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First-Line Dapagliflozin, Metformin, or Combination Therapy in Type 2 Diabetes: Vascular and Molecular Outcomes of a

Ying Jie Chee1,2, Sanchalika Acharyya1, Huiling Liew1

  • 1Tan Tock Seng Hospital, National Healthcare Group, Singapore, Singapore.

Diabetes, Obesity & Metabolism
|July 3, 2026
PubMed
Abstract

Insights

Dapagliflozin significantly reduced carotid intima-media thickness more than metformin in newly diagnosed type 2 diabetes mellitus (T2DM). This suggests potential cardioprotective effects beyond glucose lowering, warranting further investigation.

Area of Science:

  • Cardiology
  • Endocrinology
  • Pharmacology

Background:

  • Optimal first-line therapy for newly diagnosed type 2 diabetes mellitus (T2DM) is uncertain.
  • This study investigated vascular and molecular effects of dapagliflozin and metformin in T2DM.

Purpose of the Study:

  • To compare the vascular and molecular effects of dapagliflozin monotherapy, metformin monotherapy, and their combination in newly diagnosed T2DM patients.
  • To evaluate changes in reactive hyperaemia index (RHI), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT).

Main Methods:

  • Sixty participants were randomized to metformin, dapagliflozin, or combination therapy for 12 weeks.
  • Primary endpoint was change in RHI; secondary endpoints included PWV and CIMT.
  • Exploratory sphingolipid and proteomics profiling were conducted.

Main Results:

  • No significant difference in RHI between groups.
  • Dapagliflozin showed significantly greater CIMT reduction compared to metformin.
  • Sphingolipid profiling revealed dapagliflozin-specific downregulation of pro-inflammatory lactosylceramide species.

Conclusions:

  • Dapagliflozin demonstrated superior CIMT reduction versus metformin in treatment-naïve T2DM.
  • Distinct molecular signatures suggest pleiotropic cardioprotective mechanisms of dapagliflozin.
  • Findings require validation in larger, adequately powered trials.
Keywords:
carotid intima‐media thicknessmetforminproteomicssodium‐glucose transporter 2 inhibitors (covers dapagliflozin)sphingolipidstype 2 diabetes mellitus

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