{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:40:02Z","timestamp":1792194002974,"version":"4.4.0"},"reference-count":122,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T00:00:00Z","timestamp":1645574400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert hypoglycemic and diuretic effects by inhibiting the absorption of sodium and glucose from the proximal tubule. Currently available data indicate that SGLT2 inhibitors transiently enhance urinary sodium excretion and urinary volume. When combined with loop diuretics, SGLT2 inhibitors exert a synergistic natriuretic effect. The favorable diuretic profile of SGLT2 inhibitors may confer benefits to volume management in patients with heart failure but this natriuretic effect may not be the dominant mechanism for the superior long-term outcomes observed with these agents in patients with heart failure. The first part of this review explores the causes of transient natriuresis and the diuretic mechanisms of SGLT2 inhibitors. The second part provides an overview of the synergistic effects of combining SGLT2 inhibitors with loop diuretics, and the third part summarizes the mechanisms of cardiovascular protection associated with the diuretic effects of SGLT2 inhibitors.<\/jats:p>","DOI":"10.3389\/fphar.2022.800490","type":"journal-article","created":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T14:24:51Z","timestamp":1645626291000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":77,"title":["Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Water and Sodium Metabolism"],"prefix":"10.3389","volume":"13","author":[{"given":"Jun","family":"Tang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lifang","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiqi","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lihong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"629","DOI":"10.3390\/ijms20030629","article-title":"Diuretic Effects of Sodium Glucose Cotransporter 2 Inhibitors and Their Influence on the Renin-Angiotensin System","volume":"20","author":"Ansary","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"262","DOI":"10.1016\/j.jash.2014.01.007","article-title":"Effects of Sodium-Glucose Co-transporter 2 Inhibitors on Blood Pressure: a Systematic Review and Meta-Analysis","volume":"8","author":"Baker","year":"2014","journal-title":"J. Am. Soc. Hypertens."},{"key":"B3","doi-asserted-by":"publisher","first-page":"1272","DOI":"10.1038\/ki.2009.87","article-title":"Renal Sodium-Glucose Transport: Role in Diabetes Mellitus and Potential Clinical Implications","volume":"75","author":"Bakris","year":"2009","journal-title":"Kidney Int."},{"key":"B4","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1016\/s2213-8587(13)70208-0","article-title":"Efficacy and Safety of Empagliflozin Added to Existing Antidiabetes Treatment in Patients with Type 2 Diabetes and Chronic Kidney Disease: a Randomised, Double-Blind, Placebo-Controlled Trial","volume":"2","author":"Barnett","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1056\/NEJMoa2030183","article-title":"Sotagliflozin in Patients with Diabetes and Recent Worsening Heart Failure","volume":"384","author":"Bhatt","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"B6","doi-asserted-by":"publisher","first-page":"e99123","DOI":"10.1172\/jci.insight.99123","article-title":"Canagliflozin Triggers the FGF23\/1,25-Dihydroxyvitamin D\/PTH axis in Healthy Volunteers in a Randomized Crossover Study","volume":"3","author":"Blau","year":"2018","journal-title":"JCI Insight."},{"key":"B7","doi-asserted-by":"publisher","first-page":"1020","DOI":"10.1210\/jc.2011-2260","article-title":"Effects of Dapagliflozin on Body Weight, Total Fat Mass, and Regional Adipose Tissue Distribution in Patients with Type 2 Diabetes Mellitus with Inadequate Glycemic Control on Metformin","volume":"97","author":"Bolinder","year":"2012","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B8","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1002\/ejhf.2066","article-title":"Effects of Empagliflozin on Renal Sodium and Glucose Handling in Patients with Acute Heart Failure","volume":"23","author":"Boorsma","year":"2021","journal-title":"Eur. J. Heart Fail."},{"key":"B9","doi-asserted-by":"publisher","first-page":"1616","DOI":"10.1681\/asn.2020071029","article-title":"Empagliflozin Inhibits Proximal Tubule NHE3 Activity, Preserves GFR, and Restores Euvolemia in Nondiabetic Rats with Induced Heart Failure","volume":"32","author":"Borges-J\u00fanior","year":"2021","journal-title":"Jasn"},{"key":"B10","doi-asserted-by":"publisher","first-page":"e009149","DOI":"10.1161\/jaha.118.009149","article-title":"Outcomes Associated with a Strategy of Adjuvant Metolazone or High-Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis","volume":"7","author":"Brisco-Bacik","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3421","DOI":"10.1093\/eurheartj\/ehaa419","article-title":"A Randomized Controlled Trial of Dapagliflozin on Left Ventricular Hypertrophy in People with Type Two Diabetes: the DAPA-LVH Trial","volume":"41","author":"Brown","year":"2020","journal-title":"Eur. Heart J."