II University, Naples, Italy
| | - Antongiulio Faggiano
- Endocrinology Unit, Department of Clinical and Molecular Medicine, European Neuroendocrine Tumor Society (ENETS) Center of Excellence, Sapienza University of Rome, Sant'Andrea University Hospital, Rome, Italy.
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14
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García Soidán FJ, Riveiro Villanueva J. [Pharmacological treatment of type 2 diabetes mellitus]. Aten Primaria 2025; 57:103143. [PMID: 39566204 PMCID: PMC11754131 DOI: 10.1016/j.aprim.2024.103143] [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: 09/16/2024] [Revised: 10/10/2024] [Accepted: 10/11/2024] [Indexed: 11/22/2024] Open
Abstract
The treatment of type 2 diabetes is based on four fundamental pillars: diet, exercise, therapeutic education, and pharmacological therapy. There are ten groups of antidiabetic drugs that can be classified according to their mechanism of action, effects on body weight, risk of hypoglycemia, and ability to reduce the development of complications. The choice of medication will be individualized based on the preferences and characteristics of the individual, taking into consideration the presence of cardiovascular disease, heart failure, chronic kidney disease, obesity, or non-alcoholic fatty liver disease. The type 2 diabetes mellitus treatment algorithm from the RedGDPS Foundation is an evidence-based tool that can help us select the most appropriate pharmacological therapy depending on the characteristics of each patient.
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15
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Mita T, Katakami N, Yoshii H, Onuma T, Kaneto H, Osonoi T, Shiraiwa T, Yasuda T, Umayahara Y, Yamamoto T, Yokoyama H, Kuribayashi N, Matsumoto K, Gosho M, Shimomura I, Watada H, Collaborators on the Sitagliptin Preventive study of Intima media thickness Evaluation (SPIKE) Trial. Long-term efficacy and safety of early sitagliptin initiation in individuals with type 2 diabetes: an extension of the SPIKE study. Diabetol Int 2025; 16:272-284. [PMID: 40166439 PMCID: PMC11954773 DOI: 10.1007/s13340-024-00786-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 12/18/2024] [Indexed: 04/02/2025]
Abstract
Aims/instruction We previously demonstrated that sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, slowed down the progression of carotid atherosclerosis in type 2 diabetes participants who were treated with insulin and had no history of cardiovascular disease in the Sitagliptin Preventive study of Intima-Media Thickness Evaluation (SPIKE) trial. This was an extension of the SPIKE trial that examined if early sitagliptin initiation improved long-term cardiovascular outcomes. Materials and methods In the SPIKE trial, 282 participants were randomized to either sitagliptin or conventional treatment to examine the effects of sitagliptin on carotid atherosclerosis. All participants who completed the SPIKE trial were recruited to this prospective, observational, cohort study and followed for up to 520 weeks. The primary endpoint was the first occurrence of a major cardiovascular event, which included acute myocardial infarction, stroke, or total mortality. Results Events of composite primary outcome occurred in only a few participants in each group (15 [12.6%] in the sitagliptin group and eight in the conventional treatment group [6.7%]). The incidence rate of the primary outcome did not differ significantly between two groups. In post hoc Poisson regression analysis, there were no significant between-group differences in the incidence rates of composite recurrence events for the same outcomes as the primary endpoint. Conclusions Early initiation of sitagliptin as add-on therapy to insulin was not linked to reduced risk of composite cardiovascular disease. This may be due to low event numbers in both groups and/or relatively lower continuation rates of DPP-4 inhibitors in the sitagliptin group during the follow-up period. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-024-00786-7.
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Affiliation(s)
- Tomoya Mita
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 Japan
| | - Naoto Katakami
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
| | - Hidenori Yoshii
- Department of Medicine, Diabetology & Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, Shinsuna 3-3-20, Koto-ku, Tokyo 136-0075 Japan
| | - Tomio Onuma
- Department of Medicine, Diabetology & Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, Shinsuna 3-3-20, Koto-ku, Tokyo 136-0075 Japan
| | - Hideaki Kaneto
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192 Japan
| | - Takeshi Osonoi
- Naka Kinen Clinic, 745-5, Nakadai, Naka City, Ibaraki 311-0113 Japan
| | | | - Tetsuyuki Yasuda
- Osaka Police Hospital, 10-31 Kitayamacho, Tennoji-ku, Osaka, 543-0035 Japan
| | - Yutaka Umayahara
- Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558 Japan
| | - Tsunehiko Yamamoto
- Kansai Rosai Hospital, 3-1-69 Inabasou, Amagasaki-shi, Hyogo 660-8511 Japan
| | - Hiroki Yokoyama
- Jiyugaoka Medical Clinic, Internal Medicine, West 6, South 6-4-3, Obihiro, Hokkaido 080-0016 Japan
| | - Nobuichi Kuribayashi
- Misaki Internal Medicine Clinic, 6-44-9 Futawahigashi, Funabashi, Chiba 274-0805 Japan
| | - Kazunari Matsumoto
- Diabetes Center, Sasebo Chuo Hospital, 15 Yamato-cho, Sasebo, Nagasaki 857-1195 Japan
| | - Masahiko Gosho
- Department of Biostatistics, Institute of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575 Japan
| | - Iichiro Shimomura
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
| | - Hirotaka Watada
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 Japan
| | - Collaborators on the Sitagliptin Preventive study of Intima media thickness Evaluation (SPIKE) Trial
- Department of Metabolism & Endocrinology, Juntendo University Graduate School of Medicine, Hongo 2-1-1, Bunkyo-ku, Tokyo 113-8421 Japan
- Department of Metabolic Medicine, Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Suita, Osaka 565-0871 Japan
- Department of Medicine, Diabetology & Endocrinology, Juntendo Tokyo Koto Geriatric Medical Center, Shinsuna 3-3-20, Koto-ku, Tokyo 136-0075 Japan
- Department of Diabetes, Endocrinology and Metabolism, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701-0192 Japan
- Naka Kinen Clinic, 745-5, Nakadai, Naka City, Ibaraki 311-0113 Japan
- Shiraiwa Medical Clinic, 1-12-8 Hirano, Kashiwara, Osaka 582-0019 Japan
- Osaka Police Hospital, 10-31 Kitayamacho, Tennoji-ku, Osaka, 543-0035 Japan
- Osaka General Medical Center, 3-1-56 Bandai-Higashi, Sumiyoshi-ku, Osaka, 558-8558 Japan
- Kansai Rosai Hospital, 3-1-69 Inabasou, Amagasaki-shi, Hyogo 660-8511 Japan
- Jiyugaoka Medical Clinic, Internal Medicine, West 6, South 6-4-3, Obihiro, Hokkaido 080-0016 Japan
- Misaki Internal Medicine Clinic, 6-44-9 Futawahigashi, Funabashi, Chiba 274-0805 Japan
- Diabetes Center, Sasebo Chuo Hospital, 15 Yamato-cho, Sasebo, Nagasaki 857-1195 Japan
- Department of Biostatistics, Institute of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki 305-8575 Japan
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16
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Jerkins TW, Bell DSH. Stroke in the Patient With Type 2 Diabetes. Endocr Pract 2025; 31:547-553. [PMID: 39914491 DOI: 10.1016/j.eprac.2025.01.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 01/20/2025] [Accepted: 01/23/2025] [Indexed: 04/19/2025]
Abstract
OBJECTIVE Persons living with type 2 diabetes mellitus (T2DM) have a significantly greater risk of stroke (1.5 to 3 times higher than normoglycemic individuals). The traditional approach to primary and secondary stroke prevention has been control of risk factors. While this has resulted in prolongation of life in patients with diabetes, the risk for recurrent stroke in these patients still remains higher than in the normoglycemic population, and patients with T2DM post stroke have a poorer quality of life (increases in handicap and death). METHODS Multiple publications on the pathophysiology which increases stroke in T2DM were reviewed as well as new publications looking at the effect of traditional and new risk factor modification on stroke are summarized. RESULTS Traditional risk factor modification is refined with recommended levels of lipids and blood pressure and methods of anticoagulation. More recently, studies with antidiabetic drugs (glucagon-like peptide 1 RA and pioglitazone) have been shown to prevent both primary and secondary stroke in patients with diabetes. CONCLUSIONS Worldwide, stroke is the second leading cause of death and the third leading cause of disability. Both risk and the outcomes are greatly worsened by the presence of T2DM. Newer recommendations can improve these outcomes.
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Chen Q, Anijs RJS, Verlaan JPL, Scheres LJJ, Klok FA, Cannegieter SC. Novel Antidiabetic Drugs and Risk of Venous Thromboembolism: A Literature Review. Semin Thromb Hemost 2025. [PMID: 40154507 DOI: 10.1055/a-2546-0353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/01/2025]
Abstract
Novel antidiabetic drugs, particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have significantly transformed the management landscape for type 2 diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, owing to their well-established cardiorenal protective effects. Given the shared risk factors and comorbidities, it is relevant to consider the potential risk of venous thromboembolism (VTE) in individuals prescribed these novel antidiabetic medications. This literature review aims to summarize currently available evidence on VTE risk associated with novel antidiabetic drugs, including GLP-1 receptor agonists, dipeptidyl-peptidase IV (DPP-4) inhibitors, and SGLT2 inhibitors. Following a comprehensive search on PubMed using relevant keywords and backward reference searching, we identified 25 publications that directly reported on associations between these medications and VTE risk. Findings from these studies, including seven meta-analyses, reveal inconsistent results: some studies suggest that GLP-1 receptor agonists or DPP-4 inhibitors may be associated with increased risk of VTE, whereas SGLT2 inhibitors do not appear to be associated with VTE and may even be a protective factor. A notable limitation of the existing studies is the significant challenge posed by confounding in observational studies, while the randomized controlled trials (RCTs) often concluded with a limited number of VTE events, if it was studied. Furthermore, all identified studies focused on the risk of primary VTE, leaving an important knowledge gap regarding whether these novel antidiabetic drugs may influence the efficacy or safety of anticoagulants used for preventing VTE recurrence. Addressing these gaps presents an important avenue for future research.
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Affiliation(s)
- Qingui Chen
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Rayna J S Anijs
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Medicine, Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
- The Knowledge Institute of the Federation of Medical Specialists, Utrecht, The Netherlands
| | - Judith P L Verlaan
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
| | - Luuk J J Scheres
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Frederikus A Klok
- Department of Medicine, Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
| | - Suzanne C Cannegieter
- Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Medicine, Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands
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18
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Hanlon P, Butterly E, Wei L, Wightman H, Almazam SAM, Alsallumi K, Crowther J, McChrystal R, Rennison H, Hughes K, Lewsey J, Lindsay R, McGurnaghan S, Petrie J, Tomlinson LA, Wild S, Adler A, Sattar N, Phillippo DM, Dias S, Welton NJ, McAllister DA. Age and Sex Differences in Efficacy of Treatments for Type 2 Diabetes: A Network Meta-Analysis. JAMA 2025; 333:1062-1073. [PMID: 39899304 PMCID: PMC11791772 DOI: 10.1001/jama.2024.27402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2024] [Accepted: 12/10/2024] [Indexed: 02/04/2025]
Abstract
Importance Sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and dipeptidyl peptidase 4 (DPP4) inhibitors improve hyperglycemia, and SGLT2 inhibitors and GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACEs) among individuals with type 2 diabetes. It is not clear whether efficacy varies by age or sex. Objective To assess whether age or sex are associated with differences in the efficacy of SGLT2 inhibitors, GLP-1 receptor agonists, and DPP4 inhibitors. Data Sources and Study Selection The MEDLINE and Embase databases and US and Chinese clinical trial registries were searched for articles published from inception to November 2022; in August 2024, the search was updated to capture the trial results. Two reviewers screened for randomized clinical trials of SGLT2 inhibitors, GLP-1 receptor agonists, or DPP4 inhibitors vs a placebo or active comparator in adults with type 2 diabetes. Data Extraction and Synthesis Individual participant data and aggregate data were used to estimate age × treatment interactions and sex × treatment interactions in multilevel network meta-regression models. Main Outcome and Measures Hemoglobin A1c (HbA1c) and MACEs. Results Of the 601 eligible trials identified (592 trials with 309 503 participants reported HbA1c; mean age, 58.9 [SD, 10.8] years; 42.3% were female and 23 trials with 168 489 participants reported MACEs; mean age, 64.0 [SD, 8.6] years; 35.3% were female), individual participant data were obtained for 103 trials (103 reported HbA1c and 6 reported MACEs). The use of SGLT2 inhibitors (vs placebo) was associated with less HbA1c lowering with increasing age for monotherapy (absolute reduction [AR], 0.24% [95% credible interval {CrI}, 0.10% to 0.38%] per 30-year increment in age), for dual therapy (AR, 0.17% [95% CrI, 0.10% to 0.24%]), and for triple therapy (AR, 0.25% [95% CrI, 0.20% to 0.30%]). The use of GLP-1 receptor agonists was associated with greater HbA1c lowering with increasing age for monotherapy (AR, -0.18% [95% CrI, -0.31% to -0.05%] per 30-year increment in age) and for dual therapy (AR, -0.24% [95% CrI, -0.40% to -0.07%]), but not for triple therapy (AR, 0.04% [95% CrI, -0.02% to 0.11%]). The use of DPP4 inhibitors was associated with slightly better HbA1c lowering in older people for dual therapy (AR, -0.09% [95% CrI, -0.15% to -0.03%] per 30-year increment in age), but not for monotherapy (AR, -0.08% [95% CrI, -0.18% to 0.01%]) or triple therapy (AR, -0.01% [95% CrI, -0.06% to 0.05%]). The relative reduction in MACEs with use of SGLT2 inhibitors was greater in older vs younger participants per 30-year increment in age (hazard ratio, 0.76 [95% CrI, 0.62 to 0.93]), and the relative reduction in MACEs with use of GLP-1 receptor agonists was less in older vs younger participants (hazard ratio, 1.47 [95% CrI, 1.07 to 2.02]). There was no consistent evidence for sex × treatment interactions with use of SGLT2 inhibitors and GLP-1 receptor agonists. Conclusions and Relevance The SGLT2 inhibitors and GLP-1 receptor agonists were associated with lower risk of MACEs. Analysis of age × treatment interactions suggested that SGLT2 inhibitors were more cardioprotective in older than in younger people despite smaller reductions in HbA1c; GLP-1 receptor agonists were more cardioprotective in younger people.
