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Abstract: TH-PO178

The Combination of Empagliflozin and Atrasentan on Top of RAS Blockade Ameliorates Cardiorenal Syndrome in the db/db Type 2 Diabetes Mouse Model

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Vergara, Ander, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain
  • Jacobs Cachá, Conxita, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain
  • Llorens Cebrià, Carmen, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain
  • Domínguez Báez, Pamela, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain
  • Martos, Nerea, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain
  • Martínez Díaz, Irene, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain
  • Bermejo, Sheila, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain
  • Pieper, Michael P., Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany
  • Benito, Begoña, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain
  • Soler, Maria Jose, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Group or Team Name

  • Nephrology and Renal Transplant Research Group
Background

Sodium-glucose cotransporter 2 inhibitors(SGLT2i) prevent cardiovascular events in diabetic patients. Moreover, their diuretic effect could attenuate the adverse events of endothelin receptor antagonists(ERAs), which have also shown beneficial effects in diabetes. The present study aimed to evaluate the cardiorenal protective effects of the SGLT2i, ERAs and ramipril combination vs treatment with ramipril alone in the db/db mouse.

Methods

Twelve weeks old db/db mice were treated for 8 weeks with different combinations of an SGLT2i(empagliflozin,10 mg/Kg/day), an ERA(atrasentan,7 mg/Kg/day) and a renin-angiotensin system(RAS) blocker(ramipril,8 mg/Kg/day). Vehicle-treated diabetic and non-diabetic mice were included as controls. During the experiment, blood pressure(BP), glomerular filtration rate(GFR) and echocardiographic parameters were measured. Kidney and heart were collected at the end for histological studies.

Results

The triple therapy with empagliflozin, atrasentan and ramipril was superior to ramipril alone in reducing BP, preventing diabetic hyperfiltration (214μL/100g/min reduction in GFR vs 96μL/100g/min increase in non-treated db/db,p=0.040) and improving echocardiographic parameters of diastolic dysfunction, including left atrium diameter and isovolumetric relaxation time(Figure 1). Moreover, the combined therapy offered protection against diabetic injury in the kidney and heart, decreasing glomerular mesangial matrix, restoring podocyte density, and reducing both left ventricle(LV) cardiomyocyte hypertrophy (125μm2 area vs 142μm2 in non-treated db/db,p=0.032) and LV collagen deposition(Figure 1).

Conclusion

In experimental diabetes, combined therapy of ramipril, empagliflozin and atrasentan promotes both heart and kidney protective effects that outweigh the beneficial effects of ramipril alone.

Funding

  • Commercial Support