},{"key":"B12","doi-asserted-by":"publisher","first-page":"F991","DOI":"10.1152\/ajprenal.00432.2014","article-title":"Physiology and Pathophysiology of the Renal Na-K-2Cl Cotransporter (NKCC2)","volume":"307","author":"Castrop","year":"2014","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"517","DOI":"10.1016\/j.amjms.2016.08.015","article-title":"Effect of Dapagliflozin Treatment on Fluid and Electrolyte Balance in Diabetic Rats","volume":"352","author":"Chen","year":"2016","journal-title":"Am. J. Med. Sci."},{"key":"B14","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/1475-2840-13-28","article-title":"The Effect of Empagliflozin on Arterial Stiffness and Heart Rate Variability in Subjects with Uncomplicated Type 1 Diabetes Mellitus","volume":"13","author":"Cherney","year":"2014","journal-title":"Cardiovasc. Diabetol."},{"key":"B15","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/j.kint.2017.06.017","article-title":"Pooled Analysis of Phase III Trials Indicate Contrasting Influences of Renal Function on Blood Pressure, Body Weight, and HbA1c Reductions with Empagliflozin","volume":"93","author":"Cherney","year":"2018","journal-title":"Kidney Int."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1180","DOI":"10.1111\/dom.12572","article-title":"Effects of Empagliflozin on Blood Pressure and Markers of Arterial Stiffness and Vascular Resistance in Patients with Type 2 Diabetes","volume":"17","author":"Chilton","year":"2015","journal-title":"Diabetes Obes. Metab."},{"key":"B17","doi-asserted-by":"publisher","first-page":"271","DOI":"10.3389\/fphys.2019.00271","article-title":"Empagliflozin Contributes to Polyuria via Regulation of Sodium Transporters and Water Channels in Diabetic Rat Kidneys","volume":"10","author":"Chung","year":"2019","journal-title":"Front. Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1002\/ejhf.1713","article-title":"Randomized, Double-Blind, Placebo-Controlled, Multicentre Pilot Study on the Effects of Empagliflozin on Clinical Outcomes in Patients with Acute Decompensated Heart Failure (EMPA-RESPONSE-AHF)","volume":"22","author":"Damman","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"B19","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1002\/ejhf.2132","article-title":"Effect of Dapagliflozin on Anaemia in DAPA-HF","volume":"23","author":"Docherty","year":"2021","journal-title":"Eur. J. Heart Fail."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2145","DOI":"10.1016\/j.jacc.2011.10.910","article-title":"Diuretics and Ultrafiltration in Acute Decompensated Heart Failure","volume":"59","author":"Felker","year":"2012","journal-title":"J. Am. Coll. Cardiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1108","DOI":"10.2337\/dc16-0330","article-title":"CV Protection in the EMPA-REG OUTCOME Trial: A \"Thrifty Substrate\" Hypothesis","volume":"39","author":"Ferrannini","year":"2016","journal-title":"Diabetes Care."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1218","DOI":"10.1007\/s00380-020-01597-x","article-title":"Mechanisms and Prediction of Short-Term Natriuretic Effect of Sodium-Glucose Cotransporter 2 Inhibitor in Heart Failure Patients Coexisting Type 2 Diabetes Mellitus","volume":"35","author":"Fukuoka","year":"2020","journal-title":"Heart Vessels."},{"key":"B23","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1016\/j.metabol.2018.02.002","article-title":"Effects of Canagliflozin versus Glimepiride on Adipokines and Inflammatory Biomarkers in Type 2 Diabetes","volume":"85","author":"Garvey","year":"2018","journal-title":"Metabolism."},{"key":"B24","doi-asserted-by":"publisher","first-page":"693","DOI":"10.2337\/dc18-2207","article-title":"Ambulatory Blood Pressure Reduction with SGLT-2 Inhibitors: Dose-Response Meta-Analysis and Comparative Evaluation with Low-Dose Hydrochlorothiazide","volume":"42","author":"Georgianos","year":"2019","journal-title":"Diabetes Care."},{"key":"B25","doi-asserted-by":"publisher","first-page":"dgaa057","DOI":"10.1210\/clinem\/dgaa057","article-title":"Dapagliflozin Suppresses Hepcidin and Increases Erythropoiesis","volume":"105","author":"Ghanim","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"B26","doi-asserted-by":"publisher","first-page":"S3","DOI":"10.1016\/j.amjmed.2006.09.011","article-title":"Congestion in Acute Heart Failure Syndromes: an Essential Target of Evaluation and Treatment","volume":"119","author":"Gheorghiade","year":"2006","journal-title":"Am. J. Med."