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Yokomizo H, Kawanami D, Sonoda N, Ono Y, Maeda Y, Itoh J, Tohyama T, Hirose M, Watanabe H, Kishimoto J, Ogawa Y, Inoguchi T. Relationship of dietary intake and eating behaviors with glycemic control and body weight under long-term treatment with dapagliflozin: an exploratory prospective study. Diabetol Int 2025; 16:303-315. [PMID: 40166435 PMCID: PMC11954782 DOI: 10.1007/s13340-025-00794-1] [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: 08/22/2024] [Accepted: 01/09/2025] [Indexed: 04/02/2025]
Abstract
Sodium glucose cotransporter-2 (SGLT2) inhibitors improve glycemic control and reduce body weight (BW) in individuals with type 2 diabetes. However, there are still concerns that compensatory hyperphagia may affect their effects. Here, we performed an exploratory prospective study to investigate whether dietary intake and/or eating behaviors affect glycemic control and BW under long-term treatment with dapagliflozin. Fifty-three Japanese individuals with type 2 diabetes received dapagliflozin 5 mg daily for 104 weeks, with frequent assessments of HbA1c, BW, body composition, dietary intake, and eating behaviors. Dietary intake was evaluated using a brief self-administered diet history questionnaire, and eating behavior was evaluated using the Dutch Eating Behavior Questionnaire. The study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000019192). At 104 weeks, HbA1c decreased by 0.5% and BW decreased by 2.8 kg (both p < 0.001), with a dominant decrease in body fat mass by 2.2 kg (p < 0.001). No significant change was observed in calorie intake or the proportion of carbohydrates, protein, and fat. The change (∆) in HbA1c was significantly correlated with basal HbA1c, basal triglyceride levels, ∆BMI (body mass index), ∆BFP (body fat percentage), and ∆ferritin levels. The ∆BMI was significantly correlated with only the ∆BFP. Neither the ∆HbA1c nor ∆BMI was significantly correlated with dietary intake, any type of eating behavior, or changes in these parameters during this study. In conclusion, dapagliflozin treatment improved glycemic control and reduced BW without being affected by any changes in dietary intake or eating behavior over 104 weeks. Supplementary Information The online version contains supplementary material available at 10.1007/s13340-025-00794-1.
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Affiliation(s)
- Hisashi Yokomizo
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | - Daiji Kawanami
- Department of Endocrinology and Diabetes, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180 Japan
| | | | - Yasuhiro Ono
- Department of Internal Medicine, Takagi Hospital, Fukuoka, Japan
| | - Yasutaka Maeda
- MINAMI Diabetes Clinical Research Center, Clinic Masae Minami, Fukuoka, Japan
| | - Jun Itoh
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
| | - Takeshi Tohyama
- Center for Advanced Medical Open Innovation, Kyushu University, Fukuoka, Japan
| | - Masayuki Hirose
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Hiroko Watanabe
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Junji Kishimoto
- Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Yoshihiro Ogawa
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
| | - Toyoshi Inoguchi
- Fukuoka City Health Promotion Support Center, Fukuoka City Medical Association, Fukuoka, Japan
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Ikonomidis I, Pavlidis G, Pliouta L, Katogiannis K, Maratou E, Thymis J, Michalopoulou E, Prentza V, Katsanaki E, Vlachomitros D, Kountouri A, Korakas E, Andreadou I, Kouretas D, Parissis J, Lambadiari V. Effects of Glucagon-Like Peptide-1 Receptor Agonists, Sodium-Glucose Cotransporter-2 Inhibitors, and Their Combination on Neurohumoral and Mitochondrial Activation in Patients With Diabetes. J Am Heart Assoc 2025; 14:e039129. [PMID: 40008510 DOI: 10.1161/jaha.124.039129] [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: 09/26/2024] [Accepted: 01/24/2025] [Indexed: 02/27/2025]
Abstract
BACKGROUND We investigated the effects of the combined treatment with glucagon like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) on NT-proBNP (N-terminal pro-brain natriuretic peptide), GDF-15 (growth differentiation factor 15), and MOTS-c (mitochondrial-derived peptide-c) in patients with type 2 diabetes (T2D) and high or very high cardiovascular risk. METHODS We studied 163 consecutive patients with type 2 diabetes who were treated with insulin (n=40), liraglutide (n=41), empagliflozin (n=42), or their combination (GLP-1RA+SGLT-2i) (n=40) and were matched using propensity score analysis. We measured the following at baseline and 4 and 12 months of treatment: (1) NT-proBNP, GDF-15, and MOTS-c; (2) 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid), and (3) left ventricular global longitudinal strain, left atrial strain during atrial reservoir phase, and global work index using speckle-tracking imaging. RESULTS At 12 months, GLP-1RA, SGLT-2i, and their combination showed a greater reduction of NT-proBNP (-43.1% versus -54.2% versus -56.9% versus -14.7%) and GDF-15 than insulin. Only treatment with SGLT-2i and GLP-1RA+SGLT-2i improved MOTS-c. GLP-1RA, SGLT-2i, or GLP-1RA+SGLT-2i provided an increase of global longitudinal strain, left atrial strain, and global work index compared with insulin. In all patients, the reduction of NT-proBNP was associated with the improvement of global longitudinal strain, left atrial strain during atrial reservoir phase, and global work index; the decrease of GDF-15 with the increase of ABTS and MOTS-c; and the increase of MOTs-c with improved global longitudinal strain and constructive myocardial work at 12 months (P<0.05). CONCLUSIONS Twelve-month treatment with combination of GLP-1RA+SGLT-2i was associated with a greater reduction of neurohumoral markers and increase of antioxidant ability than each treatment alone and insulin. SGLT-2i appear more effective in the improvement of neurohumoral and mitochondrial activation. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifier: NCT03878706.
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Affiliation(s)
- Ignatios Ikonomidis
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - George Pavlidis
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - Loukia Pliouta
- 2nd Propaedeutic Department of Internal Medicine, Research Unit and Diabetes Center, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Athens Greece
| | - Konstantinos Katogiannis
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - Eirini Maratou
- Laboratory of Clinical Biochemistry, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Athens Greece
| | - John Thymis
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - Eleni Michalopoulou
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - Vasiliki Prentza
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - Eleni Katsanaki
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - Dimitrios Vlachomitros
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - Aikaterini Kountouri
- 2nd Propaedeutic Department of Internal Medicine, Research Unit and Diabetes Center, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Athens Greece
| | - Emmanouil Korakas
- 2nd Propaedeutic Department of Internal Medicine, Research Unit and Diabetes Center, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Athens Greece
| | - Ioanna Andreadou
- Laboratory of Pharmacology, Faculty of Pharmacy National and Kapodistrian University of Athens Athens Greece
| | - Dimitrios Kouretas
- Department of Biochemistry and Biotechnology University of Thessaly Larissa Greece
| | - John Parissis
- 2nd Department of Cardiology, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Greece
| | - Vaia Lambadiari
- 2nd Propaedeutic Department of Internal Medicine, Research Unit and Diabetes Center, School of Medicine University General Hospital "Attikon", National and Kapodistrian University of Athens Athens Greece
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Deo R, Dubin RF, Ren Y, Wang J, Feldman H, Shou H, Coresh J, Grams ME, Surapaneni AL, Cohen JB, Kansal M, Rahman M, Dobre M, He J, Kelly T, Go AS, Kimmel PL, Vasan RS, Segal MR, Li H, Ganz P. Proteomic Assessment of the Risk of Secondary Cardiovascular Events among Individuals with CKD. J Am Soc Nephrol 2025; 36:231-241. [PMID: 39325542 PMCID: PMC11801749 DOI: 10.1681/asn.0000000502] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2024] [Accepted: 09/20/2024] [Indexed: 09/28/2024] Open
Abstract
Key Points Machine learning and large-scale proteomics led to a 16-protein secondary cardiovascular risk model in patients with CKD. Hepatic fibrosis and liver X receptor activation represented biologic pathways that link kidney disease and risk of secondary cardiovascular events. An understanding of the circulating proteins associated with secondary cardiovascular events may help to identify novel therapeutic targets. Background Cardiovascular risk models have been developed primarily for incident events. Well-performing models are lacking to predict secondary cardiovascular events among people with a history of coronary heart disease, stroke, or heart failure who also have CKD. We sought to develop a proteomic risk score for cardiovascular events in individuals with CKD and a history of cardiovascular disease. Methods We measured 4638 plasma proteins among 1067 participants from the Chronic Renal Insufficiency Cohort (CRIC) and 536 individuals from the Atherosclerosis Risk in Communities (ARIC) Cohort. All had non–dialysis-dependent CKD and coronary heart disease, heart failure, or stroke at study baseline. A proteomic risk model for secondary cardiovascular events was derived by elastic net regression in CRIC, validated in ARIC, and compared with clinical models. Biologic mechanisms of secondary events were characterized through proteomic pathway analysis. Results A 16-protein risk model was superior to the Framingham Risk Score for secondary events, including a modified score that included eGFR. In CRIC, the annualized area under the receiver operating characteristic curve (area under the curve) within 1–5 years ranged between 0.77 and 0.80 for the protein model and 0.57 and 0.72 for the clinical models. These findings were replicated in the ARIC validation cohort. Biologic pathway analysis identified pathways and proteins for cardiac remodeling and fibrosis, vascular disease, and thrombosis. Conclusions The proteomic risk model for secondary cardiovascular events outperformed clinical models on the basis of traditional risk factors and eGFR.
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Affiliation(s)
- Rajat Deo
- Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ruth F. Dubin
- Department of Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Yue Ren
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Jianqiao Wang
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Harold Feldman
- Patient-Centered Outcomes Research Institute, Washington, DC
| | - Haochang Shou
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Josef Coresh
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland
- Department of Medicine, Johns Hopkins University, Baltimore, Maryland
| | - Morgan E. Grams
- Division of Precision Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York
| | - Aditya L. Surapaneni
- Division of Precision Medicine, Department of Medicine, New York University Grossman School of Medicine, New York, New York
| | - Jordana B. Cohen
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
- Renal, Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Mayank Kansal
- Division of Cardiology, University of Illinois at Chicago, Chicago, Illinois
| | - Mahboob Rahman
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Mirela Dobre
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana
| | - Tanika Kelly
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana
| | - Alan S. Go
- Division of Research, Kaiser Permanente Northern California, Oakland, California
- The Department of Health Systems Science, Kaiser Permanente Bernard J. Tyson School of Medicine, Pasadena, California
| | - Paul L. Kimmel
- Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland
| | - Ramachandran S. Vasan
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
- Section of Cardiology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts
- Department of Epidemiology, Boston University School of Public Health, Boston, Massachusetts
| | - Mark R. Segal
- Department of Epidemiology and Biostatistics, University of California, San Francisco, California
| | - Hongzhe Li
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Peter Ganz
- Division of Cardiology, Zuckerberg San Francisco General Hospital and Department of Medicine, University of California San Francisco, San Francisco, California
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Augusto SN, Suresh A, Tang WHW. Ceramides as Biomarkers of Cardiovascular Diseases and Heart Failure. Curr Heart Fail Rep 2024; 22:2. [PMID: 39560878 DOI: 10.1007/s11897-024-00689-3] [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] [Accepted: 09/17/2024] [Indexed: 11/20/2024]
Abstract
PURPOSE OF REVIEW Ceramides are lipid species that play several physiological roles in the body, including stress response, inflammation, and apoptosis, and their involvement in lipid metabolism and energy production makes them crucial in the pathophysiology of heart failure (HF). RECENT FINDINGS Several species of ceramides and ceramide signatures have recently been investigated as possible biomarkers of cardiovascular disease (CVD), and risk scores have demonstrated prognostic value in stratifying patients by risk and possibly predicting adverse cardiac events. With growing interest in targeting metabolic dysfunction, understanding the role of ceramides in CVD also opens the possibility of novel therapeutics that target ceramide metabolism to improve cardiac function and cardiac outcomes in patients. Understanding the role of ceramides in CVD opens the possibility of novel diagnostics and theragnostic targeting ceramide metabolism to improve cardiac function and cardiac outcomes in patients with heart failure.
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Affiliation(s)
- Silvio N Augusto
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA, 9500 Euclid Avenue, Desk J3-4, 44195
| | - Abhilash Suresh
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA
| | - W H Wilson Tang
- Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA, 9500 Euclid Avenue, Desk J3-4, 44195.
- Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA.
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.
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Pham LT, Mangmool S, Parichatikanond W. Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases. ACS Pharmacol Transl Sci 2024; 7:3279-3298. [PMID: 39539254 PMCID: PMC11555527 DOI: 10.1021/acsptsci.4c00240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2024] [Revised: 09/11/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.
