Sacubitril/Valsartan Augments Postprandial Plasma Concentrations Of Active Glp-1 When Combined With Sitagliptin In Men

Context: Combined inhibition of neprilysin and dipeptidyl peptidase 4 (DPP-4) has been shown to augment plasma concentrations of glucagon-like peptide-1(GLP-1) in animal models, but whether this occurs in humans is unknown.Objective: To investigate the effects of inhibition of neprilysin by sacubitril/valsartan alone or in combination with a DPP-4 inhibitor (sitagliptin) on plasma concentrations of GLP-1 in healthy men.Design: Two open-labeled crossover studies were performed in human subjects.Setting: General community.Participants: Nine and 10 healthy young men were included in study 1 and study 2, respectively.Intervention: Study participants received a standardized meal (34% carbohydrates, 45% fat, 21 % protein; total caloric content, 2106 kJ) combined with a prior dose of either sacubitril/valsartan (194/ 206 mg) or control in study 1 and in study 2, with a prior dose of sitagliptin (2 x100 mg, given similar to 10 hours apart) either alone or with sacubitril/valsartan (194/206 mg).Main Outcome Measures: Plasma concentrations of total and intact GLP-1.Results: Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% [total area under the curve (tAUC)(0-)(240min): 3929 +/- 344 vs 2348 +/- 181 minutes x pmol/L, P = 0.0023] and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (t-AUC(0-)(240min): 1021 +/- 114 vs 660 +/- 80 minutes x pmol/L, P = 0.01). Plasma concentrations of glucose, insulin, and GIP were not significantly (P > 0.10) changed upon sacubitril/valsartan treatment.Conclusions: Sacubitril/valsartan combined with a DPP-4 inhibitor led to markedly higher concentrations of intact GLP-1 than DPP-4 inhibition alone, supporting a role for both neprilysin and DPP-4 in the metabolism of GLP-1 in humans, a finding that may have therapeutic implications.