},{"key":"B27","doi-asserted-by":"publisher","first-page":"913","DOI":"10.1016\/s2213-8587(16)30162-0","article-title":"Association of the Magnitude of Weight Loss and Changes in Physical Fitness with Long-Term Cardiovascular Disease Outcomes in Overweight or Obese People with Type 2 Diabetes: a post-hoc Analysis of the Look AHEAD Randomised Clinical Trial","volume":"4","author":"Gregg","year":"2016","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B28","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1111\/j.1463-1326.2011.01517.x","article-title":"Empagliflozin, a Novel Selective Sodium Glucose Cotransporter-2 (SGLT-2) Inhibitor: Characterisation and Comparison with Other SGLT-2 Inhibitors","volume":"14","author":"Grempler","year":"2012","journal-title":"Diabetes Obes. Metab."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1161\/circulationaha.120.045691","article-title":"Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects","volume":"142","author":"Griffin","year":"","journal-title":"Circulation."},{"key":"B30","doi-asserted-by":"publisher","first-page":"1966","DOI":"10.1002\/ehf2.12759","article-title":"Sodium Glucose Cotransporter 2 Inhibitors as Diuretic Adjuvants in Acute Decompensated Heart Failure: a Case Series","volume":"7","author":"Griffin","year":"","journal-title":"ESC Heart Fail."},{"key":"B31","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/s12933-016-0489-z","article-title":"Sodium Glucose Transporter 2 (SGLT2) Inhibition with Empagliflozin Improves Cardiac Diastolic Function in a Female Rodent Model of Diabetes","volume":"16","author":"Habibi","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1111\/dom.13126","article-title":"Why Do SGLT2 Inhibitors Reduce Heart Failure Hospitalization? A Differential Volume Regulation Hypothesis","volume":"20","author":"Hallow","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"B33","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1007\/s00125-016-4158-2","article-title":"The Beneficial Effects of Empagliflozin, an SGLT2 Inhibitor, on Atherosclerosis in ApoE -\/- Mice Fed a Western Diet","volume":"60","author":"Han","year":"2017","journal-title":"Diabetologia."},{"key":"B34","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1007\/s00210-001-0521-y","article-title":"Rat NKCC2\/NKCC1 Cotransporter Selectivity for Loop Diuretic Drugs","volume":"365","author":"Hannaert","year":"2002","journal-title":"Naunyn Schmiedebergs Arch. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"752","DOI":"10.1161\/circulationaha.116.021887","article-title":"Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications","volume":"134","author":"Heerspink","year":"2016","journal-title":"Circulation."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2248","DOI":"10.1016\/j.clinthera.2016.08.008","article-title":"Acute Pharmacodynamic Effects of Empagliflozin with and without Diuretic Agents in Patients with Type 2 Diabetes Mellitus","volume":"38","author":"Heise","year":"2016","journal-title":"Clin. Ther."},{"key":"B37","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1016\/j.jacbts.2019.11.007","article-title":"SGLT2 Inhibitor-Induced Sympathoinhibition: A Novel Mechanism for Cardiorenal Protection","volume":"5","author":"Herat","year":"2020","journal-title":"JACC Basic Transl Sci."},{"key":"B38","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1093\/cvr\/cvz045","article-title":"Increased Ketone Body Oxidation Provides Additional Energy for the Failing Heart without Improving Cardiac Efficiency","volume":"115","author":"Ho","year":"2019","journal-title":"Cardiovasc. Res."},{"key":"B39","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.diabres.2017.11.016","article-title":"Increased Sugar Intake as a Form of Compensatory Hyperphagia in Patients with Type 2 Diabetes under Dapagliflozin Treatment","volume":"135","author":"Horie","year":"2018","journal-title":"Diabetes Res. Clin. Pract."},{"key":"B40","doi-asserted-by":"publisher","first-page":"e124079","DOI":"10.1172\/jci.insight.124079","article-title":"The Failing Heart Utilizes 3-hydroxybutyrate as a Metabolic Stress Defense","volume":"4","author":"Horton","year":"2019","journal-title":"JCI Insight."},{"key":"B41","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1186\/s12933-020-01042-3","article-title":"Different Effects of SGLT2 Inhibitors According to the Presence and Types of Heart Failure in Type 2 Diabetic Patients","volume":"19","author":"Hwang","year":"2020","journal-title":"Cardiovasc. Diabetol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"373","DOI":"10.14740\/jocmr2492w","article-title":"Factors Influencing Changes in Hemoglobin A1c and Body Weight during Treatment of Type 2 Diabetes with Ipragliflozin: Interim Analysis of the ASSIGN-K Study","volume":"8","author":"Iemitsu","year":"2016","journal-title":"J. Clin. Med. Res."},{"key":"B43","doi-asserted-by":"publisher","first-page":"768","DOI":"10.1007\/s12325-015-0234-0","article-title":"Pharmacokinetics, Pharmacodynamics, and Safety of Canagliflozin in Japanese Patients with Type 2 Diabetes Mellitus","volume":"32","author":"Iijima","year":"2015","journal-title":"Adv. Ther."