MO617: Liraglutide Improves Both Diabetic Nephropathy and Cardiomyopathy in the SDT Fatty Rat, A Cardiorenal Model of Type 2 Diabetes

Abstract

Abstract BACKGROUND AND AIMS The Glucagon-like peptide 1 (GLP-1) receptor agonist liraglutide (LIRA) has cardioprotective effects and may reduce the development of kidney disease in type 2 diabetic patients. We here evaluated the effects of LIRA on both kidney and heart function in the Spontaneously Diabetic Torii (SDT) fatty rat, a type 2 diabetic cardiorenal model. METHOD SDT fatty male rats were treated subcutaneously with vehicle or LIRA 0.4 mg/kg QD for 10 weeks. To measure the effects of LIRA on glomerular hyperfiltration, rats were injected with FITC-sinistrin to measure glomerular filtration rate (GFR) at 4 weeks of treatment. At 5 weeks of treatment, rats underwent unilateral nephrectomy and were put on a 0.3% salt diet to induce a GFR decline. GFR was then measured at 10 weeks of treatment, before hemodynamics measurement and echocardiography. RESULTS Compared with vehicle, LIRA induced significant body weight loss, as well as blood glucose levels reduction by up to ∼20%. During the hyperfiltration phase, LIRA attenuated hyperfiltration, with a 19% lower GFR versus vehicle (P < 0.05). In vehicle-treated animals, unilateral nephrectomy and 0.3% salt diet induced a major reduction (−56%) in GFR, as expected. After 10 weeks of treatment, LIRA markedly attenuated this GFR decline (vehicle: 9.3 ± 0.5 mL/min/kg; LIRA: 13.3 ± 0.9 mL/min/kg, P < 0.001 versus vehicle). Compared with vehicle, LIRA also lowered urine albumin-to-creatinine ratio both in the hyperfiltration and GFR decline phases, and significantly reduced kidney inflammation and fibrosis histology scores. LIRA showed significant reduction in cardiac hypertrophy, as well as both arterial and left ventricle end-systolic pressures. Moreover, LIRA normalized the diastolic dysfunction with preserved ejection fraction observed in SDT fatty rats (P < 0.001 versus vehicle). CONCLUSION In the SDT fatty rat, LIRA shows significant benefits by reducing renal hyperfiltration, preventing GFR decline, and improving cardiac hypertrophy, blood pressure and diastolic dysfunction. This preclinical model will be useful to evaluate drugs targeting the cardiorenal axis in type 2 diabetes.