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Akunjee MM, Khosla SG, Nylen ES, Sen S. SGLT2 inhibitors use in kidney disease: what did we learn? Am J Physiol Endocrinol Metab 2025; 328:E856-E868. [PMID: 40279256 DOI: 10.1152/ajpendo.00034.2025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 03/26/2025] [Accepted: 04/18/2025] [Indexed: 04/27/2025]
Abstract
Chronic kidney disease (CKD) increases the risk for cardiovascular morbidity and mortality and it's prevalence continues to rise throughout the world. Newer, more efficacious therapies, slow progression of CKD, decrease long-term sequela like end-stage kidney disease (ESKD) and cardiovascular events, improving survival. Postmarketing cardiovascular outcome trials (CVOT) have demonstrated improved cardiovascular outcomes with the use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) like canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, and sotagliflozin in patients with type 2 diabetes mellitus (T2DM), Similarly, secondary analysis of CVOT and renal outcome trials with the use of SGLT2i in patients without T2DM showed improved renal function and albuminuria. In these studies, nondiabetic CKD was defined as an estimated glomerular filtration rate (eGFR) of 20-75 mL/min/1.73 m2 with albuminuria ranging from 200 to 5,000 mg/g in the absence of diabetes. As a class effect, in addition to modulation of hemodynamic and metabolic activities, SGLT2i exert renal protection by suppressing inflammation and fibrosis. We conducted an extensive search in the PubMed database for original papers published from 2009 through 2024 using keywords such as nondiabetic kidney disease, diabetic kidney disease, SGLT2i, and kidney outcomes. Based on our research of published literature, we present a review and propose, consideration of SGLT2i in nondiabetic kidney disease for long-term cardiovascular and renal benefit (Dharia A, Khan A, Sridhar VS, Cherney DZI. Annu Rev Med 74: 369-384, 2023). We will highlight relevant translational studies to propose a possible cell-based mechanism for cardiovascular benefits noted secondary to use of SGLT2i.
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Affiliation(s)
- Munaza M Akunjee
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Shikha G Khosla
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Eric S Nylen
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
| | - Sabyasachi Sen
- Division of Endocrinology, Department of Medicine, Veterans Affairs Medical Center, Washington, District of Columbia, United States
- Division of Endocrinology, Department of Medicine, The George Washington University, Washington, District of Columbia, United States
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Yanai H, Adachi H, Hakoshima M, Katsuyama H. Significance of Endothelial Dysfunction Amelioration for Sodium-Glucose Cotransporter 2 Inhibitor-Induced Improvements in Heart Failure and Chronic Kidney Disease in Diabetic Patients. Metabolites 2023; 13:736. [PMID: 37367894 DOI: 10.3390/metabo13060736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/29/2023] [Accepted: 06/07/2023] [Indexed: 06/28/2023] Open
Abstract
Beyond lowering plasma glucose levels, sodium-glucose cotransporter 2 inhibitors (SGLT2is) significantly reduce hospitalization for heart failure (HF) and retard the progression of chronic kidney disease (CKD) in patients with type 2 diabetes. Endothelial dysfunction is not only involved in the development and progression of cardiovascular disease (CVD), but is also associated with the progression of CKD. In patients with type 2 diabetes, hyperglycemia, insulin resistance, hyperinsulinemia and dyslipidemia induce the development of endothelial dysfunction. SGLT2is have been shown to improve endothelial dysfunction, as assessed by flow-mediated vasodilation, in individuals at high risk of CVD. Along with an improvement in endothelial dysfunction, SGLT2is have been shown to improve oxidative stress, inflammation, mitochondrial dysfunction, glucotoxicity, such as the advanced signaling of glycation end products, and nitric oxide bioavailability. The improvements in endothelial dysfunction and such endothelium-derived factors may play an important role in preventing the development of coronary artery disease, coronary microvascular dysfunction and diabetic cardiomyopathy, which cause HF, and play a role in retarding CKD. The suppression of the development of HF and the progression of CKD achieved by SGLT2is might have been largely induced by their capacity to improve vascular endothelial function.