},{"key":"B44","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1161\/circulationaha.120.047077","article-title":"Dapagliflozin and Diuretic Use in Patients with Heart Failure and Reduced Ejection Fraction in DAPA-HF","volume":"142","author":"Jackson","year":"2020","journal-title":"Circulation."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1527","DOI":"10.1016\/j.jacc.2010.06.034","article-title":"Combination of Loop Diuretics with Thiazide-type Diuretics in Heart Failure","volume":"56","author":"Jentzer","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"1753944719894509","DOI":"10.1177\/1753944719894509","article-title":"Importance of Sodium-Glucose Cotransporter 2 Inhibitor Use in Diabetic Patients with Acute Heart Failure","volume":"13","author":"Kambara","year":"2019","journal-title":"Ther. Adv. Cardiovasc. Dis."},{"key":"B47","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1172\/jci116972","article-title":"The Human Kidney Low Affinity Na+\/Glucose Cotransporter SGLT2. Delineation of the Major Renal Reabsorptive Mechanism for D-Glucose","volume":"93","author":"Kanai","year":"1994","journal-title":"J. Clin. Invest."},{"key":"B48","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1111\/jch.13229","article-title":"Nocturnal Hypertension in Diabetes: Potential Target of Sodium\/Glucose Cotransporter 2 (SGLT2) Inhibition","volume":"20","author":"Kario","year":"2018","journal-title":"J. Clin. Hypertens. (Greenwich)."},{"key":"B49","doi-asserted-by":"publisher","first-page":"F760","DOI":"10.1152\/ajprenal.00369.2003","article-title":"Role of Vasopressin in Diabetes Mellitus-Induced Changes in Medullary Transport Proteins Involved in Urine Concentration in Brattleboro Rats","volume":"286","author":"Kim","year":"2004","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1944","DOI":"10.1172\/jci88532","article-title":"High Salt Intake Reprioritizes Osmolyte and Energy Metabolism for Body Fluid Conservation","volume":"127","author":"Kitada","year":"2017","journal-title":"J. Clin. Invest."},{"key":"B51","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.jphs.2021.07.006","article-title":"Sodium\/glucose Cotransporter 2 and Renoprotection: From the Perspective of Energy Regulation and Water Conservation","volume":"147","author":"Kitada","year":"2021","journal-title":"J. Pharmacol. Sci."},{"key":"B52","doi-asserted-by":"publisher","first-page":"1349","DOI":"10.1056\/NEJMra1404726","article-title":"Molecular Physiology of Water Balance","volume":"372","author":"Knepper","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"B53","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.pharmthera.2013.04.003","article-title":"Ipragliflozin and Other Sodium-Glucose Cotransporter-2 (SGLT2) Inhibitors in the Treatment of Type 2 Diabetes: Preclinical and Clinical Data","volume":"139","author":"Kurosaki","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"B54","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1186\/s12933-016-0473-7","article-title":"Empagliflozin Lessened Cardiac Injury and Reduced Visceral Adipocyte Hypertrophy in Prediabetic Rats with Metabolic Syndrome","volume":"15","author":"Kusaka","year":"2016","journal-title":"Cardiovasc. Diabetol."},{"key":"B55","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1111\/dom.12127","article-title":"Dapagliflozin a Glucose-Regulating Drug with Diuretic Properties in Subjects with Type 2 Diabetes","volume":"15","author":"Lambers Heerspink","year":"2013","journal-title":"Diabetes Obes. Metab."},{"key":"B56","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1161\/circulationaha.120.052186","article-title":"Effect of Empagliflozin on Left Ventricular Volumes in Patients with Type 2 Diabetes, or Prediabetes, and Heart Failure with Reduced Ejection Fraction (SUGAR-DM-HF)","volume":"143","author":"Lee","year":"2021","journal-title":"Circulation."},{"key":"B57","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.freeradbiomed.2017.01.035","article-title":"Dapagliflozin, a Selective SGLT2 Inhibitor, Attenuated Cardiac Fibrosis by Regulating the Macrophage Polarization via STAT3 Signaling in Infarcted Rat Hearts","volume":"104","author":"Lee","year":"2017","journal-title":"Free Radic. Biol. Med."},{"key":"B58","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s12933-019-0816-2","article-title":"SGLT2 Inhibition with Empagliflozin Attenuates Myocardial Oxidative Stress and Fibrosis in Diabetic Mice Heart","volume":"18","author":"Li","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"B59","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.lfs.2018.01.032","article-title":"The Anti-diabetic Drug Dapagliflozin Induces Vasodilation via Activation of PKG and Kv Channels","volume":"197","author":"Li","year":"2018","journal-title":"Life Sci."