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Diabetes is an independent risk factor for heart failure. Treatment with a neprilysin inhibitor-angiotensin receptor blocker (sacubitril/valsartan) was demonstrated to improve glycemia and reduce time to initiation of insulin therapy but the underlying mechanism(s) are unknown. We hypothesized that sacubitril/valsartan attenuates neprilysin-dependent degradation of GLP-1, and that combined inhibition of the other enzyme cleaving intact GLP-1, dipeptidyl peptidase 4 (DPP-4), would have synergistic effects on levels of intact GLP-1. In two open-labeled clinical trials, a total of 16 healthy men received a standardized meal (34% carbohydrates, 45% fat, 21% protein) combined with a prior single dose of sacubitril (194mg)/valsartan(206mg), sitagliptin (2x100mg), sacubitril(194mg)/valsartan(206mg) and sitagliptin (2x100mg), or control. Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% and had synergistic effects on intact GLP-1 when combined with sitagliptin. Concentrations of glucose, insulin, and GIP were not significantly changed upon sacubitril/valsartan treatment. Sacubitril/valsartan synergistically protects intact GLP-1 when combined with a DPP-4 inhibitor pointing to a therapeutic potential for the combination in patients with cardiovascular disease and diabetes. Disclosure: N.J. Wewer Albrechtsen: Research Support; Self; Mercodia, Novo Nordisk A/S. Speaker's Bureau; Self; Merck Sharp & Dohme Corp. P.D. Mark: None. L.H. Hansen: None. U.Ø. Andersen: None. B. Hartmann: None. R.D. Carr: Employee; Self; Merck & Co., Inc. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company, Merck & Co., Inc. F. Gustafsson: Advisory Panel; Self; Abbott, Corvia Medical, Inc. Consultant; Self; Bayer AG. Employee; Spouse/Partner; Novo Nordisk A/S. Research Support; Self; Novo Nordisk Foundation. Speaker's Bureau; Self; Novartis AG, Novo Nordisk A/S. C.F. Deacon: Employee; Spouse/Partner; Merck Sharp & Dohme Corp. Stock/Shareholder; Spouse/Partner; Merck & Co., Inc. Other Relationship; Self; Eli Lilly and Company, Merck Sharp & Dohme Corp. J.J. Holst: Advisory Panel; Self; Novo Nordisk A/S. J.P. Gøtze: None. P. Plomgaard: None. Funding: Rigshopitalet [ABSTRACT FROM AUTHOR]