Kidney Week

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

• Diabetic Kidney Disease: Basic - I
  November 03, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
  Abstract Time: 10:00 AM - 12:00 PM

Category: Diabetic Kidney Disease

• 601 Diabetic Kidney Disease: Basic

Authors

• Vergara, Ander, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Ander Vergara,

• Jacobs Cachá, Conxita, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Conxita Jacobs Cachá,

• Llorens Cebrià, Carmen, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Carmen Llorens Cebrià,

• Domínguez Báez, Pamela, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Pamela Domínguez Báez,

• Martos, Nerea, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Nerea Martos,

• Martínez Díaz, Irene, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Irene Martínez Díaz,

• Bermejo, Sheila, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Sheila Bermejo,

• Pieper, Michael P., Boehringer Ingelheim Pharma GmbH & Co KG, Biberach an der Riß, Germany

Michael P. Pieper,

• Benito, Begoña, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Begoña Benito,

• Soler, Maria Jose, Vall d'Hebron Institut de Recerca, Barcelona, Catalunya, Spain

Maria Jose Soler,

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 – Boheringer Ingelheim