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Affiliation(s)
- Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Chiba 272-8516, Japan
| | - Hiroki Adachi
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Chiba 272-8516, Japan
| | - Mariko Hakoshima
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Chiba 272-8516, Japan
| | - Hisayuki Katsuyama
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Chiba 272-8516, Japan
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Abstract
Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors) were originally developed as antidiabetic agents, with cardiovascular (CV) outcome trials demonstrating improved CV outcomes in patients with type 2 diabetes mellitus (T2D). Secondary analyses of CV outcome trials and later dedicated kidney outcome trials consistently reported improved kidney-related outcomes independent of T2D status and across a range of kidney function and albuminuria. Importantly, SGLT2 inhibitors are generally safe and well tolerated, with clinical trials and real-world analyses demonstrating a decrease in the risk of acute kidney injury. The kidney protective effects of SGLT2 inhibitors generally extend across different members of the class, possibly on the basis of hemodynamic, metabolic, anti-inflammatory, and antifibrotic mechanisms. In this review, we summarize the effects of SGLT2 inhibitors on kidney outcomes in diverse patient populations.
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Affiliation(s)
- Atit Dharia
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; , , , .,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Abid Khan
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; , , , .,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Vikas S Sridhar
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; , , , .,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Division of Nephrology, Department of Medicine, University Health Network, Toronto, Ontario, Canada; , , , .,Department of Medicine, University of Toronto, Toronto, Ontario, Canada
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Yokouchi G, Horio T, Matsumoto N, Fukuda K, Yoshimura R, Fujiwara R, Matsuoka Y, Sakamoto Y, Iwashima Y, Oshiro Y, Fujimoto K, Kasayuki N. Renoprotective effect of chronic treatment with sodium-glucose cotransporter 2 inhibitors and its associated factors in Japanese patients with chronic heart failure and diabetes. IJC HEART & VASCULATURE 2022; 43:101152. [DOI: 10.1016/j.ijcha.2022.101152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 11/12/2022] [Accepted: 11/18/2022] [Indexed: 11/27/2022]
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Salvatore T, Galiero R, Caturano A, Rinaldi L, Di Martino A, Albanese G, Di Salvo J, Epifani R, Marfella R, Docimo G, Lettieri M, Sardu C, Sasso FC. An Overview of the Cardiorenal Protective Mechanisms of SGLT2 Inhibitors. Int J Mol Sci 2022; 23:3651. [PMID: 35409011 PMCID: PMC8998569 DOI: 10.3390/ijms23073651] [Citation(s) in RCA: 115] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/17/2022] [Accepted: 03/24/2022] [Indexed: 02/04/2023] Open
Abstract
Sodium-glucose co-transporter 2 (SGLT2) inhibitors block glucose reabsorption in the renal proximal tubule, an insulin-independent mechanism that plays a critical role in glycemic regulation in diabetes. In addition to their glucose-lowering effects, SGLT2 inhibitors prevent both renal damage and the onset of chronic kidney disease and cardiovascular events, in particular heart failure with both reduced and preserved ejection fraction. These unexpected benefits prompted changes in treatment guidelines and scientific interest in the underlying mechanisms. Aside from the target effects of SGLT2 inhibition, a wide spectrum of beneficial actions is described for the kidney and the heart, even though the cardiac tissue does not express SGLT2 channels. Correction of cardiorenal risk factors, metabolic adjustments ameliorating myocardial substrate utilization, and optimization of ventricular loading conditions through effects on diuresis, natriuresis, and vascular function appear to be the main underlying mechanisms for the observed cardiorenal protection. Additional clinical advantages associated with using SGLT2 inhibitors are antifibrotic effects due to correction of inflammation and oxidative stress, modulation of mitochondrial function, and autophagy. Much research is required to understand the numerous and complex pathways involved in SGLT2 inhibition. This review summarizes the current known mechanisms of SGLT2-mediated cardiorenal protection.
