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

Nicolai J Wewer Albrechtsen; Peter D Mark; Dijana Terzic; Lasse H Hansen; Ulrik Ø Andersen; Bolette Hartmann; Richard D Carr; Finn Gustafsson; Carolyn F Deacon; Jens J Holst; Jens P Goetze; Peter Plomgaard

doi:10.1210/jc.2019-00515

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

Nicolai J Wewer Albrechtsen, Peter D Mark, Dijana Terzic, Lasse H Hansen, Ulrik Ø Andersen, Bolette Hartmann, Richard D Carr, Finn Gustafsson, Carolyn F Deacon, Jens J Holst, Jens P Goetze, Peter Plomgaard^*

^*Corresponding author for this work

Abstract

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.

Original language	English
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	104
Issue number	9
Pages (from-to)	3868-3876
ISSN	0021-972X
DOIs	https://doi.org/10.1210/jc.2019-00515
Publication status	Published - 1 Sept 2019

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Wewer Albrechtsen, N. J., Mark, P. D., Terzic, D., Hansen, L. H., Andersen, U. Ø., Hartmann, B., Carr, R. D., Gustafsson, F., Deacon, C. F., Holst, J. J., Goetze, J. P., & Plomgaard, P. (2019). Sacubitril/Valsartan Augments Postprandial Plasma Concentrations of Active GLP-1 When Combined With Sitagliptin in Men. Journal of Clinical Endocrinology and Metabolism, 104(9), 3868-3876. https://doi.org/10.1210/jc.2019-00515

Sacubitril/Valsartan Augments Postprandial Plasma Concentrations of Active GLP-1 When Combined With Sitagliptin in Men. / Wewer Albrechtsen, Nicolai J; Mark, Peter D; Terzic, Dijana et al.
In: Journal of Clinical Endocrinology and Metabolism, Vol. 104, No. 9, 01.09.2019, p. 3868-3876.

Research output: Contribution to journal › Journal article › Research › peer-review

Wewer Albrechtsen, NJ, Mark, PD, Terzic, D, Hansen, LH, Andersen, UØ, Hartmann, B, Carr, RD, Gustafsson, F , Deacon, CF , Holst, JJ , Goetze, JP & Plomgaard, P 2019, 'Sacubitril/Valsartan Augments Postprandial Plasma Concentrations of Active GLP-1 When Combined With Sitagliptin in Men', Journal of Clinical Endocrinology and Metabolism, vol. 104, no. 9, pp. 3868-3876. https://doi.org/10.1210/jc.2019-00515

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

abstract = "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.",

author = "{Wewer Albrechtsen}, {Nicolai J} and Mark, {Peter D} and Dijana Terzic and Hansen, {Lasse H} and Andersen, {Ulrik {\O}} and Bolette Hartmann and Carr, {Richard D} and Finn Gustafsson and Deacon, {Carolyn F} and Holst, {Jens J} and Goetze, {Jens P} and Peter Plomgaard",

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doi = "10.1210/jc.2019-00515",

language = "English",

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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.

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DO - 10.1210/jc.2019-00515

M3 - Journal article

C2 - 31074791

SN - 0021-972X

VL - 104

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JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

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ER -

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

Abstract

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