Natriuretic peptide (NP) deficiency and sustained renin-angiotensin systemactivation are associated with impaired oxidative metabolismand predispose to type-2 diabetes. We hypothesized that sacubitril/valsartan (LCZ696), which augments NP through neprilysin inhibition while blocking angiotensin II type-1 (AT1)-receptors, improves insulin sensitivity, lipid mobilization, and oxidation. After 8 weeks of treatment of obese patients with hypertension, sacubitril/valsartan 400mg q.d., but not amlodipine 10 mg q.d., was associated with a significant increase from baseline in the insulin sensitivity index (hyperinsulinemic-euglycemic clamp), and tended to be higher in patients treated with sacubitril/valsartan compared to amlodipine. Abdominal adipose tissue interstitial glycerol concentrations increased with sacubitril/valsartan, but decreased with amlodipine. Whole-body lipolysis and substrate oxidation did not change with either treatment. Results confirm that sacubitril/valsartan treatment leads to ametabolic benefit in the study population and supports the relevance of neprilysin inhibition along with AT1-receptor blockade in the regulation of human glucose and lipid metabolism.