},{"key":"B60","doi-asserted-by":"publisher","first-page":"2199","DOI":"10.2337\/db12-0052","article-title":"Why Do SGLT2 Inhibitors Inhibit Only 30-50% of Renal Glucose Reabsorption in Humans","volume":"61","author":"Liu","year":"2012","journal-title":"Diabetes."},{"key":"B61","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1159\/000496617","article-title":"Effect of Dapagliflozin Treatment on the Expression of Renal Sodium Transporters\/Channels on High-Fat Diet Diabetic Mice","volume":"142","author":"Ma","year":"2019","journal-title":"Nephron."},{"key":"B62","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1016\/j.jacc.2020.11.022","article-title":"2021 Update to the 2017 ACC Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment: Answers to 10 Pivotal Issues about Heart Failure with Reduced Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee","volume":"77","author":"Maddox","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"B63","doi-asserted-by":"publisher","first-page":"825","DOI":"10.1016\/s0002-8703(98)70041-9","article-title":"Plasma Brain Natriuretic Peptide as a Biochemical Marker of High Left Ventricular End-Diastolic Pressure in Patients with Symptomatic Left Ventricular Dysfunction","volume":"135","author":"Maeda","year":"1998","journal-title":"Am. Heart J."},{"key":"B64","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/s41581-020-00350-x","article-title":"Organ protection by SGLT2 Inhibitors: Role of Metabolic Energy and Water Conservation","volume":"17","author":"Marton","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"B65","doi-asserted-by":"publisher","first-page":"713","DOI":"10.1089\/dia.2019.0212","article-title":"Canagliflozin Improves Erythropoiesis in Diabetes Patients with Anemia of Chronic Kidney Disease","volume":"21","author":"Maruyama","year":"2019","journal-title":"Diabetes Technol. Ther."},{"key":"B66","doi-asserted-by":"publisher","first-page":"e14360","DOI":"10.14814\/phy2.14360","article-title":"Osmotic Diuresis by SGLT2 Inhibition Stimulates Vasopressin-Induced Water Reabsorption to Maintain Body Fluid Volume","volume":"8","author":"Masuda","year":"2020","journal-title":"Physiol. Rep."},{"key":"B67","doi-asserted-by":"publisher","first-page":"F653","DOI":"10.1152\/ajprenal.00143.2018","article-title":"Unmasking a Sustained Negative Effect of SGLT2 Inhibition on Body Fluid Volume in the Rat","volume":"315","author":"Masuda","year":"2018","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B68","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1186\/s12933-018-0717-9","article-title":"Effect of Canagliflozin on Left Ventricular Diastolic Function in Patients with Type 2 Diabetes","volume":"17","author":"Matsutani","year":"2018","journal-title":"Cardiovasc. Diabetol."},{"key":"B69","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1161\/circulationaha.119.044235","article-title":"Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease","volume":"141","author":"Mazer","year":"2020","journal-title":"Circulation."},{"key":"B70","doi-asserted-by":"publisher","first-page":"3599","DOI":"10.1093\/eurheartj\/ehab368","article-title":"2021 ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure","volume":"42","author":"McDonagh","year":"2021","journal-title":"Eur. Heart J."},{"key":"B71","doi-asserted-by":"publisher","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"B72","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1161\/circulationaha.120.048739","article-title":"Renal and Cardiovascular Effects of SGLT2 Inhibition in Combination with Loop Diuretics in Patients with Type 2 Diabetes and Chronic Heart Failure: The RECEDE-CHF Trial","volume":"142","author":"Mordi","year":"2020","journal-title":"Circulation."},{"key":"B73","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.2337\/dc16-0542","article-title":"Can a Shift in Fuel Energetics Explain the Beneficial Cardiorenal Outcomes in the EMPA-REG OUTCOME Study? A Unifying Hypothesis","volume":"39","author":"Mudaliar","year":"2016","journal-title":"Diabetes Care."},{"key":"B74","doi-asserted-by":"publisher","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes","volume":"377","author":"Neal","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"B75","doi-asserted-by":"publisher","first-page":"2129","DOI":"10.1161\/circulationaha.118.036459","article-title":"Cardiovascular Effects of Treatment with the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients","volume":"139","author":"Nielsen","year":"2019","journal-title":"Circulation."},{"key":"B76","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1111\/nep.13552","article-title":"Effects of the Sodium-Glucose Cotransporter 2 Inhibitor Dapagliflozin on Fluid Distribution: A Comparison Study with Furosemide and Tolvaptan","volume":"24","author":"Ohara","year":"2019","journal-title":"Nephrology (Carlton)."