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Affiliation(s)
- Linh Thi
Truc Pham
- Biopharmaceutical
Sciences Program, Faculty of Pharmacy, Mahidol
University, Bangkok, 10400 Thailand
- Department
of Pharmacology, Faculty of Pharmacy, Mahidol
University, Bangkok, 10400 Thailand
| | - Supachoke Mangmool
- Department
of Pharmaceutical Care, Faculty of Pharmacy, Chiang Mai University, Chiang
Mai, 50200 Thailand
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Mandla R, Lorenz K, Yin X, Bocher O, Huerta-Chagoya A, Arruda AL, Piron A, Horn S, Suzuki K, Hatzikotoulas K, Southam L, Taylor H, Yang K, Hrovatin K, Tong Y, Lytrivi M, Rayner NW, Meigs JB, McCarthy MI, Mahajan A, Udler MS, Spracklen CN, Boehnke M, Vujkovic M, Rotter JI, Eizirik DL, Cnop M, Lickert H, Morris AP, Zeggini E, Voight BF, Mercader JM. Multi-omics characterization of type 2 diabetes associated genetic variation. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.07.15.24310282. [PMID: 39072045 PMCID: PMC11275663 DOI: 10.1101/2024.07.15.24310282] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/30/2024]
Abstract
Discerning the mechanisms driving type 2 diabetes (T2D) pathophysiology from genome-wide association studies (GWAS) remains a challenge. To this end, we integrated omics information from 16 multi-tissue and multi-ancestry expression, protein, and metabolite quantitative trait loci (QTL) studies and 46 multi-ancestry GWAS for T2D-related traits with the largest, most ancestrally diverse T2D GWAS to date. Of the 1,289 T2D GWAS index variants, 716 (56%) demonstrated strong evidence of colocalization with a molecular or T2D-related trait, implicating 657 cis-effector genes, 1,691 distal-effector genes, 731 metabolites, and 43 T2D-related traits. We identified 773 of these cis- and distal-effector genes using either expression QTL data from understudied ancestry groups or inclusion of T2D index variants enriched in underrepresented populations, emphasizing the value of increasing population diversity in functional mapping. Linking these variants, genes, metabolites, and traits into a network, we elucidated mechanisms through which T2D-associated variation may impact disease risk. Finally, we showed that drugs targeting effector proteins were enriched in those approved to treat T2D, highlighting the potential of these results to prioritize drug targets for T2D. These results represent a leap in the molecular characterization of T2D-associated genetic variation and will aid in translating genetic findings into novel therapeutic strategies.
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Affiliation(s)
- Ravi Mandla
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Kim Lorenz
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania - Perelman School of Medicine, Philadelphia PA
| | - Xianyong Yin
- Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, China
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Ozvan Bocher
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Alicia Huerta-Chagoya
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Ana Luiza Arruda
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Graduate School of Experimental Medicine, Technical University of Munich, Munich, Germany
| | - Anthony Piron
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
- Interuniversity Institute of Bioinformatics in Brussels (IB2), Brussels, Belgium
- Machine Learning Group, Université Libre de Bruxelles, Brussels, Belgium
- Diabetes and Inflammation Laboratory, Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Susanne Horn
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Ken Suzuki
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK
- Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
- Department of Statistical Genetics, Osaka University Graduate School of Medicine, Suita, Japan
| | - Konstantinos Hatzikotoulas
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Lorraine Southam
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Henry Taylor
- Center for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA
- British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Heart and Lung Research Institute, University of Cambridge, Cambridge, UK
| | - Kaiyuan Yang
- Institute of Diabetes and Regeneration Research (IDR), Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Karin Hrovatin
- Institute of Computational Biology (ICB), Helmholtz Munich, Neuherberg, Germany
- School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany
| | - Yue Tong
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Maria Lytrivi
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
- Division of Endocrinology, Erasmus Hospital, Universite Libre de Bruxelles, Brussels, Belgium
| | - Nigel W. Rayner
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - James B. Meigs
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
| | - Mark I. McCarthy
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
- Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Anubha Mahajan
- Wellcome Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK
- Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK
| | - Miriam S. Udler
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
| | - Cassandra N. Spracklen
- Department of Biostatistics and Epidemiology, University of Massachusetts Amherst, Amherst, MA, USA
| | - Michael Boehnke
- Department of Biostatistics and Center for Statistical Genetics, University of Michigan, Ann Arbor, MI, USA
| | - Marijana Vujkovic
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Jerome I. Rotter
- Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, CA, USA
| | - Decio L. Eizirik
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
| | - Miriam Cnop
- ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles, Brussels, Belgium
- Division of Endocrinology, Erasmus Hospital, Universite Libre de Bruxelles, Brussels, Belgium
- WEL Research Institute, Wavre, Belgium
| | - Heiko Lickert
- Institute of Diabetes and Regeneration Research (IDR), Helmholtz Munich, Neuherberg, Germany
- German Center for Diabetes Research (DZD), Neuherberg, Germany
- School of Medicine, Technical University of Munich, Munich, Germany
| | - Andrew P. Morris
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- Centre for Genetics and Genomics Versus Arthritis, Centre for Musculoskeletal Research, Division of Musculoskeletal and Dermatological Sciences, University of Manchester, Manchester, UK
- Estonian Genome Centre, Institute of Genomics, University of Tartu, Tartu, Estonia
| | - Eleftheria Zeggini
- Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
- TUM School of Medicine and Health, Technical University of Munich and Klinikum Rechts der Isar, Munich, Germany
| | - Benjamin F. Voight
- Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
- Institute for Translational Medicine and Therapeutics, University of Pennsylvania - Perelman School of Medicine, Philadelphia PA
| | - Josep M. Mercader
- Programs in Metabolism and Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Diabetes Unit, Endocrine Division, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA
- Division of General Internal Medicine, Massachusetts General Hospital, Boston, MA, USA
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Ramos-Molina B, Rossell J, Pérez-Montes de Oca A, Pardina E, Genua I, Rojo-López MI, Julián MT, Alonso N, Julve J, Mauricio D. Therapeutic implications for sphingolipid metabolism in metabolic dysfunction-associated steatohepatitis. Front Endocrinol (Lausanne) 2024; 15:1400961. [PMID: 38962680 PMCID: PMC11220194 DOI: 10.3389/fendo.2024.1400961] [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: 03/14/2024] [Accepted: 06/03/2024] [Indexed: 07/05/2024] Open
Abstract
The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, has increased worldwide along with the epidemics of obesity and related dysmetabolic conditions characterized by impaired glucose metabolism and insulin signaling, such as type 2 diabetes mellitus (T2D). MASLD can be defined as an excessive accumulation of lipid droplets in hepatocytes that occurs when the hepatic lipid metabolism is totally surpassed. This metabolic lipid inflexibility constitutes a central node in the pathogenesis of MASLD and is frequently linked to the overproduction of lipotoxic species, increased cellular stress, and mitochondrial dysfunction. A compelling body of evidence suggests that the accumulation of lipid species derived from sphingolipid metabolism, such as ceramides, contributes significantly to the structural and functional tissue damage observed in more severe grades of MASLD by triggering inflammatory and fibrogenic mechanisms. In this context, MASLD can further progress to metabolic dysfunction-associated steatohepatitis (MASH), which represents the advanced form of MASLD, and hepatic fibrosis. In this review, we discuss the role of sphingolipid species as drivers of MASH and the mechanisms involved in the disease. In addition, given the absence of approved therapies and the limited options for treating MASH, we discuss the feasibility of therapeutic strategies to protect against MASH and other severe manifestations by modulating sphingolipid metabolism.
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Affiliation(s)
- Bruno Ramos-Molina
- Group of Obesity, Diabetes & Metabolism, Instituto Murciano de Investigación Biosanitaria (IMIB), Murcia, Spain
| | - Joana Rossell
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | | | - Eva Pardina
- Department de Biochemistry & Molecular Biology, Facultat de Biologia, Universitat de Barcelona (UB), Barcelona, Spain
| | - Idoia Genua
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
| | - Marina I. Rojo-López
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
| | - María Teresa Julián
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Núria Alonso
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
| | - Josep Julve
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
| | - Didac Mauricio
- Group of Endocrinology, Diabetes & Nutrition, Institut de Recerca SANT PAU, Barcelona, Spain
- Centro de Investigación Biomédica en Red (CIBER) de Diabetes y Enfermedades Metabólicas Asociadas, Instituto de Salud Carlos III, Madrid, Spain
- Department of Endocrinology & Nutrition, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
- Department of Endocrinology & Nutrition, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
- Faculty of Medicine, University of Vic/Central University of Catalonia (UVIC/UCC), Vic, Spain
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8
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Berezin AE, Berezina TA, Hoppe UC, Lichtenauer M, Berezin AA. Methods to predict heart failure in diabetes patients. Expert Rev Endocrinol Metab 2024; 19:241-256. [PMID: 38622891 DOI: 10.1080/17446651.2024.2342812] [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: 01/26/2024] [Accepted: 04/10/2024] [Indexed: 04/17/2024]
Abstract
INTRODUCTION Type 2 diabetes mellitus (T2DM) is one of the leading causes of cardiovascular disease and powerful predictor for new-onset heart failure (HF). AREAS COVERED We focus on the relevant literature covering evidence of risk stratification based on imaging predictors and circulating biomarkers to optimize approaches to preventing HF in DM patients. EXPERT OPINION Multiple diagnostic algorithms based on echocardiographic parameters of cardiac remodeling including global longitudinal strain/strain rate are likely to be promising approach to justify individuals at higher risk of incident HF. Signature of cardiometabolic status may justify HF risk among T2DM individuals with low levels of natriuretic peptides, which preserve their significance in HF with clinical presentation. However, diagnostic and predictive values of conventional guideline-directed biomarker HF strategy may be non-optimal in patients with obesity and T2DM. Alternative biomarkers affecting cardiac fibrosis, inflammation, myopathy, and adipose tissue dysfunction are plausible tools for improving accuracy natriuretic peptides among T2DM patients at higher HF risk. In summary, risk identification and management of the patients with T2DM with established HF require conventional biomarkers monitoring, while the role of alternative biomarker approach among patients with multiple CV and metabolic risk factors appears to be plausible tool for improving clinical outcomes.
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Affiliation(s)
- Alexander E Berezin
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Tetiana A Berezina
- VitaCenter, Department of Internal Medicine & Nephrology, Zaporozhye, Ukraine
| | - Uta C Hoppe
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Salzburg, Austria
| | - Michael Lichtenauer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University of Salzburg, Salzburg, Austria
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9
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Dabour MS, George MY, Daniel MR, Blaes AH, Zordoky BN. The Cardioprotective and Anticancer Effects of SGLT2 Inhibitors: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol 2024; 6:159-182. [PMID: 38774006 PMCID: PMC11103046 DOI: 10.1016/j.jaccao.2024.01.007] [Citation(s) in RCA: 23] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 05/24/2024] Open
Abstract
Sodium-glucose cotransporter-2 (SGLT2) inhibitors, originally approved for type 2 diabetes mellitus, have demonstrated efficacy in reducing cardiovascular events, particularly heart failure, in patients with and without diabetes. An intriguing research area involves exploring the potential application of SGLT2 inhibitors in cardio-oncology, aiming to mitigate the cardiovascular adverse events associated with anticancer treatments. These inhibitors present a unique dual nature, offering both cardioprotective effects and anticancer properties, conferring a double benefit for cardio-oncology patients. In this review, the authors first examine the established cardioprotective effects of SGLT2 inhibitors in heart failure and subsequently explore the existing body of evidence, including both preclinical and clinical studies, that supports the use of SGLT2 inhibitors in the context of cardio-oncology. The authors further discuss the mechanisms through which SGLT2 inhibitors protect against cardiovascular toxicity secondary to cancer treatment. Finally, they explore the potential anticancer effects of SGLT2 inhibitors along with their proposed mechanisms.
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Affiliation(s)
- Mohamed S. Dabour
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Clinical Pharmacy, Faculty of Pharmacy, Tanta University, Tanta, Egypt
| | - Mina Y. George
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt
| | - Mary R. Daniel
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA
| | - Anne H. Blaes
- Division of Hematology/Oncology/Transplantation, Medical School, University of Minnesota, Minneapolis, Minnesota, USA
| | - Beshay N. Zordoky
- Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota, USA
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10
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Ping WX, Hu S, Su JQ, Ouyang SY. Metabolic disorders in prediabetes: From mechanisms to therapeutic management. World J Diabetes 2024; 15:361-377. [PMID: 38591088 PMCID: PMC10999048 DOI: 10.4239/wjd.v15.i3.361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/04/2024] [Accepted: 02/07/2024] [Indexed: 03/15/2024] Open
Abstract
Diabetes, one of the world's top ten diseases, is known for its high mortality and complication rates and low cure rate. Prediabetes precedes the onset of diabetes, during which effective treatment can reduce diabetes risk. Prediabetes risk factors include high-calorie and high-fat diets, sedentary lifestyles, and stress. Consequences may include considerable damage to vital organs, including the retina, liver, and kidneys. Interventions for treating prediabetes include a healthy lifestyle diet and pharmacological treatments. However, while these options are effective in the short term, they may fail due to the difficulty of long-term implementation. Medications may also be used to treat prediabetes. This review examines prediabetic treatments, particularly metformin, glucagon-like peptide-1 receptor agonists, sodium glucose cotransporter 2 inhibitors, vitamin D, and herbal medicines. Given the remarkable impact of prediabetes on the progression of diabetes mellitus, it is crucial to intervene promptly and effectively to regulate prediabetes. However, the current body of research on prediabetes is limited, and there is considerable confusion surrounding clinically relevant medications. This paper aims to provide a comprehensive summary of the pathogenesis of pre-diabetes mellitus and its associated therapeutic drugs. The ultimate goal is to facilitate the clinical utilization of medications and achieve efficient and timely control of diabetes mellitus.
