Dapagliflozin-induced integrated improvements in left ventricular diastole, endothelial function, and arterial load: a randomized clinical trial.

backgroundDapagliflozin has been shown in preclinical and clinical settings to improve arterial function and left ventricular (LV) diastolic performance, yet the interrelationship between these effects has not been established.

objectiveTo determine whether improvements in endothelial function accompany-and relate to-early changes in LV diastolic function after short-term dapagliflozin in type 2 diabetes (T2D).

methodsWe conducted a prespecified secondary analysis of a prospective, open-label, active-controlled trial of patients with T2D on background metformin that were randomized to daily dapagliflozin 10 mg or glibenclamide 5 mg for 12 weeks. All patients underwent echocardiographic and endothelial function assessments at baseline and 12 weeks. The primary endpoint for echocardiographic diastolic parameters was the change in E/e'. Endpoints for endothelial function were change in brachial artery flow-mediated dilation (FMD) and nitric oxide (NO) bioavailability. Arterial load comprises arterial impedance, measured as the brachial artery resistivity index, and the afterload components, the systemic vascular resistance and the ventriculo-arterial coupling index, as a marker of arterial stiffness.

resultsAmong 96 patients (mean age 59 years; 40% female; baseline HbA1c 7.8%; 75% at intermediate risk H2FPEF score), glycemic control improved similarly in both groups (median [IQR] HbA1c change: -0.78 [0.11]% vs. -0.80 [0.10]%; between-group p = 0.887). Dapagliflozin reduced the E/e' ratio (mean change - 0.38 [0.24]; within-group p = 0.184), whereas glibenclamide increased (+ 0.79 [0.24]; p = 0.001), resulting in a significant between-group difference of - 1.17 (0.34; p = 0.001). Dapagliflozin treatment was associated with a 67% lower likelihood of being in a higher E/e' quartile (OR 0.325; 95% CI 0.147-0.715; p = 0.005). In the pooled cohort, changes in E/e' correlated directly with changes in brachial resistive index (r = 0.28; p = 0.005) and inversely with changes in NO bioavailability (r = - 0.26; p = 0.010) and FMD (r = - 0.23; p = 0.023). No significant correlations were observed for systemic vascular resistance or ventricle-arterial coupling.

conclusionsIn patients with T2D at intermediate risk for HFpEF, dapagliflozin was associated with more favorable changes in left ventricular diastolic function parameters compared with glibenclamide, accompanied by improvements in endothelial function and reductions in arterial impedance. These observations support the hypothesis of a vascular-myocardial pathway through which SGLT2 inhibition may exert cardioprotective effects in this population.

trial registrationClinicalTrials.gov Identifier NCT02919345.