Dapagliflozin preserves renal vasodilating capacity in hypertensive patients with type 2 diabetes

Background and aims: Mechanisms through which SGLT-2 inhibitors achieve cardiovascular and renal protection are still unknown. We inves- tigated whether dapagliflozin (Dapa) modulates Na and water balance and systemic and renal vascular parameters like endothelial function, arterial stiffness and renal vasodilating capacity, exploring the epigenetic regulation behind it. Materials and methods: Two groups of hypertensive patients with type 2 diabetes were studied at baseline (V0) and after four weeks (V1) of Dapa 10 mg (N = 20) or hydroclorothiazide 12.5 mg (HCT, N = 20), collecting blood and urinary samples for routine analyses, determination of plasma renin activity, aldosterone, norepinephrine, adrenaline and 24 hour-urinary electrolytes. Flow-mediated dilation of the brachial artery (FMD), baseline (RI) and dynamic renal resistive index (DRIN), carotid- femoral pulse-wave velocity (PWV) and Augmentation Index (AIx) were also measured. Circulating miRNA related to chronic heart failure (miR27a-3p, miR30e-5p, miR199a-3p) and renal function (miR130b- 3p, miR21-5p) were assessed. Results: The two groups were comparable for age, sex, BMI and HbA1c. Both Dapa and HCT marginally lowered systolic and diastolic BP values, with no effect on heart rate. Fasting glucose did not significantly vary. Estimated GFR (by CKD-EPI equation) was unmodified in both groups after treatment. Serum magnesium concentration significantly rose in Dapa group (from 1.88 ± 0.27 to 2.01 ± 0.22 mg/dl, p = 0.02 for time*treatment interaction), while urinary magnesium was unchanged. 24h diuresis and glycosuria and osmolar clearance increased in Dapa (p < 0.001 for time*treatment interaction), with no changes in sodium excretion and creatinine clearance. Dapa induced also a rise in aldoste- rone (p = 0.02 for time*treatment interaction), with no influence on cathecolamines. Nor DAPA neither HCT modified FMD and PWV. Interestingly, in Dapa group DRIN remained unmodified, while tended to increase in HCT group (p = 0.05 for time*treatment interaction). Preliminary data show differences in circulating miRNAs between the two groups. Conclusion: 4-week treatment with Dapa did not significantly influence BP, glucose values, eGFR and systemic indices of vascular function. However, in comparison to HCT, renal vasodilating capacity was pre- served in Dapa group, indicating a selective effect on renal vascular function, which may act as a mechanism of nephroprotection. Furthermore, the increase in serum magnesium might contribute to car- diovascular protection.