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Affiliation(s)
- Wen-Xin Ping
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, Fujian Province, China
| | - Shan Hu
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, Fujian Province, China
| | - Jing-Qian Su
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, Fujian Province, China
| | - Song-Ying Ouyang
- Biomedical Research Center of South China, College of Life Sciences, Fujian Normal University, Fuzhou 350117, Fujian Province, China
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11
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Cases A, Cigarrán S, Luis Górriz J, Nuñez J. Effect of SGLT2 inhibitors on anemia and their possible clinical implications. Nefrologia 2024; 44:165-172. [PMID: 38604895 DOI: 10.1016/j.nefroe.2024.03.011] [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: 08/01/2023] [Accepted: 11/11/2023] [Indexed: 04/13/2024] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular and renal benefits in patients with type 2 diabetes mellitus, heart failure, or chronic kidney disease. Since the first studies with these drugs, an initial increase in hemoglobin/hematocrit levels was observed, which was attributed to an increase in hemoconcentration associated with its diuretic effect, although it was early appearent that these drugs increased erythropoietin levels and erythropoiesis, and improved iron metabolism. Mediation studies found that the increase in hemoglobin was strongly associated with the cardiorenal benefits of these drugs. In this review, we discuss the mechanisms for improving erythropoiesis and the implication of the increase in hemoglobin on the cardiorenal prognostic benefit of these drugs.
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Affiliation(s)
- Aleix Cases
- Servei de Nefrología, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Grupo de Anemia de la S.E.N., Spain
| | | | - José Luis Górriz
- Grupo de Anemia de la S.E.N., Spain; Servicio de Nefrología, Hospital Clínico Universitario, INCLIVA, Universitat de València, Valencia, Spain.
| | - Julio Nuñez
- Servicio de Cardiología, Hospital Clínico Universitario, INCLIVA, Universitat de València, CIBER Cardiovascular, Spain
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12
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Jahn LA, Hartline LM, Nguyen T, Aylor K, Horton WB, Liu Z, Barrett EJ. Empagliflozin improves vascular insulin sensitivity and muscle perfusion in persons with type 2 diabetes. Am J Physiol Endocrinol Metab 2024; 326:E258-E267. [PMID: 38170166 PMCID: PMC11193530 DOI: 10.1152/ajpendo.00267.2023] [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: 08/22/2023] [Revised: 12/14/2023] [Accepted: 12/21/2023] [Indexed: 01/05/2024]
Abstract
Sodium glucose cotransporter 2 inhibitors (SGLT2is) improved major adverse cardiovascular events (MACE), heart failure, and renal outcomes in large trials; however, a thorough understanding of the vascular physiological changes contributing to these responses is lacking. We hypothesized that SGLT2i therapy would diminish vascular insulin resistance and improve hemodynamic function, which could improve clinical outcomes. To test this, we treated 11 persons with type 2 diabetes for 12 wk with 10 mg/day empagliflozin and measured vascular stiffness, endothelial function, peripheral and central arterial pressures, skeletal and cardiac muscle perfusion, and vascular biomarkers before and at 120 min of a euglycemic hyperinsulinemic clamp at weeks 0 and 12. We found that before empagliflozin treatment, insulin infusion lowered peripheral and central aortic systolic pressure (P < 0.05) and muscle microvascular blood flow (P < 0.01), but showed no effect on other vascular measures. Following empagliflozin, insulin infusion improved endothelial function (P = 0.02), lowered peripheral and aortic systolic (each P < 0.01), diastolic (each P < 0.05), mean arterial (each P < 0.01), and pulse pressures (each P < 0.02), altered endothelial biomarker expression, and decreased radial artery forward and backward pressure amplitude (each P = 0.02). Empagliflozin also improved insulin-mediated skeletal and cardiac muscle microvascular perfusion (each P < 0.05). We conclude that empagliflozin enhances insulin's vascular actions, which could contribute to the improved cardiorenal outcomes seen with SGLT2i therapy.NEW & NOTEWORTHY The physiological underpinnings of the cardiovascular benefits of SGLT2 inhibitors remain uncertain. We tested whether empagliflozin mitigates vascular insulin resistance in patients with type 2 diabetes. Aortic and peripheral systolic, diastolic, mean and pulse pressures, endothelial function, vascular stiffness, and heart and muscle microvascular perfusion were measured before and during an insulin infusion at baseline and after 12 wk of empagliflozin. After empagliflozin, vascular responses to insulin improved dramatically.
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Affiliation(s)
- Linda A Jahn
- Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia, United States
| | - Lee M Hartline
- Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia, United States
| | - Thi Nguyen
- Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia, United States
| | - Kevin Aylor
- Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia, United States
| | - William B Horton
- Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia, United States
| | - Zhenqi Liu
- Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia, United States
| | - Eugene J Barrett
- Division of Endocrinology, Department of Medicine, University of Virginia, School of Medicine, Charlottesville, Virginia, United States
- Department of Pharmacology, University of Virginia, School of Medicine, Charlottesville, Virginia, United States
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13
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Tziastoudi M, Pissas G, Golfinopoulos S, Filippidis G, Dousdampanis P, Eleftheriadis T, Stefanidis I. Sodium-Glucose Transporter 2 (SGLT2) Inhibitors and Iron Deficiency in Heart Failure and Chronic Kidney Disease: A Literature Review. Life (Basel) 2023; 13:2338. [PMID: 38137939 PMCID: PMC10744560 DOI: 10.3390/life13122338] [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: 11/10/2023] [Revised: 12/11/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023] Open
Abstract
Heart failure (HF) and chronic kidney disease (CKD) are associated with high mortality. In both disorders, impaired iron homeostasis, mostly in the form of a functional iron deficiency, is a frequent co-morbidity. In HF, functional iron deficiency and management by i.v. iron supplementation have been proven to affect both prognosis and functional capacity. In the same context, iron supplementation is routine for the adequate management of renal anemia in CKD. In numerous recent studies in HF and in CKD, sodium-glucose transporter 2 (SGLT2) inhibitor treatment has been proven to significantly reduce mortality. Furthermore, the same trials showed that these drugs alleviate iron deficiency and anemia. These effects of SGLT2 inhibitors may be due to an amelioration of inflammation with reduced interleukin-6 (IL-6) and to an enhancement of autophagy with increased sirtuin 1 (SIRT1), both associated with modified production of hepcidin and enhanced ferritinophagy. However, the exact pathogenic basis of the beneficial SGLT2 inhibitor action is not fully elucidated. Nevertheless, effects on iron homeostasis might be a potential explanatory mechanism for the powerful SGLT2 inhibitors' cardiovascular and renal outcome benefits. In addition, the interaction between iron supplementation and SGLT2 inhibitors and its potential impact on prognosis remains to be clarified by future studies. This review represents a significant effort to explore the complex relationships involved, seeking to elucidate the intricate mechanisms by which SGLT2 inhibitors influence iron homeostasis.
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Affiliation(s)
- Maria Tziastoudi
- Clinic of Nephrology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41334 Larisa, Greece; (G.P.); (S.G.); (G.F.); (P.D.); (T.E.)
| | | | | | | | | | | | - Ioannis Stefanidis
- Clinic of Nephrology, Faculty of Medicine, School of Health Sciences, University of Thessaly, 41334 Larisa, Greece; (G.P.); (S.G.); (G.F.); (P.D.); (T.E.)
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14
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Lorenzo M, Jacobs-Cachá C, Palau P, Amiguet M, Seller J, Núñez E, Espriella RDL, Górriz JL, Miñana G, Sanchis J, Bayés-Genis A, Soler MJ, Packer M, Núñez J. Short-Term Changes in Peak VO 2 After Initiation of Dapagliflozin in Heart Failure Across Iron Status. JACC. HEART FAILURE 2023; 11:1611-1622. [PMID: 37676213 DOI: 10.1016/j.jchf.2023.07.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 07/07/2023] [Accepted: 07/11/2023] [Indexed: 09/08/2023]
Abstract
BACKGROUND Some studies have indicated that sodium-glucose cotransporter-2 (SGLT2) inhibitors promote an increase in cell iron use. OBJECTIVES The aim of this study was to examine, in patients with stable heart failure with reduced left ventricular ejection fraction (HFrEF), the effect of dapagliflozin on ferrokinetic parameters and whether short-term changes in peak oxygen consumption (Vo2) after dapagliflozin treatment are influenced by baseline and serial ferrokinetic status. METHODS This was an exploratory analysis of a randomized, double-blind clinical trial that evaluated the effect of dapagliflozin vs placebo on peak Vo2 in patients with HFrEF (NCT04197635) and included 76 of the 90 patients initially enrolled in the trial. Changes in peak Vo2 at 1 and 3 months were explored according to baseline and longitudinal ferrokinetic parameters (natural logarithm [ln] ferritin, transferrin saturation index [TSAT], soluble transferrin receptor, and hepcidin). Linear mixed-effect regression was used for the analyses. RESULTS Compared with placebo, dapagliflozin led to a significant decrease in 3-month ln ferritin (P = 0.040) and an increase in 1-month ln soluble transferrin receptor (P = 0.023). Between-treatment comparisons revealed a stepwise increase in peak Vo2 in the dapagliflozin group at 1 and 3 months, which was especially apparent at lower baseline values of TSAT and ferritin (P < 0.05). Lower time-varying values of TSAT (1 and 3 months) also identified patients with greater improvements in peak Vo2. CONCLUSIONS In patients with stable HFrEF, treatment with dapagliflozin resulted in short-term increases in peak Vo2, which were most marked in patients with surrogates of greater iron deficiency at baseline and during treatment. (Short-Term Effects of Dapagliflozin on Peak Vo2 in HFrEF [DAPA-VO2]; NCT04197635).
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Affiliation(s)
- Miguel Lorenzo
- Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; INCLIVA, Valencia, Spain
| | | | - Patricia Palau
- Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; INCLIVA, Valencia, Spain
| | - Martina Amiguet
- Cardiology Department, Hospital General Universitario de Castellón, Castellón de la Plana, Spain
| | - Julia Seller
- Cardiology Department, Hospital de Dénia-Marina Salud, Alicante, Spain; Fundación Para Fomento de Investigación Sanitaria y Biomédica CV-Fisabio, Valencia, Spain
| | | | - Rafael de la Espriella
- Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; INCLIVA, Valencia, Spain
| | - Jose Luis Górriz
- Universitat de València, Valencia, Spain; Nephrology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain
| | - Gema Miñana
- Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; INCLIVA, Valencia, Spain; Universitat de València, Valencia, Spain; CIBER Cardiovascular, Madrid, Spain
| | - Juan Sanchis
- Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; INCLIVA, Valencia, Spain; Universitat de València, Valencia, Spain; CIBER Cardiovascular, Madrid, Spain
| | - Antoni Bayés-Genis
- CIBER Cardiovascular, Madrid, Spain; Cardiology Department, Hospital Germans Trias i Pujol, Badalona, Spain
| | | | - Milton Packer
- Baylor Heart and Vascular Institute, Dallas, Texas, USA
| | - Julio Núñez
- Cardiology Department, Hospital Clínico Universitario de Valencia, Valencia, Spain; INCLIVA, Valencia, Spain; Universitat de València, Valencia, Spain; CIBER Cardiovascular, Madrid, Spain.
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15
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Angermann CE, Santos-Gallego CG, Requena-Ibanez JA, Sehner S, Zeller T, Gerhardt LMS, Maack C, Sanz J, Frantz S, Fuster V, Ertl G, Badimon JJ. Empagliflozin effects on iron metabolism as a possible mechanism for improved clinical outcomes in non-diabetic patients with systolic heart failure. NATURE CARDIOVASCULAR RESEARCH 2023; 2:1032-1043. [PMID: 39196095 PMCID: PMC11358002 DOI: 10.1038/s44161-023-00352-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 09/21/2023] [Indexed: 08/29/2024]
Abstract
Sodium-glucose co-transporter-2 (SGLT2) inhibitors improve clinical outcomes in patients with heart failure (HF), but mechanisms of action are incompletely understood. In the EMPA-TROPISM trial, empagliflozin reversed cardiac remodeling and increased physical capacity in stable non-diabetic patients with systolic HF. Here we explore, post hoc, whether treatment effects in this cohort, comprising patients who had a high prevalence of iron deficiency, were related to iron metabolism. Myocardial iron content estimated by cardiac magnetic resonance T2* quantification increased after initiation of empagliflozin but not placebo (treatment effect: P = 0.01). T2* changes significantly correlated with changes in left ventricular volumes, mass and ejection fraction, peak oxygen consumption and 6-minute walking distance; concomitant changes in red blood cell indices were consistent with augmented hematopoiesis. Exploratory causal mediation analysis findings indicated that changes in myocardial iron content after treatment with empagliflozin may be an important mechanism to explain its beneficial clinical effects in patients with HF.ClinicalTrials.gov: NCT03485222 .