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Affiliation(s)
- Teresa Salvatore
- Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via De Crecchio 7, 80138 Naples, Italy
| | - Raffaele Galiero
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Alfredo Caturano
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Luca Rinaldi
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Anna Di Martino
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Gaetana Albanese
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Jessica Di Salvo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Raffaella Epifani
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Raffaele Marfella
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
- Mediterrannea Cardiocentro, 80122 Napoli, Italy
| | - Giovanni Docimo
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Miriam Lettieri
- Division of Cardiovascular Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, 3.31 Core Technology Facility, 46 Grafton Street, Manchester M13 9NT, UK
| | - Celestino Sardu
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
| | - Ferdinando Carlo Sasso
- Department of Advanced Medical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Luigi Miraglia 2, 80138 Naples, Italy
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Liu H, Sridhar VS, Boulet J, Dharia A, Khan A, Lawler PR, Cherney DZI. Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease. Metabolism 2022; 126:154918. [PMID: 34699838 DOI: 10.1016/j.metabol.2021.154918] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/14/2021] [Accepted: 10/19/2021] [Indexed: 12/23/2022]
Abstract
Type 2 diabetes (T2D) is one of the most common causes of chronic kidney disease (CKD) and cardiovascular (CV) disease. Until recently, glycemic and BP control were the cornerstones for preventing progression of CKD and CV disease associated with T2D. However, there has been a paradigm shift in treatment since the publication of the first clinical trial demonstrating benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in 2015. SGLT2 inhibitors have been shown to reduce the risk of major adverse CV events and progression of kidney disease in the setting of T2D. However, the elucidation of mechanisms of underlying these clinical benefits is the subject of ongoing investigation. Experimental studies have shown that SGLT2 inhibitors have diverse pleiotropic effects such as modulation of neurohormones such as the renin-angiotensin-aldosterone system, increasing hematocrit, altering energy substrate use, and attenuating systemic inflammation and oxidative stress, all of which have been implicated in the CV and kidney protective effects of SGLT2 inhibitors. In this review, we highlight biomarkers linked with diabetic kidney disease and heart failure and discuss how SGLT2 inhibitor-associated changes potentially mediate the cardiorenal protection observed with these therapies.
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Affiliation(s)
- Hongyan Liu
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
| | - Vikas S Sridhar
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jacinthe Boulet
- Department of Medicine, Division of Cardiology, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Atit Dharia
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Abid Khan
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Patrick R Lawler
- Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON, Canada; Division of Cardiology and Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Sciences, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
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Nashawi M, Ahmed MS, Amin T, Abualfoul M, Chilton R. Cardiovascular benefits from SGLT2 inhibition in type 2 diabetes mellitus patients is not impaired with phosphate flux related to pharmacotherapy. World J Cardiol 2021; 13:676-694. [PMID: 35070111 PMCID: PMC8716977 DOI: 10.4330/wjc.v13.i12.676] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 08/02/2021] [Accepted: 11/30/2021] [Indexed: 02/06/2023] Open
Abstract
The beneficial cardiorenal outcomes of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) have been substantiated by multiple clinical trials, resulting in increased interest in the multifarious pathways by which their mechanisms act. The principal effect of SGLT2i (-flozin drugs) can be appreciated in their ability to block the SGLT2 protein within the kidneys, inhibiting glucose reabsorption, and causing an associated osmotic diuresis. This ameliorates plasma glucose elevations and the negative cardiorenal sequelae associated with the latter. These include aberrant mitochondrial metabolism and oxidative stress burden, endothelial cell dysfunction, pernicious neurohormonal activation, and the development of inimical hemodynamics. Positive outcomes within these domains have been validated with SGLT2i administration. However, by modulating the sodium-glucose cotransporter in the proximal tubule (PT), SGLT2i consequently promotes sodium-phosphate cotransporter activity with phosphate retention. Phosphatemia, even at physiologic levels, poses a risk in cardiovascular disease burden, more so in patients with type 2 diabetes mellitus (T2DM). There also exists an association between phosphatemia and renal impairment, the latter hampering cardiovascular function through an array of physiologic roles, such as fluid regulation, hormonal tone, and neuromodulation. Moreover, increased phosphate flux is associated with an associated increase in fibroblast growth factor 23 levels, also detrimental to homeostatic cardiometabolic function. A contemporary commentary concerning this notion unifying cardiovascular outcome trial data with the translational biology of phosphate is scant within the literature. Given the apparent beneficial outcomes associated with SGLT2i administration notwithstanding negative effects of phosphatemia, we discuss in this review the effects of phosphate on the cardiometabolic status in patients with T2DM and cardiorenal disease, as well as the mechanisms by which SGLT2i counteract or overcome them to achieve their net effects. Content drawn to develop this conversation begins with proceedings in the basic sciences and works towards clinical trial data.
