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J Clin Endocrinol Metab. 2019 May 10. pii: jc.2019-00515. doi: 10.1210/jc.2019-00515. [Epub ahead of print]

Sacubitril/valsartan augments postprandial plasma concentrations of active GLP-1 when combined with sitagliptin in men.

Author information

1
Department of Clinical Biochemistry, University of Copenhagen, Copenhagen, Denmark.
2
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
3
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
4
Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
5
MSD, Copenhagen, Denmark.
6
University College London, London, UK.
7
Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
8
Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

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 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.

PMID:
31074791
DOI:
10.1210/jc.2019-00515

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