{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:03:54Z","timestamp":1786122234573,"version":"build-2736575974"},"reference-count":49,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T00:00:00Z","timestamp":1783036800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["MOH\u2010000014"],"award-info":[{"award-number":["MOH\u2010000014"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>The optimal first\u2010line pharmacological therapy for newly diagnosed type 2 diabetes mellitus (T2DM) remains uncertain. This trial compared the vascular and molecular effects of dapagliflozin monotherapy, metformin monotherapy, and their combination in this population.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and Methods<\/jats:title>\n                    <jats:p>\n                      Sixty participants were randomised 1:1:1 to metformin 500\u2009mg twice daily (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200919), dapagliflozin 10\u2009mg once daily (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200920), or dapagliflozin\u2010metformin combination (\n                      <jats:italic>n<\/jats:italic>\n                      \u2009=\u200921) for 12\u2009weeks. The primary endpoint was change in reactive hyperaemia index (RHI) from baseline. Secondary endpoints were pulse wave velocity (PWV) and carotid intima\u2010media thickness (CIMT), analysed by ANCOVA. Exploratory sphingolipid and proteomics profiling was performed using partial least squares discriminant analysis and ROC curve analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RHI did not differ significantly between groups (primary endpoint). Dapagliflozin produced significantly greater CIMT reduction versus metformin as a secondary endpoint (\u22120.058\u2009mm; 95% CI \u22120.106 to \u22120.010;\n                      <jats:italic>p<\/jats:italic>\n                      \u2009=\u20090.018). PWV changes were non\u2010significant between groups. Sphingolipid profiling identified dapagliflozin\u2010specific downregulation of pro\u2010inflammatory lactosylceramide species, particularly LacCer(d18:0) (AUC 0.814). Proteomics revealed upregulation of EpCAM and downregulation of endothelial adhesion molecules (JAM\u2010A, PECAM\u20101, vWF) and tissue plasminogen activator with dapagliflozin compared with metformin.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In treatment\u2010na\u00efve newly diagnosed T2DM, dapagliflozin produced significantly greater CIMT reduction versus metformin, accompanied by distinct sphingolipid and proteomic signatures suggesting pleiotropic cardioprotective mechanisms. These hypothesis\u2010generating findings warrant validation in larger adequately powered trials.<\/jats:p>\n                    <jats:p>\n                      <jats:bold>Trial Registration:<\/jats:bold>\n                      ClinicalTrials.gov identifier: NCT05440591.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.71056","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T09:46:04Z","timestamp":1783071964000},"page":"8568-8580","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["First\u2010Line Dapagliflozin, Metformin, or Combination Therapy in Type 2 Diabetes: Vascular and Molecular Outcomes of a Randomised Controlled Trial"],"prefix":"10.1111","volume":"28","author":[{"given":"Ying Jie","family":"Chee","sequence":"first","affiliation":[{"name":"Tan Tock Seng Hospital, National Healthcare Group  Singapore Singapore"},{"name":"Lee Kong Chian 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