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
- Diabetes Mellitus and Obesity: Basic - Experimental - II
November 03, 2017 | Location: Hall H, Morial Convention Center
Abstract Time: 10:00 AM - 10:00 AM
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 –