{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T03:30:52Z","timestamp":1794022252764,"version":"4.8.0"},"reference-count":23,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2017,11,15]],"date-time":"2017-11-15T00:00:00Z","timestamp":1510704000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2018,3]]},"abstract":"<jats:p>The effect of a sodium glucose cotransporter 2 inhibitor (SGLT2i) in reducing heart failure hospitalization in the EMPA\u2010REG OUTCOMES trial has raised the possibility of using these agents to treat established heart failure. We hypothesize that osmotic diuresis induced by SGLT2 inhibition, a distinctly different diuretic mechanism than that of other diuretic classes, results in greater electrolyte\u2010free water clearance and, ultimately, in greater fluid clearance from the interstitial fluid (IF) space than from the circulation, potentially resulting in congestion relief with minimal impact on blood volume, arterial filling and organ perfusion. We utilize a mathematical model to illustrate that electrolyte\u2010free water clearance results in a greater reduction in IF volume compared to blood volume, and that this difference may be mediated by peripheral sequestration of osmotically inactive sodium. By coupling the model with data on plasma and urinary sodium and water in healthy subjects who received either the SGLT2i dapagliflozin or loop diuretic bumetanide, we predict that dapagliflozin produces a 2\u2010fold greater reduction in IF volume compared to blood volume, while the reduction in IF volume with bumetanide is only 78% of the reduction in blood volume. Heart failure is characterized by excess fluid accumulation, in both the vascular compartment and interstitial space, yet many heart failure patients have arterial underfilling because of low cardiac output, which may be aggravated by conventional diuretic treatment. Thus, we hypothesize that, by reducing IF volume to a greater extent than blood volume, SGLT2 inhibitors might provide better control of congestion without reducing arterial filling and perfusion.<\/jats:p>","DOI":"10.1111\/dom.13126","type":"journal-article","created":{"date-parts":[[2017,10,12]],"date-time":"2017-10-12T08:52:44Z","timestamp":1507798364000},"page":"479-487","source":"Crossref","is-referenced-by-count":466,"title":["Why do\n                    <scp>SGLT2<\/scp>\n                    inhibitors reduce heart failure hospitalization?\n                    <scp>A<\/scp>\n                    differential volume regulation hypothesis"],"prefix":"10.1111","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8156-2245","authenticated-orcid":false,"given":"Karen M.","family":"Hallow","sequence":"first","affiliation":[{"name":"School of Chemical, Materials, and Biomedical Engineering University of Georgia  Athens Georgia"},{"name":"Department of Epidemiology and Biostatistics University of Georgia  Athens Georgia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Helmlinger","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines AstraZeneca  Waltham Massachusetts"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Greasley","sequence":"additional","affiliation":[{"name":"Early Clinical Development, Innovative Medicines AstraZeneca  Gothenburg Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6317-3975","authenticated-orcid":false,"given":"John J. V.","family":"McMurray","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular and Medical Sciences University of Glasgow  Glasgow UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Boulton","sequence":"additional","affiliation":[{"name":"Quantitative Clinical Pharmacology, Early Clinical Development, Innovative Medicines AstraZeneca  Gaithersburg Maryland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2017,11,15]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504720"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehv728"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1611925"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc16-0330"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1159\/000057604"},{"key":"e_1_2_5_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfr428"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1525-139X.2009.00569.x"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0141336"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.mnh.0000441151.55320.c3"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1097\/01.hjh.0000500051.20830.98"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-113-2-155"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2006111302"},{"key":"e_1_2_5_14_1","first-page":"517","article-title":"In right or biventricular chronic heart failure addition of thiazides to loop diuretics to achieve a sequential blockade of the nephron is associated with increased risk of dilutional hyponatremia: results of a case\u2010control study","volume":"60","author":"De Vecchis R","year":"2012","journal-title":"Minerva Cardioangiol"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.7326\/0003-4819-103-1-1"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-8703(99)70113-4"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1097\/00000441-200001000-00002"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1037\/h0077057"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1161\/01.HYP.0000221039.17735.1a"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1159\/000164149"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2016.09.001"},{"key":"e_1_2_5_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2016.08.008"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016060662"},{"key":"e_1_2_5_24_1","doi-asserted-by":"publisher","DOI":"10.2169\/internalmedicine.55.6367"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fdom.13126","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/pdf\/10.1111\/dom.13126","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T05:41:21Z","timestamp":1761889281000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/10.1111\/dom.13126"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,15]]},"references-count":23,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2018,3]]}},"alternative-id":["10.1111\/dom.13126"],"URL":"https:\/\/doi.org\/10.1111\/dom.13126","archive":["Portico"],"relation":{},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,15]]}}}