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Affiliation(s)
- Mouhamed Nashawi
- Department of Internal Medicine, Baylor Scott and White All Saints Medical Center, Fort Worth, TX 76132, United States.
| | - Mahmoud S Ahmed
- Division of Medicine-Cardiology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Toka Amin
- Division of Medicine-Cardiology, UT Health San Antonio, San Antonio, TX 78229, United States
| | - Mujahed Abualfoul
- Department of Internal Medicine, Faculty of Medicine, Cairo University, Dallas, TX 75203, United States
| | - Robert Chilton
- Department of Internal Medicine, Methodist Dallas Medical Center, Dallas, TX 75203, United States
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Yanai H. Acute Effects of Preventing Heart Failure by Sodium-Glucose Cotransporter 2 Inhibitors. Cardiol Res 2021; 12:324-326. [PMID: 34691331 PMCID: PMC8510658 DOI: 10.14740/cr1315] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Accepted: 08/13/2021] [Indexed: 01/10/2023] Open
Affiliation(s)
- Hidekatsu Yanai
- Department of Diabetes, Endocrinology and Metabolism, National Center for Global Health and Medicine Kohnodai Hospital, 1-7-1 Kohnodai, Ichikawa, Chiba 272-0034, Japan.
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Pabel S, Hamdani N, Luedde M, Sossalla S. SGLT2 Inhibitors and Their Mode of Action in Heart Failure-Has the Mystery Been Unravelled? Curr Heart Fail Rep 2021; 18:315-328. [PMID: 34523061 PMCID: PMC8484236 DOI: 10.1007/s11897-021-00529-8] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/09/2021] [Indexed: 12/12/2022]
Abstract
PURPOSE OF REVIEW SGLT2 inhibitors (SGLT2i) are new drugs for patients with heart failure (HF) irrespective of diabetes. However, the mechanisms of SGLT2i in HF remain elusive. This article discusses the current clinical evidence for using SGLT2i in different types of heart failure and provides an overview about the possible underlying mechanisms. RECENT FINDINGS Clinical and basic data strongly support and extend the use of SGLT2i in HF. Improvement of conventional secondary risk factors is unlikely to explain the prognostic benefits of these drugs in HF. However, different multidirectional mechanisms of SGLT2i could improve HF status including volume regulation, cardiorenal mechanisms, metabolic effects, improved cardiac remodelling, direct effects on cardiac contractility and ion-homeostasis, reduction of inflammation and oxidative stress as well as an impact on autophagy and adipokines. Further translational studies are needed to determine the mechanisms of SGLT2i in HF. However, basic and clinical evidence encourage the use of SGLT2i in HFrEF and possibly HFpEF.
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Affiliation(s)
- Steffen Pabel
- Department of Internal Medicine II, University Medical Centre Regensburg, Regensburg, Germany
| | - Nazha Hamdani
- Department of Molecular and Experimental Cardiology and Department of Cardiology, St. Josef-Hospital, Ruhr University Bochum, Bochum, Germany
| | - Mark Luedde
- Department of Cardiology and Angiology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Samuel Sossalla
- Department of Internal Medicine II, University Medical Centre Regensburg, Regensburg, Germany. .,Clinic for Cardiology and Pneumology, Georg-August University Göttingen, and DZHK (German Centre for Cardiovascular Research), partner site Göttingen, Göttingen, Germany.
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Multi-Organ Protective Effects of Sodium Glucose Cotransporter 2 Inhibitors. Int J Mol Sci 2021; 22:ijms22094416. [PMID: 33922546 PMCID: PMC8122906 DOI: 10.3390/ijms22094416] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022] Open
Abstract
Sodium glucose cotransporter 2 inhibitors (SGLT2i) block the reabsorption of glucose by inhibiting SGLT2, thus improving glucose control by promoting the renal excretion of glucose, without requiring insulin secretion. This pharmacological property of SGLT2i reduces body weight and improves insulin resistance in diabetic patients. Such beneficial metabolic changes caused by SGLT2i are expected to be useful not only for glucose metabolism, but also for the protection for various organs. Recent randomized controlled trials (RCTs) on cardiovascular diseases (EMPA-REG OUTCOME trial and CANVAS program) showed that SGLT2i prevented cardiovascular death and the development of heart failure. RCTs on renal events (EMPA-REG OUTCOME trial, CANVAS program, and CREDENCE trial) showed that SGLT2i suppressed the progression of kidney disease. Furthermore, SGLT2i effectively lowered the liver fat content, and our study demonstrated that SGLT2i reduced the degree of hepatic fibrosis in patients at high-risk of hepatic fibrosis. Such promising properties of SGLT2i for cardiovascular, renal, and hepatic protection provide us the chance to think about the underlying mechanisms for SGLT2i-induced improvement of multiple organs. SGLT2i have various mechanisms for organ protection beyond glucose-lowering effects, such as an increase in fatty acids utilization for hepatic protection, osmotic diuresis for cardiac protection, an improvement of insulin resistance for anti-atherogenesis, and an improvement of tubuloglomerular feedback for renal protection.
