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Abstract: PO0720

Added Benefit of SGLT-2 Inhibitor with ACE Inhibition in a Mouse Model of Severe Diabetic Nephropathy

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Kota, Savithri B., Janssen Research and Development LLC, Boston, New Jersey, United States
  • Chipashvili, Vaja, Janssen Research and Development LLC, Boston, New Jersey, United States
  • Farrington, Krista P., Janssen Research and Development LLC, Boston, New Jersey, United States
  • Zheng, Gang, Janssen Research and Development LLC, Boston, New Jersey, United States
  • Chen, Tao, Janssen Research and Development LLC, Boston, New Jersey, United States
  • Klass, Maria, Janssen Research and Development LLC, Boston, New Jersey, United States
  • Gao, Bin, Janssen Research and Development LLC, Boston, New Jersey, United States
  • Gonzalez-Villalobos, Romer Andres, Janssen Research and Development LLC, Boston, New Jersey, United States
  • Magnone, Maria chiara, Janssen Research and Development LLC, Boston, New Jersey, United States
  • Breyer, Matthew Douglas, Janssen Research and Development LLC, Boston, New Jersey, United States
Background

The clinical success of sodium glucose cotransporter 2 inhibitor (SGLT2i) for the treatment of diabetic kidney disease (DKD) has ushered in a new phase in the discovery and development of novel drugs for DKD. As the development of SGLT2i did not follow the traditional drug discovery paradigm exemplified by testing efficacy in a relevant preclinical model, here we present the evaluation of combinatorial therapy of SGLT2i and standard of care in the hypertensive Renin AAV db/db uninephrectomy mouse model of severe DKD.

Methods

Severe DKD was established by AAV mediated hepatic overexpression of renin in uninephrectomized db/db mice. Mice were treated with Lisinopril (ACEi) in drinking water and SGLT2i (JNJ39933673) in diet, at a dose of 5 mpk for 8 weeks. Study groups included untreated DKD control (N=11), Lisinopril treated (N=11), Lisinopril + SGLT2i treated (N=11) and LacZ AAV control (N=10).

Results

SGLT2i significantly reduced blood glucose levels upon treatment inception (Day-3 vs. Day 4; 465.1+33.1 vs. 258.7+24.8; mean + sem, mg/dl, p=0.001). ACEi reduced systolic blood pressure by 21 mm of Hg within 2 weeks of treatment (p=0.02), which was further reduced by 20 mm of Hg by SGLT2i co-treatment on week 7 (p=0.03). While ACEi treatment alone reduced UACR by 15% to 35% below baseline, dual treatment with SGLT2i led to a reduction of UACR by 49% to 67% during the 8 weeks treatment phase (p= n.s), leaving a residual albuminuria of 5561 ug/mg. Plasma creatinine doubled during the study period and was blunted only by ACEi+SGLT2i (No treatment vs. ACEi+SGLT2i; 0.38+0.06 vs. 0.24+0.02; mean ± sem; mg/dl, p=n.s). Histological assessments revealed additive benefits of ACEi+SGLT2i, in measures of glomerular, vascular and tubulointerstitial lesions. Reduced plasma levels of sTnfr1 reflected therapeutic benefits of SGLT2i on top of ACEi.

Conclusion

Our study demonstrates the possibility of testing combinatorial therapies in this translational preclinical model of severe DKD. Residual injury in ACEi+SGLT2i animals should enable testing of novel agents in this model on this new standard of care for CKD.

Funding

  • Commercial Support –