Abstract
BackgroundSodium-glucose cotransporter-2 inhibitors reduce blood pressure (BP) and renal and cardiovascular events in patients with type 2 diabetes through not fully elucidated mechanisms. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms.MethodsNeuro-hormonal and vascular variables, together with 24 h diuresis, urinary sodium, glucose, isoprostanes and free-water clearance were assessed before and after a 2-day treatment with dapagliflozin 10 mg QD in sixteen type 2 diabetic patients; data were compared with those obtained in ten patients treated with hydrochlorothiazide 12.5 mg QD. Brachial artery endothelium-dependent and independent vasodilation (by flow-mediated dilation) and pulse wave velocity were assessed. Renal resistive index was obtained at rest and after glyceryl trinitrate administration. Differences were analysed by repeated measures ANOVA, considering treatment as between factor and time as within factor; Bonferroni post hoc comparison test was also used.ResultsDapagliflozin decreased systolic BP and induced an increase in 24 h diuresis to a similar extent of hydrochlorothiazide; 24 h urinary glucose and serum magnesium were also increased. 24 h urinary sodium and fasting blood glucose were unchanged. Oxidative stress was reduced, as by a decline in urinary isoprostanes. Flow-mediated dilation was significantly increased (2.8 ± 2.2 to 4.0 ± 2.1%, p < 0.05), and pulse-wave-velocity was reduced (10.1 ± 1.6 to 8.9 ± 1.6 m/s, p < 0.05), even after correction for mean BP. Renal resistive index was reduced (0.62 ± 0.04 to 0.59 ± 0.05, p < 0.05). These vascular modifications were not observed in hydrochlorothiazide-treated individuals.ConclusionsAn acute treatment with dapagliflozin significantly improves systemic endothelial function, arterial stiffness and renal resistive index; this effect is independent of changes in BP and occurs in the presence of stable natriuresis, suggesting a fast, direct beneficial effect on the vasculature, possibly mediated by oxidative stress reduction.
Highlights
The interaction between renal hemodynamics and blood pressure (BP) is a complex issue, and this balance plays a key role in the sodium and water reabsorption by renal tubule
Given the relatively unexpected significant BP reduction after only 2 days of dapagliflozin treatment, ten type 2 diabetes (T2D) patients were selected after the completion of the sixteen cases on the basis of the same inclusion criteria; they followed the same protocol but receiving hydrochlorothiazide (HCT), and served as control group, to test whether the results obtained in cases could be related to the mode of action of dapagliflozin or, more extensively, to its diuretic and BP-lowering effect
Humoral parameters did not vary in the two treatment arms, with the exception of serum magnesium concentration, which significantly rose (p = 0.003 for the interaction time*treatment) only in the dapagliflozin group
Summary
The interaction between renal hemodynamics and BP is a complex issue, and this balance plays a key role in the sodium and water reabsorption by renal tubule. A raise in systemic BP influences intraglomerular pressure; an elevated renal interstitial hydrostatic pressure, direct consequence of systemic hypertension, rapidly inhibits sodium reabsorption by the proximal tubule, and the kidney responds by increasing sodium excretion; physiological mechanisms governing this adaptive response are only partially clarified [1]. Endothelium takes part in this complex mechanism: it has been suggested that pressure-mediated increases in vascular shear stress stimulate endothelial nitric oxide (NO) production, a signal able to reduce tubular sodium reabsorption [2, 3]; reactive oxygen and nitrogen species are key modulators of the pressure-natriuresis response [4]. By inhibiting the transporter protein SGLT2 in the kidney, they reduce renal glucose reabsorption, promoting its urinary excretion. Aim of this study was to investigate whether dapagliflozin is able to acutely modify systemic and renal vascular function, as well as putative mechanisms
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