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Affiliation(s)
- Christiane E Angermann
- Comprehensive Heart Failure Center, Würzburg University and University Hospital Würzburg, and Department of Medicine 1, University Hospital Würzburg, Würzburg, Germany.
| | - Carlos G Santos-Gallego
- Atherothrombosis Research Unit, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Juan Antonio Requena-Ibanez
- Atherothrombosis Research Unit, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Susanne Sehner
- Institute of Medical Biometry and Epidemiology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Tanja Zeller
- University Center of Cardiovascular Science, University Heart and Vascular Center, University Hospital Hamburg-Eppendorf, and German Center of Cardiovascular Research, Partner Site Hamburg - Kiel - Lübeck, Hamburg, Germany
| | - Louisa M S Gerhardt
- Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA
- Department of Medicine V, University Medical Centre Mannheim, Mannheim, Germany
| | - Christoph Maack
- Comprehensive Heart Failure Center, Würzburg University and University Hospital Würzburg, and Department of Medicine 1, University Hospital Würzburg, Würzburg, Germany
| | - Javier Sanz
- Atherothrombosis Research Unit, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stefan Frantz
- Comprehensive Heart Failure Center, Würzburg University and University Hospital Würzburg, and Department of Medicine 1, University Hospital Würzburg, Würzburg, Germany
| | - Valentin Fuster
- Atherothrombosis Research Unit, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Georg Ertl
- Comprehensive Heart Failure Center, Würzburg University and University Hospital Würzburg, and Department of Medicine 1, University Hospital Würzburg, Würzburg, Germany
| | - Juan J Badimon
- Atherothrombosis Research Unit, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Mount Sinai Heart, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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16
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Zhang Y, He Y, Liu S, Deng L, Zuo Y, Huang K, Liao B, Li G, Feng J. SGLT2 Inhibitors in Aging-Related Cardiovascular Disease: A Review of Potential Mechanisms. Am J Cardiovasc Drugs 2023; 23:641-662. [PMID: 37620652 DOI: 10.1007/s40256-023-00602-8] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/31/2023] [Indexed: 08/26/2023]
Abstract
Population aging combined with higher susceptibility to cardiovascular diseases in older adults is increasing the incidence of conditions such as atherosclerosis, myocardial infarction, heart failure, myocardial hypertrophy, myocardial fibrosis, arrhythmia, and hypertension. sodium-glucose cotransporter 2 inhibitors (SGLT2i) were originally developed as a novel oral drug for patients with type 2 diabetes mellitus. Unexpectedly, recent studies have shown that, beyond their effect on hyperglycemia, SGLT2i also have a variety of beneficial effects on cardiovascular disease. Experimental models of cardiovascular disease have shown that SGLT2i ameliorate the process of aging-related cardiovascular disease by inhibiting inflammation, reducing oxidative stress, and reversing endothelial dysfunction. In this review, we discuss the role of SGLT2i in aging-related cardiovascular disease and propose the use of SGLT2i to prevent and treat these conditions in older adults.
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Affiliation(s)
- Yali Zhang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Yufeng He
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Siqi Liu
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Li Deng
- Department of Rheumatology, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Yumei Zuo
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Keming Huang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China
| | - Bin Liao
- Department of Cardiac Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Guang Li
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
| | - Jian Feng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, Key Laboratory of Medical Electrophysiology, Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, China.
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17
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Dubin RF, Deo R, Ren Y, Wang J, Zheng Z, Shou H, Go AS, Parsa A, Lash JP, Rahman M, Hsu CY, Weir MR, Chen J, Anderson A, Grams ME, Surapaneni A, Coresh J, Li H, Kimmel PL, Vasan RS, Feldman H, Segal MR, Ganz P. Proteomics of CKD progression in the chronic renal insufficiency cohort. Nat Commun 2023; 14:6340. [PMID: 37816758 PMCID: PMC10564759 DOI: 10.1038/s41467-023-41642-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2023] [Accepted: 09/13/2023] [Indexed: 10/12/2023] Open
Abstract
Progression of chronic kidney disease (CKD) portends myriad complications, including kidney failure. In this study, we analyze associations of 4638 plasma proteins among 3235 participants of the Chronic Renal Insufficiency Cohort Study with the primary outcome of 50% decline in estimated glomerular filtration rate or kidney failure over 10 years. We validate key findings in the Atherosclerosis Risk in the Communities study. We identify 100 circulating proteins that are associated with the primary outcome after multivariable adjustment, using a Bonferroni statistical threshold of significance. Individual protein associations and biological pathway analyses highlight the roles of bone morphogenetic proteins, ephrin signaling, and prothrombin activation. A 65-protein risk model for the primary outcome has excellent discrimination (C-statistic[95%CI] 0.862 [0.835, 0.889]), and 14/65 proteins are druggable targets. Potentially causal associations for five proteins, to our knowledge not previously reported, are supported by Mendelian randomization: EGFL9, LRP-11, MXRA7, IL-1 sRII and ILT-2. Modifiable protein risk markers can guide therapeutic drug development aimed at slowing CKD progression.
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Affiliation(s)
- Ruth F Dubin
- Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
| | - Rajat Deo
- Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Yue Ren
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Jianqiao Wang
- Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Zihe Zheng
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Haochang Shou
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Alan S Go
- Division of Research, Kaiser Permanente Northern California, Oakland, the Department of Health Systems Science, Oakland, CA, USA
| | - Afshin Parsa
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - James P Lash
- Department of Medicine, University of Illinois Chicago, Chicago, IL, USA
| | - Mahboob Rahman
- Department of Medicine, University Hospitals Cleveland Medical Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA
| | - Chi-Yuan Hsu
- Division of Research, Kaiser Permanente Northern California, Oakland, the Department of Health Systems Science, Oakland, CA, USA
- Division of Nephrology, University of California San Francisco, San Francisco, CA, USA
| | - Matthew R Weir
- Division of Nephrology, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD, USA
| | - Jing Chen
- Department of Epidemiology, Tulane University, New Orleans, LA, USA
| | - Amanda Anderson
- Department of Epidemiology, Tulane University, New Orleans, LA, USA
| | - Morgan E Grams
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Division of Precision Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Aditya Surapaneni
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
- Division of Precision Medicine, New York University Grossman School of Medicine, New York, NY, USA
| | - Josef Coresh
- Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD, USA
- Department of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Hongzhe Li
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Paul L Kimmel
- Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA
| | - Ramachandran S Vasan
- University of Texas School of Public Health San Antonio and the University of Texas Health Sciences Center in San Antonio. Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Harold Feldman
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mark R Segal
- Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA
| | - Peter Ganz
- Division of Cardiology, University of California, San Francisco, San Francisco, CA, USA
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18
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Packer M. SGLT2 inhibitors: role in protective reprogramming of cardiac nutrient transport and metabolism. Nat Rev Cardiol 2023; 20:443-462. [PMID: 36609604 DOI: 10.1038/s41569-022-00824-4] [Citation(s) in RCA: 88] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/29/2022] [Indexed: 01/09/2023]
Abstract
Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce heart failure events by direct action on the failing heart that is independent of changes in renal tubular function. In the failing heart, nutrient transport into cardiomyocytes is increased, but nutrient utilization is impaired, leading to deficient ATP production and the cytosolic accumulation of deleterious glucose and lipid by-products. These by-products trigger downregulation of cytoprotective nutrient-deprivation pathways, thereby promoting cellular stress and undermining cellular survival. SGLT2 inhibitors restore cellular homeostasis through three complementary mechanisms: they might bind directly to nutrient-deprivation and nutrient-surplus sensors to promote their cytoprotective actions; they can increase the synthesis of ATP by promoting mitochondrial health (mediated by increasing autophagic flux) and potentially by alleviating the cytosolic deficiency in ferrous iron; and they might directly inhibit glucose transporter type 1, thereby diminishing the cytosolic accumulation of toxic metabolic by-products and promoting the oxidation of long-chain fatty acids. The increase in autophagic flux mediated by SGLT2 inhibitors also promotes the clearance of harmful glucose and lipid by-products and the disposal of dysfunctional mitochondria, allowing for mitochondrial renewal through mitochondrial biogenesis. This Review describes the orchestrated interplay between nutrient transport and metabolism and nutrient-deprivation and nutrient-surplus signalling, to explain how SGLT2 inhibitors reverse the profound nutrient, metabolic and cellular abnormalities observed in heart failure, thereby restoring the myocardium to a healthy molecular and cellular phenotype.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Dallas, TX, USA.
- Imperial College London, London, UK.
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19
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Stöllberger C, Finsterer J, Schneider B. Adverse events and drug-drug interactions of sodium glucose co-transporter 2 inhibitors in patients treated for heart failure. Expert Rev Cardiovasc Ther 2023; 21:803-816. [PMID: 37856368 DOI: 10.1080/14779072.2023.2273900] [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: 08/16/2023] [Accepted: 10/18/2023] [Indexed: 10/21/2023]
Abstract
INTRODUCTION Sodium glucose co-transporter 2-inhibitors (SGLT2-I), antihyperglycemic agents, are increasingly prescribed in chronic heart failure (CHF). Their risk for drug-drug interactions (DDI) seems low. Safety-data derive mainly from diabetes-patients. This review aims to summarize adverse-events (AE) and DDI of the SGLT2-I dapagliflozin, empagliflozin and sotagliflozin in patients with CHF. AREAS COVERED Literature-search-terms in PubMed were 'adverse event/drug-drug interaction' and 'heart failure AND 'dapagliflozin' OR 'empagliflozin' OR 'sotagliflozin.'AEreported in randomized controlled trials (RCT) comprisegenitaland urinary-tract infections, hypotension, ketoacidosis, renal impairment, hypoglycemia, limb-amputations, Fournier's gangrene, bone-fractures, hepatopathy, pancreatitis, diarrhea, malignancy and venous thromboembolism. Their incidence is largely unknown, since they were not consistently evaluated in RCT of CHF. Further AE from meta-analyses, pharmacovigilance reports, case-series and case-reports include erythrocytosis, hypertriglyceridemia, myopathy, sarcopenia, skin problems, ventricular tachycardia, and urinary retention. The maximal observation period of RCT in CHF was 26 months.DDI were mainly studied in healthy volunteers for 3-8 days. In CHF or diabetes-patients, DDI were reported with interleukin-17-inhibitors, linezolid, lithium, tacrolimus, valproate, angiotensin-receptor-neprilysin-inhibitors and intravenous iron. EXPERT OPINION Guidelines recommend treatment with SGLT2-I for CHF but no data on AE during long-term therapy and only little information on DDI are available, which stresses the need for further research. Evidence-based recommendations for ketoacidosis-prevention are desirable.
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20
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Deo R, Dubin RF, Ren Y, Murthy AC, Wang J, Zheng H, Zheng Z, Feldman H, Shou H, Coresh J, Grams M, Surapaneni AL, Bhat Z, Cohen JB, Rahman M, He J, Saraf SL, Go AS, Kimmel PL, Vasan RS, Segal MR, Li H, Ganz P. Proteomic cardiovascular risk assessment in chronic kidney disease. Eur Heart J 2023; 44:2095-2110. [PMID: 37014015 PMCID: PMC10281556 DOI: 10.1093/eurheartj/ehad115] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 01/21/2023] [Accepted: 02/16/2023] [Indexed: 04/05/2023] Open
Abstract
AIMS Chronic kidney disease (CKD) is widely prevalent and independently increases cardiovascular risk. Cardiovascular risk prediction tools derived in the general population perform poorly in CKD. Through large-scale proteomics discovery, this study aimed to create more accurate cardiovascular risk models. METHODS AND RESULTS Elastic net regression was used to derive a proteomic risk model for incident cardiovascular risk in 2182 participants from the Chronic Renal Insufficiency Cohort. The model was then validated in 485 participants from the Atherosclerosis Risk in Communities cohort. All participants had CKD and no history of cardiovascular disease at study baseline when ∼5000 proteins were measured. The proteomic risk model, which consisted of 32 proteins, was superior to both the 2013 ACC/AHA Pooled Cohort Equation and a modified Pooled Cohort Equation that included estimated glomerular filtrate rate. The Chronic Renal Insufficiency Cohort internal validation set demonstrated annualized receiver operating characteristic area under the curve values from 1 to 10 years ranging between 0.84 and 0.89 for the protein and 0.70 and 0.73 for the clinical models. Similar findings were observed in the Atherosclerosis Risk in Communities validation cohort. For nearly half of the individual proteins independently associated with cardiovascular risk, Mendelian randomization suggested a causal link to cardiovascular events or risk factors. Pathway analyses revealed enrichment of proteins involved in immunologic function, vascular and neuronal development, and hepatic fibrosis. CONCLUSION In two sizeable populations with CKD, a proteomic risk model for incident cardiovascular disease surpassed clinical risk models recommended in clinical practice, even after including estimated glomerular filtration rate. New biological insights may prioritize the development of therapeutic strategies for cardiovascular risk reduction in the CKD population.
