Sacubitril/Valsartan Augments Postprandial Plasma Concentrations of Active GLP-1 When Combined With Sitagliptin in Men

TY - JOUR

T1 - Sacubitril/Valsartan Augments Postprandial Plasma Concentrations of Active GLP-1 When Combined With Sitagliptin in Men

AU - Wewer Albrechtsen, Nicolai J

AU - Mark, Peter D

AU - Terzic, Dijana

AU - Hansen, Lasse H

AU - Andersen, Ulrik Ø

AU - Hartmann, Bolette

AU - Carr, Richard D

AU - Gustafsson, Finn

AU - Deacon, Carolyn F

AU - Holst, Jens J

AU - Goetze, Jens P

AU - Plomgaard, Peter

PY - 2019/9/1

Y1 - 2019/9/1

N2 - 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 3100 mg, given ;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 6 344 vs 2348 6 181 minutes 3 pmol/L, P 5 0.0023] and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0-240min: 1021 6 114 vs 660 6 80 minutes 3 pmol/L, P 5 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.

AB - 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 3100 mg, given ;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 6 344 vs 2348 6 181 minutes 3 pmol/L, P 5 0.0023] and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0-240min: 1021 6 114 vs 660 6 80 minutes 3 pmol/L, P 5 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.

U2 - 10.1210/jc.2019-00515

DO - 10.1210/jc.2019-00515

M3 - Journal article

C2 - 31074791

SN - 0021-972X

VL - 104

SP - 3868

EP - 3876

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 9

ER -