COMBINING RENIN-ANGIOTENSIN SYSTEM (RAS) BLOCKADE AND SODIUM-GLUCOSE COTRANSPORTER-2 (SGLT2) INHIBITION IN EXPERIMENTAL DIABETES RESULTS IN SYNERGISTIC BENEFICIAL EFFECTS

Abstract

Objective: To study the combined effect of RAS blockade and SGLT2i in experimental diabetes. Design and method: TGR (mREN2)27 rats (a model of angiotensin II-dependent hypertension) were made diabetic with streptozotocin for 12 weeks and treated with either vehicle, the angiotensin receptor blocker valsartan (VAL: 4 mg/kg/day), the SGLT2 inhibitor empagliflozin (EMPA: 10 mg/kg/day) or their combination during the final 3 weeks. Mean arterial blood pressure (MAP) was measured by telemetry. Results: MAP before treatment was 120 ± 14 mm Hg. Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate (GFR). EMPA did not lower MAP, while VAL did (by 29 ± 7 mm Hg), and when combined the MAP drop was largest (44 ± 6 mm Hg). Only EMPA+VAL reduced the heart weight/tibia length ratio (P = 0.04 vs. vehicle). VAL, but not EMPA, increased plasma renin, and the largest renin rise was observed during EMPA+VAL (P < 0.0001 vs. vehicle) Although both VAL and EMPA alone tended to diminish albuminuria, the reduction was significant (P = 0.01 vs. vehicle) only when both drugs were combined (vehicle, VAL, EMPA and EMPA+VAL 108 ± 18, 89 ± 24, 55 ± 8 and 26 ± 6 ug/mL, respectively). This was accompanied by a reduction in glomerulosclerosis index and no change in GFR. EMPA either alone or in combination with VAL increased water intake and urine production and induced urinary glucose loss, and as a consequence reduced blood glucose and body weight. Renal expression of the fibrosis and inflammatory markers TIMP2, collagen 1alpha 1, fibronectin, Neph1, nephrin was lowest in the dual treatment group. Conclusions: RAS blockade and SGLT2i display synergistic beneficial effects on blood pressure, kidney jury and cardiac hypertrophy in a rat with hypertension and diabetes.