Enhanced Cardiorenal Protective Effects of Combining SGLT2 Inhibition, Endothelin Receptor Antagonism and RAS Blockade in Type 2 Diabetic Mice

Abstract

Treatments with sodium–glucose 2 cotransporter inhibitors (SGLT2i) or endothelin receptor antagonists (ERA) have shown cardiorenal protective effects. The present study aimed to evaluate the cardiorenal beneficial effects of the combination of SGLT2i and ERA on top of renin–angiotensin system (RAS) blockade. Type 2 diabetic mice (db/db) were treated with different combinations of an SGLT2i (empagliflozin), an ERA (atrasentan), and an angiotensin-converting enzyme inhibitor (ramipril) for 8 weeks. Vehicle-treated diabetic mice and non-diabetic mice were included as controls. Weight, blood glucose, blood pressure, and kidney and heart function were monitored during the study. Kidneys and heart were collected for histological examination and to study the intrarenal RAS. Treatment with empagliflozin alone or combined significantly decreased blood glucose compared to vehicle-treated db/db. The dual and triple therapies achieved significantly greater reductions in diastolic blood pressure than ramipril alone. Compared to vehicle-treated db/db, empagliflozin combined with ramipril or in triple therapy significantly prevented GFR increase, but only the triple combination exerted greater protection against podocyte loss. In the heart, empagliflozin alone or combined reduced cardiac isovolumetric relaxation time (IVRT) and left atrium (LA) diameter as compared to vehicle-treated db/db. However, only the triple therapy was able to reduce cardiomyocyte area. Importantly, the add-on triple therapy further enhanced the intrarenal ACE2/Ang(1-7)/Mas protective arm of the RAS. These data suggest that triple therapy with empagliflozin, atrasentan and ramipril show synergistic cardiorenal protective effects in a type 2 diabetic mouse model.

Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects

“…The latter occurred in a blood pressure-independent manner, supporting a local effect of SGLT2 inhibition in the kidney. It has been argued that this may involve upregulation of the Ang-(1-7)-Mas receptor axis in the kidney [10,22], but our data do not support this possibility. In fact, renal Ang-(1-7) levels during vehicle treatment corresponded with around 5% of those of Ang II, in full agreement with earlier observations [9,14], and became even lower during dual blockade, that is, when the most beneficial pattern was observed.…”

Niaoduqing alleviates podocyte injury in high glucose model via regulating multiple targets and AGE/RAGE pathway: Network pharmacology and experimental validation

“…The application of SGLT-2i can reduce the progression of DN through promoting ketone body induced mechanistic target of rapamycin complex 1 (mTORC1) signaling inhibition (Tomita et al, 2020) The protective effect of SGLT-2i is also related to the inhibition of EMT and aberrant glycolysis (Li et al, 2020c). Compared with the individual application, the combination of SGLT-2i, ACEI and endothelin receptor antagonism can enhance their cardiac and renal protective effects in Type 2 diabetic model (Vergara et al, 2022). Tsuprykov O showed that dipeptidyl peptidase-4 (DPP-4) inhibitor, Linagliptin, has the comparable efficacy to ARB in preventing CKD progression in the 5/6 nephrectomy rats models.…”

Endothelin Receptor Antagonists in Kidney Disease

“…This suggests that the dual therapy approach can have therapeutic potential [ 89 ]. A recent study of Vergara, A. et al [ 90 ] tested the capacity of an SGLT2 inhibitor (empagliflozin) and/or an ERA (atrasentan) on top of RAS blockade with ramipril to protect the diabetic kidney in experimental diabetic nephropathy using db/db mice. This study revealed that triple therapy with empagliflozin, atrasentan and ramipril maintained the impact of each therapy alone and added to organ protection.…”