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Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett J, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Vinh PN, Schou M, Tereshchenko S, Køber L, Kosiborod MN, Langkilde AM, Martinez FA, Ponikowski P, Sabatine MS, Sjöstrand M, Solomon SD, Johanson P, Greasley PJ, Boulton D, Bengtsson O, Jhund PS, McMurray JJV. Effect of Dapagliflozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes. JAMA 2020; 323:1353-1368. [PMID: 32219386 PMCID: PMC7157181 DOI: 10.1001/jama.2020.1906] [Citation(s) in RCA: 347] [Impact Index Per Article: 69.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
IMPORTANCE Additional treatments are needed for heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 (SGLT2) inhibitors may be an effective treatment for patients with HFrEF, even those without diabetes. OBJECTIVE To evaluate the effects of dapagliflozin in patients with HFrEF with and without diabetes. DESIGN, SETTING, AND PARTICIPANTS Exploratory analysis of a phase 3 randomized trial conducted at 410 sites in 20 countries. Patients with New York Heart Association classification II to IV with an ejection fraction less than or equal to 40% and elevated plasma N-terminal pro B-type natriuretic peptide were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. INTERVENTIONS Addition of once-daily 10 mg of dapagliflozin or placebo to recommended therapy. MAIN OUTCOMES AND MEASURES The primary outcome was the composite of an episode of worsening heart failure or cardiovascular death. This outcome was analyzed by baseline diabetes status and, in patients without diabetes, by glycated hemoglobin level less than 5.7% vs greater than or equal to 5.7%. RESULTS Among 4744 patients randomized (mean age, 66 years; 1109 [23%] women; 2605 [55%] without diabetes), 4742 completed the trial. Among participants without diabetes, the primary outcome occurred in 171 of 1298 (13.2%) in the dapagliflozin group and 231 of 1307 (17.7%) in the placebo group (hazard ratio, 0.73 [95% CI, 0.60-0.88]). In patients with diabetes, the primary outcome occurred in 215 of 1075 (20.0%) in the dapagliflozin group and 271 of 1064 (25.5%) in the placebo group (hazard ratio, 0.75 [95% CI, 0.63-0.90]) (P value for interaction = .80). Among patients without diabetes and a glycated hemoglobin level less than 5.7%, the primary outcome occurred in 53 of 438 patients (12.1%) in the dapagliflozin group and 71 of 419 (16.9%) in the placebo group (hazard ratio, 0.67 [95% CI, 0.47-0.96]). In patients with a glycated hemoglobin of at least 5.7%, the primary outcome occurred in 118 of 860 patients (13.7%) in the dapagliflozin group and 160 of 888 (18.0%) in the placebo group (hazard ratio, 0.74 [95% CI, 0.59-0.94]) (P value for interaction = .72). Volume depletion was reported as an adverse event in 7.3% of patients in the dapagliflozin group and 6.1% in the placebo group among patients without diabetes and in 7.8% of patients in the dapagliflozin group and 7.8% in the placebo group among patients with diabetes. A kidney adverse event was reported in 4.8% of patients in the dapagliflozin group and 6.0% in the placebo group among patients without diabetes and in 8.5% of patients in the dapagliflozin group and 8.7% in the placebo group among patients with diabetes. CONCLUSIONS AND RELEVANCE In this exploratory analysis of a randomized trial of patients with HFrEF, dapagliflozin compared with placebo, when added to recommended therapy, significantly reduced the risk of worsening heart failure or cardiovascular death independently of diabetes status. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT03036124.
