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We hypothesized that empaglifozin (EMPA) could modulate ectopic fat stores and myocardial energetics in high-fat-high-sucrose (HFHS) diet mice and in type 2 diabetics (T2D).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>C57BL\/6 HFHS mice (<jats:italic>n<\/jats:italic>\u2009=\u200924) and T2D subjects (<jats:italic>n<\/jats:italic>\u2009=\u200956) were randomly assigned to 12\u00a0weeks of treatment with EMPA (30\u00a0mg\/kg in mice, 10\u00a0mg\/day in humans) or with placebo. A 4.7\u00a0T or 3\u00a0T MRI with <jats:sup>1<\/jats:sup>H-MRS evaluation\u2013myocardial fat (primary endpoint) and liver fat content (LFC)\u2013were performed at baseline and at 12\u00a0weeks. In humans, standard cardiac MRI was coupled with myocardial energetics (PCr\/ATP) measured with <jats:sup>31<\/jats:sup>P-MRS. Subcutaneous (SAT) abdominal, visceral (VAT), epicardial and pancreatic fat were also evaluated.<\/jats:p>\n                <jats:p>The primary efficacy endpoint was the change in epicardial fat volume between EMPA and placebo from baseline to 12\u00a0weeks. Secondary endpoints were the differences in PCr\/ATP ratio, myocardial, liver and pancreatic fat content, SAT and VAT between groups at 12\u00a0weeks.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>In mice fed HFHS, EMPA significantly improved glucose tolerance and increased blood ketone bodies (KB) and \u03b2-hydroxybutyrate levels (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) compared to placebo. Mice fed HFHS had increased myocardial and liver fat content compared to standard diet mice. EMPA significantly attenuated liver fat content by 55%, (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) but had no effect on myocardial fat.<\/jats:p>\n                <jats:p>In the human study, all the 56 patients had normal LV function with mean LVEF\u2009=\u200963.4\u2009\u00b1\u20097.9%. Compared to placebo, T2D patients treated with EMPA significantly lost weight (\u2212\u20092.6\u00a0kg [\u2212\u20091.2;\u2009\u2212\u20093.7]) and improved their HbA1c by 0.88\u2009\u00b1\u20090.74%. Hematocrit and EPO levels were significantly increased in the EMPA group compared to placebo (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, <jats:italic>p<\/jats:italic>\u2009=\u20090.041). EMPA significantly increased glycosuria and plasma KB levels compared to placebo (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001, <jats:italic>p<\/jats:italic>\u2009=\u20090.012, respectively), and significantly reduced liver fat content (\u2212\u200927\u2009\u00b1\u200923\u00a0vs.\u2009\u2212\u20092\u2009\u00b1\u200924%, <jats:italic>p<\/jats:italic>\u2009=\u20090.0005) and visceral fat (\u2212\u20097.8% [\u2212\u200915.3;\u2009\u2212\u20095.6] vs.\u2009\u2212\u20090.1% [\u2212\u20091.1;6.5], <jats:italic>p<\/jats:italic>\u2009=\u20090.043), but had no effect on myocardial or epicardial fat. At 12\u00a0weeks, no significant change was observed in the myocardial PCr\/ATP (<jats:italic>p<\/jats:italic>\u2009=\u20090.57 between groups).<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>EMPA effectively reduced liver fat in mice and humans without changing epicardial, myocardial fat or myocardial energetics, rebutting the thrifty substrate hypothesis for cardiovascular protection of SGLT2 inhibitors.<\/jats:p>\n                <jats:p><jats:italic>Trial registration<\/jats:italic> NCT, NCT03118336. Registered 18 April 2017, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03118336\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT03118336<\/jats:ext-link><\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12933-021-01237-2","type":"journal-article","created":{"date-parts":[[2021,3,1]],"date-time":"2021-03-01T06:03:04Z","timestamp":1614578584000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":152,"title":["Effect of empagliflozin on ectopic fat stores and myocardial energetics in type 2 diabetes: the EMPACEF study"],"prefix":"10.1186","volume":"20","clinical-trial-number":[{"clinical-trial-number":"nct03118336","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4180-158X","authenticated-orcid":false,"given":"B.","family":"Gaborit","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P.","family":"Ancel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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