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.