1370-P: Semaglutide Demonstrates Cardiorenal Benefits in the SDT Fatty Rat, a New Model of Cardiovascular–Kidney–Metabolic Syndrome

Introduction and Objective: The high prevalence of cardiovascular-kidney-metabolic (CKM) syndrome in the population requires novel therapeutics to reduce cardiovascular death, and to this aim, predictive animal models are needed. Here we evaluated the effects of the GLP-1 receptor agonist semaglutide (SEMA) on kidney dysfunction and left ventricle diastolic dysfunction in the Spontaneously Diabetic Torii (SDT) fatty rat, a new type 2 diabetic animal model of CKM syndrome. Methods: Male, 6-week-old SDT fatty rats were treated with vehicle or SEMA 15 nmol/kg s.c. Q3D for 12 weeks. At 6 weeks and 12 weeks of treatment, urine parameters and glomerular filtration rate (GFR) were measured, and cardiac function was investigated by echocardiography. Results: Compared to vehicle, SEMA significantly reduced body weight, %HbA1c and blood glucose levels. Vehicle-treated SDT fatty rats showed hyperfiltration with high GFR values at treatment start and at 6 weeks of treatment, followed by a marked GFR decline (-47%) at 12 weeks. After 6 weeks of treatment, SEMA significantly improved hyperfiltration with a 25 % reduction in GFR (p<0.05 vs. vehicle), while it limited the GFR decline (-27%) at 12 weeks. Additionally, SEMA significantly lowered albuminuria and proteinuria at both 6 and 12 weeks of treatment. Echocardiography performed at 6 and 12 weeks of treatment demonstrated that SEMA did not alter left ventricle ejection fraction but improved diastolic dysfunction of SDT fatty rats. SEMA reduced left ventricle dilation with lower left ventricle internal diameter and significantly reduced end-diastolic volume. A positive effect was observed on cardiac hypertrophy with significant reduction in left ventricle wall thickness and heart weight. Additionally, SEMA significantly lowered the E/E’ ratio, increased E’/A’ ratio, and reduced isovolumic relaxation time. Conclusion: SEMA demonstrates cardiorenal benefits in the SDT fatty rat. This model will be useful to evaluate novel therapies targeting CKM syndrome versus SEMA as standard of care. Disclosure F. Briand: Employee; Current; PHYSIOGENEX. Stock/Shareholder; Current; PHYSIOGENEX. G. Bourdier: None. E. Grasset: None. M. Shinohara: None. R. Assaly: Employee; Current; Cardiomedex. C. Dubroca: None. T. Sulpice: None.