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Affiliation(s)
- Rajat Deo
- Division of Cardiovascular Medicine, Electrophysiology Section, Perelman School of Medicine at the University of Pennsylvania, One Convention Avenue, Level 2 / City Side, Philadelphia, PA 19104, USA
| | - Ruth F Dubin
- Division of Nephrology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390, USA
| | - Yue Ren
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 215 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
| | - Ashwin C Murthy
- Division of Cardiovascular Medicine, Electrophysiology Section, Perelman School of Medicine at the University of Pennsylvania, One Convention Avenue, Level 2 / City Side, Philadelphia, PA 19104, USA
| | - Jianqiao Wang
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 215 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
| | - Haotian Zheng
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 215 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
| | - Zihe Zheng
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 215 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
| | - Harold Feldman
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 215 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
| | - Haochang Shou
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 215 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
| | - Josef Coresh
- Department of Epidemiology; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA
- Department of Medicine, Johns Hopkins University, 2024 E. Monument Street, Room 2-635, Suite 2-600, Baltimore, MD 21287, USA
| | - Morgan Grams
- Department of Epidemiology; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA
- Department of Medicine, Johns Hopkins University, 2024 E. Monument Street, Room 2-635, Suite 2-600, Baltimore, MD 21287, USA
| | - Aditya L Surapaneni
- Department of Epidemiology; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University Bloomberg School of Public Health, 615 N Wolfe St, Baltimore, MD 21205, USA
| | - Zeenat Bhat
- Division of Nephrology, University of Michigan, 5100 Brehm Tower, 1000 Wall Street, Ann Arbor, MI 48105, USA
| | - Jordana B Cohen
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 215 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
- Renal, Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, 831 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
| | - Mahboob Rahman
- Department of Medicine, Case Western Reserve University School of Medicine, 11100 Euclid Avenue, Wearn Bldg. 3 Floor. Rm 352, Cleveland, OH 44106, USA
| | - Jiang He
- Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal Street, SL 18, New Orleans, LA 70112, USA
| | - Santosh L Saraf
- Division of Hematology and Oncology, University of Illinois at Chicago, 1740 West Taylor Street, Chicago, IL 60612, USA
| | - Alan S Go
- Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612, USA
- Departments of Epidemiology, Biostatistics and Medicine, University of California at San Francisco, San Francisco, CA, USA
| | - Paul L Kimmel
- Division of Kidney, Urologic, and Hematologic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA
| | - Ramachandran S Vasan
- Section of Preventive Medicine and Epidemiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- Section of Cardiology, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
- Department of Epidemiology, Boston University School of Public Health, Boston, MA, USA
| | - Mark R Segal
- Department of Epidemiology and Biostatistics, University of California, 550 16th Street, 2nd Floor, Box #0560, San Francisco, CA 94143, USA
| | - Hongzhe Li
- Department of Biostatistics, Epidemiology, and Informatics, Perelman School of Medicine, University of Pennsylvania, 215 Blockley Hall, 423 Guardian Drive, Philadelphia, PA 19104, USA
| | - Peter Ganz
- Division of Cardiology, Zuckerberg San Francisco General Hospital and Department of Medicine, University of California, San Francisco, 1001 Potrero Avenue, 5G1, San Francisco, CA 94110, USA
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21
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Reppo I, Jakobson M, Volke V. Effects of Semaglutide and Empagliflozin on Inflammatory Markers in Patients with Type 2 Diabetes. Int J Mol Sci 2023; 24:ijms24065714. [PMID: 36982786 PMCID: PMC10054691 DOI: 10.3390/ijms24065714] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/07/2023] [Accepted: 03/10/2023] [Indexed: 03/19/2023] Open
Abstract
Low-grade inflammation is associated with complications of type 2 diabetes. Glucagon-like peptide-1 receptor agonists and sodium-glucose transporter-2 inhibitors have shown cardioprotective effects that are independent of their glucose-lowering effects. Cardio-protection could be mediated by the anti-inflammatory effects of these medications, but there is currently limited evidence to support this hypothesis. We conducted a prospective clinical study in patients with type 2 diabetes requiring treatment intensification. Ten patients were assigned to receive empagliflozin 10 mg and 10 patients to receive s/c semaglutide (titrated to 1 mg once a week) in a non-randomised manner. All parameters were measured at baseline and after 3 months. Fasting plasma glucose and glycated haemoglobin improved significantly in both treatment groups, with no between-group differences. Body weight and body mass index reduced significantly more in the semaglutide group, whereas waist circumference decreased only in the empagliflozin group. There was a trend for high-sensitivity CRP reduction in both treatment groups that did not reach statistical significance. Interleukin-6 and the neutrophil-to-lymphocyte ratio did not change in either group. Ferritin and uric acid decreased significantly only in the empagliflozin group, and ceruloplasmin decreased significantly only in the semaglutide group. Though there were clinically meaningful improvements in diabetes control in both treatment arms, we could detect only minor changes in some inflammatory markers.
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Affiliation(s)
- Ingrid Reppo
- Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
- Endocrinology Unit, Tartu University Hospital, 50406 Tartu, Estonia
| | - Maili Jakobson
- Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
| | - Vallo Volke
- Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia
- Endocrinology Unit, Tartu University Hospital, 50406 Tartu, Estonia
- Correspondence:
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22
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Packer M. Potential Interactions When Prescribing SGLT2 Inhibitors and Intravenous Iron in Combination in Heart Failure. JACC. HEART FAILURE 2023; 11:106-114. [PMID: 36396554 DOI: 10.1016/j.jchf.2022.10.004] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 10/26/2022] [Accepted: 10/27/2022] [Indexed: 11/08/2022]
Abstract
In patients with heart failure, sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown to decrease hepcidin and ferritin and increase transferrin receptor protein, changes that are typically indicative of worsening absolute iron deficiency, as would be seen with poor dietary intake or gastrointestinal bleeding, neither of which is provoked by SGLT2 inhibitors. Therefore, 2 alternative conceptual frameworks may explain the observed pattern of changes in iron homeostasis proteins. According to the "cytosolic iron depletion hypothesis," the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor is related to a decline in cytosolic Fe2+ that occurs after drug-induced erythropoietin-related increase in iron use. Erythropoietin-mimetics (eg, darbepoietin) elicit this type of iron-deficiency pattern of response, and it is typically accompanied by erythropoietin resistance that is alleviated by intravenous iron supplementation. In contrast, according to the "cytosolic iron repletion hypothesis," the effect of SGLT2 inhibitors to decrease hepcidin and ferritin and increase transferrin receptor represents a direct action of these drugs: 1) to reverse inflammation-related increases in hepcidin and ferritin, and, thus, alleviate functional blocks on iron utilization; and 2) to increase in sirtuin-1 signaling, which suppresses hepcidin, accelerates the degradation of ferritin, and up-regulates transferrin receptor protein. Through either or both mechanisms, direct suppression of hepcidin and ferritin would be expected to increase cytosolic Fe2+, thus allowing an unattenuated erythrocytic response to erythropoietin without the need for intravenous iron supplementation. The totality of clinical evidence supports the "cytosolic iron repletion hypothesis" because SGLT2 inhibitors elicit a full and sustained erythrocytosis in response to erythropoietin, even in overtly iron-deficient patients and in the absence of intravenous iron therapy. Therefore, the emergence of an iron-deficiency pattern of response during SGLT2 inhibition does not reflect worsening iron stores that are in need of replenishment, but instead, represents potential alleviation of a state of inflammation-related functional iron deficiency that is commonly seen in patients with chronic heart failure. Treatment with intravenous iron may be unnecessary and theoretically deleterious.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Dallas, Texas, USA; Imperial College, London, United Kingdom.
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23
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Packer M. Alleviation of functional iron deficiency by SGLT2 inhibition in patients with type 2 diabetes. Diabetes Obes Metab 2022; 25:1143-1146. [PMID: 36583283 DOI: 10.1111/dom.14963] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/10/2022] [Accepted: 12/25/2022] [Indexed: 12/31/2022]
Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Dallas, TX, USA
- Imperial College, London, UK
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24
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Affiliation(s)
- Clemens Gutmann
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre, 125 Coldharbour Lane, London SE5 9NU, UK
| | | | - Manuel Mayr
- School of Cardiovascular and Metabolic Medicine & Sciences, King's College London British Heart Foundation Centre, 125 Coldharbour Lane, London SE5 9NU, UK
- Division of Cardiology, Medical University of Vienna, Austria
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25
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Katano S, Yano T, Kouzu H, Nagaoka R, Numazawa R, Yamano K, Fujisawa Y, Ohori K, Nagano N, Fujito T, Nishikawa R, Ohwada W, Katayose M, Sato T, Kuno A, Furuhashi M. Elevated circulating level of β-aminoisobutyric acid (BAIBA) in heart failure patients with type 2 diabetes receiving sodium-glucose cotransporter 2 inhibitors. Cardiovasc Diabetol 2022; 21:285. [PMID: 36539818 PMCID: PMC9768967 DOI: 10.1186/s12933-022-01727-x] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Accepted: 12/14/2022] [Indexed: 12/24/2022] Open
Abstract
AIMS The mechanism by which a sodium-glucose cotransporter inhibitor (SGLT2i) induces favorable effects on diabetes and cardiovascular diseases including heart failure (HF) remains poorly understood. Metabolomics including amino acid profiling enables detection of alterations in whole body metabolism. The aim of this study was to determine whether plasma amino acid profiles are modulated by SGLT2i use in HF patients with type 2 diabetes mellitus (T2DM). METHODS We retrospectively examined 81 HF patients with T2DM (68 ± 11 years old; 78% male). Plasma amino acid concentrations in a fasting state after stabilization of HF were determined using ultraperformance liquid chromatography. To minimize potential selection bias in the retrospective analyses, the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an inverse probability of treatment weighting (IPTW)-adjusted analysis. RESULTS Of amino acids measurable in the present assay, plasma β-aminoisobutyric acid (BAIBA), an exercise-induced myokine-like molecule also known as 3-aminoisobutyric acid or 3-amino-2-methyproponic acid, was detected in 77% of all patients and the proportion of patients in whom plasma BAIBA was detected was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (93% vs. 67%, p = 0.01). Analyses in patients in whom plasma BAIBA was detected showed that plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i (6.76 ± 4.72 vs. 4.56 ± 2.93 nmol/ml, p = 0.03). In multivariate logistic regression analyses that were adjusted for age and sex, SGLT2i use was independently associated with BAIBA detection. The independent association between BAIBA and SGLT2i use remained after inclusion of body mass index, HF with reduced ejection fraction, ischemic etiology, renal function, NT-proBNP, albumin, hemoglobin, and HbA1c into the Cox proportional hazards model. When the differences in baseline characteristics between patients receiving an SGLT2i and patients not receiving an SGLT2i were controlled by using an IPTW-adjusted analysis, least squares mean of plasma BAIBA concentration was significantly higher in patients receiving an SGLT2i than in patients not receiving an SGLT2i. CONCLUSION SGLT2i use is closely associated with increased circulating BAIBA concentration in HF patients with T2DM.
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Affiliation(s)
- Satoshi Katano
- Division of Rehabilitation, Sapporo Medical University Hospital, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Toshiyuki Yano
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan.
| | - Hidemichi Kouzu
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Ryohei Nagaoka
- Division of Rehabilitation, Sapporo Medical University Hospital, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Ryo Numazawa
- Graduate School of Medicine, Sapporo Medical University, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Kotaro Yamano
- Division of Rehabilitation, Sapporo Medical University Hospital, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Yusuke Fujisawa
- Division of Rehabilitation, Sapporo Medical University Hospital, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Katsuhiko Ohori
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
- Department of Cardiology, Hokkaido Cardiovascular Hospital, Sapporo, Japan
| | - Nobutaka Nagano
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Takefumi Fujito
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Ryo Nishikawa
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Wataru Ohwada
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Masaki Katayose
- Second Division of Physical Therapy, Sapporo Medical University School of Health Science, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Tatsuya Sato
- Department of Cellular Physiology and Signal Transduction, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Atsushi Kuno
- Department of Pharmacology, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
| | - Masato Furuhashi
- Department of Cardiovascular, Renal and Metabolic Medicine, Sapporo Medical University School of Medicine, South-1, West-16, Chuo-ku, Sapporo, 060-8543, Japan
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The Therapeutic Role of SGLT-2 Inhibitors in Acute Heart Failure: From Pathophysiologic Mechanisms to Clinical Evidence with Pooled Analysis of Relevant Studies across Safety and Efficacy Endpoints of Interest. LIFE (BASEL, SWITZERLAND) 2022; 12:life12122062. [PMID: 36556427 PMCID: PMC9782870 DOI: 10.3390/life12122062] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 11/30/2022] [Accepted: 12/07/2022] [Indexed: 12/13/2022]
Abstract
(1) Background: Sodium-glucose co-transporter-2 (SGLT-2) inhibitors constitute a novel drug class with remarkable cardiovascular benefits for patients with chronic heart failure (HF). Recently, this class has been utilized in acute HF as an additional treatment option to classic diuretics, which remain the cornerstone of treatment. (2) Methods: We attempted to identify those pathophysiologic mechanisms targeted by SGLT-2 inhibitors, which could be of benefit to patients with acute HF. We then conducted a comprehensive review of the literature within the PubMed database in order to identify relevant studies, both randomized controlled trials (RCTs) and observational studies, assessing the safety and efficacy of SGLT-2 inhibitors in acute HF. (3) Results: SGLT-2 inhibitors induce significant osmotic diuresis and natriuresis, decrease interstitial fluid volume and blood pressure, improve left ventricular (LV) function, ameliorate LV remodeling and prevent atrial arrhythmia occurrence, mechanisms that seem to be beneficial in acute HF. However, currently available studies, including six RCTs and two real-world studies, provide conflicting results concerning the true efficacy of SGLT-2 inhibitors, including "hard" surrogate endpoints. (4) Conclusions: Current evidence appears insufficient to substantiate the use of SGLT-2 inhibitors in acute HF. Further trials are required to shed more light on this issue.