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Affiliation(s)
- Peter Hanlon
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Elaine Butterly
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Lili Wei
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Heather Wightman
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | | | - Khalid Alsallumi
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Jamie Crowther
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Ryan McChrystal
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Heidi Rennison
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Katherine Hughes
- Department of Diabetes, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, Glasgow, UK
| | - Jim Lewsey
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Robert Lindsay
- University of Glasgow BHF Glasgow Cardiovascular Research Centre, Glasgow, Glasgow, UK
| | - Stuart McGurnaghan
- Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
| | - John Petrie
- School of Health and Wellbeing, University of Glasgow, Glasgow, UK
| | - Laurie A Tomlinson
- Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK
| | - Sarah Wild
- Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Amanda Adler
- Diabetes Trials Unit, University of Oxford, Oxford, UK
| | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK
| | - David M Phillippo
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
| | - Sofia Dias
- Centre for Reviews and Dissemination, University of York, York, UK
| | - Nicky J Welton
- Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK
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19
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Hung JY, Zhong J, Ou HT, Su PF. Efficient estimation of the cox model when incorporating the subgroup restricted mean survival time. J Biopharm Stat 2025:1-22. [PMID: 40079137 DOI: 10.1080/10543406.2024.2444242] [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: 08/06/2024] [Accepted: 12/15/2024] [Indexed: 03/14/2025]
Abstract
The restricted mean survival time has been widely used in the field of medical research because of its clear physical and simple clinical interpretation. In this paper, we propose an efficient estimation that incorporates the auxiliary restricted mean survival information into the estimation of the proportional hazard (PH) model. Compared to conventional models that do not incorporate available auxiliary information, the proposed method improves efficiency in estimating regression parameters by utilizing the double empirical likelihood method. We prove that the estimator asymptotically follows a multivariate normal distribution with a covariance matrix that can be consistently estimated. To address scenarios where the PH assumption is violated, we also extended the method to the stratified Cox model. In addition, simulation studies show that the proposed estimators are more efficient than those derived from the conventional partial likelihood approach. A type 2 diabetes dataset is then used to evaluate the risk of antidiabetic drugs and demonstrate the proposed method.
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Affiliation(s)
- Jo-Ying Hung
- Department of Statistics, National Cheng Kung University, Tainan, Taiwan
| | - Junjiang Zhong
- School of Mathematics and Statistics, Xiamen University of Technology, Xiamen, China
| | - Huang-Tz Ou
- Institute of Clinical Pharmacy and Pharmaceutical Sciences, Department of Pharmacy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Pei-Fang Su
- Department of Statistics, National Cheng Kung University, Tainan, Taiwan
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20
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Lin YM, Wu JY, Lee MC, Su CL, Toh HS, Chang WT, Chen SY, Kuo FH, Tang HJ, Liao CT. Comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors in atherosclerotic cardiovascular disease phenotypes: a systematic review and meta-analysis. EUROPEAN HEART JOURNAL. CARDIOVASCULAR PHARMACOTHERAPY 2025; 11:174-189. [PMID: 39923808 PMCID: PMC11905764 DOI: 10.1093/ehjcvp/pvae093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/25/2024] [Revised: 10/30/2024] [Accepted: 12/18/2024] [Indexed: 02/11/2025]
Abstract
BACKGROUND Atherosclerotic cardiovascular disease (ASCVD) encompasses various phenotypes with elevated risks of major adverse cardiovascular events (MACEs). This study aimed to assess the comparative cardiovascular effectiveness of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) across diverse ASCVD phenotypes. METHODS AND RESULTS We conducted a systematic review and meta-analysis of randomized controlled trials evaluating GLP-1 RAs or SGLT2is against placebo or standard care in ASCVD patients. Primary outcomes included MACE, defined as cardiovascular mortality, non-fatal myocardial infarction, and non-fatal stroke. Risk ratios (RRs) with 95% confidence interval (CI) were calculated using a random-effects model.Twenty-six trials (151 789 patients) were included. Both GLP-1 RAs and SGLT2is significantly reduced MACE rates in ASCVD patients (RR 0.85; 95% CI 0.80-0.91 for both). GLP-1 RAs showed significant effectiveness in peripheral artery disease (RR 0.86; 95% CI 0.76-0.98) and post-acute cardiovascular events (RR 0.90; 95% CI 0.83-0.97). In ASCVD with heart failure, both drug classes reduced MACE (GLP-1 RAs: RR 0.73; 95% CI 0.63-0.84; SGLT2is: RR 0.86; 95% CI 0.78-0.95). SGLT2is significantly reduced MACE in ASCVD with chronic kidney disease (RR 0.84; 95% CI 0.72-0.99), particularly in severe albuminuria (RR 0.61; 95% CI 0.37-0.99). CONCLUSION GLP-1 RAs and SGLT2is exhibit distinct cardiovascular effectiveness profiles across ASCVD phenotypes. GLP-1 RAs show particular benefits in peripheral artery disease and post-acute cardiovascular events, while SGLT2is demonstrate unique advantages in ASCVD with comorbid chronic kidney disease. Both are effective in heart failure. These findings support tailored treatment strategies for diverse ASCVD participants based on specific comorbidities and risk factors.
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Affiliation(s)
- Yu-Min Lin
- Division of Cardiology, Department of Internal Medicine, Chi Mei Hospital, Chiali, Tainan City, 722, Taiwan
| | - Jheng-Yan Wu
- Department of Nutrition, Chi Mei Medical Centre, Tainan City, 710, Taiwan
- Department of Public Health, College of Medicine, National Cheng Kung University, Tainan City, 704, Taiwan
| | - Mei-Chuan Lee
- Department of Pharmacy, Chi Mei Medical Centre, Tainan City, 710, Taiwan
| | - Chen-Lun Su
- Department of Internal Medicine, Chi Mei Medical Centre, Tainan City, 710, Taiwan
| | - Han Siong Toh
- Department of Intensive Care Medicine, Chi Mei Medical Centre, Tainan City, 710, Taiwan
- Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan City, 704, Taiwan
| | - Wei-Ting Chang
- Division of Cardiovascular Medicine, Chi Mei Medical Centre, School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung City, 804, Taiwan
| | - Sih-Yao Chen
- Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Centre, 704, Taiwan
| | - Fang-Hsiu Kuo
- Division of Cardiology, Department of Internal Medicine, Chi Mei Medical Centre, 704, Taiwan
| | - Hsin-Ju Tang
- Department of Nursing, Chang Gung University of Science and Technology, Chiayi County, 613, Taiwan
| | - Chia-Te Liao
- Division of Cardiovascular Medicine, Chi Mei Medical Centre, School of Medicine, College of Medicine, National Sun Yat-sen University, Kaohsiung City, 804, Taiwan
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21
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Tang H, Zhang B, Lu Y, Donahoo WT, Singh Ospina N, Kotecha P, Lu Y, Tong J, Smith SM, Rosenberg EI, Kimmel SE, Bian J, Guo J, Chen Y. Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials. Diabetes Obes Metab 2025; 27:1444-1455. [PMID: 39723481 DOI: 10.1111/dom.16147] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2024] [Revised: 12/07/2024] [Accepted: 12/10/2024] [Indexed: 12/28/2024]
Abstract
AIM To comprehensively evaluate the benefits and risks of glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i). MATERIALS AND METHODS A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2023 to identify randomized cardiovascular and kidney outcome trials that enrolled adults with type 2 diabetes, heart failure, or chronic kidney disease and compared DPP4i, GLP-1RAs, or SGLT2i to placebo. Twenty-one outcomes (e.g., major adverse cardiovascular events [MACE], stroke, and hospitalization for heart failure [HHF]) were assessed. Data were pooled using population-averaged odds ratios (ORs) with 95% CIs. RESULTS Twenty-six trials enrolling 198 177 participants were included. GLP-1RAs were most effective in lowering the risks of MACE (OR, 0.85, [95% CI, 0.79 to 0.92]) and stroke (0.84 [0.77, 0.91]), but increased the risk of thyroid cancer (1.58 [1.36, 2.50]). SGLT2i showed the greatest benefits in reducing the risk of HHF (0.68 [0.64, 0.73]) and improving composite renal outcomes (0.67 [0.58, 0.77]), but increased the risk of genital infections (3.11 [2.15, 4.50]). DPP4i were associated with a lower risk of certain psychiatric disorders, Parkinson's disease (0.54 [0.32, 0.92]), and amputation (0.70 [0.86, 0.93]), but an increased risk of neuropathy (1.10 [1.02, 1.18]) and pancreatitis (1.63 [1.40, 1.91]). The weighted origami plot suggested that GLP-1RAs were more suitable for reducing macrovascular and microvascular outcomes, while DPP4i might be better for neurodegenerative diseases and cancer concerns. CONCLUSIONS Given the distinct benefit-risk profiles, the selection of glucose-lowering drugs should be individualized based on patient characteristics and risk factors.
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Affiliation(s)
- Huilin Tang
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA
| | - Bingyu Zhang
- The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA
- The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Yiwen Lu
- The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA
- The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - William T Donahoo
- Division of Endocrinology, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Naykky Singh Ospina
- Division of Endocrinology, Department of Medicine, University of Florida College of Medicine, Gainesville, Florida, USA
| | - Pareeta Kotecha
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA
| | - Ying Lu
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA
| | - Jiayi Tong
- The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
| | - Steven M Smith
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA
- Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA
| | - Eric I Rosenberg
- Division of General Internal Medicine, Department of Medicine, University of Florida, Gainesville, Florida, USA
| | - Stephen E Kimmel
- Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Jiang Bian
- Department of Health Outcomes and Biomedical Informatics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Jingchuan Guo
- Department of Pharmaceutical Outcomes and Policy, University of Florida College of Pharmacy, Gainesville, Florida, USA
- Center for Drug Evaluation and Safety, University of Florida, Gainesville, Florida, USA
| | - Yong Chen
- The Center for Health AI and Synthesis of Evidence (CHASE), University of Pennsylvania, Philadelphia, Pennsylvania, USA
- The Graduate Group in Applied Mathematics and Computational Science, School of Arts and Sciences, University of Pennsylvania, Philadelphia, Pennsylvania, USA
- Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA
- Leonard Davis Institute of Health Economics, Philadelphia, Pennsylvania, USA
- Penn Medicine Center for Evidence-based Practice (CEP), Philadelphia, Pennsylvania, USA
- Penn Institute for Biomedical Informatics (IBI), Philadelphia, Pennsylvania, USA
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22
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Griffin KE, Snyder K, Javid AH, Hackstadt A, Greevy R, Grijalva CG, Roumie CL. Use of SGLT2i Versus DPP-4i as an Add-on Therapy and the Risk of PAD-Related Surgical Events (Amputation, Stent Placement, or Vascular Surgery): A Cohort Study in Veterans With Diabetes. Diabetes Care 2025; 48:361-370. [PMID: 39977627 PMCID: PMC11870292 DOI: 10.2337/dc24-1546] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2024] [Accepted: 10/31/2024] [Indexed: 02/22/2025]
Abstract
OBJECTIVE To compare the risk of composite peripheral artery disease (PAD) surgical outcome, including peripheral revascularization and amputation procedures, between new users of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and dipeptidyl peptidase 4 inhibitors (DPP-4is). RESEARCH DESIGN AND METHODS This retrospective cohort study of U.S. veterans age ≥18 years with diabetes who received care from the Veterans Health Administration was performed from 1 October 2000 to 31 December 2021. Data were linked to Medicare, Medicaid, and the National Death Index. New use of SGLT2i or DPP-4i medications as an add-on to metformin, sulfonylurea, or insulin treatment alone or in combination was evaluated for an association with PAD surgical procedure for peripheral revascularization and amputation. A Cox proportional hazards model for time-to-PAD event analysis compared the risk of a PAD event between SGLT2is and DPP-4is in a propensity score-weighted cohort with a competing risk of death and allowance for events to occur up to 90 days or 360 days after stopping SGLT2is. RESULTS The weighted cohort included 76,072 SGLT2i vs. 75,833 DPP-4i use episodes. The median age was 69 years, HbA1c was 8.4% (interquartile range [IQR] 7.5-9.4%), and the median diabetes duration was 10.1 (IQR 6.6-14.6) years. There were 874 and 780 PAD events among SGLT2i and DPP-4i users, respectively, for an event rate of 11.2 (95% CI 10.5-11.9) and 10.0 (9.4-10.6) per 1,000 person-years (adjusted hazard ratio [aHR] 1.18 [95% CI 1.08-1.29]). When PAD events were allowed for 360 days after SGLT2i use ended, the aHR was 1.16 (95% CI 1.06-1.26). CONCLUSIONS SGLT2i as an add-on diabetes therapy was associated with an increased cause-specific hazard of PAD surgeries compared with DPP-4i.