},{"key":"B77","doi-asserted-by":"publisher","first-page":"F712","DOI":"10.1152\/ajprenal.00264.2020","article-title":"A Role for Tubular Na+\/H+ Exchanger NHE3 in the Natriuretic Effect of the SGLT2 Inhibitor Empagliflozin","volume":"319","author":"Onishi","year":"2020","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B78","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1093\/ndt\/gfz294","article-title":"The Impact of Empagliflozin on Kidney Injury Molecule-1: a Subanalysis of the Effects of Empagliflozin on Cardiac Structure, Function, and Circulating Biomarkers in Patients with Type 2 Diabetes CardioLink-6 Trial","volume":"35","author":"Opingari","year":"2020","journal-title":"Nephrol. Dial. Transpl."},{"key":"B79","doi-asserted-by":"publisher","first-page":"1548","DOI":"10.1161\/circulationaha.117.030418","article-title":"Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism that Links the Pathophysiology and Treatment of Diabetes Mellitus with that of Heart Failure","volume":"136","author":"Packer","year":"2017","journal-title":"Circulation."},{"key":"B80","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1161\/circulationaha.120.051783","article-title":"Effect of Empagliflozin on the Clinical Stability of Patients with Heart Failure and a Reduced Ejection Fraction","volume":"143","author":"Packer","year":"","journal-title":"Circulation."},{"key":"B81","doi-asserted-by":"publisher","first-page":"1381","DOI":"10.1016\/j.jacc.2021.01.033","article-title":"Empagliflozin in Patients with Heart Failure, Reduced Ejection Fraction, and Volume Overload: EMPEROR-Reduced Trial","volume":"77","author":"Packer","year":"","journal-title":"J. Am. Coll. Cardiol."},{"key":"B82","doi-asserted-by":"publisher","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure","volume":"383","author":"Packer","year":"2020","journal-title":"N. Engl. J. Med."},{"key":"B83","doi-asserted-by":"publisher","first-page":"1025","DOI":"10.1001\/jamacardio.2017.2275","article-title":"Effects of Sodium-Glucose Cotransporter 2 Inhibitors for the Treatment of Patients with Heart Failure: Proposal of a Novel Mechanism of Action","volume":"2","author":"Packer","year":"2017","journal-title":"JAMA Cardiol."},{"key":"B84","doi-asserted-by":"publisher","first-page":"2028","DOI":"10.1681\/asn.2013060588","article-title":"Functional Role of Glucose Metabolism, Osmotic Stress, and Sodium-Glucose Cotransporter Isoform-Mediated Transport on Na+\/H+ Exchanger Isoform 3 Activity in the Renal Proximal Tubule","volume":"25","author":"Pessoa","year":"2014","journal-title":"J. Am. Soc. Nephrol."},{"key":"B85","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1186\/s12933-017-0511-0","article-title":"Effects of Canagliflozin, a Sodium Glucose Co-transporter 2 Inhibitor, on Blood Pressure and Markers of Arterial Stiffness in Patients with Type 2 Diabetes Mellitus: a Post Hoc Analysis","volume":"16","author":"Pfeifer","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"B86","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1111\/dom.13224","article-title":"Intra- and Inter-subject Variability for Increases in Serum Ketone Bodies in Patients with Type 2 Diabetes Treated with the Sodium Glucose Co-transporter 2 Inhibitor Canagliflozin","volume":"20","author":"Polidori","year":"2018","journal-title":"Diabetes Obes. Metab."},{"key":"B87","doi-asserted-by":"publisher","first-page":"F946","DOI":"10.1152\/ajprenal.1991.260.6.F946","article-title":"Tubular Sodium Handling and Tubuloglomerular Feedback in Experimental Diabetes Mellitus","volume":"260","author":"Pollock","year":"1991","journal-title":"Am. J. Physiol."},{"key":"B88","doi-asserted-by":"publisher","first-page":"691","DOI":"10.1016\/s2213-8587(14)70120-2","article-title":"Comparison of Empagliflozin and Glimepiride as Add-On to Metformin in Patients with Type 2 Diabetes: a 104-week Randomised, Active-Controlled, Double-Blind, Phase 3 Trial","volume":"2","author":"Ridderstr\u00e5le","year":"2014","journal-title":"Lancet Diabetes Endocrinol."},{"key":"B89","doi-asserted-by":"publisher","first-page":"F963","DOI":"10.1152\/ajprenal.00259.2012","article-title":"Natriuretic Effect by Exendin-4, but Not the DPP-4 Inhibitor Alogliptin, Is Mediated via the GLP-1 Receptor and Preserved in Obese Type 2 Diabetic Mice","volume":"303","author":"Rieg","year":"2012","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B90","doi-asserted-by":"publisher","first-page":"1815","DOI":"10.2337\/dc13-3055","article-title":"Improved Glucose Control with Weight Loss, Lower Insulin Doses, and No Increased Hypoglycemia with Empagliflozin Added to Titrated Multiple Daily Injections of Insulin in Obese Inadequately Controlled Type 2 Diabetes","volume":"37","author":"Rosenstock","year":"2014","journal-title":"Diabetes Care."},{"key":"B91","doi-asserted-by":"publisher","first-page":"1985","DOI":"10.1161\/circulationaha.118.038881","article-title":"Possible Mechanism of Hematocrit Elevation by Sodium Glucose Cotransporter 2 Inhibitors and Associated Beneficial Renal and Cardiovascular Effects","volume":"139","author":"Sano","year":"2019","journal-title":"Circulation."