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Their effects on<jats:sc>l<\/jats:sc>-arginine (Arg) related risk markers asymmetric and symmetric dimethylarginine (ADMA and SDMA) and the protective biomarker L-homoarginine (hArg) linking T2D to cardiovascular and renal disease have not yet been reported.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Plasma and 24-h urine samples taken before and after 6\u00a0weeks of treatment were available from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with empagliflozin (71 patients analyzed, NCT02471963) and dapagliflozin (59 patients analyzed, NCT02383238). In these samples, concentrations of hArg, Arg, ADMA, SDMA, and creatinine were determined by liquid-chromatography coupled to tandem mass-spectrometry. Additionally, intraindividual changes of the biomarkers in plasma were correlated with intraindividual changes of clinical parameters.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Treatment with empagliflozin and dapagliflozin was associated with a reduction of plasma hArg by 17.5% and 13.7% (both p\u2009&lt;\u20090.001), respectively, and increase in plasma SDMA concentration of 6.7% and 3.6%, respectively (p\u2009&lt;\u20090.001 and p\u2009&lt;\u20090.05), while plasma Arg and ADMA concentrations were not significantly altered. 24-h urinary excretion of ADMA was reduced by 15.2% after treatment with empagliflozin (p\u2009&lt;\u20090.001) but not after dapagliflozin treatment, while excretion of the other markers was not significantly altered. Renal clearance of SDMA was reduced by 9.1% and 3.9% for both drugs (both p\u2009&lt;\u20090.05). A reduction in ADMA clearance was observable after empagliflozin treatment only (\u2212\u200915.5%, p\u2009&lt;\u20090.001), but not after dapagliflozin. Renal clearance of hArg and Arg was not significantly altered. Treatment effects on<jats:sc>l<\/jats:sc>-arginine related biomarkers were not constantly correlated with effects on glycated hemoglobin, fasting plasma glucose, body mass index, and systolic blood pressure.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Treatment with SGLT-2 inhibitors has divergent effects on Arg-related biomarkers and could affect risk estimates associated with these markers. The observed effects are unlikely to explain the known cardiovascular and renal benefits of treatment with empagliflozin or dapagliflozin but still may indicate new therapeutic approaches in patients treated with SGLT-2 inhibitors.<\/jats:p><jats:p><jats:italic>Trial registration<\/jats:italic><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>: NCT02471963 (registered 15th June 2015, retrospectively registered) and NCT02383238.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12933-021-01436-x","type":"journal-article","created":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T14:02:48Z","timestamp":1641477768000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Effects of treatment with SGLT-2 inhibitors on arginine-related cardiovascular and renal biomarkers"],"prefix":"10.1186","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1729-4231","authenticated-orcid":false,"given":"Arne","family":"Gessner","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Gemeinhardt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agnes","family":"Bosch","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis","family":"Kannenkeril","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Staerk","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Mayr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin F.","family":"Fromm","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roland E.","family":"Schmieder","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renke","family":"Maas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,1,6]]},"reference":[{"issue":"2","key":"1436_CR1","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1681\/ASN.2012070718","volume":"24","author":"M Afkarian","year":"2013","unstructured":"Afkarian M, Sachs MC, Kestenbaum B, Hirsch IB, Tuttle KR, Himmelfarb J, de Boer IH. 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The study protocol of each trial was approved by the German drug authority and Local Ethics Committee (University of Erlangen-N\u00fcrnberg), and the studies were conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice guidelines.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"A. Gessner was involved in research projects at his institution by Boehringer Ingelheim. M.F. Fromm has received consultancy fees from Boehringer Ingelheim and lecture fees from Janssen-Cilag. He has received third-party funds for research projects at his institution by Boehringer Ingelheim, Dr. R. Pfleger GmbH, and Heidelberg Pharma Research GmbH.R.E. Schmieder has received speaker fees and advisory board fees from Boehringer Ingelheim and AstraZeneca. The other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"4"}}