Back
Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and some glucagon-like-1 receptor agonist (GLP1-RA) have demonstrated to delay diabetic nephropathy (DN) progression. Potentially, the combination of these two drug classes on top of the standard of care with renin angiotensin system blockade (RASi) could exert additive renal protection. We aimed to evaluate the cardiorenal protective effects of the combination of SGLT2i and GLP1-RA on top of RASi versus the monotherapies in experimental diabetes.
Uninefrectomized (UNx) twelve weeks old male and female 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 RASi (ramipril, 8 mg/Kg/day). Vehicle-treated UNx db/db and non-diabetic (db/m) UNx mice were included as controls. Body weight (BW), blood glucose (BG), blood pressure (BP), glomerular filtration rate (GFR) and urine albumin-to-creatinine ratio (UACR) were measured. Kidney was collected at the end of the experiment for histological examination.
After 8 weeks of treatment, the vehicle-treated UNx db/db showed increased BW, BG and food and water intake as compared to the vehicle-treated UNx db/m (Figure 1A and 1B, p=0.002 and p<0.001). Treatment with empagliflozin or semaglutide did not affect BW but both drugs reduced BG showing a greater effect when combined (mean glucose 322, 304 and 209 mg/dL at the end of treatment for empagliflozin, semaglutide and their combination). All treatments significantly decreased mean BP as compared to vehicle-treated UNx db/db due to its ramipril component (Fig 1C). GFR and UACR were higher at the end of the experiment in the vehicle-treated UNx db/db compared to UNx db/m (395 μL/100g/min higher GFR, p<0.001, and 6578 μg/mg higher UACR, p<0.001) (Figure 1D and 1E). Only empagliflozin alleviated diabetic hyperfiltration but this effect was only significant in male mice receiving the combination (237 μL/100g/min lower compared to UNx db/db, p=0.049). Additionally, semaglutide or its combination with empagliflozin on top of RASi reduced UACR. Both empagliflozin and semaglutide were able to restore glomerular podocyte density, but only the combination of both drugs was able to reduce glomerular mesangial matrix expansion (p=0.001) (Figure 1F).
Our preliminary results show that the addition of semaglutide to empagliflozin therapy on top of RASi has a synergistic effect in BG and glomerular mesangial matrix expansion reduction. Further, only empagliflozin shows protective effects against diabetic hyperfiltration, which seems to be more evident in male mice and increased by the addition of semaglutide.