#4581 evaluation of the beneficial effects of sglt2 inhibitors and glp-1 receptor agonist on top of ras blockade in experimental diabetic nephropathy

Abstract Background and Aims Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and some glucagon-like-1 receptor agonists (GLP1-RA) have demonstrated to delay diabetic nephropathy (DN) progression. Potentially, the combination of these two therapeutic approaches on top of the standard of care with renin angiotensin system (RAS) blockers could exert additive cardiorenal protection in the diabetic milieu. The present study aimed to evaluate the cardiorenal protective effects of the combination of SGLT2i and GLP1-RA on top of RAS blockade versus the monotherapies on top of RAS blockade in experimental diabetes. Method Twelve weeks old male and female uninefrectomized (UNx) db/db mice were treated for 8 weeks with an SGLT2i (empagliflozin, 10 mg/Kg/day five days a week) and/or a GLP1-RA (semaglutide, 10.0 nmol/kg twice per week) on top of a RAS blocker (ramipril, 8 mg/Kg/day). Vehicle-treated UNx db/db and non-diabetic (db/m) mice were included as controls. During the experiment weight, food and water intake, blood glucose, blood pressure (BP) and glomerular filtration rate (GFR) were measured. Kidney and heart were collected at the end of the experiment. Results The vehicle-treated UNx db/db showed increased body weight, food and water intake and blood glucose as compared to the vehicle-treated UNx db/m (Fig. 1A, B and C, p = 0.03, p<0.001 and p<0.0001, respectively). The GFR slope (ΔGFR, difference between final and basal GFR) was also significantly higher in the vehicle-treated UNx db/db vs the vehicle-treated UNx db/m (Fig. 1D, p = 0.02), a typical feature of incipient DN. All treatments significantly decreased systolic and diastolic BP as compared to vehicle-treated UNx db/db due to its ramipril component (Fig. 1E). Further, both empagliflozin and semaglutide (alone or combined) on top of ramipril lowered blood glucose in UNx db/db (Fig. 1C, p<0.001 vs vehicle UNx db/db in all cases) but semaglutide component maximized this effect. Food and water intake was decreased in UNx db/db treated with semaglutide on top of RAS blockade (alone or combined with empagliflozin) as compared to vehicle-treated UNx db/db (Fig. 1B) although no differences in body weight were noted between treated and untreated UNx db/db (Fig. 1A). A trend towards ΔGFR decline was observed in UNx db/db treated with empagliflozin and semaglutide on top of RAS blockade (Fig. 1D). Finally, heart weight but not kidney weight was significantly lower in all treated UNx db/db as compared to vehicle-treated UNx db/db (Fig. 1F). Conclusion Our preliminary results show that addition of semaglutide to empagliflozin therapy on top of RAS blockade could have synergic hypoglycemic effects. Further, although more research is needed, both empagliflozin and semaglutide in combination with ramipril trended to ameliorate diabetic hyperfiltration and decreased heart weight in a DN mouse model which suggests cardiorenal beneficial effects.