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Affiliation(s)
- Katherine E. Griffin
- Geriatric Research Education Clinical Center, Tennessee Valley Health Care System, Nashville, TN
| | - Kathryn Snyder
- Geriatric Research Education Clinical Center, Tennessee Valley Health Care System, Nashville, TN
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Amir H. Javid
- Geriatric Research Education Clinical Center, Tennessee Valley Health Care System, Nashville, TN
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN
| | - Amber Hackstadt
- Geriatric Research Education Clinical Center, Tennessee Valley Health Care System, Nashville, TN
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN
| | - Robert Greevy
- Geriatric Research Education Clinical Center, Tennessee Valley Health Care System, Nashville, TN
- Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN
| | - Carlos G. Grijalva
- Geriatric Research Education Clinical Center, Tennessee Valley Health Care System, Nashville, TN
- Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN
| | - Christianne L. Roumie
- Geriatric Research Education Clinical Center, Tennessee Valley Health Care System, Nashville, TN
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
- Department of Health Policy, Vanderbilt University Medical Center, Nashville, TN
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23
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Bussmann B, Ayagama T, Liu K, Li D, Herring N. Bayliss Starling Prize Lecture 2023: Neuropeptide-Y being 'unsympathetic' to the broken hearted. J Physiol 2025; 603:1841-1864. [PMID: 38847435 PMCID: PMC11955873 DOI: 10.1113/jp285370] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2024] [Accepted: 05/01/2024] [Indexed: 04/01/2025] Open
Abstract
William Bayliss and Ernest Starling are not only famous as pioneers in cardiovascular physiology, but also responsible for the discovery of the first hormone (from the Greek 'excite or arouse'), the intestinal signalling molecule and neuropeptide secretin in 1902. Our research group focuses on neuropeptides and neuromodulators that influence cardiovascular autonomic control as potential biomarkers in disease and tractable targets for therapeutic intervention. Acute myocardial infarction (AMI) and chronic heart failure (CHF) result in high levels of cardiac sympathetic stimulation, which is a poor prognostic indicator. Although beta-blockers improve mortality in these conditions by preventing the action of the neurotransmitter noradrenaline, a substantial residual risk remains. Recently, we have identified the sympathetic co-transmitter neuropeptide-Y (NPY) as being released during AMI, leading to larger infarcts and life-threatening arrhythmia in both animal models and patients. Here, we discuss recently published data demonstrating that peripheral venous NPY levels are associated with heart failure hospitalisation and mortality after AMI, and all cause cardiovascular mortality in CHF, even when adjusting for known risk factors (including brain natriuretic peptide). We have investigated the mechanistic basis for these observations in human and rat stellate ganglia and cardiac tissue, manipulating NPY neurochemistry at the same time as using state-of-the-art imaging techniques, to establish the receptor pathways responsible for NPY signalling. We propose NPY as a new mechanistic biomarker in AMI and CHF patients and aim to determine whether specific NPY receptor blockers can prevent arrhythmia and attenuate the development of heart failure.
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Affiliation(s)
- Benjamin Bussmann
- Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - Thamali Ayagama
- Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - Kun Liu
- Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - Dan Li
- Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
| | - Neil Herring
- Burdon Sanderson Cardiac Science Centre, Department of Physiology, Anatomy and GeneticsUniversity of OxfordOxfordUK
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24
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Sullivan AE, Courvan MCS, Aday AW, Wasserman DH, Niswender KD, Shardelow EM, Wells EK, Wells QS, Freiberg MS, Beckman JA. The Role of Serum Free Fatty Acids in Endothelium-Dependent Microvascular Function. Endocrinol Diabetes Metab 2025; 8:e70031. [PMID: 39888728 PMCID: PMC11784902 DOI: 10.1002/edm2.70031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/28/2024] [Accepted: 01/11/2025] [Indexed: 02/02/2025] Open
Abstract
BACKGROUND Elevated serum free fatty acid (FFA) concentration is associated with insulin resistance and is a hallmark of metabolic syndrome. A pathological feature of insulin resistance is impaired endothelial function. OBJECTIVE To investigate the effect of FFA reduction with either acipimox, a nicotinic acid derivative that impairs lipolysis, or salsalate, a salicylate that reduces basal and inflammation-induced lipolysis, on insulin-mediated endothelium-dependent vasodilation. METHODS This was a post hoc, combined analysis of two randomised, double-blind, placebo-controlled crossover trials. Sixteen subjects were recruited (6 with metabolic syndrome and 10 controls) and randomised to acipimox 250 mg orally every 6 h for 7 days or placebo. Nineteen subjects were recruited (13 with metabolic syndrome and 6 controls) and randomised to receive salsalate 4.5 g/day for 4 weeks or placebo. The primary outcome was the association between FFA concentration and insulin-mediated vasodilation, measured by venous-occlusion strain-gauge plethysmography at baseline and following FFA modulation with the study drugs. RESULTS At baseline, FFA concentration (R = -0.35, p = 0.043) and insulin sensitivity (HOMA-IR: R = -0.42, p = 0.016, Adipo-IR: R = -0.39, p = 0.025) predicted insulin-mediated vasodilation. FFA levels were significantly reduced after drug pretreatment (0.604 vs. 0.491 mmol/L, p = 0.036) while insulin levels, insulin sensitivity and inflammatory markers were unchanged. Despite a reduction in circulating FFA with drug therapy, neither insulin-stimulated vasodilation nor insulin sensitivity improved. CONCLUSIONS Short-term reduction of FFA concentration does not improve insulin-stimulated vasodilation in patients with metabolic syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT00759291 and NCT00760019 (formerly NCT00762827).
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Affiliation(s)
- Alexander E. Sullivan
- Division of Cardiovascular Medicine, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | | | - Aaron W. Aday
- Division of Cardiovascular Medicine, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Vanderbilt Translational and Clinical Cardiovascular Research Center, Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - David H. Wasserman
- Department of Molecular Physiology and BiophysicsVanderbilt University School of MedicineNashvilleTennesseeUSA
| | - Kevin D. Niswender
- Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Department of Veteran AffairsTennessee Valley Healthcare SystemNashvilleTennesseeUSA
| | - Emily M. Shardelow
- Vanderbilt University Medical CenterProgram for Metabolic Bone DisordersNashvilleTennesseeUSA
| | - Emily K. Wells
- Division of Cardiovascular Medicine, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Vanderbilt Translational and Clinical Cardiovascular Research Center, Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Quinn S. Wells
- Division of Cardiovascular Medicine, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Vanderbilt Translational and Clinical Cardiovascular Research Center, Division of Cardiovascular MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Matthew S. Freiberg
- Division of Cardiovascular Medicine, Department of MedicineVanderbilt University Medical CenterNashvilleTennesseeUSA
- Geriatric Research Education and Clinical Centers (GRECC)Veterans Affairs Tennessee Valley Healthcare SystemNashvilleTennesseeUSA
| | - Joshua A. Beckman
- Division of Vascular Medicine, Department of MedicineUniversity of Texas SouthwesternDallasTexasUSA
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25
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Jiang Z, Zhao L, Xin M, Wan Y, Xu S, Yue X, Jin X, Cui R, Li Y, Kim W, Wu H, Cheng XW. Dipeptidyl peptidase-4 deficiency prevents chronic stress-induced cardiac remodeling and dysfunction in mice. FASEB J 2025; 39:e70398. [PMID: 39968759 PMCID: PMC11836924 DOI: 10.1096/fj.202402328r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 01/14/2025] [Accepted: 02/05/2025] [Indexed: 02/20/2025]
Abstract
Exposure to chronic psychosocial stress is a risk factor for metabolic cardiovascular disorders. Dipeptidyl peptidase-4 (DPP-4) plays essential roles in human pathobiology, and we recently showed that DPP-4 levels are increased by chronic stress in murine models. We here investigated the role of DPP-4 in stress-related cardiac injury and dysfunction in mice, focusing on oxidative stress and cardiac apoptosis. Male mice were randomly assigned to non-stress and two-week immobilized-stress groups for biological and morphological studies. On day 14 post-stress, stress had increased blood pressure, heart weight, cardiac myocyte size, and interstitial fibrosis, impaired cardiac diastolic function, and increased plasma levels of DPP-4 and glucose. The stressed mice also had increased levels of monocyte chemoattractant protein-1, inteleukin-6, gp91phox, matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of MMP-1/-2, caspase-8, and Bax genes and/or proteins and lowered levels of Bcl-2, p-Akt, and endothelial nitric oxide synthase (eNOS) proteins. DPP-4 inhibition by either a genetic or pharmacological approach ameliorated the stress-induced targeted molecular and morphological changes. In vitro, DPP-4 inhibition also mitigated the alterations in the targeted caspase-8, Bcl-2, eNOS, and p-Akt proteins in H9c2 cardiomyocytes in response to H2O2. DPP-4 inhibition appeared to improve the stress-induced cardiac injury and dysfunction in mice, possibly via the improvement of oxidative stress and apoptosis, suggesting that DPP-4 could become a novel therapeutic target for chronic psychological stress-related metabolic cardiovascular disorders.
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Affiliation(s)
- Zhe Jiang
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
| | - Longguo Zhao
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
| | - Minglong Xin
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
| | - Ying Wan
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
| | - Shengnan Xu
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
- Department of CardiologyThe Second Hospital of Jilin UniversityChangchunJilinChina
| | - Xueling Yue
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
| | - Xianglan Jin
- Department of AnesthesiologyYanbian University HospitalYanjiJilinChina
| | - Rihua Cui
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
| | - Yanglong Li
- Department of RadiologyYanbian University HospitalYanjiJilinChina
| | - Weon Kim
- Division of Cardiology, Department of Internal MedicineKyung Hee University Hospital, Kyung Hee UniversitySeoulRepublic of Korea
| | - Hongxian Wu
- Department of Cardiology, Zhongshan HospitalFudan University, Shanghai Institute of Cardiovascular Diseases, National Clinical Research Center for Interventional MedicineShanghaiChina
| | - Xian Wu Cheng
- Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular DiseaseYanbian University HospitalYanjiJilinChina
- Department of Community Healthcare and GeriatricsNagoya University Graduate School of MedicineNagoyaJapan
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Kishimori T, Kato T, Wada A, Tani A, Yamaji R, Koike J, Iwasaki Y, Matsumoto T, Yagi T, Okada M. Comparative Outcomes of Glucagon-Like Peptide-1 Receptor Agonists to Dipeptidyl Peptidase 4 Inhibitors in Patients With Heart Failure and Type 2 Diabetes. J Am Heart Assoc 2025; 14:e037510. [PMID: 39921523 PMCID: PMC12074738 DOI: 10.1161/jaha.124.037510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Accepted: 01/07/2025] [Indexed: 02/10/2025]
Abstract
BACKGROUND Clinical trials showed that glucagon-like peptide-1 receptor agonist (GLP1-RA) significantly improved the control of diabetes and reduced body weight compared with dipeptidyl peptidase 4 inhibitor (DPP-4i). However, it is unclear whether GLP1-RA is effective compared with DPP-4i in patients with heart failure (HF) with type 2 diabetes (T2D). The purpose of this study was to evaluate the risk of GLP1-RA compared with DPP-4i in all-cause death and hospitalization in patients with HF and T2D. METHODS This multicenter retrospective observational study using TriNetX, a global health care data and analytics platform, included patients with HF and T2D who had received GLP1-RA or DPP-4i from January 1, 2018, to December 31, 2022. Primary outcome was 12-month incidence of all-cause death. Secondary outcome was hospitalization. We used odds ratios (ORs) and 95% CIs to evaluate outcome measures. RESULTS Among 1 005 097 patients with HF and T2D, 57 965 initiated GLP1-RA and 77 098 initiated DPP-4i. After propensity score matching, the number of participants in both the GLP1-RA group and the DPP-4i group was 36 557. The proportion of 12-month incidence of all-cause death was lower in the GLP1-RA group than in the DPP-4i group (5.9% [2140/36 557] versus 8.5% [3103/36 557]; OR, 0.67 [95% CI, 0.63-0.71]).The proportion of 12-month incidence of hospitalization was also lower in the GLP1-RA group than in the DPP-4i group (42.3% [15 455/36 557] versus 48.5% [17 733/36 557]; OR, 0.78 [95% CI, 0.76-0.80]). CONCLUSIONS Use of GLP1-RA for patients with HF and T2D was associated with reduced 12-month incidence of all-cause death and hospitalization compared with DPP-4i.
