384-P: Comparative Efficacy of Irbesartan and Sotagliflozin in a Nonhuman Primate (NHP) Model of Diabetic Kidney Disease

Introduction and Objective: Renin-angiotensin system (RAS) inhibition has become the standard of care but new agents have emerged in the treatment of diabetic kidney disease (DKD) and its complications. Thus, the efficacy of irbesartan (IB), a RAS inhibitor, and sotagliflozin (SG), a dual SGLT1/2 inhibitor, on renal functional markers was evaluated in the most relevant animal model that closely approximates the human DKD phenotype. Methods:Male cynomolgus monkeys with DKD [fasting blood glucose 281±82 mg/dL; 24h urine albumin creatinine ratio (UACR) 589±340 mg/g; glomerular filtration rate (GFR) 49±20 mL/min/1.73m2] from the high-fat diet NHP colony were selected for the study. Animals were dosed daily by oral gavage for 4 weeks with either vehicle (VH, n=8), IB at 3 mg/kg (n=12), or SG (n=5) at weekly escalating doses of 10, 12 and 14 mg/kg. Serial UACR, GFR and blood pressure (BP) measurements were done. Results:UACR reductions were recorded for both IB and SG groups compared to the VH. Percent changes (%) from baseline of UACR were higher with IB treatment (-34±31 >-3±50 >23±23%; IB>SG>VH) but minimal sustained reductions were noted at the end of the 4-week washout period with SG (-7±53 vs 22±42%; SG vs IB). Marked sustained improvement in GFR was recorded in the SG group (27±16>16±93>9±43 %; SG>IB>VH) at the end of the washout period. Decreases in systolic BP (SBP; -11±8 %) and mean arterial pressure (MAP; -2±14%) were noted with IB during dosing with return to baseline at the end of the washout period. Decreased SBP (-8±8%), diastolic BP (-9±14 %) and MAP (-9±10%) during dosing, which continued until the end of washout, were seen in the SG group. Conclusion:Treatments with IB and SG resulted in improvements in albuminuria and GFR with BP reductions. Sustained effects in renal function were noted with SG implying enhanced renoprotection with SGLT1/2 inhibition in this NHP model which is considered a vital translational model for testing novel interventions for DKD. Disclosure F.P. De Villa: None. R.M. Perez: None. Z.Z. Hua: None. L. Yang: None.