{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:50:46Z","timestamp":1788828646634,"version":"build-2803163510"},"reference-count":60,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2018,4,25]],"date-time":"2018-04-25T00:00:00Z","timestamp":1524614400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"NuSirt Biopharma"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Aliment Pharmacol Ther"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>Summary<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Sirtuin 1 (Sirt1) is suppressed in non\u2010alcoholic fatty liver disease (<jats:styled-content style=\"fixed-case\">NAFLD<\/jats:styled-content>), while its\u2019 stimulation or overexpression results in reduced disease severity in pre\u2010clinical <jats:styled-content style=\"fixed-case\">NAFLD<\/jats:styled-content> models. Leucine allosterically activates Sirt1 and synergise with other Sirt\/<jats:styled-content style=\"fixed-case\">AMPK<\/jats:styled-content>\/<jats:styled-content style=\"fixed-case\">NO<\/jats:styled-content> pathway activators. We developed a triple combination of leucine, metformin and sildenafil (<jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>\u20100200), which was effective in a mouse model of non\u2010alcoholic steatohepatitis (<jats:styled-content style=\"fixed-case\">NASH<\/jats:styled-content>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Aim<\/jats:title><jats:p>To report the results from a Phase 2, randomised clinical trial of of <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>\u20100200 in 91 subjects with <jats:styled-content style=\"fixed-case\">NAFLD<\/jats:styled-content> (liver fat \u226515% by magnetic resonance imaging\u2010proton\u2010density fat fraction (<jats:styled-content style=\"fixed-case\">MRI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PDFF<\/jats:styled-content>)).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Subjects were randomised to placebo, low\u2010dose (1.1\u00a0g leucine\/0.5\u00a0g metformin\/0.5\u00a0mg sildenafil) or high\u2010dose <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>\u20100200 (1.1\u00a0g leucine\/0.5\u00a0g metformin\/1.0\u00a0mg sildenafil) b.d. for 16\u00a0weeks; change in hepatic fat was assessed via <jats:styled-content style=\"fixed-case\">MRI<\/jats:styled-content>\u2010<jats:styled-content style=\"fixed-case\">PDFF<\/jats:styled-content>, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50\u00a0U\/L; n\u00a0=\u00a035).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the full cohort, active treatments did not separate from placebo. High dose <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>\u20100200 reduced hepatic fat by 15.7% (relative change from baseline) in the high <jats:styled-content style=\"fixed-case\">ALT<\/jats:styled-content> group (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a00.005) while low dose <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>\u20100200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose\u2010responsive treatment effects in both overall and high <jats:styled-content style=\"fixed-case\">ALT<\/jats:styled-content> cohorts, with significant decreases in metabolically active lipids and up\u2010regulation of fatty acid oxidation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These data support further evaluation of high\u2010dose <jats:styled-content style=\"fixed-case\">NS<\/jats:styled-content>\u20100200 for treating <jats:styled-content style=\"fixed-case\">NASH<\/jats:styled-content>, especially in those with elevated <jats:styled-content style=\"fixed-case\">ALT<\/jats:styled-content> (NCT 02546609).<\/jats:p><\/jats:sec>","DOI":"10.1111\/apt.14674","type":"journal-article","created":{"date-parts":[[2018,4,26]],"date-time":"2018-04-26T05:56:16Z","timestamp":1524722176000},"page":"1639-1651","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Randomised clinical trial: a leucine\u2010metformin\u2010sildenafil combination (<scp>NS<\/scp>\u20100200) vs placebo in patients with non\u2010alcoholic fatty liver disease"],"prefix":"10.1111","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4082-3178","authenticated-orcid":false,"given":"N.","family":"Chalasani","sequence":"first","affiliation":[{"name":"Indiana University School of Medicine Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R.","family":"Vuppalanchi","sequence":"additional","affiliation":[{"name":"Indiana University School of Medicine Indianapolis IN USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M.","family":"Rinella","sequence":"additional","affiliation":[{"name":"Northwestern University Chicago IL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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