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Affiliation(s)
| | - Takao Kato
- Department of Cardiovascular MedicineKyoto University Graduate School of MedicineKyotoJapan
| | - Atsuyuki Wada
- Department of Cardiovascular MedicineOmi Medical CenterKusatsuJapan
| | - Akira Tani
- Department of Cardiovascular MedicineOmi Medical CenterKusatsuJapan
| | - Ryosuke Yamaji
- Department of Cardiovascular MedicineOmi Medical CenterKusatsuJapan
| | - Jumpei Koike
- Department of Cardiovascular MedicineOmi Medical CenterKusatsuJapan
| | | | | | - Takafumi Yagi
- Department of Cardiovascular MedicineOmi Medical CenterKusatsuJapan
| | - Masaharu Okada
- Department of Cardiovascular MedicineOmi Medical CenterKusatsuJapan
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27
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Cho Y, Shin SH, Park MA, Suh YJ, Park S, Jang JH, Kim DY, Kim SH. The effect of SGLT2 inhibitor in patients with type 2 diabetes and atrial fibrillation. PLoS One 2025; 20:e0314454. [PMID: 39919084 PMCID: PMC11805423 DOI: 10.1371/journal.pone.0314454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Accepted: 11/11/2024] [Indexed: 02/09/2025] Open
Abstract
BACKGROUND Sodium glucose cotransporter 2 (SGLT2) inhibitors improve clinical outcomes in several populations including type 2 diabetes (T2D), chronic renal insufficiency, and heart failure (HF). However, limited data exist on their effects on atrial fibrillation (AF). METHODS We conducted a retrospective cohort study using the National Health Insurance Service database. A total of 4,771 patients with T2D and AF who were newly prescribed SGLT2 inhibitors or DPP4 inhibitors were selected and matched in a 1:2 ratio by propensity score with 37 confounding variables. We assessed the effect of SGLT2 inhibitors on the composite outcome of either HF hospitalization or death. RESULTS Over a median follow-up of 31 months, patients on SGLT2 inhibitors were associated with a lower risk of hospitalizations for HF or mortality compared to those on DPP4 inhibitors (HR 0.61; 95% CI 0.44-0.85; P = 0.004). SGLT2 inhibitor use was also associated with a lower risk of mortality (HR 0.61; 95% CI 0.39-0.94; P = 0.025) and CV mortality (HR 0.43; 95% CI 0.21-0.86; P = 0.018), but not of MI (HR 1.22 [95% CI 0.72-2.09]; P = 0.461) or stroke (HR 1.00 [95% CI 0.75-1.33]; P = 0.980). The incidence of hospitalizations for HF, although statistically insignificant, tended to be lower in the SGLT2 inhibitor group (HR 0.63 [95% CI 0.39-1.02]; P = 0.062). CONCLUSION In a nationwide cohort of patients with T2D and AF, SGLT2 inhibitor was associated with a lower risk of mortality, which may suggest that SGLT2 inhibitors may be considered as the first-line antidiabetic medication in patients with T2D and AF.
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Affiliation(s)
- Yongin Cho
- Department of Endocrinology and Metabolism, Inha University College of Medicine, Incheon, Republic of Korea
| | - Sung-Hee Shin
- Department of Cardiology, Inha University College of Medicine, Incheon, Republic of Korea
| | - Min-Ae Park
- Department of Data Science, Hanmi Pharm Co., Ltd, Republic of Korea
| | - Young Ju Suh
- Department of Biomedical Sciences, Inha University College of Medicine, Incheon, Korea
| | - Sojeong Park
- Department of Data Science, Hanmi Pharm Co., Ltd, Republic of Korea
| | - Ji-Hun Jang
- Department of Cardiology, Inha University College of Medicine, Incheon, Republic of Korea
| | - Dae-Young Kim
- Department of Cardiology, Inha University College of Medicine, Incheon, Republic of Korea
| | - So Hun Kim
- Department of Endocrinology and Metabolism, Inha University College of Medicine, Incheon, Republic of Korea
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Toker D, Chiang JN, Vespa PM, Schnakers C, Monti MM. The Dipeptidyl Peptidase-4 Inhibitor Saxagliptin as a Candidate Treatment for Disorders of Consciousness: A Deep Learning and Retrospective Clinical Analysis. Neurocrit Care 2025:10.1007/s12028-025-02217-0. [PMID: 39904872 DOI: 10.1007/s12028-025-02217-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 01/13/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND Despite advancements in the neuroscience of consciousness, no new medications for disorders of consciousness (DOC) have been discovered in more than a decade. Repurposing existing US Food and Drug Administration (FDA)-approved drugs for DOC is crucial for improving clinical management and patient outcomes. METHODS To identify potential new treatments among existing FDA-approved drugs, we used a deep learning-based drug screening model to predict the efficacy of drugs as awakening agents based on their three-dimensional molecular structure. A retrospective cohort study from March 2012 to October 2024 tested the model's predictions, focusing on changes in Glasgow Coma Scale (GCS) scores in 4047 patients in a coma from traumatic, vascular, or anoxic brain injury. RESULTS Our deep learning drug screens identified saxagliptin, a dipeptidyl peptidase-4 inhibitor, as a promising awakening drug for both acute and prolonged DOC. The retrospective clinical analysis showed that saxagliptin was associated with the highest recovery rate from acute coma among diabetes medications. After matching patients by age, sex, initial GCS score, coma etiology, and glycemic status, brain-injured patients with diabetes on incretin-based therapies, including dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 analogues, recovered from coma at significantly higher rates compared to both brain-injured patients with diabetes on non-incretin-based diabetes medications (95% confidence interval of 1.8-14.1% higher recovery rate, P = 0.0331) and brain-injured patients without diabetes (95% confidence interval of 2-21% higher recovery rate, P = 0.0272). Post matching, brain-injured patients with diabetes on incretin-based therapies also recovered at a significantly higher rate than patients treated with amantadine (95% confidence interval for the difference 2.4-25.1.0%, P = 0.0364). A review of preclinical studies identified several pathways through which saxagliptin and other incretin-based medications may aid awakening from both acute and chronic DOC: restoring monoaminergic and GABAergic neurotransmission, reducing brain inflammation and oxidative damage, clearing hyperphosphorylated tau and amyloid-β, normalizing thalamocortical glucose metabolism, increasing neural plasticity, and mitigating excitotoxic brain damage. CONCLUSIONS Our findings suggest incretin-based medications in general, and saxagliptin in particular, as potential novel therapeutic agents for DOC. Further prospective clinical trials are needed to confirm their efficacy and safety in DOC.
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Affiliation(s)
- Daniel Toker
- Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
| | - Jeffrey N Chiang
- Department of Computational Medicine, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Paul M Vespa
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
| | - Caroline Schnakers
- Research Institute, Casa Colina Hospital and Centers for Healthcare, Pomona, CA, USA
| | - Martin M Monti
- Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA
- Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA
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Cordes J, Glynn RJ, Walker AM, Schneeweiss SS. Geospatial distribution of the adoption of dipeptidyl-peptidase-4 inhibitors for type 2 diabetes among Medicare beneficiaries. Spat Spatiotemporal Epidemiol 2025; 52:100711. [PMID: 39955125 PMCID: PMC11830116 DOI: 10.1016/j.sste.2025.100711] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 12/28/2024] [Accepted: 01/08/2025] [Indexed: 02/17/2025]
Abstract
OBJECTIVE To characterize the geospatial distribution of the adoption of dipeptidyl-peptidase-4 inhibitor (DPP-4i) antidiabetics versus second generation sulfonylureas (SU). METHODS Using Medicare claims data 2012-2017, two cohorts were built with new-users of either sitagliptin or saxagliptin each versus active comparator SU. For each ZIP Code tabulation area (ZCTA), the proportion DPP-4i prescribing was used in a local indicator of spatial association hotspot analysis. Multilevel logistic models were used to quantify the variation in medication use at the individual, ZCTA, state, and region levels. RESULTS DPP-4i utilization proportion was low (sitagliptin median = 0.22; interquartile range 0.15 to 0.33; saxagliptin median = 0.025; 0.00 to 0.069). Clustering was observed for sitagliptin (Moran's I = 0.32) and saxagliptin (Moran's I = 0.20). States and ZCTAs accounted for 8.1 % and 13.3 % of variation in sitagliptin and saxagliptin prescribing, respectively. CONCLUSIONS Variation across ZCTAs suggests neighborhood factors may be important determinants of prescribing.
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Affiliation(s)
- Jack Cordes
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
| | - Robert J Glynn
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Alexander M Walker
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Sebastian S Schneeweiss
- Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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30
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Harris DD, Stone C, Broadwin M, Kanuparthy M, Sabe SA, Nho JW, Hamze J, Abid MR, Sellke FW. Dipeptidyl peptidase-4 inhibitor linagliptin improves fibrosis, apoptosis, and cardiac function in a large animal model of chronic myocardial ischemia. J Pharmacol Exp Ther 2025; 392:100532. [PMID: 40023609 DOI: 10.1016/j.jpet.2024.100532] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Accepted: 12/16/2024] [Indexed: 03/04/2025] Open
Abstract
Interest is increasing in using novel diabetic medications, such as glucagon-like peptide 1 (GLP-1) receptor agonists, to manage coronary artery disease. Dipeptidyl peptidase-4 (DPP-4) inhibitors enhance GLP-1 activity through the same pathway as GLP-1 agonists; however, DPP-4 inhibitors have not been fully evaluated in the setting of ischemic heart disease. We chose to study the DPP-4 inhibitor linagliptin (LIN) in a porcine model of chronic coronary ischemia. Seventeen Yorkshire swine underwent left thoracotomy and ameroid constrictor placement over the left circumflex coronary artery at age 11 weeks. Two weeks thereafter, swine received either vehicle without drug (n = 9) or LIN 2.5 mg (n = 8). Following the elapse of 5 weeks of treatment, swine underwent terminal harvest. LIN significantly increased stroke volume, ejection fraction, cardiac output, and ischemic myocardial perfusion, while decreasing Tau (all P < .05). Trichrome staining showed a marked reduction in ischemic myocardial interstitial and perivascular fibrosis, accompanied by decreased levels of transforming growth factor-β (all P < .05). Apoptosis, measured by terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling staining, was significantly reduced, and accompanied by decreases in apoptosis-inducing factor, BCL2-associated agonist of cell death, caspase-9, and cleaved caspase-9 (all P < .05). Additionally, there were significant increases in phosphoinositide 3-kinase, phospho-protein kinase B, 5' adenosine monophosphate-activated protein kinase, phospho-5' adenosine monophosphate-activated protein kinase, and endothelial nitric oxide synthase, and significant reductions in collagen 18 and angiostatin (all P < .05). LIN significantly improved left ventricular function, cellular survival, and attenuated adverse remodeling, all likely secondary to augmented perfusion ischemic myocardial perfusion. Given that this increased perfusion occurred independently of changes in vascular density, treatment likely resulted in enhanced microvascular reactivity. These benefits warrant further investigation of LIN to fully understand its potential as a therapy for ischemic heart disease. SIGNIFICANCE STATEMENT: Linagliptin significantly improved cardiac cellular survival, left ventricular function, and attenuated adverse myocardial remodeling in a clinically relevant, large animal model of chronic ischemic cardiomyopathy. This warrants further investigation of linagliptin to fully understand its therapeutic potential.
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Affiliation(s)
- Dwight Douglas Harris
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Christopher Stone
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Mark Broadwin
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Meghamsh Kanuparthy
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Sharif A Sabe
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Ju-Woo Nho
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Jad Hamze
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - M Ruhul Abid
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Frank W Sellke
- Division of Cardiothoracic Surgery, Cardiovascular Research Center, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island.
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Lee WH, Kipp ZA, Pauss SN, Martinez GJ, Bates EA, Badmus OO, Stec DE, Hinds TD. Heme oxygenase, biliverdin reductase, and bilirubin pathways regulate oxidative stress and insulin resistance: a focus on diabetes and therapeutics. Clin Sci (Lond) 2025; 139:CS20242825. [PMID: 39873298 DOI: 10.1042/cs20242825] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 12/18/2024] [Accepted: 12/20/2024] [Indexed: 01/30/2025]
Abstract
Metabolic and insulin-resistant diseases, such as type 2 diabetes mellitus (T2DM), have become major health issues worldwide. The prevalence of insulin resistance in the general population ranges from 15.5% to 44.6%. Shockingly, the global T2DM population is anticipated to double by 2050 compared with 2021. Prior studies indicate that oxidative stress and inflammation are instrumental in causing insulin resistance and instigating metabolic diseases. Numerous methods and drugs have been designed to combat insulin resistance, including metformin, thiazolidinediones (TZDs), sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP1RA), and dipeptidyl peptidase 4 inhibitors (DPP4i). Bilirubin is an antioxidant with fat-burning actions by binding to the PPARα nuclear receptor transcription factor, improving insulin sensitivity, reducing inflammation, and reversing metabolic dysfunction. Potential treatment with antioxidants like bilirubin and increasing the enzyme that produces it, heme oxygenase (HMOX), has also gained attention. This review discusses the relationships between bilirubin, HMOX, and insulin sensitivity, how T2DM medications affect HMOX levels and activity, and potentially using bilirubin nanoparticles to treat insulin resistance. We explore the sex differences between these treatments in the HMOX system and how bilirubin levels are affected. We discuss the emerging concept that bilirubin bioconversion to urobilin may have a role in metabolic diseases. This comprehensive review summarizes our understanding of bilirubin functioning as a hormone, discusses the HMOX isoforms and their beneficial mechanisms, analyzes the sex differences that might cause a dichotomy in responses, and examines the potential use of HMOX and bilirubin nanoparticle therapies in treating metabolic diseases.