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Packer M. How can sodium-glucose cotransporter 2 inhibitors stimulate erythrocytosis in patients who are iron-deficient? Implications for understanding iron homeostasis in heart failure. Eur J Heart Fail 2022; 24:2287-2296. [PMID: 36377108 PMCID: PMC10100235 DOI: 10.1002/ejhf.2731] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2022] [Revised: 11/02/2022] [Accepted: 11/06/2022] [Indexed: 11/17/2022] Open
Abstract
Many patients with heart failure have an iron-deficient state, which can limit erythropoiesis in erythroid precursors and ATP production in cardiomyocytes. Yet, treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitors produces consistent increases in haemoglobin and haematocrit, even in patients who are iron-deficient before treatment, and this effect remains unattenuated throughout treatment even though SGLT2 inhibitors further aggravate biomarkers of iron deficiency. Heart failure is often accompanied by systemic inflammation, which activates hepcidin, thus impairing the duodenal absorption of iron and the release of iron from macrophages and hepatocytes, leading to a decline in circulating iron. Inflammation and oxidative stress also promote the synthesis of ferritin and suppress ferritinophagy, thus impairing the release of intracellular iron stores and leading to the depletion of bioreactive cytosolic Fe2+ . By alleviating inflammation and oxidative stress, SGLT2 inhibitors down-regulate hepcidin, upregulate transferrin receptor protein 1 and reduce ferritin; the net result is to increase the levels of cytosolic Fe2+ available to mitochondria, thus enabling the synthesis of heme (in erythroid precursors) and ATP (in cardiomyocytes). The finding that SGLT2 inhibitors can induce erythrocytosis without iron supplementation suggests that the abnormalities in iron diagnostic tests in patients with mild-to-moderate heart failure are likely to be functional, rather than absolute, that is, they are related to inflammation-mediated trapping of iron by hepcidin and ferritin, which is reversed by treatment with SGLT2 inhibitors. An increase in bioreactive cytosolic Fe2+ is also likely to augment mitochondrial production of ATP in cardiomyocytes, thus retarding the progression of heart failure. These effects on iron metabolism are consistent with (i) proteomics analyses of placebo-controlled trials, which have shown that biomarkers of iron homeostasis represent the most consistent effect of SGLT2 inhibitors; and (ii) statistical mediation analyses, which have reported striking parallelism of the effect of SGLT2 inhibitors to promote erythrocytosis and reduce heart failure events.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular InstituteDallasTXUSA
- Imperial CollegeLondonUK
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Wang D, Liu J, Zhong L, Li S, Zhou L, Zhang Q, Li M, Xiao X. The effect of sodium-glucose cotransporter 2 inhibitors on biomarkers of inflammation: A systematic review and meta-analysis of randomized controlled trials. Front Pharmacol 2022; 13:1045235. [PMID: 36467062 PMCID: PMC9717685 DOI: 10.3389/fphar.2022.1045235] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/26/2022] [Indexed: 10/27/2023] Open
Abstract
Aims: Inflammatory biomarkers may play vital roles in the pathophysiology of diabetes and diabetic cardiorenal complications. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have a potential cardiovascular and renal protective effect in type 2 diabetes. The aim of this meta-analysis was to quantify the effects of SGLT2 inhibitors on biomarkers of inflammation in randomized controlled trials (RCTs). Methods: PubMed, Cochrane Library, EMBASE, and Web of Science were searched for eligible RCTs of adults with type 2 diabetes (T2D) with no time limit (updated to 12 October 2022). The biomarkers selected included C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, leptin, adiponectin, ferritin, plasminogen activator inhibitor (PAI)-1, and vascular cell adhesion molecule-1. Data were analyzed using a random-effect model in Review Manager 5.4. Results: Thirty-four studies with 6,261 patients (68.6% male) were eligible for this meta-analysis. The mean age of the participants was 62.57(±11.13) years old, and the median treatment duration length with follow-up was 24 weeks. Generally, the included trials were of good methodological quality. The meta-analysis revealed that ferritin levels were significantly reduced in SGLT2 inhibitor treatment groups versus placebo or standard diabetes therapies (SMD: -1.21; 95% CI: -1.91, -0.52, p < 0.001). The effects of CRP (SMD: 0.25; 95% CI: -0.47, -0.03, p = 0.02) and leptin (SMD: -0.22; 95% CI: -0.43, -0.01, p = 0.04) were reduced, and the effects of adiponectin were improved (SMD: 0.28; 95% CI: 0.15, 0.41, p < 0.001) in placebo-controlled studies. PAI-1 levels were significantly reduced in studies controlled for diabetes therapies (SMD: -0.38; 95% CI: -0.61, -0.15, p = 0.001). Conclusion: This analysis provides strong evidence supporting anti-inflammatory effects of SGLT2 inhibitors in T2D subjects. The mechanisms and possible targets for the inflammation reducing and cardiorenal protective properties of SGLT2 inhibitors remain to be explored.
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Affiliation(s)
- Dongmei Wang
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jieying Liu
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
- Department of Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Ling Zhong
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Shunhua Li
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Liyuan Zhou
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Qian Zhang
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Ming Li
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xinhua Xiao
- Department of Endocrinology, NHC Key Laboratory of Endocrinology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Packer M. Critical Reanalysis of the Mechanisms Underlying the Cardiorenal Benefits of SGLT2 Inhibitors and Reaffirmation of the Nutrient Deprivation Signaling/Autophagy Hypothesis. Circulation 2022; 146:1383-1405. [PMID: 36315602 PMCID: PMC9624240 DOI: 10.1161/circulationaha.122.061732] [Citation(s) in RCA: 237] [Impact Index Per Article: 79.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Accepted: 08/10/2022] [Indexed: 02/06/2023]
Abstract
SGLT2 (sodium-glucose cotransporter 2) inhibitors produce a distinctive pattern of benefits on the evolution and progression of cardiomyopathy and nephropathy, which is characterized by a reduction in oxidative and endoplasmic reticulum stress, restoration of mitochondrial health and enhanced mitochondrial biogenesis, a decrease in proinflammatory and profibrotic pathways, and preservation of cellular and organ integrity and viability. A substantial body of evidence indicates that this characteristic pattern of responses can be explained by the action of SGLT2 inhibitors to promote cellular housekeeping by enhancing autophagic flux, an effect that may be related to the action of these drugs to produce simultaneous upregulation of nutrient deprivation signaling and downregulation of nutrient surplus signaling, as manifested by an increase in the expression and activity of AMPK (adenosine monophosphate-activated protein kinase), SIRT1 (sirtuin 1), SIRT3 (sirtuin 3), SIRT6 (sirtuin 6), and PGC1-α (peroxisome proliferator-activated receptor γ coactivator 1-α) and decreased activation of mTOR (mammalian target of rapamycin). The distinctive pattern of cardioprotective and renoprotective effects of SGLT2 inhibitors is abolished by specific inhibition or knockdown of autophagy, AMPK, and sirtuins. In the clinical setting, the pattern of differentially increased proteins identified in proteomics analyses of blood collected in randomized trials is consistent with these findings. Clinical studies have also shown that SGLT2 inhibitors promote gluconeogenesis, ketogenesis, and erythrocytosis and reduce uricemia, the hallmarks of nutrient deprivation signaling and the principal statistical mediators of the ability of SGLT2 inhibitors to reduce the risk of heart failure and serious renal events. The action of SGLT2 inhibitors to augment autophagic flux is seen in isolated cells and tissues that do not express SGLT2 and are not exposed to changes in environmental glucose or ketones and may be related to an ability of these drugs to bind directly to sirtuins or mTOR. Changes in renal or cardiovascular physiology or metabolism cannot explain the benefits of SGLT2 inhibitors either experimentally or clinically. The direct molecular effects of SGLT2 inhibitors in isolated cells are consistent with the concept that SGLT2 acts as a nutrient surplus sensor, and thus, its inhibition causes enhanced nutrient deprivation signaling and its attendant cytoprotective effects, which can be abolished by specific inhibition or knockdown of AMPK, sirtuins, and autophagic flux.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Dallas, TX. Imperial College, London, United Kingdom
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30
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Zannad F, Ferreira JP, Butler J, Filippatos G, Januzzi JL, Sumin M, Zwick M, Saadati M, Pocock SJ, Sattar N, Anker SD, Packer M. Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR programme. Eur Heart J 2022; 43:4991-5002. [PMID: 36017745 PMCID: PMC9769969 DOI: 10.1093/eurheartj/ehac495] [Citation(s) in RCA: 104] [Impact Index Per Article: 34.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2022] [Revised: 08/15/2022] [Accepted: 08/25/2022] [Indexed: 01/12/2023] Open
Abstract
AIMS Sodium-glucose co-transporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in diverse patient populations, but their mechanism of action requires further study. The aim is to explore the effect of empagliflozin on the circulating levels of intracellular proteins in patients with heart failure, using large-scale proteomics. METHODS AND RESULTS Over 1250 circulating proteins were measured at baseline, Week 12, and Week 52 in 1134 patients from EMPEROR-Reduced and EMPEROR-Preserved, using the Olink® Explore 1536 platform. Statistical and bioinformatical analyses identified differentially expressed proteins (empagliflozin vs. placebo), which were then linked to demonstrated biological actions in the heart and kidneys. At Week 12, 32 of 1283 proteins fulfilled our threshold for being differentially expressed, i.e. their levels were changed by ≥10% with a false discovery rate <1% (empagliflozin vs. placebo). Among these, nine proteins demonstrated the largest treatment effect of empagliflozin: insulin-like growth factor-binding protein 1, transferrin receptor protein 1, carbonic anhydrase 2, erythropoietin, protein-glutamine gamma-glutamyltransferase 2, thymosin beta-10, U-type mitochondrial creatine kinase, insulin-like growth factor-binding protein 4, and adipocyte fatty acid-binding protein 4. The changes of the proteins from baseline to Week 52 were generally concordant with the changes from the baseline to Week 12, except empagliflozin reduced levels of kidney injury molecule-1 by ≥10% at Week 52, but not at Week 12. The most common biological action of differentially expressed proteins appeared to be the promotion of autophagic flux in the heart, kidney or endothelium, a feature of 6 proteins. Other effects of differentially expressed proteins on the heart included the reduction of oxidative stress, inhibition of inflammation and fibrosis, and the enhancement of mitochondrial health and energy, repair, and regenerative capacity. The actions of differentially expressed proteins in the kidney involved promotion of autophagy, integrity and regeneration, suppression of renal inflammation and fibrosis, and modulation of renal tubular sodium reabsorption. CONCLUSIONS Changes in circulating protein levels in patients with heart failure are consistent with the findings of experimental studies that have shown that the effects of SGLT2 inhibitors are likely related to actions on the heart and kidney to promote autophagic flux, nutrient deprivation signalling and transmembrane sodium transport.
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Affiliation(s)
- Faiez Zannad
- Corresponding author. Tel: +33 3 83 15 73 15, Fax: +33 3 83 15 73 24, Emails: ;
| | - João Pedro Ferreira
- Corresponding author. Tel: +33 3 83 15 73 15, Fax: +33 3 83 15 73 24, Emails: ;
| | - Javed Butler
- Heart and Vascular Research, Baylor Scott and White Research Institute, 34 Live Oak St Ste 501, Dallas, TX 75204, USA,University of Mississippi Medical Center, 2500 North State Street Jackson, MS 39216, USA
| | - Gerasimos Filippatos
- Heart Failure Unit, National and Kapodistrian University of Athens School of Medicine, Mikras Asias 75, Athina 115 27 Athens, Greece
| | - James L Januzzi
- Massachusetts General Hospital, Harvard Medical School, 55 Fruit St, Boston, MA 02114USA,The Baim Institute for Clinical Research, 930 Commonwealth Ave #3, Boston, MA 02215USA
| | - Mikhail Sumin
- Boehringer Ingelheim International GmbH, Binger Str. 173, 55218 Ingelheim am RheinGermany
| | - Matthias Zwick
- Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400 Biberach an der RissGermany
| | - Maral Saadati
- Elderbrook Solutions GmbH on behalf of Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str. 65, 88400 Biberach an der Riss, Germany
| | - Stuart J Pocock
- London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HTUK
| | - Naveed Sattar
- BHF, UK School of Cardiovascular and Metabolic Health, University of Glasgow, 126 University Place, Glasgow G12 8TAUK
| | - Stefan D Anker
- Department of Cardiology (CVK) Berlin Institute of Health Center for Regenerative Therapies (BCRT) German Centre for Cardiovascular Research (DZHK) partner site Berlin, Charité Universitätsmedizin Berlin, Charité, Campus Virchow-Klinikum, Augustenburger Platz 1, D-13353 Berlin, Germany,Institute of Heart Diseases, Wroclaw Medical University, Borowska Street 213, 50-556 Warsaw, Poland
| | - Milton Packer
- Baylor Heart and Vascular Hospital, Baylor University Medical Center, 621 N Hall St, Dallas, TX 75226, USA,Imperial College, London, Exhibition Rd, South Kensington, London SW7 2BX, UK
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31
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Williams SA, Ostroff R, Hinterberg MA, Coresh J, Ballantyne CM, Matsushita K, Mueller CE, Walter J, Jonasson C, Holman RR, Shah SH, Sattar N, Taylor R, Lean ME, Kato S, Shimokawa H, Sakata Y, Nochioka K, Parikh CR, Coca SG, Omland T, Chadwick J, Astling D, Hagar Y, Kureshi N, Loupy K, Paterson C, Primus J, Simpson M, Trujillo NP, Ganz P. A proteomic surrogate for cardiovascular outcomes that is sensitive to multiple mechanisms of change in risk. Sci Transl Med 2022; 14:eabj9625. [PMID: 35385337 DOI: 10.1126/scitranslmed.abj9625] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
A reliable, individualized, and dynamic surrogate of cardiovascular risk, synoptic for key biologic mechanisms, could shorten the path for drug development, enhance drug cost-effectiveness and improve patient outcomes. We used highly multiplexed proteomics to address these objectives, measuring about 5000 proteins in each of 32,130 archived plasma samples from 22,849 participants in nine clinical studies. We used machine learning to derive a 27-protein model predicting 4-year likelihood of myocardial infarction, stroke, heart failure, or death. The 27 proteins encompassed 10 biologic systems, and 12 were associated with relevant causal genetic traits. We independently validated results in 11,609 participants. Compared to a clinical model, the ratio of observed events in quintile 5 to quintile 1 was 6.7 for proteins versus 2.9 for the clinical model, AUCs (95% CI) were 0.73 (0.72 to 0.74) versus 0.64 (0.62 to 0.65), c-statistics were 0.71 (0.69 to 0.72) versus 0.62 (0.60 to 0.63), and the net reclassification index was +0.43. Adding the clinical model to the proteins only improved discrimination metrics by 0.01 to 0.02. Event rates in four predefined protein risk categories were 5.6, 11.2, 20.0, and 43.4% within 4 years; median time to event was 1.71 years. Protein predictions were directionally concordant with changed outcomes. Adverse risks were predicted for aging, approaching an event, anthracycline chemotherapy, diabetes, smoking, rheumatoid arthritis, cancer history, cardiovascular disease, high systolic blood pressure, and lipids. Reduced risks were predicted for weight loss and exenatide. The 27-protein model has potential as a "universal" surrogate end point for cardiovascular risk.
