Effects of Dapagliflozin on Endothelial Dysfunction in Type 2 Diabetes With Established Ischemic Heart Disease (EDIFIED)

Abstract

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.

Impact of glycemic control on the association of endothelial dysfunction and coronary artery disease in patients with type 2 diabetes mellitus

“…In the EDIFIED trial, a 12-week therapy with dapagliflozin, in addition to insulin and metformin therapies, resulted in significant reductions in HbA1c, fasting blood glucose, and surrogate markers of endothelial function. Furthermore, there was a significant association between reduction in HbA1c and improvement in FMD in the dapagliflozin group [ 49 ]. These observations together with our present findings should have an impetus on further investigations regarding the protective role of new anti-diabetic agents especially SGLT2 on endothelial function and their ability to suppress the progression of coronary atherosclerosis.…”

Effect of Sodium-Glucose Cotransporter-2 Inhibitors on Endothelial Function: A Systematic Review of Preclinical Studies

“…The DEFENCE study found a significant improvement in endothelial function in patients with T2D receiving dapagliflozin 5 mg/day as an add-on therapy to metformin 750 mg/day [ 18 ]. Similarly, T2D patients with ischemic heart disease showed a significant reduction in surrogate markers for endothelial function following 12 weeks of dapagliflozin monotherapy [ 19 ]. An investigation by Solini et al suggested that dapagliflozin might have a protective cardioprotective effect in preserving vasodilating capacity [ 20 ].…”

Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial

“…Three previous studies in T2DM reported inconsistent dapagliflozin effects on FMD [ 22 – 24 ]. The first study showed improvement in FMD after two days of treatment [ 23 ]; however, the authors reported no effect after 4 weeks of treatment [ 25 ].…”

“…In a second trial, although FMD was not significantly changed in the intention-to-treat analysis, a post hoc analysis indicated that an improvement was detected in a subgroup of patients with HbA1c > 7.0% at baseline. In the last study, 12-week treatment with dapagliflozin was compared with placebo, and although the change in FMD was inversely proportional to the change in HbA1c (r = − 0.4; p = 0.017), there was no significant improvement in FMD after dapagliflozin [ 24 ]. The main limitations of these trials were the selection of patients with FMD close to normal values as well as the suboptimal and unbalanced reduction in blood glucose in the study arms [ 24 ].…”

“…In the last study, 12-week treatment with dapagliflozin was compared with placebo, and although the change in FMD was inversely proportional to the change in HbA1c (r = − 0.4; p = 0.017), there was no significant improvement in FMD after dapagliflozin [ 24 ]. The main limitations of these trials were the selection of patients with FMD close to normal values as well as the suboptimal and unbalanced reduction in blood glucose in the study arms [ 24 ]. Hence, we carefully considered the equipoise of glycemic control and the presence of artery wall disease and dysfunction as requirements for designing the present trial.…”