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Affiliation(s)
- Wang-Hsin Lee
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Zachary A Kipp
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Sally N Pauss
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Genesee J Martinez
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Evelyn A Bates
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
| | - Olufunto O Badmus
- Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, USA
| | - David E Stec
- Department of Physiology & Biophysics, Cardiorenal and Metabolic Diseases Research Center, University of Mississippi Medical Center, Jackson, USA
| | - Terry D Hinds
- Drug & Disease Discovery D3 Research Center, Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, KY, USA
- Barnstable Brown Diabetes Center, University of Kentucky College of Medicine, Lexington, KY, USA
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
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Mader A, Haeberli D, Larcher B, Dopheide JF, Saely CH, Heinzle CF, Amann P, Schindewolf M, Festa A, Drexel H. Contribution of type 2 diabetes to major adverse cardiovascular events (MACE) in a long-term observational study with different stages of atherosclerosis. Sci Rep 2025; 15:2792. [PMID: 39843486 PMCID: PMC11754429 DOI: 10.1038/s41598-024-84985-x] [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: 04/24/2024] [Accepted: 12/30/2024] [Indexed: 01/24/2025] Open
Abstract
The impact of diabetes on incident cardiovascular disease in relation to the extent of atherosclerotic disease remains unclear. We aimed to investigate major adverse cardiovascular events (MACE) in patients with or without type 2 diabetes (T2DM) presenting with two extremes of atherosclerotic disease, those with angiographically documented minor coronary atherosclerotic lesions and those with symptomatic peripheral artery disease. We included 1238 patients from two prospective, long-term cohort studies. Patients underwent coronary angiography and/or sonography in order to assess the grade of atherosclerosis and were defined as having no signs of Atherosclerosis (n = 332; Group I), minor atherosclerosis (n = 425; Group II) and major atherosclerosis (n = 481; Group III). Cardiovascular events were recorded over a median follow-up period of 7.1 years (Q1 = 3.6 years, Q2 = 7.1 years, Q3 = 11.3 years), covering a total of 9533 patient years. We tested the hypothesis that T2DM infers the same relative risk increase irrespective of the atherosclerosis stage, considering 3-point MACE as the primary endpoint. Incident MACE was reported in 681 patients (51%). MACE occurred more frequently in patients with T2DM than in patients without T2DM (p < 0.001). Further, MACE occurred more frequently in group III (58.1%), than group II (34.1%) or group I (19.1%) (group I vs. group II vs. group III, p < 0.001). In a cox-regression-model, T2DM was a significant predictor of MACE in univariate analyses (HR = 2.43 [1.88-3.14], p < 0.001) and after multivariate adjustment for cardiovascular risk factors, as well as the different grades of atherosclerosis (HR = 1.37 [1.02-1.84], p = 0.034). Also, atherosclerosis grades predicted MACE (HR = 3.19 [2.75-3.70], p < 0.001) in univariate analyses, and also after multivariate adjustment for known cardiovascular risk factors, including T2DM (HR = 1.61 [1.31-1.98], p < 0.001). Finally, when testing for interactions between T2DM and stages of atherosclerosis on MACE we could not find any significant interaction (HR = 1.14 [0.86-1.52], p = 0.364). We conclude that T2DM infers an increased risk for MACE across anatomically and morphologically distinct stages of atherosclerosis.
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Affiliation(s)
- Arthur Mader
- VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.
- Medicine I, Academic Teaching Hospital Feldkirch, Feldkirch, Austria.
| | | | - Barbara Larcher
- VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Medicine I, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
| | - Jörn F Dopheide
- VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Angiology, Spital Thun, Thun, Switzerland
| | - Christoph H Saely
- VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Medicine I, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Private University of the Principality of Liechtenstein, Triesen, Liechtenstein
| | | | - Peter Amann
- VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
| | - Marc Schindewolf
- Angiology, Inselspital Bern, Bern, Switzerland
- Clincal Investigation Unit, Inselspital, Bern, Switzerland
| | - Andreas Festa
- VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Private University of the Principality of Liechtenstein, Triesen, Liechtenstein
| | - Heinz Drexel
- VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria
- Private University of the Principality of Liechtenstein, Triesen, Liechtenstein
- Vorarlberger Landeskrankenhausbetriebsgesellschaft, Feldkirch, Austria
- Drexel University College of Medicine, Philadelphia, PA, USA
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Shah MU, Roebuck A, Srinivasan B, Ward JK, Squires PE, Hills CE, Lee K. Diagnosis and management of type 2 diabetes mellitus in patients with ischaemic heart disease and acute coronary syndromes - a review of evidence and recommendations. Front Endocrinol (Lausanne) 2025; 15:1499681. [PMID: 39911238 PMCID: PMC11794822 DOI: 10.3389/fendo.2024.1499681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 12/26/2024] [Indexed: 02/07/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) represents a major healthcare condition of the 21st century. It is characterised by persistently elevated blood glucose occurring as a result of peripheral insulin resistance and reduced insulin production which may lead to multiple long-term health conditions such as retinopathy, neuropathy, and nephropathy. The estimated number of individuals suffering from diabetes mellitus (DM) is expected to rise to 591 million by the year 2035 with 4.4 million in the United Kingdom (UK) alone, 90% of which is attributed to T2DM. Moreover, a significant proportion of individuals may have undetected diabetes mellitus, especially among those presenting with symptoms of ischaemic heart disease (IHD). This is particularly important in those individuals presenting with acute coronary syndromes (ACS) who are at the highest risk of complications and sudden cardiac death. Identifying abnormal levels of common biochemical markers of diabetes, such as capillary blood glucose or glycated haemoglobin (HbA1c) in these patients is important for early diagnosis, which will then allow for timely intervention to improve outcomes. However, a significant proportion of individuals who meet the criteria for the diagnosis of diabetes remain undiagnosed, representing missed opportunities for early intervention. This may result in a prolonged period of untreated hyperglycaemia, which can result resulting in significant further microvascular and macrovascular complications. There is an increased risk of IHD, heart failure, cerebrovascular accidents (CVA), and peripheral artery disease (PVD). These account accounting for 50% of deaths in patients with T2DM. Cardiovascular diseases in the context of diabetes particular represent a significant cause of morbidity and mortality with a two to three times higher risk of cardiovascular disease in individuals with T2DM than in those without the condition normo-glycaemia. In the United Kingdom UK alone, around 120 amputations, 770 CVA, 590 heart attacks, and more than 2300 presentations with heart failure per week are attributed to diabetes DM. with One 1 in six 6 hospital beds and around 10% of the healthcare budget may be being spent on managing diabetes DM or its complications. Therefore, it represents a significant burden on our healthcare system.
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Affiliation(s)
- Muhammad Usman Shah
- Cardiorenal Group, Diabetes, Metabolism, & Inflammation, Joseph Bank Laboratories, University of Lincoln, Lincoln, United Kingdom
- Lincoln Heart Centre, United Lincolnshire Hospitals, Lincoln, United Kingdom
| | - Alun Roebuck
- Lincoln Heart Centre, United Lincolnshire Hospitals, Lincoln, United Kingdom
| | - Bala Srinivasan
- Department of Diabetes and Endocrinology, United Lincolnshire Hospitals, Lincoln, United Kingdom
| | - Joanna Kate Ward
- Cardiorenal Group, Diabetes, Metabolism, & Inflammation, Joseph Bank Laboratories, University of Lincoln, Lincoln, United Kingdom
| | - Paul Edward Squires
- Cardiorenal Group, Diabetes, Metabolism, & Inflammation, Joseph Bank Laboratories, University of Lincoln, Lincoln, United Kingdom
| | - Claire Elizabeth Hills
- Cardiorenal Group, Diabetes, Metabolism, & Inflammation, Joseph Bank Laboratories, University of Lincoln, Lincoln, United Kingdom
| | - Kelvin Lee
- Cardiorenal Group, Diabetes, Metabolism, & Inflammation, Joseph Bank Laboratories, University of Lincoln, Lincoln, United Kingdom
- Lincoln Heart Centre, United Lincolnshire Hospitals, Lincoln, United Kingdom
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Sabbour H, Almahmeed W, Alawadi F, Shehab A, Al Zubaidi A, Bashier A, Ghulam AR, Rashid F, Zaky H, Heshmat Kassemn H, Adi J, Tahir J, Hafidh K, Farghali M, Hassanien M, Januzzi J. Emirates consensus recommendations on cardiovascular risk management in type 2 diabetes. Front Endocrinol (Lausanne) 2025; 15:1395630. [PMID: 39835266 PMCID: PMC11742931 DOI: 10.3389/fendo.2024.1395630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 09/24/2024] [Indexed: 01/22/2025] Open
Abstract
Background The combination of cardiovascular disease and diabetes is a highly prevalent condition in the United Arab Emirates. Development and dissemination of evidence-based regional recommendations for optimal screening, treatment and referrals of people with diabetes and high cardiovascular risk is an important priority. Consensus panel An expert panel of diabetologists, endocrinologists and cardiologists from the Emirates Cardiac Society and Emirates Diabetes and Endocrine Society as well as different entities in the UAE, discussed and reviewed evidence and also a consensus report from the American Diabetes Association to formulate contextualized recommendations that could be applied for optimal management of cardiovascular risk in people with diabetes in the UAE. Consensus findings The combination of heart failure and other cardiovascular risks is a highly prevalent finding among people with diabetes in the United Arab Emirates. The causal inter-relationships between diabetes and heart failure are multifactorial and regular assessments of symptoms and steps for mitigation of risk factors are an important priority. The universal definition and classification of heart failure provides a useful framework for recommending optimal screening, treatment, and referral strategies to diabetic individuals at various stages of the cardiovascular continuum. Routine measurement (at least yearly) of natriuretic peptides and high-sensitivity troponins can help identify patients requiring cardiac imaging referrals. However, recommending routine measurements of natriuretic peptides and/or high-sensitivity troponins to all diabetic individuals must balance clinical judgment and cost implications. While SGLT2i must be an important part of the standard of care, insulin, GLP1 receptor agonists and/or metformin can be useful for additional glycemic control. Conclusion The consensus panel hopes that the recommendations presented herein can offer guidance for optimal screening, treatment and referral of people with a concomitance of diabetes and high cardiovascular risk in the United Arab Emirates.
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Affiliation(s)
- Hani Sabbour
- Mediclinic Hospital, Abu Dhabi, United Arab Emirates
- Imperial College London Diabetes Center, Abu Dhabi, United Arab Emirates
- Warren Alpert School of Medicine, Brown University, Providence, RI, United States
| | - Wael Almahmeed
- Cardiology, Cleveland Clinic, Abu Dhabi, United Arab Emirates
- Heart, Vascular and Thoracic Institute, Cleveland Clinic, Abu Dhabi, United Arab Emirates
| | - Fatheya Alawadi
- Endocrine Section, Dubai Hospital, Dubai Academic Health Corporation (DAHC), Dubai, United Arab Emirates
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Science (MBRU), Dubai, United Arab Emirates
| | - Abdullah Shehab
- Cardiology Division, Mediclinic Hospitals, Al Ain, United Arab Emirates
| | | | - Alaaeldin Bashier
- Endocrine Section, Dubai Hospital, Dubai Academic Health Corporation (DAHC), Dubai, United Arab Emirates
| | - Abdul Rauf Ghulam
- Benefits Design and Strategic Purchasing Department, Healthcare, Abu Dhabi, United Arab Emirates
| | | | - Hosam Zaky
- Cardiology Department, Dubai Hospital, Dubai Academic Health Corporation (DAHC), Dubai, United Arab Emirates
| | - Hussien Heshmat Kassemn
- Cardiology Department, Zulekha Hospitals, Dubai, United Arab Emirates
- Cardiology Department, Cairo University, Cairo, Egypt
| | - Jamila Bin Adi
- The Emirates Society of Internal Medicine, Internal Medicine Rashid Hospital, Dubai Health Authority, Dubai, United Arab Emirates
| | - Juwairia Tahir
- The Emirates Cardiac Society, Rashid Hospital, Dubai, United Arab Emirates
| | - Khadija Hafidh
- Internal Medicine Department, Rashid Hospital, Dubai Academic Health Corporation (DAHC), Dubai, United Arab Emirates
| | - Mohammed Farghali
- Medical Department, Dubai Medical College, Dubai, United Arab Emirates
| | - Mohamed Hassanien
- Endocrine Section, Dubai Hospital, Dubai Academic Health Corporation (DAHC), Dubai, United Arab Emirates
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Science (MBRU), Dubai, United Arab Emirates
| | - James Januzzi
- Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States
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Bilal A, Pratley R. Diabetes and cardiovascular disease in older adults. Ann N Y Acad Sci 2025; 1543:42-67. [PMID: 39666834 DOI: 10.1111/nyas.15259] [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] [Indexed: 12/14/2024]
Abstract
An aging population combined with a rapidly increasing prevalence of diabetes foreshadows a global epidemic of cardiovascular and kidney disease that threatens to halt improvements in life and health-span and will have particularly severe consequences in older adults. The management of diabetes has been transformed with the recent development of newer anti-hyperglycemic agents that have demonstrated superior efficacy. However, the utility of these drugs extends beyond glycemic control to benefits for managing obesity, cardiovascular disease (CVD), chronic kidney disease, and heart failure. Numerous cardiovascular and kidney outcomes trials of these drugs have played an instrumental role in shaping current guidelines for the management of diabetes and CVD. Older adults with diabetes are diverse in terms of their comorbidities, diabetic complications, and cognitive and functional status. Therefore, there is an unmet need for personalized management of diabetes and CVD in this population. In this review, we provide an overview of the epidemiological burden and management of diabetes and CVD in older adults. We then focus on randomized cardiovascular and kidney outcome trials with anti-hyperglycemic agents to propose an evidence-based approach to the management of diabetes in older adults with high risk of cardiovascular and kidney disease.
