Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study

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.

Glycated hemoglobin correlates with arterial stiffness and endothelial dysfunction in patients with resistant hypertension and uncontrolled diabetes mellitus

“…Treatment of type 2 DM by reducing HbA 1c levels using novel oral hypoglycemic agents such as sodium‐glucose cotransporter inhibitors have shown promising results with significant reductions in BP, weight, endothelial dysfunction, arterial stiffness, and microalbuminuria in patients with hypertension and those with DM. Thus, pleiotropic effects of these drugs, which are conceivably BP‐ and glucose‐independent, could represent the mechanism of cardiovascular protection in this drug class …”

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

“…Combined with the haemodynamic effects of reduced plasma volume, which are described later, decreases in cardiac load with SGLT‐2is may provide improvements in left ventricular diastolic function . Further, BP and markers of arterial stiffness, vascular resistance and cardiac workload have been shown to improve with empagliflozin and dapagliflozin treatment in patients with T2D, which may also reduce CV risk …”

“…64 Further, BP and markers of arterial stiffness, vascular resistance and cardiac workload have been shown to improve with empagliflozin and dapagliflozin treatment in patients with T2D, which may also reduce CV risk. 5,[65][66][67] Small increases in LDL and HDL cholesterol and decreases in triglycerides have been observed with SGLT-2is. 3,45,68 In a diabetic mouse model expressing human cholesterol ester transfer protein and apolipoprotein B100, SGLT-2 inhibition was associated with increased LDL cholesterol and reduced triglycerides, as well as increased lipoprotein lipase activity, decreased postprandial lipidaemia and increased clearance of very LDL cholesterol.…”

“…[3][4][5] This indicates that the cardioprotective effects of SGLT-2is cannot be attributed solely to decreases in BP. 73 Reductions in arterial stiffness, which have been observed with empagliflozin and dapagliflozin treatment, [65][66][67] may also contribute to CV benefits. A reduction in BP is one of the key determinants of myocardial oxygen consumption, providing potential benefits in diabetic cardiomyopathy, according to the law of LaPlace, and is commonly targeted in HF therapy.…”

Prognostic value of arterial stiffness measurements in cardiovascular disease, diabetes, and its complications: The potential role of sodium‐glucose co‐transporter‐2 inhibitors

“…At a clinical level, relevant literature concerning the effects of this novel antidiabetic class on arterial stiffness is rather limited. In a small observational study enrolling 26 patients in total, it was shown that dapagliflozin (n = 16) compared to hydrochlorothiazide (n = 10) induces a significant, acute reduction of PWV after 2 days of treatment (dapagliflozin group: change from 10.1 ± 1.6 to 8.8 ± 1.6 m/s; hydrochlorothiazide group: change from 11.0 ± 2.8 to 11.1 ± 2.6 m/s, P < .05) . It was also noticed that this acute effect on arterial stiffness was independent of blood pressure reduction, possibly associated with suppression of oxidative stress and amelioration of endothelial dysfunction …”