Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation

Aims/hypothesis Sodium-glucose cotransporter 2 (SGLT2) inhibitors (SGLT2i) constitute a novel class of glucose-lowering (type 2) kidney-targeted agents. We recently reported that the SGLT2i empagliflozin (EMPA) reduced cardiac cytosolic Na+ ([Na+](c)) and cytosolic Ca2+ ([Ca2+](c)) concentrations through inhibition of Na+/H+ exchanger (NHE). Here, we examine (1) whether the SGLT2i dapagliflozin (DAPA) and canagliflozin (CANA) also inhibit NHE and reduce [Na+](c); (2) a structural model for the interaction of SGLT2i to NHE; (3) to what extent SGLT2i affect the haemodynamic and metabolic performance of isolated hearts of healthy mice. Methods Cardiac NHE activity and [Na+](c) in mouse cardiomyocytes were measured in the presence of clinically relevant concentrations of EMPA (1 mu mol/l), DAPA (1 mu mol/l), CANA (3 mu mol/l) or vehicle. NHE docking simulation studies were applied to explore potential binding sites for SGTL2i. Constant-flow Langendorff-perfused mouse hearts were subjected to SGLT2i for 30 min, and cardiovascular function, O-2 consumption and energetics (phosphocreatine (PCr)/ATP) were determined. Results EMPA, DAPA and CANA inhibited NHE activity (measured through low pH recovery after NH4+ pulse: EMPA 6.69 +/- 0.09, DAPA 6.77 +/- 0.12 and CANA 6.80 +/- 0.18 vs vehicle 7.09 +/- 0.09; p <0.001 for all three comparisons) and reduced [Na+](c) (in mmol/l: EMPA 10.0 +/- 0.5, DAPA 10.7 +/- 0.7 and CANA 11.0 +/- 0.9 vs vehicle 12.7 +/- 0.7; p <0.001). Docking studies provided high binding affinity of all three SGLT2i with the extracellular Na+-binding site of NHE. EMPA and CANA, but not DAPA, induced coronary vasodilation of the intact heart. PCr/ATP remained unaffected. Conclusions/interpretation EMPA, DAPA and CANA directly inhibit cardiac NHE flux and reduce [Na+](c), possibly by binding with the Na+-binding site of NHE-1. Furthermore, EMPA and CANA affect the healthy heart by inducing vasodilation. The [Na+](c)-lowering class effect of SGLT2i is a potential approach to combat elevated [Na+](c) that is known to occur in heart failure and diabete

Dual hormone fully closed loop in type 1 diabetes: a randomised trial in the Netherlands – study protocol

Introduction The management of type 1 diabetes (T1DM) has undergone significant advancements with the availability of novel technologies, notably continuous and flash glucose monitoring (CGM and FGM, respectively) and hybrid closed loop (HCL) therapy. The dual hormone fully closed loop (DHFCL) approach with insulin and glucagon infusion has shown promising effects in small studies on glycaemic regulation and quality of life in T1DM.Methods and analysis The Dual Hormone Fully Closed Loop for Type 1 Diabetes (DARE) study is a non-commercial 12-month open-label, two-arm randomised parallel-group trial. The primary aim of this study is to determine the long-term effects on glycaemic control, patient-reported outcome measurements and cost-effectiveness of the DHFCL compared with usual care, that is, HCL or treatment with multiple daily insulin injections+FGM/CGM. We will include 240 adult patients with T1DM in 14 hospitals in the Netherlands. Individuals will be randomised 1:1 to the DHFCL or continuation of their current care.Ethics and dissemination Ethical approval has been obtained from the Medical Research Ethics Committee NedMec, Utrecht, the Netherlands. Findings will be disseminated through peer-reviewed publications and presentations at local, national and international conferences.Trial registration number NCT05669547