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Affiliation(s)
- Anika Bilal
- AdventHealth Translational Research Institute, Orlando, Florida, USA
| | - Richard Pratley
- AdventHealth Translational Research Institute, Orlando, Florida, USA
- AdventHealth Diabetes Institute, Orlando, Florida, USA
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Shi S, Li X, Chen Y, Li J, Dai Y. Cardiovascular Therapy Benefits of Novel Antidiabetic Drugs in Patients With Type 2 Diabetes Mellitus Complicated With Cardiovascular Disease: A Network Meta-Analysis. J Diabetes 2025; 17:e70044. [PMID: 39789833 PMCID: PMC11717902 DOI: 10.1111/1753-0407.70044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 12/04/2024] [Accepted: 12/08/2024] [Indexed: 01/12/2025] Open
Abstract
OBJECTIVE Provide an evidence-based basis for the selection of cardiovascular benefit drugs in Type 2 diabetes mellitus (T2DM) patients with cardiovascular disease (CVD). METHODS Conduct a comprehensive search of all relevant literature from PubMed, Embase, Web of Science, Cochrane Library, and Clinical Trials.gov from their establishment until December 13, 2023, and select randomized controlled trials (RCTs) that meet the pre-established inclusion and exclusion criteria. Use the Cochrane bias risk assessment tool to evaluate the quality of the included literature. Use R 4.3.2 software to conduct network meta-analysis for drug category comparison. RESULTS A total of 24 large-scale randomized controlled trials (RCTs) were included, including 19 intervention measures, and 172 803 patients participated in the study. The results of the network meta-analysis show that: GLP1RA (OR 0.89, 95% CI 0.81-0.97) and SGLT2i (OR 0.91, 95% CI 0.83-0.99) can reduce the occurrence of major adverse cardiovascular events (MACE), GLP1RA (OR 0.88, 95% CI 0.79-0.97) and SGLT2i (OR 0.89, 95% CI 0.81-0.99) reduced the risk of cardiovascular death. SGLT2i (OR 0.68, 95% CI 0.62-0.75) reduced the occurrence of hospitalization for heart failure, GLP1RA (OR 0.88, 95% CI 0.81-0.97) and SGLT2i (OR 0.89, 95% CI 0.80-0.97) reduced the occurrence of all-cause death. CONCLUSION In the comparison of new hypoglycemic drug classes, GLP1RA and SGLT2i reduced MACE, cardiovascular mortality and all-cause mortality in T2DM patients with CVD, with no significant difference in efficacy, and DPP4i was noninferior to placebo. Only GLP1RA reduced the risk of nonfatal stroke, and only SGLT2i reduced the risk of HHF.
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Affiliation(s)
- Saixian Shi
- School of PharmacySouthwest Medical UniversityLuzhouSichuan ProvinceChina
- Pangang Xichang HospitalXichangSichuan ProvinceChina
| | - Xiaofeng Li
- School of PharmacySouthwest Medical UniversityLuzhouSichuan ProvinceChina
| | - Ye Chen
- School of PharmacySouthwest Medical UniversityLuzhouSichuan ProvinceChina
| | - Jiahao Li
- School of PharmacySouthwest Medical UniversityLuzhouSichuan ProvinceChina
| | - Yan Dai
- Department of PharmacyAffiliated Hospital of Southwest Medical UniversityLuzhouSichuan ProvinceChina
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American Diabetes Association Professional Practice Committee, ElSayed NA, McCoy RG, Aleppo G, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Das SR, Echouffo-Tcheugui JB, Ekhlaspour L, Garg R, Khunti K, Kosiborod MN, Lal R, Lingvay I, Matfin G, Pandya N, Pekas EJ, Pilla SJ, Polsky S, Segal AR, Seley JJ, Stanton RC, Bannuru RR. 10. Cardiovascular Disease and Risk Management: Standards of Care in Diabetes-2025. Diabetes Care 2025; 48:S207-S238. [PMID: 39651970 PMCID: PMC11635050 DOI: 10.2337/dc25-s010] [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] [Indexed: 12/14/2024]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
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Lee JE, Kim BG, Won JC. Molecular Pathways in Diabetic Cardiomyopathy and the Role of Anti-hyperglycemic Drugs Beyond Their Glucose Lowering Effect. J Lipid Atheroscler 2025; 14:54-76. [PMID: 39911956 PMCID: PMC11791414 DOI: 10.12997/jla.2025.14.1.54] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 09/02/2024] [Accepted: 09/27/2024] [Indexed: 02/07/2025] Open
Abstract
Epidemiological evidence has shown that diabetes is associated with overt heart failure (HF) and worse clinical outcomes. However, the presence of a distinct primary diabetic cardiomyopathy (DCM) has not been easy to prove because the association between diabetes and HF is confounded by hypertension, obesity, microvascular dysfunction, and autonomic neuropathy. In addition, the molecular mechanisms underlying DCM are not yet fully understood, DCM usually remains asymptomatic in the early stage, and no specific biomarkers have been identified. Nonetheless, several mechanistic associations at the systemic, cardiac, and cellular/molecular levels explain different aspects of myocardial dysfunction, including impaired cardiac relaxation, compliance, and contractility. In this review, we focus on recent clinical and preclinical advances in our understanding of the molecular mechanisms of DCM and the role of anti-hyperglycemic agents in preventing DCM beyond their glucose lowering effect.
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Affiliation(s)
- Jie-Eun Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Health Insurance Service Ilsan Hospital, Goyang, Korea
| | - Byung Gyu Kim
- Division of Cardiology, Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea
| | - Jong Chul Won
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Sanggye Paik Hospital, Inje University College of Medicine, Seoul, Korea
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Zhang S, Sidra F, Alvarez CA, Kinaan M, Lingvay I, Mansi IA. Healthcare utilization, mortality, and cardiovascular events following GLP1-RA initiation in chronic kidney disease. Nat Commun 2024; 15:10623. [PMID: 39639039 PMCID: PMC11621321 DOI: 10.1038/s41467-024-54009-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 10/28/2024] [Indexed: 12/07/2024] Open
Abstract
Treatment with glucagon-like peptide-1 receptor agonists (GLP1-RA) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) may attenuate kidney disease progression and cardiovascular events but their real-world impact on healthcare utilization and mortality in this population are not well-defined. Here, we emulate a clinical trial that compares outcomes following initiation of GLP1-RA vs Dipeptidyl peptidase-4 inhibitors (DPP4i), as active comparators, in U.S. veterans aged 35 years of older with moderate to advanced CKD during fiscal years 2006 to 2021. Primary outcome was rate of acute healthcare utilization. Secondary outcomes were all-cause mortality and a composite of acute cardiovascular events. After propensity score matching (16,076 pairs) and 2.2 years mean follow-up duration, use of GLP1-RA in patients with moderate to advanced CKD was associated with lower annual rate of acute healthcare utilization and all-cause mortality. There was no significant difference in acute cardiovascular events.
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Affiliation(s)
- Shuyao Zhang
- Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Fnu Sidra
- Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- The Jones Center for Diabetes & Endocrine Wellness, Macon, GA, USA
| | - Carlos A Alvarez
- Department of Pharmacy Practice and Center for Excellence in Real World Evidence, Texas Tech University Health Science Center, Dallas, TX, USA
| | - Mustafa Kinaan
- Endocrinology, Diabetes, and Metabolism Fellowship, UCF HCA Healthcare GME, Orlando, FL, USA
- Department of Internal Medicine, University of Central Florida, College of Medicine, Orlando, FL, USA
| | - Ildiko Lingvay
- Department of Internal Medicine, Division of Endocrinology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- Peter O'Donnell Jr. School of Public Health, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ishak A Mansi
- Department of Internal Medicine, University of Central Florida, College of Medicine, Orlando, FL, USA.
- Education Services, Orlando VA Healthcare System, Orlando, FL, USA.
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Wang Y, Yu C, Zheng X, Wang Y, Zhang W. Effects of dipeptidyl peptidase 4 inhibitors on the risk of acute respiratory failure in patients with type 2 diabetes mellitus: a meta-analysis of cardiovascular outcomes trials. Endocr J 2024; 71:1175-1181. [PMID: 39261020 PMCID: PMC11778361 DOI: 10.1507/endocrj.ej24-0164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 08/16/2024] [Indexed: 09/13/2024] Open
Abstract
Dipeptidyl peptidase 4 (DPP-4) inhibitors are new antidiabetic drugs. Their effects on the respiratory system remain unclear. This study aimed to determine the association between DDP-4 inhibitors and acute respiratory failure (ARF) among patients with type 2 diabetes mellitus (T2DM). A meta-analysis was performed by searching the PubMed, Embase, and CENTRAL databases up to July 3rd, 2024, to identify randomized controlled, double-blind, and placebo controlled-cardiovascular outcomes trials (CVOTs) that enrolled participants with T2DM. A total of 6,532 studies were initially retrieved; ultimately, 5 large CVOTs enrolling 47,714 adult T2DM patients were included in the meta-analysis. Overall, there were a nonsignificant increase in the risk of ARF in the DDP-4 inhibitor group compared with the placebo group (RR, 1.72; 95% CI, 0.59 to 4.97; p = 0.319). This is the first meta-analysis to evaluate the association between DDP-4 inhibitors and ARF among T2DM patients. In general, these findings suggest that DPP-4 inhibitors may slightly, but non-significantly, increase the risk of ARF in T2DM patients. As few studies are available and few ARF events occurred, further well-designed large-scale studies need to be performed.
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Affiliation(s)
- Yan Wang
- College of Agroforestry and Medicine, The Open University of China, Beijing, 100039, People’s Republic of China
| | - Caiyuan Yu
- College of Agroforestry and Medicine, The Open University of China, Beijing, 100039, People’s Republic of China
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, 999078, People’s Republic of China
| | - Xiaoyan Zheng
- College of Agroforestry and Medicine, The Open University of China, Beijing, 100039, People’s Republic of China
| | - Yaya Wang
- College of Agroforestry and Medicine, The Open University of China, Beijing, 100039, People’s Republic of China
| | - Wei Zhang
- State Key Laboratory of Quality Research in Chinese Medicines, Macau Institute for Applied Research in Medicine and Health, Macau University of Science and Technology, Macau, 999078, People’s Republic of China
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Kafai Yahyavi S, Kristensen PL, Hjorthøj C, Hansen KB, Krogh J. The use of composite endpoints in cardiovascular outcome trials for diabetes: A review of 22 randomized clinical trials published since 2008. Diabetes Obes Metab 2024; 26:5537-5545. [PMID: 39223850 DOI: 10.1111/dom.15907] [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: 05/21/2024] [Revised: 08/08/2024] [Accepted: 08/12/2024] [Indexed: 09/04/2024]
Abstract
AIM To describe the use of composite endpoints (CEs) in cardiovascular outcome trials (CVOTs) of type 2 diabetes and to evaluate the significance of the individual outcomes included within these CEs from the perspectives of both patients and clinicians. Secondary objectives were to estimate the gradient of treatment effects and events across outcomes. MATERIALS AND METHODS Eligible studies were randomized controlled trials assessing CV outcomes for patients with diabetes from 2008 and onwards. Trials were identified by searching the reports from the CVOT Summit of the Diabetes & CV Disease EASD (European Association for the Study of Diabetes) Study Group. The individual outcomes comprising the CE were compared for differences in importance for patients and clinicians, proportion of events, and effect size. RESULTS We included 22 trials randomizing a mean of 8098 patients to an active intervention or a comparator group for an average of 33 months (standard deviation 16). All primary outcomes were CEs, and from a patient perspective there was no gradient of importance across outcomes in 22 of 22 (100%) CEs, while the gradient was small in 22 of 22 (100%) from a clinician perspective. The gradient of effect was moderate to large in 9 of 18 (50%) reporting studies, while assessment of events was available in 15 of 22 studies (68%), finding that three of 15 (20%) had a gradient of effect of more than 5% points between included outcomes. In 10 of 22 (45%) trial reports, the results were not clearly presented as based on a CE. CONCLUSIONS To avoid misinterpretation, clinicians and regulatory authorities should be careful when interpreting the results of trials, of which the main outcomes are CEs.
