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We sought to assess the effect of empagliflozin on estimated fluid volumes in patients with type 2 diabetes and cardiovascular disease (CVD).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The study was a <jats:italic>post-hoc<\/jats:italic> analysis of the EMBLEM trial (UMIN000024502), an investigator-initiated, multi-center, placebo-controlled, double-blinded, randomized-controlled trial designed primarily to evaluate the effect of 24\u00a0weeks of empagliflozin treatment on vascular endothelial function in patients with type 2 diabetes and established CVD. The analysis compared serial changes between empagliflozin (10\u00a0mg once daily, n\u2009=\u200952) and placebo (n\u2009=\u200953) in estimated plasma volume (ePV), calculated by the Straus formula and estimated the extracellular volume (eEV), determined by the body surface area, measured at baseline and 4, 12, and 24\u00a0weeks after initiation of treatment. Correlations were examined between the changes from baseline to week 24 in each estimated fluid volume parameter and several clinical variables of interest, including N-terminal pro-brain natriuretic peptide (NT-proBNP) concentration.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In an analysis using mixed-effects models for repeated measures, relative to placebo empagliflozin reduced ePV by \u2212\u20092.23% (95% CI \u2212\u20095.72 to 1.25) at week 4, \u2212\u20098.07% (\u2212\u200912.76 to \u2212\u20093.37) at week 12, and \u2212\u20095.60% (\u2212\u20099.87 to \u2212\u20091.32) at week 24; eEV by \u2212\u200970.3\u00a0mL (95% CI \u2212\u2009136.8 to \u2212\u20093.8) at week 4, \u2212\u2009135.9\u00a0mL (\u2212\u2009209.6 to \u2212\u200962.3) at week 12, and \u2212\u2009144.4\u00a0mL (\u2212\u2009226.3 to \u2212\u200962.4) at week 24. The effect of empagliflozin on these parameters was mostly consistent across various patient clinical characteristics. The change in log-transformed NT-proBNP was positively correlated with change in ePV (r\u2009=\u20090.351, p\u2009=\u20090.015), but not with change in eEV.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our data demonstrated that initiation of empagliflozin treatment substantially reduced estimated fluid volume parameters in patients with type 2 diabetes and CVD, and that this effect was maintained for 24\u00a0weeks. Given the early beneficial effect of empagliflozin on cardiovascular outcomes seen in similar patient populations, our findings provide an important insight into the key mechanisms underlying the clinical benefit of the drug.<\/jats:p>\n                <jats:p><jats:italic>Trial registration<\/jats:italic> University Medical Information Network Clinical Trial Registry, number 000024502<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12933-021-01295-6","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T06:04:01Z","timestamp":1624860241000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Reduction of estimated fluid volumes following initiation of empagliflozin in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the placebo-controlled, randomized EMBLEM trial"],"prefix":"10.1186","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3352-7661","authenticated-orcid":false,"given":"Atsushi","family":"Tanaka","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michio","family":"Shimabukuro","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiroki","family":"Teragawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yosuke","family":"Okada","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshinari","family":"Takamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isao","family":"Taguchi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeru","family":"Toyoda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hirofumi","family":"Tomiyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichiro","family":"Ueda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yukihito","family":"Higashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koichi","family":"Node","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"name":"the EMBLEM Investigators","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"issue":"10166","key":"1295_CR1","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/S0140-6736(18)32590-X","volume":"393","author":"TA Zelniker","year":"2019","unstructured":"Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, et al. 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Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg. 2019;19(3):907\u201319.","journal-title":"Am J Transplant Off J Am Soc Transplant Am Soc Transplant Surg"}],"container-title":["Cardiovascular Diabetology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12933-021-01295-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12933-021-01295-6\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12933-021-01295-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T06:04:09Z","timestamp":1624860249000},"score":1,"resource":{"primary":{"URL":"https:\/\/cardiab.biomedcentral.com\/articles\/10.1186\/s12933-021-01295-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,28]]},"references-count":37,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1295"],"URL":"https:\/\/doi.org\/10.1186\/s12933-021-01295-6","relation":{},"ISSN":["1475-2840"],"issn-type":[{"value":"1475-2840","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,28]]},"assertion":[{"value":"18 March 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 April 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 June 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The ethical committees of the participating institutions approved the study protocol. Written informed consent for participation in the study was obtained from all the subjects.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"All authors have read and approved the submission of the manuscript. The manuscript has not been published and is not being considered for publication elsewhere, in whole or in part, in any language. If the manuscript is accepted, we approve it for publication in Cardiovascular Diabetology.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"AT received honoraria from Boehringer Ingelheim; and research funding from GlaxoSmithKline. MS received honorarium and endowed chair from Boehringer Ingelheim. HirokT received lecture fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo, Kowa, Takeda, Mitsubishi Tanabe, and Sanwa Kagaku Kenkyusyo. YO received lecture fees from Astellas, AstraZeneca, MSD, Ono, Mitsubishi Tanabe, Bayer, Novo Nordisk, Eli Lilly, Boehringer Ingelheim, Daiichi Sankyo, Kissei, Novartis, Kowa, and Sanwa Kagaku Kenkyusho; and research funds from Kowa and Mitsubishi Tanabe. TT received honoraria from MSD, Astellas, AstraZeneca, Mitsubishi Tanabe, Boehringer Ingelheim, Novo Nordisk, and Taisho Toyama; research funding from Kowa; and scholarships from Novartis, AstraZeneca, Astellas, and Novo Nordisk. HirofT received research funding from Omron Health Care, Asahi Calpis Wellness, and Teijin. SU received research grants from Bristol-Myers Squibb and Kowa; non-purpose research grants from Bristol-Myers Squibb, Chugai, MSD, Pfizer, and Takeda; and lecture fees from Boehringer Ingelheim and MSD. YH received consulting fees from Mitsubishi Tanabe related to this study, as well as honoraria and grants from Teijin, Boehringer Ingelheim, MSD, Sanofi, AstraZeneca, Kyowa Hakko Kirin, Takeda, Astellas, Daiichi Sankyo, Mochida, Nihon Kohden, Shionogi, Nippon Sigmax, Sanwa Kagaku Kenkyusho, Unex, and Kao; honoraria from Radiometer, Omron, Sumitomo Dainippon, Otsuka, Torii, Kowa, Fujiyakuhin, Amgen, Nippon Shinyaku, Itamar, Bayer, Eli Lilly, and Ono. KN received research grants from Asahi Kasei, Astellas, Bayer, Boehringer Ingelheim, Mitsubishi Tanabe, Teijin, and Terumo; scholarships from Astellas, Bayer, Bristol-Myers Squibb, Daiichi Sankyo, Daiichi Sankyo Healthcare, Takeda, and Teijin; and personal fees from Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo Healthcare, Eli Lilly, Kowa, Mitsubishi Tanabe, MSD, Novartis, Ono, Takeda, and Teijin. All other authors declare no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"105"}}