{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T05:01:31Z","timestamp":1791003691899,"version":"4.1.0"},"reference-count":43,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2018,2,20]]},"abstract":"<jats:sec xml:lang=\"en\"><jats:title>Background<\/jats:title><jats:p xml:lang=\"en\">Dapagliflozin inhibits the sodium\u2010glucose\u2013linked transporter 2 in the renal proximal tubule, thereby promoting glycosuria to reduce hyperglycemia in type 2 diabetes mellitus. Because these patients may require loop diuretics, and sodium\u2010glucose\u2013linked transporter 2 inhibition causes an osmotic diuresis, we evaluated the diuretic interaction between dapagliflozin and bumetanide.<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Methods and Results<\/jats:title><jats:p xml:lang=\"en\">Healthy subjects (n=42) receiving a fixed diet with \u2248110\u00a0mmol\u00b7d<jats:sup>\u22121<\/jats:sup>of Na<jats:sup>+<\/jats:sup>were randomized to bumetanide (1\u00a0mg\u00b7d<jats:sup>\u22121<\/jats:sup>), dapagliflozin (10\u00a0mg\u00b7d<jats:sup>\u22121<\/jats:sup>), or both for 7\u00a0days, followed by 7\u00a0days of both. There were no meaningful pharmacokinetic interactions. Na<jats:sup>+<\/jats:sup>excretion increased modestly with the first dose of dapagliflozin (22\u00b16\u00a0mmol\u00b7d<jats:sup>\u22121<\/jats:sup>;<jats:italic>P<\/jats:italic>&lt;0.005) but by more (<jats:italic>P<\/jats:italic>&lt;0.005) with the first dose of bumetanide (74\u00b17\u00a0mmol\u00b7d<jats:sup>\u22121<\/jats:sup>;<jats:italic>P<\/jats:italic>&lt;0.005), which was not significantly different from both diuretics together (80\u00b15\u00a0mmol\u00b7d<jats:sup>\u22121<\/jats:sup>;<jats:italic>P<\/jats:italic>&lt;0.005). However, Na<jats:sup>+<\/jats:sup>excretion with dapagliflozin was 190% greater (<jats:italic>P<\/jats:italic>&lt;0.005) when added after 1\u00a0week of bumetanide (64\u00b16\u00a0mmol\u00b7d<jats:sup>\u22121<\/jats:sup>), and Na<jats:sup>+<\/jats:sup>excretion with bumetanide was 36% greater (<jats:italic>P<\/jats:italic>&lt;0.005) when added after 1\u00a0week of dapagliflozin (101\u00b18\u00a0mmol\u00b7d<jats:sup>\u22121<\/jats:sup>). Serum urate was increased 4% by bumetanide but reduced 40% by dapagliflozin or 20% by combined therapy (<jats:italic>P<\/jats:italic>&lt;0.05).<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Conclusions<\/jats:title><jats:p xml:lang=\"en\">First\u2010dose Na<jats:sup>+<\/jats:sup>excretion with bumetanide and dapagliflozin is not additive, but the weekly administration of one diuretic enhances the initial Na<jats:sup>+<\/jats:sup>excretion with the other, thereby demonstrating mutual adaptive natriuretic synergy. Combined therapy reverses bumetanide\u2010induced hyperuricemia. This requires further study in diabetic patients with hyperglycemia who have enhanced glycosuria and natriuresis with dapagliflozin.<\/jats:p><\/jats:sec><jats:sec xml:lang=\"en\"><jats:title>Clinical Trial Registration<\/jats:title><jats:p xml:lang=\"en\">URL:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"http:\/\/www.clinicaltrials.gov\">http:\/\/www.clinicaltrials.gov<\/jats:ext-link>. Unique identifier: NCT00930865.<\/jats:p><\/jats:sec>","DOI":"10.1161\/jaha.117.007046","type":"journal-article","created":{"date-parts":[[2018,2,12]],"date-time":"2018-02-12T16:19:31Z","timestamp":1518452371000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":124,"title":["Interaction Between the Sodium\u2010Glucose\u2013Linked Transporter 2 Inhibitor Dapagliflozin and the Loop Diuretic Bumetanide in Normal Human Subjects"],"prefix":"10.1161","volume":"7","author":[{"given":"Christopher S.","family":"Wilcox","sequence":"first","affiliation":[{"name":"Division of Nephrology and Hypertension, and Hypertension Research Center, Georgetown University, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen","family":"Shen","sequence":"additional","affiliation":[{"name":"Division of Nephrology and Hypertension, and Hypertension Research Center, Georgetown University, Washington, DC"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David W.","family":"Boulton","sequence":"additional","affiliation":[{"name":"AstraZeneca, Gaithersburg, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce R.","family":"Leslie","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb, Princeton, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven C.","family":"Griffen","sequence":"additional","affiliation":[{"name":"Bristol\u2010Myers Squibb, Princeton, NJ"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm701272q"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.109.029165"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1177\/2042018814553965"},{"key":"e_1_3_5_5_2","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016050510"},{"key":"e_1_3_5_6_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00357.2011"},{"key":"e_1_3_5_7_2","doi-asserted-by":"publisher","DOI":"10.2165\/00003495-199100413-00004"},{"key":"e_1_3_5_8_2","doi-asserted-by":"publisher","DOI":"10.1002\/ejhf.633"},{"key":"e_1_3_5_9_2","doi-asserted-by":"publisher","DOI":"10.33160\/yam.2017.06.001"},{"key":"e_1_3_5_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11897-017-0319-y"},{"key":"e_1_3_5_11_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1504720"},{"key":"e_1_3_5_12_2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-014-0337-y"},{"key":"e_1_3_5_13_2","first-page":"1702","volume-title":"Brenner & Rector's the Kidney","author":"Hoorn EJ","year":"2016","unstructured":"Hoorn EJ, Wilcox CS, Ellison DH. 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