},{"key":"B92","doi-asserted-by":"publisher","first-page":"1931","DOI":"10.1016\/j.jacc.2019.01.056","article-title":"Empagliflozin Ameliorates Adverse Left Ventricular Remodeling in Nondiabetic Heart Failure by Enhancing Myocardial Energetics","volume":"73","author":"Santos-Gallego","year":"2019","journal-title":"J. Am. Coll. Cardiol."},{"key":"B93","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.jacc.2020.11.008","article-title":"Randomized Trial of Empagliflozin in Nondiabetic Patients with Heart Failure and Reduced Ejection Fraction","volume":"77","author":"Santos-Gallego","year":"2021","journal-title":"J. Am. Coll. Cardiol."},{"key":"B94","doi-asserted-by":"publisher","first-page":"440","DOI":"10.2337\/dc20-2604","article-title":"Natriuretic Effect of Two Weeks of Dapagliflozin Treatment in Patients with Type 2 Diabetes and Preserved Kidney Function during Standardized Sodium Intake: Results of the DAPASALT Trial","volume":"44","author":"Scholtes","year":"2021","journal-title":"Diabetes Care."},{"key":"B95","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1016\/0002-9343(84)90281-x","article-title":"Blood Volume Following Diuresis Induced by Furosemide","volume":"76","author":"Schuster","year":"1984","journal-title":"Am. J. Med."},{"key":"B96","doi-asserted-by":"publisher","first-page":"e006135","DOI":"10.1161\/jaha.117.006135","article-title":"Sodium and Fluid Excretion with Torsemide in Healthy Subjects Is Limited by the Short Duration of Diuretic Action","volume":"6","author":"Shah","year":"2017","journal-title":"J. Am. Heart Assoc."},{"key":"B97","doi-asserted-by":"publisher","first-page":"1356","DOI":"10.2337\/dc19-2187","article-title":"Dapagliflozin versus Placebo on Left Ventricular Remodeling in Patients with Diabetes and Heart Failure: The REFORM Trial","volume":"43","author":"Singh","year":"2020","journal-title":"Diabetes Care."},{"key":"B98","doi-asserted-by":"publisher","first-page":"138","DOI":"10.1186\/s12933-017-0621-8","article-title":"Dapagliflozin Acutely Improves Endothelial Dysfunction, Reduces Aortic Stiffness and Renal Resistive index in Type 2 Diabetic Patients: a Pilot Study","volume":"16","author":"Solini","year":"2017","journal-title":"Cardiovasc. Diabetol."},{"key":"B99","doi-asserted-by":"publisher","first-page":"467","DOI":"10.5551\/jat.40873","article-title":"Dapagliflozin Reduces Fat Mass without Affecting Muscle Mass in Type 2 Diabetes","volume":"25","author":"Sugiyama","year":"2018","journal-title":"J. Atheroscler. Thromb."},{"key":"B100","doi-asserted-by":"publisher","first-page":"1210","DOI":"10.1056\/NEJMoa1214865","article-title":"Treatment of Anemia with Darbepoetin Alfa in Systolic Heart Failure","volume":"368","author":"Swedberg","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B101","doi-asserted-by":"publisher","first-page":"436","DOI":"10.1007\/s12325-016-0457-8","article-title":"Factors Affecting Canagliflozin-Induced Transient Urine Volume Increase in Patients with Type 2 Diabetes Mellitus","volume":"34","author":"Tanaka","year":"2017","journal-title":"Adv. Ther."},{"key":"B102","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1016\/j.jacc.2013.05.027","article-title":"Timing of Hemoconcentration during Treatment of Acute Decompensated Heart Failure and Subsequent Survival: Importance of Sustained Decongestion","volume":"62","author":"Testani","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"B103","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1161\/circheartfailure.113.000895","article-title":"Loop Diuretic Efficiency: a Metric of Diuretic Responsiveness with Prognostic Importance in Acute Decompensated Heart Failure","volume":"7","author":"Testani","year":"2014","journal-title":"Circ. Heart Fail."},{"key":"B104","doi-asserted-by":"publisher","first-page":"R75","DOI":"10.1152\/ajpregu.00357.2011","article-title":"Acute and Chronic Effects of SGLT2 Blockade on Glomerular and Tubular Function in the Early Diabetic Rat","volume":"302","author":"Thomson","year":"2012","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"B105","doi-asserted-by":"publisher","first-page":"1693","DOI":"10.1161\/circulationaha.119.042375","article-title":"Effect of Empagliflozin on Left Ventricular Mass in Patients with Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial","volume":"140","author":"Verma","year":"2019","journal-title":"Circulation."},{"key":"B106","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1007\/s00232-001-0036-y","article-title":"Changes in Sodium or Glucose Filtration Rate Modulate Expression of Glucose Transporters in Renal Proximal Tubular Cells of Rat","volume":"182","author":"Vestri","year":"2001","journal-title":"J. Membr. Biol."