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Affiliation(s)
| | | | | | - Josef Coresh
- Johns Hopkins University, Baltimore, MD 21218, USA
| | | | | | - Christian E Mueller
- Cardiovascular Research Institute, University of Basel, Basel 4001, Switzerland
| | - Joan Walter
- Cardiovascular Research Institute, University of Basel, Basel 4001, Switzerland.,Institute of Diagnostic and Interventional Radiology, University Hospital Zürich, University of Zürich, Zürich 7491, Switzerland
| | - Christian Jonasson
- Jebsen Centre for Genetic Epidemiology, Department of Public Health and Nursing, Norwegian University of Science and Technology, Trondheim 7491, Norway
| | - Rury R Holman
- Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DU, UK
| | - Svati H Shah
- Division of Cardiology, Duke Department of Medicine, and Duke Molecular Physiology Institute, Duke University, Durham, NC 27710, USA
| | - Naveed Sattar
- Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Roy Taylor
- Newcastle Magnetic Resonance Centre, University of Newcastle upon Tyne, Newcastle upon Tyne NE1 7RU, UK
| | - Michael E Lean
- School of Medicine, Nursing and Dentistry, University of Glasgow, Glasgow G12 8QQ, UK
| | | | - Hiroaki Shimokawa
- Tohoku University Graduate School of Medicine, Sendai 980-8576, Japan.,Graduate School, International University of Health and Welfare, Narita 286-8686, Japan
| | - Yasuhiko Sakata
- Tohoku University Graduate School of Medicine, Sendai 980-8576, Japan
| | - Kotaro Nochioka
- Tohoku University Graduate School of Medicine, Sendai 980-8576, Japan
| | | | - Steven G Coca
- Mt Sinai Clinical and Translational Science Research Unit, Icahn School of Medicine at Mount Sinai, New York, NY 11766, USA
| | - Torbjørn Omland
- Department of Cardiology, Akershus University Hospital and University of Oslo, Oslo 1478, Norway
| | | | | | | | | | | | | | | | | | | | - Peter Ganz
- Zuckerberg San Francisco General Hospital, University of California, San Francisco, San Francisco, CA 94110, USA
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Ceramides and phospholipids in plasma extracellular vesicles are associated with high risk of major cardiovascular events after carotid endarterectomy. Sci Rep 2022; 12:5521. [PMID: 35365690 PMCID: PMC8975809 DOI: 10.1038/s41598-022-09225-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2021] [Accepted: 02/28/2022] [Indexed: 11/26/2022] Open
Abstract
Ceramides and phosphatidylcholines (PCs) are bioactive lipids and lipid bilayer membrane components. Distinct ceramides/PCs (ratios) predict cardiovascular outcome in patients with coronary artery disease. Extracellular vesicles (EVs) are proposed biomarkers for cardiovascular disease and contain ceramides/PCs. Ceramides/PCs have not been studied in patients undergoing carotid endarterectomy (CEA) nor in EVs. We therefore investigated whether levels of ceramides/PCs in plasma and EVs are associated with postoperative risk of major adverse cardiovascular events (MACE) following CEA. In 873 patients undergoing CEA of the Athero-Express biobank, we quantitatively measured seven ceramides/PCs in preoperative blood samples: Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), Cer(d18:1/24:1), PC(14:0/22:6), PC(16:0/16:0) and PC(16:0/22:5) in plasma and two plasma EV-subfractions (LDL and TEX). We analyzed the association of ceramides, PCs and their predefined ratios with the three-year postoperative risk of MACE (including stroke, myocardial infarction and cardiovascular death). A total of 138 patients (16%) developed MACE during the three-year follow-up. In the LDL-EV subfraction, higher levels of Cer(d18:1/24:1) and Cer(d18:1/16:0)/PC(16:0/22:5) ratio were significantly associated with an increased risk of MACE (adjusted HR per SD [95% CI] 1.24 [1.01–1.53] and 1.26 [1.04–1.52], respectively). In the TEX-EV subfraction, three ratios Cer(d18:1/16:0)/Cer(d18:1/24:0), Cer(d18:1/18:0)/Cer(d18:1/24:0) and Cer(d18:1/24:1)/Cer(d18:1/24:0) were positively associated with MACE (adjusted HR per SD 1.34 [1.06–1.70], 1.24 [1.01–1.51] and 1.31 [1.08–1.58], respectively). In conclusion, distinct ceramides and PCs in plasma EVs determined in preoperative blood were independently associated with an increased 3-year risk of MACE after CEA. These lipids are therefore potential markers to identify high-risk CEA patients qualifying for secondary preventive add-on therapy.
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Omar M, Jensen J, Kistorp C, Højlund K, Videbæk L, Tuxen C, Larsen JH, Andersen CF, Gustafsson F, Køber L, Schou M, Møller JE. The effect of empagliflozin on growth differentiation factor 15 in patients with heart failure: a randomized controlled trial (Empire HF Biomarker). Cardiovasc Diabetol 2022; 21:34. [PMID: 35219331 PMCID: PMC8882292 DOI: 10.1186/s12933-022-01463-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 02/09/2022] [Indexed: 02/07/2023] Open
Abstract
Background Plasma growth differentiation factor-15 (GDF-15) biomarker levels increase in response to inflammation and tissue injury, and increased levels of GDF-15 are associated with increased risk of mortality in patients with heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter-2 (SGLT2) inhibitors, which improve outcome in HFrEF, have been shown to increase plasma GDF-15 in diabetic patients. We aimed to investigate the effect of empagliflozin on GDF-15 in HFrEF patients. Methods This Empire HF Biomarker substudy was from the multicentre, randomized, double-blind, placebo-controlled Empire HF trial that included 190 patients from June 29, 2017, to September 10, 2019. Stable ambulatory HFrEF patients with ejection fraction of ≤ 40% were randomly assigned (1:1) to empagliflozin 10 mg once daily, or matching placebo for 12 weeks. Changes from baseline to 12 weeks in plasma levels of GDF-15, high-sensitive C-reactive protein (hsCRP), and high-sensitive troponin T (hsTNT) were assessed. Results A total of 187 patients who were included in this study, mean age was 64 ± 11 years; 85% male, 12% with type 2 diabetes, mean ejection fraction 29 ± 8, with no differences between the groups. Baseline median plasma GDF-15 was 1189 (918–1720) pg/mL with empagliflozin, and 1299 (952–1823) pg/mL for placebo. Empagliflozin increased plasma GDF-15 compared to placebo (adjusted between-groups treatment effect; ratio of change (1·09 [95% confidence interval (CI), 1.03–1.15]: p = 0.0040). The increase in plasma GDF15 was inversely associated with a decrease in left ventricular end-systolic (R = – 0.23, p = 0.031), and end-diastolic volume (R = – 0.29, p = 0.0066). There was no change in plasma hsCRP (1.09 [95%CI, 0.86–1.38]: p = 0.48) or plasma hsTNT (1.07 [95%CI, 0.97–1.19]: p = 0.18) compared to placebo. Patients with diabetes and treated with metformin demonstrated no increase in plasma GDF-15 with empagliflozin, p for interaction = 0·01. Conclusion Empagliflozin increased plasma levels of GDF-15 in patients with HFrEF, with no concomitant increase in hsTNT nor hsCRP. Trial registration: The Empire HF trial is registered with ClinicalTrials.gov, NCT03198585. Supplementary Information The online version contains supplementary material available at 10.1186/s12933-022-01463-2.
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Du S, Shi H, Xiong L, Wang P, Shi Y. Canagliflozin mitigates ferroptosis and improves myocardial oxidative stress in mice with diabetic cardiomyopathy. Front Endocrinol (Lausanne) 2022; 13:1011669. [PMID: 36313744 PMCID: PMC9616119 DOI: 10.3389/fendo.2022.1011669] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Accepted: 09/27/2022] [Indexed: 11/13/2022] Open
Abstract
Canagliflozin (Cana), an anti-diabetes drug belongs to sodium-glucose cotransporter 2 inhibitor, is gaining interest because of its extra cardiovascular benefits. Ferroptosis is a new mode of cell death, which can promote the occurrence of diabetic cardiomyopathy (DCM). Whether Cana can alleviate DCM by inhibiting ferroptosis is the focus of this study. Here, we induced DCM models in diabetic C57BL6 mice and treated with Cana. Meanwhile, in order to exclude its hypoglycemic effect, the high glucose model in H9C2 cells were established. In the in vivo study, we observed that Cana could effectively alleviate the damage of cardiac function in DCM mice, including the increasing of lactate dehydrogenase (LDH) and cardiac troponin I (cTnI), the alleviating of myocardial fiber breakage, inflammation, collagen fiber deposition and mitochondrial structural disorder. We evaluated reactive oxygen species (ROS) levels by DCFH-DA and BODIPY 581/591 C11, in vitro Cana reduced ROS and lipid ROS in H9C2 cells induced by high glucose. Meanwhile, JC-1 fluorochrome assay showed that the decreased mitochondrial membrane potential (MMP) was increased by Cana. Furthermore, the inhibitory effects of Cana on myocardial oxidative stress and ferroptosis were verified in vivo and in vitro by protein carbonyl (PCO), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione (GSH). As a key inducer of ferroptosis, the deposition of total iron and Fe2+ can be inhibited by Cana both in vivo and in vitro. In addition, western blot results indicated that the expression of ferritin heavy-chain (FTN-H) was down-regulated, and cystine-glutamate antiporter (xCT) was up-regulated by Cana in DCM mice and cells, suggesting that Cana inhibit ferroptosis by balancing cardiac iron homeostasis and promoting the system Xc-/GSH/GPX4 axis in DCM. These findings underscore the fact that ferroptosis plays an important role in the development and progression of DCM and targeting ferroptosis may be a novel strategy for prevention and treatment. In conclusion, Cana may exert some of its cardiovascular benefits by attenuating ferroptosis.
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Affiliation(s)
- Shuqin Du
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Jiaxing, China
- Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, China
- School of Pharmacy, Zhejiang University of Technology, Hangzhou, China
- School of Medicine, Jiaxing University, Jiaxing, China
| | - Hanqiang Shi
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Jiaxing, China
- Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, China
| | - Lie Xiong
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Jiaxing, China
- Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, China
| | - Ping Wang
- School of Pharmacy, Zhejiang University of Technology, Hangzhou, China
| | - Yanbo Shi
- Central Laboratory of Molecular Medicine Research Center, Jiaxing Traditional Chinese Medicine (TCM) Hospital Affiliated to Zhejiang University of Traditional Chinese Medicine, Jiaxing, China
- Jiaxing Key Laboratory of Diabetic Angiopathy Research, Jiaxing, China
- *Correspondence: Yanbo Shi,
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Sen T, Li J, Neuen BL, Arnott C, Neal B, Perkovic V, Mahaffey KW, Shaw W, Canovatchel W, Hansen MK, Heerspink HJL. Association Between Circulating GDF-15 and Cardio-Renal Outcomes and Effect of Canagliflozin: Results From the CANVAS Trial. J Am Heart Assoc 2021; 10:e021661. [PMID: 34854308 PMCID: PMC9075362 DOI: 10.1161/jaha.121.021661] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Background Studies have suggested that sodium glucose co‐transporter 2 inhibitors exert anti‐inflammatory effects. We examined the association of baseline growth differentiation factor‐15 (GDF‐15), a marker of inflammation and cellular injury, with cardiovascular events, hospitalization for heart failure (HF), and kidney outcomes in patients with type 2 diabetes in the CANVAS (Canagliflozin Cardiovascular Assessment Study) and determined the effect of the sodium glucose co‐transporter 2 inhibitor canagliflozin on circulating GDF‐15. Methods and Results The CANVAS trial randomized 4330 people with type 2 diabetes at high cardiovascular risk to canagliflozin or placebo. The association between baseline GDF‐15 and cardiovascular (non‐fatal myocardial infarction, non‐fatal stroke, cardiovascular death), HF, and kidney (40% estimated glomerular filtration rate decline, end‐stage kidney disease, renal death) outcomes was assessed using multivariable adjusted Cox regression models. During median follow‐up of 6.1 years (N=3549 participants with available samples), 555 cardiovascular, 129 HF, and 137 kidney outcomes occurred. Each doubling in baseline GDF‐15 was significantly associated with a higher risk of cardiovascular (hazard ratio [HR], 1.2; 95% CI, 1.0‒1.3), HF (HR, 1.5; 95% CI, 1.2‒2.0) and kidney (HR, 1.5; 95% CI, 1.2‒2.0) outcomes. Baseline GDF‐15 did not modify canagliflozin’s effect on cardiovascular, HF, and kidney outcomes. Canaglifozin treatment modestly lowered GDF‐15 compared with placebo; however, GDF‐15 did not mediate the protective effect of canagliflozin on cardiovascular, HF, or kidney outcomes. Conclusions In patients with type 2 diabetes at high cardiovascular risk, higher GDF‐15 levels were associated with a higher risk of cardiovascular, HF, and kidney outcomes. Canagliflozin modestly lowered GDF‐15, but GDF‐15 reduction did not mediate the protective effect of canagliflozin.
