Effect of Sacubitril/Valsartan vs. Valsartan on Vascular and Neural Complications in Type 2 Diabetic Rats

Abstract

Previously we had shown that a vasopeptidase inhibitor, combination drug containing angiotensin converting enzyme and neprilysin inhibitors, was an effective treatment for diabetes vascular and neural complications. However, once in clinical trials, side effects prevented further development of this class of drugs. This lead to development of sacubitril/valsartan, combination drug similar to vasopeptidase inhibitors containing angiotensin II receptor blocker and neprilysin inhibitor that we hypothesized would be also an effective treatment for diabetic peripheral neuropathy. Using a rat model of type 2 diabetes, early and late intervention protocols, 4 and 12 weeks post hyperglycemia, respectively, rats were treated daily by gavage with valsartan or sacubitril/valsartan for 12 weeks followed by an extensive evaluation of vascular and neural endpoints. The results demonstrated that efficacy of sacubitril/valsartan in improving vascular and neural function was superior to valsartan alone. In the late intervention protocol, treatment of the diabetic rats was initiated well after the appearance of vascular and neural complications. Sacubitril/valsartan treatment was found to not only slow progression of vascular and neural deficits but also stimulate restoration of vascular reactivity, motor and sensory nerve conduction velocities and sensitivity/regeneration of sensory nerves of the skin and cornea. These studies suggest that sacubitril/valsartan may be an effective treatment for diabetic peripheral neuropathy and since it already has FDA approval for treatment of heart failure advancing this drug to clinical trials could proceed quickly. Disclosure M.A. Yorek: None.