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Affiliation(s)
- Sam Kafai Yahyavi
- Division of Translational Endocrinology, Department of Endocrinology and Internal Medicine, Copenhagen University Hospital, Copenhagen, Denmark
- Group of Skeletal, Mineral and Gonadal Endocrinology, Department of Growth and Reproduction, Rigshospitalet, Copenhagen, Denmark
| | - Peter Lommer Kristensen
- Department of Endocrinology and Nephrology, Nordsjællands Hospital, Hillerød, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Carsten Hjorthøj
- Copenhagen Research Centre for Mental Health, Copenhagen University Hospital, Copenhagen, Denmark
- Department of Public Health, Section of Epidemiology, University of Copenhagen, Copenhagen, Denmark
| | | | - Jesper Krogh
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- Clinic for Pituitary Disorders, Department of Medicine, Zealand University Hospital, Køge, Denmark
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Eroglu TE, Coronel R, Folke F, Gislason G. Glucagon-like peptide-1 receptor agonist use is associated with reduced risk of out-of-hospital cardiac arrest in women with type 2 diabetes: A nationwide nested case-control study. Resusc Plus 2024; 20:100821. [PMID: 39569410 PMCID: PMC11577171 DOI: 10.1016/j.resplu.2024.100821] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 10/25/2024] [Accepted: 10/26/2024] [Indexed: 11/22/2024] Open
Abstract
Objective Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) improve cardiovascular outcomes in patients with type 2 diabetes, but few studies have studied the risk of out-of-hospital cardiac arrest (OHCA). We investigated whether GLP-1 RA use reduce OHCA risk in type 2 diabetes when compared to dipeptidyl peptidase-4 inhibitor (DPP-4i) use. Methods We identified all patients having a redeemed prescription of a glucose-lowering drug between 1995 and 2019 and excluded patients with a first-time redeemed prescription consisting of insulin. Within this cohort, we nested a case-control population comprising all OHCA-cases from presumed cardiac causes between 2013 and 2019. OHCA-cases were matched 1:5 to non-OHCA controls of the same sex and age on the date of OHCA. The odds ratios (ORs) and corresponding 95% confidence intervals (95%-CIs) of OHCA were reported comparing GLP-1 RAs versus DPP-4is. Results We identified 3,618 OHCA-cases from presumed cardiac causes and matched them to 18,090 non-OHCA controls. GLP-1 RAs were used by 269 (7.44%) cases and 1297 (7.17%) controls, and conferred no increase in the overall odds of OHCA compared with DPP-4i use (OR:0.89, 95%-CI 0.74-1.07). However, stratification according to sex revealed that OHCA risk was significantly reduced in women (OR:0.59, 95%-CI 0.40-0.86) but not in men (OR:1.01, 95%-CI 0.82-1.26, P-value interaction:0.0093). The OR of OHCA did not vary significantly when stratifying for age, duration of diabetes, chronic kidney disease, or presence of cardiovascular disease. Conclusion Our findings indicate that GLP-1 RA use is not associated with a reduced risk of OHCA in Danish individuals with type 2 diabetes when compared to DPP-4is.
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Affiliation(s)
- Talip E. Eroglu
- Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Gentofte Hospitalsvej 6, PO Box 635, DK-2900 Hellerup, Denmark
| | - Ruben Coronel
- Amsterdam UMC, Academic Medical Center, University of Amsterdam, Department of Experimental and Clinical Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, the Netherlands
| | - Fredrik Folke
- Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Gentofte Hospitalsvej 6, PO Box 635, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, University of Copenhagen, Blegdamsvej 3B, DK-2200 Copenhagen, Denmark
| | - Gunnar Gislason
- Department of Cardiology, Copenhagen University Hospital - Herlev and Gentofte, Gentofte Hospitalsvej 6, PO Box 635, DK-2900 Hellerup, Denmark
- The Danish Heart Foundation, Department of Research, Vognmagergade 7, DK-1120 Copenhagen, Denmark
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Zhang X, Tong WK, Xia Q, Tang Z. The impact of dipeptidyl peptidase 4 inhibitors on health-related quality of life in patients with type 2 diabetes mellitus: a systematic review and meta-analysis. Qual Life Res 2024; 33:3175-3188. [PMID: 39096426 DOI: 10.1007/s11136-024-03753-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2024] [Indexed: 08/05/2024]
Abstract
PURPOSE To evaluate the impact of dipeptidyl peptidase 4 (DPP-4) inhibitors on Health-related quality of life (HRQOL) in patients with type 2 diabetes mellitus (T2DM) compared with other hypoglycemic agents. METHODS A systematic review and meta-analysis based on randomized controlled trials was conducted following the Cochrane Handbook and PRISMA. Studies were identified by searching PubMed (MEDLINE), EMBASE, Web of Science, CNKI, WANGFANG DATA, VIP DATABASE, Google Scholar, and Cochrane Central Register of Controlled Trials from database inception to Dec 30, 2023. The main result was HRQOL scores. The outcomes were extracted using the mean difference (MD) from each study. Sensitivity analysis and subgroup analysis were also performed. RESULTS Forty studies (4,579 participants) were included, with 32 pooled for meta-analysis. DPP-4 inhibitors alongside conventional treatment significantly enhanced HRQOL compared to conventional treatment alone (MD = 9.85, 95% CI [7.98-11.71], P < 0.001; heterogeneity, I2 = 94%, P < 0.001), as assessed by SF-36 using a random-effects model. No additional benefit was found when measured by DTR-QOL using a fixed-effects model (MD = 2.29, 95% CI [-0.06-4.64], P = 0.06; heterogeneity, I2 = 49%, P = 0.1) and compared to SGLT-2 inhibitors. Subgroup analysis indicated that DPP-4 inhibitors favored patients ≥ 60 years old on medication for ≥ 6 months. CONCLUSIONS DPP-4 inhibitors were superior for T2DM HRQOL improvement. More long-term, multicenter evidence is needed to generalize findings and compare them with newer hypoglycemic agents. SYSTEMATIC REVIEW REGISTRATION PROSPERO: CRD42023440134.
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Affiliation(s)
- Xinyue Zhang
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China
| | - Wai Kei Tong
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China
| | - Qian Xia
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China
| | - Zhijia Tang
- Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Pudong New District, Shanghai, 201203, China.
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Sisti A, Zullo A, Gutman R. A Bayesian method for adverse effects estimation in observational studies with truncation by death. Stat Methods Med Res 2024; 33:2079-2097. [PMID: 39501712 PMCID: PMC11955163 DOI: 10.1177/09622802241283170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2024]
Abstract
Death among subjects is common in observational studies evaluating the causal effects of interventions among geriatric or severely ill patients. High mortality rates complicate the comparison of the prevalence of adverse events between interventions. This problem is often referred to as outcome "truncation" by death. A possible solution is to estimate the survivor average causal effect, an estimand that evaluates the effects of interventions among those who would have survived under both treatment assignments. However, because the survivor average causal effect does not include subjects who would have died under one or both arms, it does not consider the relationship between adverse events and death. We propose a Bayesian method which imputes the unobserved mortality and adverse event outcomes for each participant under the intervention they did not receive. Using the imputed outcomes we define a composite ordinal outcome for each patient, combining the occurrence of death and the adverse event in an increasing scale of severity. This allows for the comparison of the effects of the interventions on death and the adverse event simultaneously among the entire sample. We implement the procedure to analyze the incidence of heart failure among geriatric patients being treated for Type II diabetes with sulfonylureas or dipeptidyl peptidase-4 inhibitors.
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Affiliation(s)
- Anthony Sisti
- Department of Biostatistics, Brown University, Providence, RI, USA
| | - Andrew Zullo
- Department of Epidemiology, Brown University, Providence, RI, USA
- Department of Health Services, Policy and Practice, Brown University, Providence, RI, USA
| | - Roee Gutman
- Department of Biostatistics, Brown University, Providence, RI, USA
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Orozco-Beltrán D, Brotons-Cuixart C, Banegas JR, Gil-Guillen VF, Cebrián-Cuenca AM, Martín-Rioboó E, Jordá-Baldó A, Vicuña J, Navarro-Pérez J. [Cardiovascular preventive recommendations. PAPPS 2024 thematic updates]. Aten Primaria 2024; 56 Suppl 1:103123. [PMID: 39613355 PMCID: PMC11705607 DOI: 10.1016/j.aprim.2024.103123] [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: 08/01/2024] [Revised: 09/22/2024] [Accepted: 09/23/2024] [Indexed: 12/01/2024] Open
Abstract
The recommendations of the semFYC's Program for Preventive Activities and Health Promotion (PAPPS) for the prevention of vascular diseases (VD) are presented. New in this edition are new sections such as obesity, chronic kidney disease and metabolic hepatic steatosis, as well as a 'Don't Do' section in the different pathologies treated. The sections have been updated: epidemiological review, where the current morbidity and mortality of CVD in Spain and its evolution as well as the main risk factors are described; vascular risk (VR) and recommendations for the calculation of CV risk; main risk factors such as arterial hypertension, dyslipidemia and diabetes mellitus, describing the method for their diagnosis, therapeutic objectives and recommendations for lifestyle measures and pharmacological treatment; indications for antiplatelet therapy, and recommendations for screening of atrial fibrillation, and recommendations for management of chronic conditions. The quality of testing and the strength of the recommendation are included in the main recommendations.
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Affiliation(s)
- Domingo Orozco-Beltrán
- Medicina Familiar y Comunitaria, Unidad de Investigación CS Cabo Huertas, Departamento San Juan de Alicante. Departamento de Medicina Clínica. Centro de Investigación en Atención Primaria. Universidad Miguel Hernández, San Juan de Alicante, España.
| | - Carlos Brotons-Cuixart
- Medicina Familiar y Comunitaria. Institut de Recerca Sant Pau (IR SANT PAU). Equipo de Atención Primaria Sardenya, Barcelona, España
| | - José R Banegas
- Medicina Preventiva y Salud Pública, Universidad Autónoma de Madrid y CIBERESP, Madrid, España
| | - Vicente F Gil-Guillen
- Medicina Familiar y Comunitaria. Hospital Universitario de Elda. Departamento de Medicina Clínica. Centro de Investigación en Atención Primaria. Universidad Miguel Hernández, San Juan de Alicante, España
| | - Ana M Cebrián-Cuenca
- Medicina Familiar y Comunitaria, Centro de Salud Cartagena Casco Antiguo, Cartagena, Murcia, España. Instituto de Investigación Biomédica de Murcia (IMIB), Universidad Católica de Murcia, Murcia, España
| | - Enrique Martín-Rioboó
- Medicina Familiar y Comunitaria, Centro de Salud Poniente, Córdoba. Departamento de Medicina. Universidad de Córdoba. Grupo PAPPS, Córdoba, España
| | - Ariana Jordá-Baldó
- Medicina Familiar y Comunitaria. Centro de Salud Plasencia II, Plasencia, Cáceres, España
| | - Johanna Vicuña
- Medicina Preventiva y Salud Pública. Hospital de la Sant Creu i Sant Pau, Barcelona, España
| | - Jorge Navarro-Pérez
- Medicina Familiar y Comunitaria, Centro de Salud Salvador Pau (Valencia). Departamento de Medicina. Universidad de Valencia. Instituto de Investigación INCLIVA, Valencia, España
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Khan F, Hussain T, Chaudhry TZ, Payal F, Shehryar A, Rehman A, Ramadhan A, Hayat MT, Dabas MM, Khan M. Comparing the Efficacy and Long-Term Outcomes of Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors, Dipeptidyl Peptidase-4 (DPP-4) Inhibitors, Metformin, and Insulin in the Management of Type 2 Diabetes Mellitus. Cureus 2024; 16:e74400. [PMID: 39723311 PMCID: PMC11669386 DOI: 10.7759/cureus.74400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/24/2024] [Indexed: 12/28/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder characterized by hyperglycemia, insulin resistance, and decreased insulin secretion. With its rising global prevalence, effective management strategies are critical to reducing morbidity and mortality. This systematic review compares the efficacy, safety, and long-term outcomes of four major pharmacological treatments for T2DM: sodium-glucose cotransporter-2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, and insulin. We focused on randomized controlled trials (RCTs) published within the last five years (2019-2024) to provide an up-to-date assessment of glycemic control, cardiovascular and renal benefits, weight effects, and the risk of hypoglycemia. The review highlights that while all four medication classes effectively reduce HbA1c levels, SGLT2 inhibitors stand out for their additional cardiovascular and renal benefits, including significant reductions in major adverse cardiovascular events and chronic kidney disease progression. Metformin remains a cornerstone first-line therapy due to its safety, efficacy, and affordability. DPP-4 inhibitors are a weight-neutral, well-tolerated option, although their efficacy may diminish over time. Insulin, while the most potent glucose-lowering agent, carries a higher risk of hypoglycemia and weight gain. Our findings emphasize the importance of personalized, patient-centered approaches that account for the distinct therapeutic profiles of these treatments. Future research should prioritize head-to-head comparisons and optimal therapy sequencing to refine treatment guidelines for diverse patient populations.
