Treatment with Either SGLT2 Inhibitors or GLP-1 Receptor Agonists Rescues GFR Decline in a Multifactorial Cardiovascular-Kidney-Metabolic Syndrome Mouse Model

Background: A multifactorial diet-induced hypertension-accelerated mouse model with obesity, diabetes and hypertension was developed which results in diabetic and chronic kidney disease (DKD/CKD) and heart failure with preserved ejection fraction (HFpEF). Therapeutic efficacy of standard-of-care therapy with either the ACE-inhibitor Lisinopril, the SGLT2-inhibitor Dapagliflozin or the GLP1 receptor agonist Semaglutide was studied on kidney function and cardiac pathology. Methods: Male KKAy mice underwent uninephrectomy (UNX). After recovery mice received high fat diet (45%LARD) and 50 mg/L LNNA in drinking water (wk0). At week 4, mice recieved either Lisinopril (2.5 mg/kg/day in drinking water), Dapagliflozin (5 mg/kg/day food ad-mix) or Semaglutide (0.12 mg/kg/day subcutaneous injections). Body weight, blood glucose, food and water intake and albuminuria were determined regularly. GFR was measured transdermally by FITC-sinistrin clearance. Mice were terminated at week 16 and kidney and cardiac histology was scored. Non-induced and induced non-treated mice were used as controls. Results: Treatment of KKAy mice on HFD+LNNA with Dapagliflozin increased water intake and reduced blood glucose immediately. GFR decline was reduced at week 12. Treatment with Semaglutide immediately decreased body weight to non-induced control levels. Food and water intake were reduced as was blood glucose. GFR decline was reduced at week 12. Body mass composition at week 6 showed a large significant decrease in fat mass and to a lesser extent a decrease in lean mass upon Semaglutide treatment. Treatment with Lisinopril did not have effect on either body weight, blood glucose nor GFR compared to untreated controls. Pathological scoring is ongoing. Conclusion: Male KKAy mice on HFD and LNNA developed DKD resulting in CKD and HFpEF. Treatment with either Dapagliflozin or Semaglutide rescued GFR decline and lowered blood glucose levels. Semaglutide also reduced body weight gain. These effects of the standard-of-care compounds indicates the clinal relevance of the model demonstrating that it is suitable for compound efficacy studies in both early and more advanced stages of CKM syndrome.