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

Abstract

Background The glucose-lowering independent effect of sodium glucose cotransporter-2 inhibitors (SGLT2i) on arterial wall function has not yet been clarified. This study aims to assess whether SGLT2i treatment can attenuate endothelial dysfunction related to type 2 diabetes mellitus (T2D) compared with glucose-lowering equivalent therapy. Methods In a prospective, open-label, single-center, randomized clinical trial, 98 patients with T2DM and carotid intima-media thickness above the 75th percentile were randomized 1:1 to 12 weeks of therapy with dapagliflozin or glibenclamide in addition to metformin in glucose-lowering equivalent regimens. The coprimary endpoints were 1-min flow-mediated dilation (FMD) at rest and 1-min FMD after 15 min of ischemia followed by 15 min of reperfusion time (I/R). Results Ninety-seven patients (61% males, 57 ± 7 years) completed the study. The median HbA1c decreased by − 0.8 (0.7)% and -0.7 (0.95)% following dapagliflozin and glibenclamide, respectively. The first coprimary endpoint, i.e., rest FMD changed by + 3.3(8.2)% and − 1.2(7.5)% for the dapagliflozin and glibenclamide arms, respectively (p = 0.0001). Differences between study arms in the second coprimary endpoint were not significant. Plasma nitrite 1 min after rest FMD was higher for dapagliflozin [308(220) nmol/L] than for glibenclamide (258[110] nmol/L; p = 0.028). The resistive indices at 1 min [0.90 (0.11) vs. 0.93 (0.07); p = 0.03] and 5 min [0.93 (0.07) vs. 0.95 (0.05); p = 0.02] were higher for the glibenclamide group than for the dapagliflozin group. Plasma biomarkers for inflammation and oxidative stress did not differ between the treatments. Conclusions Dapagliflozin improved micro- and macrovascular endothelial function compared to glibenclamide, regardless of glycemic control in patients with T2DM and subclinical carotid atherosclerotic disease.

Cardiovascular Benefits from Gliflozins: Effects on Endothelial Function

“…Instead, the change in FMD after I/R was not different between the two regimens. In an intragroup exploratory analysis, the study demonstrated that dapagliflozin improved FMD in individuals with severe arterial wall dysfunction when compared to glibenclamide, as well as when compared with baseline values [126]. The positive results on FMD obtained in this study likely depend on the recruitment of patients with more severe arterial wall dysfunction than prior trials and on a carefully balanced reduction in blood glucose in the two study arms.…”

“…The recently published ADDENDA-BHS2 aimed to evaluate whether dapagliflozin, regardless of its glucose-lowering effect, could mitigate the ED and increase the endothelial resilience to I/R injury in T2DM patients with atherosclerotic disease [126]. The study demonstrated that a 12-week course of treatment improved vasomotor function in both macro-and microcirculation as compared to glibenclamide, in a setting of comparable glucose lowering between the two groups.…”

Possible Mechanisms of Action of SGLT2 Inhibitors in Heart Failure

“…More recently, in a study of 97 patients with DM2, Sposito et al showed that treatment with dapagliflozin improved endothelial function relative to glibenclamide as determined by Doppler-recorded reactive vasodilation. 44 These findings indicate that the effect of SGLT1 inhibitors on sympathetic tone and vascular remodeling can contribute to their benefits for patients with HF.…”

Effects of Sodium-Glucose Co-Transporter 2 Inhibitors on Vascular Cell Function and Arterial Remodeling

“…Dapagliflozin also augments peripheral microvascular endothelial function in patients with poorly controlled T2DM that corresponds to reductions in patient's blood pressure and abdominal fat mass [57]. Furthermore, an active-controlled trial found that dapagliflozin corrects endothelial dysfunction in T2DM patients with atherosclerotic disease [58]. In contrast, a prospective, randomized, blinded end point study showed that dapagliflozin preserves renal artery vasodilating capacity in T2DM patients with hypertension, but it fails to modify FMD [59].…”