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Affiliation(s)
- Farhan Khan
- Internal Medicine, Rehman Medical Institute, Peshawar, PAK
| | - Tanjil Hussain
- Internal Medicine, London North West Hospitals NHS Trust, London, GBR
| | | | - Fnu Payal
- Internal Medicine, Ghulam Muhammad Mahar Medical College, Karachi, PAK
| | | | | | - Afif Ramadhan
- Internal Medicine, Gadjah Mada University, Yogyakarta, IDN
| | - Muhammad Tassaduq Hayat
- Internal Medicine, Chandka Medical College, Larkana, PAK
- Internal Medicine, Shaheed Mohtarma Benazir Bhutto Medical University, Larkana, PAK
| | | | - Mustafa Khan
- General Surgery, Nishtar Medical University, Multan, PAK
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Vigara LA, Villanego F, Orellana C, Eady M, Sánchez MG, Alonso M, García MB, Amaro JM, García T, Mazuecos A. Use of glucagon-like peptide type 1 receptor agonists in kidney transplant recipients. Nefrologia 2024; 44:885-893. [PMID: 39645509 DOI: 10.1016/j.nefroe.2024.11.007] [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: 03/29/2023] [Revised: 06/22/2023] [Accepted: 06/23/2023] [Indexed: 12/09/2024] Open
Abstract
INTRODUCTION In kidney transplant (KT) recipients diabetes mellitus (DM) are associated with an increased mortality and a poorer graft survival. Glucagon-like peptide 1 receptor agonists (GLP1-RA) have demonstrated cardiovascular and renal benefits in the general population. However, there is lacking evidence in KT recipients. OBJECTIVE To analyze the efficacy and safety of glucagon-like peptide 1 receptor GLP1-RA in a cohort of KT recipients. METHODS Multicenter retrospective cohort study of KT patients with DM who started subcutaneous GLP1-RA in 3 hospitals in the province of Cádiz between February 2016 and July 2022. Estimated glomerular filtration rate (eGFR), proteinuria, and weight at baseline and after 6 and 12 months were collected. We analyzed glycemic control, blood pressure, lipid profile, and doses and trough levels of tacrolimus. We document episodes of acute rejection (AR), de novo donor-specific antibodies (dnDSA), and adverse effects. RESULTS During this period, 96 KT with DM started treatment with GLP1-RA, of which 84 had a minimum follow-up of 6 months and 61 were followed for 12 months. A significant reduction was observed in proteinuria (-19.1 mg/g, p = 0.000; -46.6 mg/g, p = 0.000), weight (-3.6 kg, p = 0.000; -3.6 kg, p = 0.000), glycosylated hemoglobin (-0.7%, p = 0.000; -0.9%, p = 0.000), systolic blood pressure (-7.5 mmHg, p = 0.013; -7.3 mmHg, p = 0.004), total cholesterol (-11.5 mg/dL, p = 0.001; -15.6 mg/dl, p = 0.002) and LDL cholesterol (-9.2 mg/dl, p = 0.002; -16.8 mg/dl, p = 0.000) at 6 months and 1 year of follow-up. The eGFR remained stable and the dose and trough levels of tacrolimus did not change. No episodes of AR or development of dnDSA were observed during follow-up. CONCLUSIONS GLP1-RA in KT patients can be a safe and effective option for the management of DM in KT.
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Affiliation(s)
- Luis Alberto Vigara
- Department of Nephrology, Puerta del Mar University Hospital, Cádiz, Spain; Department of Nephrology, Jerez de la Frontera University Hospital, Cádiz, Spain.
| | | | - Cristhian Orellana
- Department of Nephrology, Puerta del Mar University Hospital, Cádiz, Spain
| | - Myriam Eady
- Department of Nephrology, Jerez de la Frontera University Hospital, Cádiz, Spain
| | | | - Marta Alonso
- Department of Nephrology, Puerta del Mar University Hospital, Cádiz, Spain
| | - María Belén García
- Department of Nephrology, Jerez de la Frontera University Hospital, Cádiz, Spain
| | - José Manuel Amaro
- Department of Nephrology, Puerta del Mar University Hospital, Cádiz, Spain
| | - Teresa García
- Department of Nephrology, Puerta del Mar University Hospital, Cádiz, Spain
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Horii T, Oikawa Y, Kidowaki K, Shimada A, Mihara K. Factor affecting severe atherothrombotic cerebral infarction in patients with type 2 diabetes mellitus: Large-scale claim database analysis of Japan. J Diabetes Investig 2024; 15:1651-1662. [PMID: 39238289 PMCID: PMC11527821 DOI: 10.1111/jdi.14284] [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: 04/30/2024] [Revised: 06/28/2024] [Accepted: 07/22/2024] [Indexed: 09/07/2024] Open
Abstract
AIMS This study aimed to investigate the factors associated with the exacerbation of the severity of atherothrombotic brain infarction at discharge in patients with type 2 diabetes using a large-scale claims database. MATERIALS AND METHODS This retrospective cross-sectional study utilized the Medical Data Vision administrative claims database, a nationwide database in Japan using acute care hospital data, and the Diagnosis Procedure Combination system. Diagnosis Procedure Combination data collected between April 1, 2008, and December 31, 2022, were extracted. Patients with type 2 diabetes were included. Severe atherothrombotic brain infarction was defined as a modified Rankin scale score of ≥3. RESULTS Severe atherothrombotic brain infarction occurred in 43,916/99,864 (44.0%) patients with type 2 diabetes. The odds ratio for severe atherothrombotic brain infarction increased significantly per 10 year increments in age (odds ratio: 1.69, 95% confidence interval: 1.66-1.71). A body mass index of <25 kg/m2, with a body mass index of ≥25 kg/m2 as reference, also increased the risk for severe atherothrombotic brain infarction (odds ratio: 1.11, 95% confidence interval: 1.08-1.15). The odds ratios in insulin and dipeptidyl peptidase 4 inhibitor use were significantly higher than 1. In particular, statin use (odds ratio: 0.85, 95% confidence interval: 0.83-0.88), fibrate use (odds ratio: 0.68, 95% confidence interval: 0.59-0.78), aspirin use (odds ratio: 0.78, 95% confidence interval: 0.75-0.80), and P2Y12 inhibitor use (odds ratio: 0.88, 95% confidence interval: 0.85-0.91) were associated with a lower odds ratio for severe atherothrombotic brain infarction. CONCLUSIONS The active management of lipid levels using statins and fibrates may be beneficial in preventing the exacerbation of atherothrombotic brain infarction in type 2 diabetes patients.
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Affiliation(s)
- Takeshi Horii
- Department of Pharmacy, Faculty of PharmacyMusashino UniversityTokyoJapan
- Department of Endocrinology and Diabetes, School of MedicineSaitama Medical UniversitySaitamaJapan
| | - Yoichi Oikawa
- Department of Endocrinology and Diabetes, School of MedicineSaitama Medical UniversitySaitamaJapan
| | - Kasumi Kidowaki
- Department of Pharmacy, Faculty of PharmacyMusashino UniversityTokyoJapan
| | - Akira Shimada
- Department of Endocrinology and Diabetes, School of MedicineSaitama Medical UniversitySaitamaJapan
| | - Kiyoshi Mihara
- Department of Pharmacy, Faculty of PharmacyMusashino UniversityTokyoJapan
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Mahapatro A, Bozorgi A, Obulareddy SU, Jain SM, Reddy Korsapati R, Kumar A, Patel K, Soltani Moghadam S, Arya A, Jameel Alotaibi A, Keivanlou MH, Hassanipour S, Hasanpour M, Amini-Salehi E. Glucagon-like peptide-1 agonists in cardiovascular diseases: a bibliometric analysis from inception to 2023. Ann Med Surg (Lond) 2024; 86:6602-6618. [PMID: 39525800 PMCID: PMC11543192 DOI: 10.1097/ms9.0000000000002592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2024] [Accepted: 09/15/2024] [Indexed: 11/16/2024] Open
Abstract
Background In recent years, glucagon-like peptide-1 (GLP-1) agonists have garnered increasing attention for their potential cardiovascular benefits beyond glycemic control in patients with diabetes. Understanding the research landscape surrounding GLP-1 agonists and cardiovascular diseases (CVDs) is crucial for informing clinical practice and guiding future research endeavors. This bibliometric analysis aimed to comprehensively assess the scholarly output and trends in this field, shedding light on the evolving landscape of GLP-1 agonists' role in cardiovascular health. Methods The publications concerning GLP-1 agonists in CVDs were gathered from the Web of Science Core Collection, and visualizations were created utilizing Excel 2019, Cite Space, and VOS viewer software. Results and Conclusion Using bibliometric and visual methods, the research hotspots and trends regarding GLP-1 agonists in cardiovascular diseases were pinpointed. Additionally, a thriving interest in GLP-1 agonists research within cardiovascular medicine was observed, with a notable surge in publications from 2016 onwards. The analysis revealed that the United States and China are the leading contributors, accounting for over 50% of the total publications. The University of Copenhagen and the University of Toronto emerged as the most prolific institutions in this field. Co-citation analysis highlighted the influential role of landmark clinical trials, such as the LEADER, ELIXA, and EXSCEL. Keyword trend analysis identified the emergence of newer GLP-1 agonists, such as tirzepatide and semaglutide, as well as a growing focus on topics like 'healthy obesity' and chronic kidney disease. These findings suggest that the research landscape is evolving, with a focus on expanding the therapeutic applications of GLP-1 agonists beyond glycemic control. Overall, this bibliometric analysis provided insights into the current state and future directions of research on GLP-1 agonists and their impact on cardiovascular health, guiding future research endeavors, and informing clinical practice.
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Affiliation(s)
| | - Ali Bozorgi
- Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Shika M. Jain
- MVJ Medical College and Research Hospital, Bengaluru, India
| | | | | | - Kristina Patel
- Shenyang North New Area, Shenyang, Liaoning Province, People’s Republic of China
| | - Saman Soltani Moghadam
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Arash Arya
- Department of Internal Medicine III, Halle University Hospital, Halle (Saale), Germany
| | | | | | - Soheil Hassanipour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Maryam Hasanpour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Ehsan Amini-Salehi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
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50
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Sinclair MR, Ardehali M, Diamantidis CJ, Corsino L. The diabetes cardiovascular outcomes trials and racial and ethnic minority enrollment: impact, barriers, and potential solutions. Front Public Health 2024; 12:1412874. [PMID: 39525461 PMCID: PMC11545964 DOI: 10.3389/fpubh.2024.1412874] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 09/13/2024] [Indexed: 11/16/2024] Open
Abstract
Type 2 diabetes (T2D) affects millions of individuals worldwide and is a well-documented risk factor for cardiovascular (CV) disease and chronic kidney disease, both of which are leading causes of mortality. Racial and ethnic minority groups in the US, including but not limited to Hispanic/Latino, non-Hispanic Black, and Southeast Asian individuals, are disproportionately burdened by both T2D and its adverse outcomes. In recent years, there have been numerous cardiovascular outcomes trials (CVOTs) on novel antidiabetic therapies, including the dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors. CVOTs's initial aim was to demonstrate the cardiovascular safety of these drugs. Unexpected CV and kidney protective effects were found, specifically among the GLP-1 RAs and the SGLT2 inhibitors. These benefits informed the new paradigm of the management of patients with T2D. However, some experts argued that the lack of racial and ethnic minority group representation in these trials represented a challenge. While the downstream effects of this lack of representation must be further elucidated, it is clear and recognized that efforts need to be made to include a more representative sample in future CVOTs, specifically including individuals from those groups most burdened by T2D and its complications, if clinicians are to have an accurate picture of the benefits and potential pitfalls of utilizing these drugs in a real-world setting. In this comprehensive review, we briefly summarize the significant findings from the CVOTs, report the lack of representation of Hispanic/Latino, non-Hispanic Black, and Southeast Asian individuals in the CVOTs, investigate the barriers to recruiting racial and ethnic minority groups into clinical trials, and suggest potential solutions to overcome these obstacles at the patient-, provider-, and sponsor/system-level in future trials.
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Affiliation(s)
- Matthew R. Sinclair
- Department of Medicine, Division of Nephrology, Duke University School of Medicine, Durham, NC, United States
- Duke Clinical Research Institute, Durham, NC, United States
| | - Mariam Ardehali
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, United States
| | - Clarissa J. Diamantidis
- Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, United States
| | - Leonor Corsino
- Department of Medicine, Division of Endocrinology, Metabolism, and Nutrition, Duke University School of Medicine, Durham, NC, United States
- Duke Department of Population Health Sciences, Durham, NC, United States
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