Abstract: FR-PO592

Dapagliflozin Alone or Combined with Ramipril Improves Hyperglycemia and Hypertension and Prevents Kidney Complications and GFR Decline in the Nephrectomized SDT Fatty Rat Model of Diabetic Nephropathy

Session Information

Category: Diabetes

  • 501 Diabetes Mellitus and Obesity: Basic - Experimental

Authors

  • Briand, Francois, PHYSIOGENEX, LABEGE, France
  • Shinohara, Masami, CLEA Japan, Inc., Meguro, Japan
  • Brousseau, Emmanuel, PHYSIOGENEX, LABEGE, France
  • Ohta, Takeshi, Japan Tobacco Inc., Osaka, Japan
  • Kageyama, Yasushi, CLEA Japan, Inc., Meguro, Japan
  • Sulpice, Thierry, PHYSIOGENEX, LABEGE, France
Background

Combination of sodium glucose cotransporter 2 inhibitor (SGLT2i) and angiotensin converting enzyme inhibitor (ACEi) represents a potential therapeutic strategy to prevent diabetic nephropathy progression to end stage renal disease (ESRD). Here we evaluated SGLT2i dapagliflozin (DAPA) alone or combined with ACEi ramipril (RAMI) in the uni-nephrectomized Spontaneously Diabetic Torii (SDT) fatty rat. This hypertensive/obese/type 2 diabetic model develops advanced renal complications and >50% glomerular filtration rate (GFR) decline within 10 weeks.

Methods

One week after unilateral nephrectomy, SDT fatty rats were put on a chow diet with 0.3% salt in drinking water for 10 weeks. Rats were treated without (CTRL) or with DAPA 1mg/kg/day alone or with DAPA + RAMI both at 1mg/kg/day in the diet upon diet start (10-week treatment).

Results

Compared to CTRL, DAPA reduced hyperglycemia by 70%, and % HbA1c by 4.7% (both p<0.001). DAPA reduced systolic and diastolic blood pressure by 17 and 14% (both p<0.05). While CTRL rats showed a 64% GFR decline (as measured by FITC-inulin injection) at 5 weeks of treatment, DAPA markedly prevented this decline with a 71% higher GFR vs. CTRL (p<0.01). At the end of the 10-week treatment, DAPA significantly reduced glomerulosclerosis, inflammation and fibrosis histopathology scores. However, GFR values were not different between CTRL and DAPA, even after a wash-out period, excluding a tubuloglomerular feedback effect.
As DAPA alone, DAPA + RAMI reduced hyperglycemia by 74%, and % HbA1c by 4.7% (both p<0.001 vs. CTRL). DAPA + RAMI further reduced systolic and diastolic blood pressure by 29 and 24% (both p<0.01 vs. CTRL). As well, DAPA + RAMI prevented GFR decline at 5 weeks of treatment (39% higher, p<0.05), but also at 10 weeks of treatment (63% higher, p<0.05 vs. CTRL).

Conclusion

In the 10-week Unx SDT fatty rat, DAPA alone prevents kidney complications, while the combination with RAMI adds benefits by better delaying GFR decline. Our data suggest that SGLT2i/ACEi combination prevents progression to ESRD.

Funding

  • Commercial Support