First‐Line Dapagliflozin, Metformin, or Combination Therapy in Type 2 Diabetes: Vascular and Molecular Outcomes of a Randomised Controlled Trial

AIMS: The optimal first-line 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. MATERIALS AND METHODS: Sixty participants were randomised 1:1:1 to metformin 500 mg twice daily (n = 19), dapagliflozin 10 mg once daily (n = 20), or dapagliflozin-metformin combination (n = 21) for 12 weeks. The primary endpoint was change in reactive hyperaemia index (RHI) from baseline. Secondary endpoints were pulse wave velocity (PWV) and carotid intima-media thickness (CIMT), analysed by ANCOVA. Exploratory sphingolipid and proteomics profiling was performed using partial least squares discriminant analysis and ROC curve analysis. RESULTS: RHI did not differ significantly between groups (primary endpoint). Dapagliflozin produced significantly greater CIMT reduction versus metformin as a secondary endpoint (-0.058 mm; 95% CI -0.106 to -0.010; p = 0.018). PWV changes were non-significant between groups. Sphingolipid profiling identified dapagliflozin-specific downregulation of pro-inflammatory lactosylceramide species, particularly LacCer(d18:0) (AUC 0.814). Proteomics revealed upregulation of EpCAM and downregulation of endothelial adhesion molecules (JAM-A, PECAM-1, vWF) and tissue plasminogen activator with dapagliflozin compared with metformin. CONCLUSIONS: In treatment-naïve newly diagnosed T2DM, dapagliflozin produced significantly greater CIMT reduction versus metformin, accompanied by distinct sphingolipid and proteomic signatures suggesting pleiotropic cardioprotective mechanisms. These hypothesis-generating findings warrant validation in larger adequately powered trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT05440591.