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Affiliation(s)
- Mark C. Petrie
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Subodh Verma
- Division of Cardiac Surgery, St Michael’s Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Kieran F. Docherty
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Silvio E. Inzucchi
- Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
| | - Inder Anand
- Department of Cardiology, University of Minnesota, Minneapolis
| | - Jan Bělohlávek
- Second Department of Internal Medicine, Cardiovascular Medicine, General Teaching Hospital, First Faculty of Medicine, Charles University, Prague, Czech Republic
| | - Michael Böhm
- Department of Medicine, Saarland University Hospital, Homburg/Saar, Germany
| | - Chern-En Chiang
- Division of Cardiology, Taipei Veterans General Hospital, Taipei, Taiwan
- National Yang-Ming University, Taipei, Taiwan
| | | | - Rudolf A. de Boer
- Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Akshay S. Desai
- Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Mirta Diez
- Division of Cardiology, Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina
| | - Jaroslaw Drozdz
- Department Cardiology, Medical University of Lodz, Lodz, Poland
| | - Andre Dukát
- Fifth Department of Internal Medicine, Comenius University in Bratislava, Bratislava, Slovakia
| | - Junbo Ge
- Shanghai Institute of Cardiovascular Disease, Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, China
| | - Jonathan Howlett
- Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Tzvetana Katova
- Clinic of Cardiology, National Cardiology Hospital, Sofia, Bulgaria
| | - Masafumi Kitakaze
- Cardiovascular Division of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan
| | - Charlotta E. A. Ljungman
- Institute of Medicine, Department of Molecular and Clinical Medicine/Cardiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Béla Merkely
- Heart and Vascular Center, Semmelweis University, Budapest, Hungary
| | - Jose C. Nicolau
- Instituto do Coracao (InCor), Hospital das Clínicas Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Eileen O'Meara
- Department of Cardiology, Montreal Heart Institute, Montreal, Ontario, Canada
| | - Pham Nguyen Vinh
- Department of Internal Medicine, Tan Tao University, Tan Duc, Vietnam
| | - Morten Schou
- Department of Cardiology, Gentofte University Hospital Copenhagen, Copenhagen, Denmark
| | - Sergey Tereshchenko
- Department of Myocardial Disease and Heart Failure, National Medical Research Center of Cardiology, Moscow, Russia
| | - Lars Køber
- Department of Cardiology Copenhagen University Hospital, Copenhagen, Denmark
| | - Mikhail N. Kosiborod
- St Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City
| | - Anna Maria Langkilde
- Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | | | - Piotr Ponikowski
- Center for Heart Diseases, University Hospital, Wroclaw Medical University, Wroclaw, Poland
| | - Marc S. Sabatine
- Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Mikaela Sjöstrand
- Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Scott D. Solomon
- Cardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts
| | - Per Johanson
- Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Peter J. Greasley
- Early Discovery and Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - David Boulton
- Clinical Pharmacology and Safety Sciences, BioPharmaceuticals R&D, AstraZeneca, Gaithersburg, Maryland
| | - Olof Bengtsson
- Late Stage Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Pardeep S. Jhund
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - John J. V. McMurray
- British Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
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12
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Donadei C, Angeletti A, Cantarelli C, D'Agati VD, La Manna G, Fiaccadori E, Horwitz JK, Xiong H, Guglielmo C, Hartzell S, Madsen JC, Maggiore U, Heeger PS, Cravedi P. Erythropoietin inhibits SGK1-dependent TH17 induction and TH17-dependent kidney disease. JCI Insight 2019; 5:127428. [PMID: 31013255 DOI: 10.1172/jci.insight.127428] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
IL-17-producing CD4+ cells (TH17) are pathogenically linked to autoimmunity including to autoimmune kidney disease. Erythropoietin's (EPO) newly recognized immunoregulatory functions and its predominant intra-renal source suggested that EPO physiologically regulates TH17 differentiation, thereby serving as a barrier to the development of autoimmune kidney disease. Using in vitro studies of human and murine cells and in vivo models, we show that EPO ligation of its receptor (EPO-R) on CD4+ T cells directly inhibits TH17 generation and promotes trans-differentiation of TH17 into IL-17-FOXP3+CD4+ T cells. Mechanistically, EPO/EPO-R ligation abrogates upregulation of SGK1 gene expression and blocks p38 activity to prevent SGK1 phosphorylation, thereby inhibiting RORC-mediated transcription of IL-17 and IL-23 receptor genes. In a murine model of TH17-dependent aristolochic acid (ArA)-induced, interstitial kidney disease associated with reduced renal EPO production, we demonstrate that transgenic EPO overexpression or recombinant EPO (rEPO) administration limits TH17 formation and clinical/histological disease expression. EPO/EPO-R ligations on CD4+ T cells abrogate, while absence of T cell-expressed EPO-R augments, TH17 induction and clinical/histological expression of pristane-induced glomerulonephritis (associated with decreased intrarenal EPO). rEPO prevents spontaneous glomerulonephritis and TH17 generation in MRL-lpr mice. Together, our findings indicate that EPO physiologically and therapeutically modulate TH17 cells to limit expression of TH17-associated autoimmune kidney disease.
