Objectives To evaluate the effect of the sodium-glucose cotransporter 2 inhibitor (SGLT2-I) dapagliflozin on endothelial function in patients with high-risk type 2 diabetes mellitus (T2DM). Methods This was a prospective, double-blind, randomized, placebo-controlled, clinical trial of patients with T2DM with underlying ischemic heart disease who were receiving metformin and insulin therapy (n = 81). After 12-weeks of additional therapy with either dapagliflozin (n = 40) or placebo (n = 41), systemic endothelial function was evaluated by change in flow-mediated dilation (ΔFMD), change in nitroglycerin-mediated dilation (ΔNMD) and surrogate markers including intercellular adhesion molecule 1 (ICAM-1), endothelial nitric oxide synthase (eNOS), high-sensitivity C-reactive protein (hs-CRP), and lipoprotein(a) (Lp[a]). Glycemic and lipid profiles were also measured. Results The dapagliflozin group demonstrated significant reductions of hemoglobin A1c (HbA1c) and fasting blood glucose (FBG) compared to the placebo group (ΔHbA1c –0.83 ± 1.47% vs –0.16 ± 1.25%, P = 0.042 and ΔFBG vs –0.73 ± 4.55 mmol/L vs –1.90 ± 4.40 mmol/L, P = 0.015, respectively). The placebo group showed worsening of ΔFMD while the dapagliflozin group maintained similar measurements pre- and posttherapy (P = not significant). There was a reduction in ICAM-1 levels in the dapagliflozin group (–83.9 ± 205.9 ng/mL, P < 0.02), which remained unchanged in the placebo group (–11.0 ± 169.1 ng/mL, P = 0.699). Univariate correlation analysis revealed a significant negative correlation between HbA1c and ΔFMD within the active group. Conclusion A 12-week therapy with dapagliflozin, in addition to insulin and metformin therapies, in high-risk patients resulted in significant reductions in HbA1c, FBG, and surrogate markers of the endothelial function. Although the dapagliflozin group demonstrated a significant association between reduction in HbA1c and improvement in FMD, there was no significant difference in FMD between the 2 groups.