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

Y1 - 2019

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 males 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 of 2106kJ) combined with a prior dose of either sacubitril/valsartan (194/206mg) or control in study 1, and in study 2, with a prior dose of sitagliptin (2x100mg, given ∼10 hours apart) either alone or with sacubitril/valsartan (194/206mg).MAIN OUTCOME MEASURES: Plasma concentrations of total and intact GLP-1.RESULTS: Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% (tAUC0-240min: 3929±344 vs. 2348±181 min × pmol/L P=0.0023), and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0-240min: 1021±114 vs. 660±80 min × 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 lead 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 which 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 males 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 of 2106kJ) combined with a prior dose of either sacubitril/valsartan (194/206mg) or control in study 1, and in study 2, with a prior dose of sitagliptin (2x100mg, given ∼10 hours apart) either alone or with sacubitril/valsartan (194/206mg).MAIN OUTCOME MEASURES: Plasma concentrations of total and intact GLP-1.RESULTS: Sacubitril/valsartan increased postprandial plasma concentrations of total GLP-1 by 67% (tAUC0-240min: 3929±344 vs. 2348±181 min × pmol/L P=0.0023), and increased concentrations of intact GLP-1 plasma concentrations more than sitagliptin alone (tAUC0-240min: 1021±114 vs. 660±80 min × 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 lead 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 which may have therapeutic implications.

U2 - 10.1210/jc.2019-00515

DO - 10.1210/jc.2019-00515

M3 - Journal article

C2 - 31074791

VL - 104

SP - 3868

EP - 3876

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 9

ER -