BackgroundIndividuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity.MethodsBlood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4–6 mmol/L) and hyperglycaemia (blood glucose 9–11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily).ResultsIn response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 ± 9 to 109 ± 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% ± 16 to -57% ± 17, p = 0.0001), carotid (+1.3 ± 1 7.0 to -5.7 ± 17.0%, p < 0.0001) and aortic positions (+0.1 ± 13.4 to -6.2 ± 14.3%, p < 0.0001) declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p ≤ 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia (5.7 ± 1.1 to 5.2 ± 0.9 m/s, p = 0.0017). HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions.ConclusionsEmpagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects.Trial registrationClinical trial registration: NCT01392560

(DM) suggest that increased nitric oxide (NO) bioactivity contributes to renal hyperfiltration. However, the role of NO in mediating hyperfiltration has not been fully elucidated in humans. Our aim was to examine the effect of NO synthase inhibition on renal and peripheral vascular function in normotensive subjects with uncomplicated type 1 DM. Renal function and brachial artery flow-mediated vasodilatation (FMD) were measured before and after an intravenous infusion of the NO synthase inhibitor N G -nitro-Larginine methyl ester (L-NMMA) in 21 healthy control and 37 type 1 DM patients. Measurements in DM participants were made under clamped euglycemic conditions. The effect of L-NMMA on circulating and urinary NO metabolites (NOx) and cGMP and on urinary prostanoids was also determined. Baseline characteristics were similar in the two groups. For analysis, the DM patients were divided into those with hyperfiltration (DM-H, n ϭ 18) and normal glomerular filtration rate (GFR) levels (DM-N, n ϭ 19). Baseline urine NOx and cGMP were highest in DM-H. L-NMMA led to a decline in GFR in DM-H (152 Ϯ 16 to 140 Ϯ 11 ml·min Ϫ1 ·1.73 m Ϫ2 ) but not DM-N or healthy control participants. The decline in effective renal plasma flow in response to L-NMMA (806 Ϯ 112 to 539 Ϯ 80 ml·min Ϫ1 ·1.73 m Ϫ2 ) in DM-H was also exaggerated compared with the other groups (repeated measures ANOVA, P Ͻ 0.05), along with declines in urinary NOx metabolites and cGMP. Baseline FMD was lowest in DM-H compared with the other groups and did not change in response to L-NMMA. L-NMMA reduced FMD and plasma markers of NO bioactivity in the healthy control and DM-N groups. In patients with uncomplicated type 1 DM, renal hyperfiltration is associated with increased NO bioactivity in the kidney and reduced NO bioactivity in the systemic circulation, suggesting a paradoxical state of high renal and low systemic vascular NO bioactivity. endothelial function; hyperfiltration; nitric oxide; type 1 diabetes GLOMERULAR HYPERFILTRATION is an early renal hemodynamic change in animal and human studies of diabetes mellitus (DM) and may help to predict the risk for the subsequent development of diabetic nephropathy (38). The pathogenesis of hyperfiltration is complex and involves both tubuloglomerular feedback and hemodynamic abnormalities. Renal hemodynamic changes associated with hyperfiltration include afferent vasodilatation and efferent constriction. Hyperfiltration is, however, only partially corrected after selective cyclooxygenase-2 inhibition (predominant afferent constriction) or renin angiotensin system (RAS) blockade (predominant efferent vasodilatation) in humans with uncomplicated type 1 DM (8, 54). These findings suggest the presence of nonprostaglandin, non-RAS-dependent hemodynamic mechanisms that perpetuate the hyperfiltration state (60).Functional expression studies in DM models have determined that endothelial nitric oxide (NO) synthase (eNOS) expression is consistently upregulated and localized to the afferent arteriole, renal cortex, and medull...