Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes

Nicolai J Wewer Albrechtsen; Andreas Møller; Christoffer Martinussen; Lise L Gluud; Elias B Rashu; Michael M Richter; Peter Plomgaard; Jens P Goetze; Sasha Kjeldsen; Lasse Holst Hansen; Finn Gustafsson; Carolyn F Deacon; Jens J Holst; Sten Madsbad; Kirstine N Bojsen-Møller

doi:10.1111/dom.14789

Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes

Nicolai J Wewer Albrechtsen, Andreas Møller, Christoffer Martinussen, Lise L Gluud, Elias B Rashu, Michael M Richter, Peter Plomgaard, Jens P Goetze, Sasha Kjeldsen, Lasse Holst Hansen, Finn Gustafsson, Carolyn F Deacon, Jens J Holst, Sten Madsbad, Kirstine N Bojsen-Møller

14 Citationer (Scopus)

Abstract

AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1.

METHODS: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.

RESULTS: Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change.

CONCLUSIONS: The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.

CLINICALTRIALS: gov (NCT03893526).

Originalsprog	Engelsk
Artikelnummer	14789
Tidsskrift	Diabetes, Obesity and Metabolism
Vol/bind	24
Udgave nummer	10
Sider (fra-til)	2017-2026
Antal sider	10
ISSN	1462-8902
DOI	https://doi.org/10.1111/dom.14789
Status	Udgivet - okt. 2022

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10.1111/dom.14789

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Wewer Albrechtsen, N. J., Møller, A., Martinussen, C., Gluud, L. L., Rashu, E. B., Richter, M. M., Plomgaard, P., Goetze, J. P., Kjeldsen, S., Hansen, L. H., Gustafsson, F., Deacon, C. F., Holst, J. J., Madsbad, S., & Bojsen-Møller, K. N. (2022). Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes. Diabetes, Obesity and Metabolism, 24(10), 2017-2026. Artikel 14789. https://doi.org/10.1111/dom.14789

Wewer Albrechtsen, NJ , Møller, A , Martinussen, C , Gluud, LL , Rashu, EB, Richter, MM, Plomgaard, P, Goetze, JP, Kjeldsen, S, Hansen, LH, Gustafsson, F, Deacon, CF, Holst, JJ, Madsbad, S & Bojsen-Møller, KN 2022, 'Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes', Diabetes, Obesity and Metabolism, bind 24, nr. 10, 14789, s. 2017-2026. https://doi.org/10.1111/dom.14789

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title = "Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes",

abstract = "AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1.METHODS: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.RESULTS: Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change.CONCLUSIONS: The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.CLINICALTRIALS: gov (NCT03893526).",

keywords = "clinical trial, drug mechanism, GLP-1, glucagon, glycaemic control",

author = "{Wewer Albrechtsen}, {Nicolai J} and Andreas M{\o}ller and Christoffer Martinussen and Gluud, {Lise L} and Rashu, {Elias B} and Richter, {Michael M} and Peter Plomgaard and Goetze, {Jens P} and Sasha Kjeldsen and Hansen, {Lasse Holst} and Finn Gustafsson and Deacon, {Carolyn F} and Holst, {Jens J} and Sten Madsbad and Bojsen-M{\o}ller, {Kirstine N}",

year = "2022",

month = oct,

doi = "10.1111/dom.14789",

language = "English",

volume = "24",

pages = "2017--2026",

journal = "Diabetes, Obesity and Metabolism",

issn = "1462-8902",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "10",

}

TY - JOUR

T1 - Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes

AU - Wewer Albrechtsen, Nicolai J

AU - Møller, Andreas

AU - Martinussen, Christoffer

AU - Gluud, Lise L

AU - Rashu, Elias B

AU - Richter, Michael M

AU - Plomgaard, Peter

AU - Goetze, Jens P

AU - Kjeldsen, Sasha

AU - Hansen, Lasse Holst

AU - Gustafsson, Finn

AU - Deacon, Carolyn F

AU - Holst, Jens J

AU - Madsbad, Sten

AU - Bojsen-Møller, Kirstine N

PY - 2022/10

Y1 - 2022/10

N2 - AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1.METHODS: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.RESULTS: Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change.CONCLUSIONS: The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.CLINICALTRIALS: gov (NCT03893526).

AB - AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for the treatment of heart failure. Recently, a post-hoc analysis of a 3-year randomized controlled trial showed improved glycaemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a dipeptidyl peptidase-4 inhibitor increases active glucagon-like peptide-1 (GLP-1) in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a dipeptidyl peptidase-4 inhibitor would lower postprandial glucose concentrations (primary outcome) in patients with type 2 diabetes via increased active GLP-1.METHODS: We performed a crossover trial in 12 patients with obesity and type 2 diabetes. A mixed meal was ingested following five respective interventions: (a) a single dose of sacubitril/valsartan; (b) sitagliptin; (c) sacubitril/valsartan + sitagliptin; (d) control (no treatment); and (e) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.RESULTS: Postprandial plasma glucose increased by 57% (incremental area under the curve 0-240 min) (p = .0003) and increased peak plasma glucose by 1.7 mM (95% CI: 0.6-2.9) (p = .003) after sacubitril/valsartan compared with control, whereas postprandial glucose levels did not change significantly after sacubitril/valsartan + sitagliptin. Glucagon, GLP-1 and C-peptide concentrations increased after sacubitril/valsartan, but insulin and glucose-dependent insulinotropic polypeptide did not change.CONCLUSIONS: The glucose-lowering effects of long-term sacubitril/valsartan treatment reported in patients with heart failure and type 2 diabetes may not depend on changes in entero-pancreatic hormones. Neprilysin inhibition results in hyperglucagonaemia and this may explain the worsen glucose tolerance observed in this study.CLINICALTRIALS: gov (NCT03893526).

KW - clinical trial

KW - drug mechanism

KW - GLP-1

KW - glucagon

KW - glycaemic control

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U2 - 10.1111/dom.14789

DO - 10.1111/dom.14789

M3 - Journal article

C2 - 35676803

SN - 1462-8902

VL - 24

SP - 2017

EP - 2026

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

IS - 10

M1 - 14789

ER -

Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes

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