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Affiliation(s)
- Chiara Donadei
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Nephrology Dialysis and Renal Transplantation Unit, S. Orsola University Hospital, Bologna, Italy
| | - Andrea Angeletti
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Nephrology Dialysis and Renal Transplantation Unit, S. Orsola University Hospital, Bologna, Italy
| | - Chiara Cantarelli
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.,Dipartimento di Medicina e Chirurgia (Università di Parma), UO Nefrologia (Azienda Ospedaliera-Universitaria Parma), Parma, Italy
| | - Vivette D D'Agati
- Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, New York, USA
| | - Gaetano La Manna
- Nephrology Dialysis and Renal Transplantation Unit, S. Orsola University Hospital, Bologna, Italy
| | - Enrico Fiaccadori
- Dipartimento di Medicina e Chirurgia (Università di Parma), UO Nefrologia (Azienda Ospedaliera-Universitaria Parma), Parma, Italy
| | - Julian K Horwitz
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Huabao Xiong
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Chiara Guglielmo
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Susan Hartzell
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Joren C Madsen
- Center for Transplantation Sciences and Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Umberto Maggiore
- Dipartimento di Medicina e Chirurgia (Università di Parma), UO Nefrologia (Azienda Ospedaliera-Universitaria Parma), Parma, Italy
| | - Peter S Heeger
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Paolo Cravedi
- Department of Medicine, Translational Transplant Research Center, Precision Institute of Immunology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
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13
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de Albuquerque Rocha N, Neeland IJ, McCullough PA, Toto RD, McGuire DK. Effects of sodium glucose co-transporter 2 inhibitors on the kidney. Diab Vasc Dis Res 2018; 15:375-386. [PMID: 29963920 DOI: 10.1177/1479164118783756] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Sodium-glucose cotransporter 2 inhibitors are antihyperglycaemic medications with an emerging evidence base for cardiovascular and kidney disease risk reduction. Sodium-glucose cotransporter 2 inhibitors medications lower plasma glucose by inhibiting glucose reabsorption in the proximal tubule of the kidney independent of insulin. Furthermore, they reduce intraglomerular pressure by restoring tubuloglomerular feedback. Large cardiovascular outcome trials of both empagliflozin and canagliflozin have consistently shown beneficial kidney effects that go beyond glycaemic control, such as reducing risk for incident nephropathy and progression of chronic kidney disease. The mechanisms by which sodium-glucose cotransporter 2 inhibitors improve kidney outcomes are not clear. Proposed hypotheses underpinning the kidney benefits include kidney-specific effects such as decreased intraglomerular pressure, activation of angiotensin-(1-7) and the Mas receptor leading to decreased inflammation, decrease in overall kidney oxygen consumption, rise in erythropoietin levels, inhibition of the renal sodium-hydrogen exchanger and secondary kidney effects related to improvements in HbA1c and blood pressure. This review will focus on describing the mechanisms of action of sodium-glucose cotransporter 2 inhibitors in the kidney, clinical efficacy data on their use in patients with chronic kidney disease, postulated physiologic underpinnings of kidney protection observed with sodium-glucose cotransporter 2 inhibitors and the promise and potential pitfalls for their use in patients with chronic kidney disease.