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Affiliation(s)
- Taha Sen
- Department of Clinical Pharmacy and PharmacologyUniversity of GroningenThe Netherlands
| | - Jingwei Li
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Brendon L. Neuen
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Clare Arnott
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Bruce Neal
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Vlado Perkovic
- The George Institute for Global HealthUNSW SydneySydneyAustralia
| | - Kenneth W. Mahaffey
- Department of MedicineStanford Center for Clinical ResearchStanford University School of MedicineStanfordCA
| | - Wayne Shaw
- Janssen Research & Development, LLCRaritanNJ
| | | | | | - Hiddo J. L. Heerspink
- Department of Clinical Pharmacy and PharmacologyUniversity of GroningenThe Netherlands
- The George Institute for Global HealthUNSW SydneySydneyAustralia
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Packer M. Differential Pathophysiological Mechanisms in Heart Failure With a Reduced or Preserved Ejection Fraction in Diabetes. JACC-HEART FAILURE 2021; 9:535-549. [PMID: 34325884 DOI: 10.1016/j.jchf.2021.05.019] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/17/2021] [Accepted: 05/27/2021] [Indexed: 12/11/2022]
Abstract
Diabetes promotes the development of both heart failure with a reduced ejection fraction and heart failure with a preserved ejection fraction through diverse mechanisms, which are likely mediated through hyperinsulinemia rather than hyperglycemia. Diabetes promotes nutrient surplus signaling (through Akt and mammalian target of rapamycin complex 1) and inhibits nutrient deprivation signaling (through sirtuin-1 and its downstream effectors); this suppresses autophagy and promotes endoplasmic reticulum and oxidative stress and mitochondrial dysfunction, thereby undermining the health of diabetic cardiomyocytes. The hyperinsulinemia of diabetes may also activate sodium-hydrogen exchangers in cardiomyocytes (leading to injury and loss) and in the proximal renal tubules (leading to sodium retention). Diabetes may cause epicardial adipose tissue expansion, and the resulting secretion of proinflammatory adipocytokines onto the adjoining myocardium can lead to coronary microcirculatory dysfunction and myocardial inflammation and fibrosis. Interestingly, sodium-glucose cotransporter 2 (SGLT2) inhibitors-the only class of antidiabetic medication that reduces serious heart failure events-may act to mitigate each of these mechanisms. SGLT2 inhibitors up-regulate sirtuin-1 and its downstream effectors and autophagic flux, thus explaining the actions of these drugs to reduce oxidative stress, normalize mitochondrial structure and function, and mute proinflammatory pathways in the stressed myocardium. Inhibition of SGLT2 may also lead to a reduction in the activity of sodium-hydrogen exchangers in the kidney (leading to diuresis) and in the heart (attenuating the development of cardiac hypertrophy and systolic dysfunction). Finally, SGLT2 inhibitors reduce the mass and mute the adverse biology of epicardial adipose tissue (and reduce the secretion of leptin), thus explaining the capacity of these drugs to mitigate myocardial inflammation, microcirculatory dysfunction, and fibrosis, and improve ventricular filling dynamics. The pathophysiological mechanisms by which SGLT2 inhibitors may benefit heart failure likely differ depending on ejection fraction, but each represents interference with distinct pathways by which hyperinsulinemia may adversely affect cardiac structure and function.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, USA; Imperial College, London, United Kingdom.
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SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism. Heart Fail Rev 2021; 27:961-980. [PMID: 33713009 DOI: 10.1007/s10741-021-10096-8] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2021] [Indexed: 02/07/2023]
Abstract
Heart failure (HF) often coexists with insulin resistance (IR), and the incidence of HF in type 2 diabetes mellitus (T2DM) patients is significantly higher. The reciprocal relationship between HF and IR has long been recognized, and the integration complicates the therapy of both. A number of mechanisms ascribe to the progression of cardiac IR, in which the main factors are the shift of myocardial substrate metabolism. Studies have found that SGLT2 inhibitors, an anti-diabetic drug, can improve the cardiac prognosis of patients with T2DM, which may be at least partially due to the relief of cardiac IR. Basic and clinical studies have revealed the important role of cardiac IR in the pathogenesis and progression of HF, and studies suggest that energy metabolism plays an important role in the pathogenesis of cardiac IR and HF. SGLT2 inhibitors mediated cardiovascular benefits through various mechanisms such as improving substrate utilization and improving myocardial energy. The regulation of SGLT2 inhibitors on cardiac energy status including carbohydrates, fatty acids (FA), amino acids and ketones, ATP transfer to the cytoplasm, and mitochondrial functional status have received extensive attention in HF, but its specific mechanism of action is still unclear. Therefore, this article reviews the relationship between IR and HF from the perspective of energy metabolism; subsequently, targeting energy metabolism discusses the pivotal role of SGLT2 inhibitors in improving cardiac IR and HF based on basic and clinical research evidences, and sought to clarify the molecular mechanism involved. (Fig. 1).
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Liu Z, Ma X, Ilyas I, Zheng X, Luo S, Little PJ, Kamato D, Sahebkar A, Wu W, Weng J, Xu S. Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics. Theranostics 2021; 11:4502-4515. [PMID: 33754074 PMCID: PMC7977463 DOI: 10.7150/thno.54498] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 01/17/2021] [Indexed: 02/06/2023] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are new oral drugs for the therapy of patients with type 2 diabetes mellitus (T2DM). Research in the past decade has shown that drugs of the SGLT2i class, such as empagliflozin, canagliflozin, and dapagliflozin, have pleiotropic effects in preventing cardiovascular diseases beyond their favorable impact on hyperglycemia. Of clinical relevance, recent landmark cardiovascular outcome trials have demonstrated that SGLT2i reduce major adverse cardiovascular events, hospitalization for heart failure, and cardiovascular death in T2DM patients with/without cardiovascular diseases (including atherosclerotic cardiovascular diseases and various types of heart failure). The major pharmacological action of SGLT2i is through inhibiting glucose re-absorption in the kidney and thus promoting glucose excretion. Studies in experimental models of atherosclerosis have shown that SGLT2i ameliorate the progression of atherosclerosis by mechanisms including inhibition of vascular inflammation, reduction in oxidative stress, reversing endothelial dysfunction, reducing foam cell formation and preventing platelet activation. Here, we summarize the anti-atherosclerotic actions and mechanisms of action of SGLT2i, with an aim to emphasize the clinical utility of this class of agents in preventing the insidious cardiovascular complications accompanying diabetes.
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Affiliation(s)
- Zhenghong Liu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xiaoxuan Ma
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Iqra Ilyas
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xueying Zheng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Sihui Luo
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Peter J. Little
- Sunshine Coast Health Institute, University of the Sunshine Coast, Birtinya, QLD 4575, Australia
- School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Danielle Kamato
- School of Pharmacy, Pharmacy Australia Centre of Excellence, the University of Queensland, Woolloongabba, Queensland 4102, Australia
| | - Amirhossein Sahebkar
- Halal Research Center of IRI, FDA, Tehran, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad. Iran
| | - Weiming Wu
- Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu, China
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Suowen Xu
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
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Katzmann JL, Mason AM, März W, Kleber ME, Niessner A, Blüher M, Speer T, Laufs U. Genetic Variation in Sodium-glucose Cotransporter 2 and Heart Failure. Clin Pharmacol Ther 2021; 110:149-158. [PMID: 33405238 DOI: 10.1002/cpt.2153] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/04/2020] [Indexed: 12/31/2022]
Abstract
Inhibition of sodium-glucose cotransporter 2 (SGLT2) represents an emerging pharmaceutical approach for the treatment of heart failure. The mechanisms by which SGLT2 inhibitors reduce the risk of heart failure are not well understood. The objective of this study was to investigate the association between single nucleotide polymorphisms (SNPs) in the SLC5A2 gene, encoding SGLT2, and heart failure, and to assess potential mediators of this association. Regression and mediation analyses were conducted with individual participant data of the UK Biobank (n = 416,737) and validated in the cardiovascular high-risk cohort of the LUdwigshafen RIsk and Cardiovascular Health study (LURIC; n = 3316). Two intronic SNPs associated with SLC5A2 expression were included in a genetic score, which was associated with lower risk of heart failure in UK Biobank (odds ratio 0.97, 95% confidence interval, 0.95-0.99, P = 0.016). This association was also present in participants without type 2 diabetes or coronary artery disease (CAD). The associations of the genetic score with HbA1c, high-density lipoprotein cholesterol, uric acid, systolic blood pressure, waist circumference, and body composition mediated 35% of the effect of the score on heart failure risk. No associations of the genetic SGLT2 score with atherosclerotic cardiovascular disease outcomes or markers of volume status were observed, which was confirmed in the LURIC study. Variations in the gene encoding SGLT2 were associated with the risk of prevalent or incident heart failure. This association was mediated by several mechanisms and did not depend on the presence of type 2 diabetes or previous CAD events.
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Affiliation(s)
- Julius L Katzmann
- Department of Cardiology, University Hospital Leipzig, Leipzig, Germany
| | - Amy M Mason
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
| | - Winfried März
- Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.,SYNLAB Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.,Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Graz, Austria
| | - Marcus E Kleber
- Fifth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Alexander Niessner
- Department of Internal Medicine II, Medical University of Vienna, Vienna, Austria
| | - 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
| | - Thimoteus Speer
- Department of Internal Medicine IV (Nephrology and Hypertension), Saarland University, Homburg, Germany
| | - Ulrich Laufs
- Department of Cardiology, University Hospital Leipzig, Leipzig, Germany
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Katsiki N, Ferrannini E. Anti-inflammatory properties of antidiabetic drugs: A "promised land" in the COVID-19 era? J Diabetes Complications 2020; 34:107723. [PMID: 32900588 PMCID: PMC7448766 DOI: 10.1016/j.jdiacomp.2020.107723] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 08/21/2020] [Accepted: 08/21/2020] [Indexed: 12/13/2022]
Abstract
Inflammation is implicated in the development and severity of the coronavirus disease 2019 (COVID-19), as well as in the pathophysiology of diabetes. Diabetes, especially when uncontrolled, is also recognized as an important risk factor for COVID-19 morbidity and mortality. Furthermore, certain inflammatory markers [i.e. C-reactive protein (CRP), interleukin-6 (IL-6) and ferritin] were reported as strong predictors of worse outcomes in COVID-19 positive patients. The same biomarkers have been associated with poor glycemic control. Therefore, achieving euglycemia in patients with diabetes is even more important in the era of the COVID-19 pandemic. Based on the above, it is clinically interesting to elucidate whether antidiabetic drugs may reduce inflammation, thus possibly minimizing the risk for COVID-19 development and severity. The present narrative review discusses the potential anti-inflammatory properties of certain antidiabetic drugs (i.e. metformin, pioglitazone, sitagliptin, linagliptin, vildagliptin, alogliptin, saxagliptin, liraglutide, dulaglutide, exenatide, lixisenatide, semaglutide, empagliflozin, dapagliflozin, canagliflozin), with a focus on CRP, IL-6 and ferritin.
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Affiliation(s)
- Niki Katsiki
- First Department of Internal Medicine, Diabetes Center, Division of Endocrinology and Metabolism, Medical School, Aristotle University of Thessaloniki, AHEPA Hospital, Thessaloniki, Greece
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Ganz P, Deo R, Dubin RF. Proteomics for personalized cardiovascular risk assessment: in pursuit of the Holy Grail. Eur Heart J 2020; 41:4008-4010. [PMID: 32901246 DOI: 10.1093/eurheartj/ehaa661] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Affiliation(s)
- Peter Ganz
- Cardiovascular Division, Zuckerberg San Francisco General Hospital, University of California, San Francisco, 1001 Potrero Avenue, San Francisco, CA 94110, USA
| | - Rajat Deo
- Division of Cardiology, Electrophysiology Section, University of Pennsylvania, Philadelphia, 3400 Spruce Street, 9 Founders Cardiology, Philadelphia, PA 19104, USA
| | - Ruth F Dubin
- Division of Nephrology, San Francisco VA Medical Center, University of California, San Francisco, 4150 Clement St, San Francisco, CA 94121, USA
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