},{"key":"B107","doi-asserted-by":"publisher","first-page":"1318","DOI":"10.1016\/j.jacc.2009.10.061","article-title":"Prediction of Cardiovascular Events and All-Cause Mortality with Arterial Stiffness: a Systematic Review and Meta-Analysis","volume":"55","author":"Vlachopoulos","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"B108","doi-asserted-by":"publisher","first-page":"421","DOI":"10.3389\/fendo.2018.00421","article-title":"The Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Sympathetic Nervous Activity","volume":"9","author":"Wan","year":"2018","journal-title":"Front. Endocrinol. (Lausanne)."},{"key":"B109","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1056\/NEJMoa1515920","article-title":"Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes","volume":"375","author":"Wanner","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"B110","doi-asserted-by":"publisher","first-page":"F1098","DOI":"10.1152\/ajprenal.00505.2014","article-title":"A Mathematical Model of the Rat Nephron: Glucose Transport","volume":"308","author":"Weinstein","year":"2015","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"B111","doi-asserted-by":"publisher","first-page":"e007046","DOI":"10.1161\/jaha.117.007046","article-title":"Interaction between the Sodium-Glucose-Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects","volume":"7","author":"Wilcox","year":"2018","journal-title":"J. Am. Heart Assoc."},{"key":"B112","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"B113","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1152\/physrev.00055.2009","article-title":"Biology of Human Sodium Glucose Transporters","volume":"91","author":"Wright","year":"2011","journal-title":"Physiol. Rev."},{"key":"B114","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.ebiom.2017.05.028","article-title":"SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-Induced Obese Mice","volume":"20","author":"Xu","year":"2017","journal-title":"EBioMedicine."},{"key":"B115","doi-asserted-by":"publisher","first-page":"e147","DOI":"10.1016\/j.jacc.2013.05.019","article-title":"2013 ACCF\/AHA Guideline for the Management of Heart Failure: a Report of the American College of Cardiology Foundation\/American Heart Association Task Force on Practice Guidelines","volume":"62","author":"Yancy","year":"2013","journal-title":"J. Am. Coll. Cardiol."},{"key":"B116","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1038\/hr.2017.14","article-title":"Arterial Pressure Lability Is Improved by Sodium-Glucose Cotransporter 2 Inhibitor in Streptozotocin-Induced Diabetic Rats","volume":"40","author":"Yoshikawa","year":"2017","journal-title":"Hypertens. Res."},{"key":"B117","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1038\/nm.3804","article-title":"The Ketone Metabolite \u03b2-Hydroxybutyrate Blocks NLRP3 Inflammasome-Mediated Inflammatory Disease","volume":"21","author":"Youm","year":"2015","journal-title":"Nat. Med."},{"key":"B118","doi-asserted-by":"publisher","first-page":"636","DOI":"10.1002\/jcph.1769","article-title":"Predicted Cardiac Hemodynamic Consequences of the Renal Actions of SGLT2i in the DAPA-HF Study Population: A Mathematical Modeling Analysis","volume":"61","author":"Yu","year":"2021","journal-title":"J. Clin. Pharmacol."},{"key":"B119","doi-asserted-by":"publisher","first-page":"862","DOI":"10.1002\/ejhf.1473","article-title":"Sodium-glucose Co-transporter 2 Inhibition with Empagliflozin Improves Cardiac Function in Non-diabetic Rats with Left Ventricular Dysfunction after Myocardial Infarction","volume":"21","author":"Yurista","year":"2019","journal-title":"Eur. J. Heart Fail."},{"key":"B120","doi-asserted-by":"publisher","first-page":"e016173","DOI":"10.1161\/jaha.119.016173","article-title":"Acute and Chronic Effects of SGLT2 Inhibitor Empagliflozin on Renal Oxygenation and Blood Pressure Control in Nondiabetic Normotensive Subjects: A Randomized, Placebo-Controlled Trial","volume":"9","author":"Zanchi","year":"2020","journal-title":"J. Am. Heart Assoc."},{"key":"B121","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1186\/s12933-019-0914-1","article-title":"Dapagliflozin Improves Left Ventricular Remodeling and Aorta Sympathetic Tone in a Pig Model of Heart Failure with Preserved Ejection Fraction","volume":"18","author":"Zhang","year":"2019","journal-title":"Cardiovasc. Diabetol."},{"key":"B122","doi-asserted-by":"publisher","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.800490\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,23]],"date-time":"2022-02-23T14:25:00Z","timestamp":1645626300000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2022.800490\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,23]]},"references-count":122,"alternative-id":["10.3389\/fphar.2022.800490"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2022.800490","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,23]]},"article-number":"800490"}}