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Affiliation(s)
- Natalia de Albuquerque Rocha
- 1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- 2 Department of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Ian J Neeland
- 1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- 2 Department of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Peter A McCullough
- 3 Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, TX, USA
| | - Robert D Toto
- 1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- 4 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
- 5 Department of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Darren K McGuire
- 1 Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
- 2 Department of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
- 4 Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX, USA
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14
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Abdelgadir E, Rashid F, Bashier A, Ali R. SGLT-2 Inhibitors and Cardiovascular Protection: Lessons and Gaps in Understanding the Current Outcome Trials and Possible Benefits of Combining SGLT-2 Inhibitors With GLP-1 Agonists. J Clin Med Res 2018; 10:615-625. [PMID: 29977418 PMCID: PMC6031247 DOI: 10.14740/jocmr3467w] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Accepted: 06/04/2018] [Indexed: 12/21/2022] Open
Abstract
Landmark trials on diabetes control have shown variable results in terms of cardiovascular benefits, with the majority showing a favorable effect of glycemic control on microvascular and, more recently, macrovascular complications. However, some trials pointed out a CV hazard with tight diabetes mellitus (DM) control. Most of those trials were assessing the impact of glycemic control, more than evaluating the effect of a certain medication. In the last decade, food and drugs administration (FDA) has mandated that all new hypoglycemic agents run a CV outcome trial (CVOT) for safety in order to grant and sustain approval. The most stunning results came from relatively new agents in the field of diabetes management, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the glucagon-like peptide-1 agonists (GLP-1 agonists), details of these CVOTs will be addressed later in this document. SGLT2i effect on the cardiovascular system remains an area of extensive research. We aimed in this review to summarize what is the current evidence of cardiovascular protection upon using SGLT2i. Moreover, we wanted to raise a point that may be strongly adopted in the future, combining SGLT2i plus GLP-1 agonists, having a cardiovascular privilege in both molecules.
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15
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Hakoshima M, Yanai H, Kakuta K, Adachi H. Sodium-Glucose Cotransporter 2 Inhibitors Reduce Prandial Insulin Doses in Type 2 Diabetic Patients Treated With the Intensive Insulin Therapy. J Clin Med Res 2018; 10:493-498. [PMID: 29707091 PMCID: PMC5916538 DOI: 10.14740/jocmr3392w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 03/12/2018] [Indexed: 12/18/2022] Open
Abstract
Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are anti-diabetic drugs which improve blood glucose control by blocking reabsorption of glucose from the proximal tubule of kidney. Anti-atherosclerotic properties and cardiovascular protective effects of SGLT2i have been demonstrated by recent studies; however, the efficacy and safety of addition of SGLT2i to the intensive insulin therapy remain largely unknown. Methods We retrospectively picked up patients hospitalized for treatment of type 2 diabetes, who had been treated by the intensive insulin therapy and whose treatment using by SGLT2i started during their hospitalization. Such patients were picked up between June 2014 and May 2017 based on medical charts. Results We found 12 eligible patients. Observation period was 10.2 ± 4.7 days, and SGLT2i was started at 12.2 ± 12.9 days after the admission. During observation period, nobody developed hypoglycemia. In spite of showing decrease of blood glucose (non-significant) before each meal, the addition of SGLT2i significantly reduced daily prandial insulin doses by approximately 4.6 units/day (-66%). The SGLT2i addition also decreased body weight by approximately 1.3 kg. Conclusion Present study demonstrated that the addition of SGLT2i to intensive insulin therapy reduced prandial insulin doses and body weight, without the development of hypoglycemia. This result may be due to SGLT2i-mediated improvement of postprandial hyperglycemia by increasing urinary glucose excretion not via insulin secretion.
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Affiliation(s)
- Mariko Hakoshima
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Hidekatsu Yanai
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan.,Clinical Research and Trial Center, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Kouki Kakuta
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
| | - Hiroki Adachi
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
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16
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Yanai H. Sodium-glucose cotransporter 2 inhibitors and death and heart failure in type 2 diabetes. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:470. [PMID: 29285503 DOI: 10.21037/atm.2017.09.22] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Hidekatsu Yanai
- Department of Internal Medicine, National Center for Global Health and Medicine Kohnodai Hospital, Chiba, Japan
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17
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Koguchi A, Adachi H, Yanai H. The Application of Sodium-Glucose Cotransporter 2 Inhibitors to Chronic Kidney Disease Stage 4. J Clin Med Res 2017; 9:1029-1031. [PMID: 29163740 PMCID: PMC5687911 DOI: 10.14740/jocmr3220w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 10/12/2017] [Indexed: 01/14/2023] Open
Affiliation(s)
- Ayako Koguchi
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba, Japan.,Department of Neurology, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan
| | - Hiroki Adachi
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba, Japan
| | - Hidekatsu Yanai
- Department of Internal Medicine, National Center for Global Health and Medicine, Kohnodai Hospital, Chiba, Japan.,Department of Neurology, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan
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