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

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

13 Citations (Scopus)

47 Downloads (Pure)

Abstract

AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for treatment of heart failure. Recently, a posthoc analysis of a 3-year RCT showed improved glycemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a DPP-4 inhibitor increases active GLP-1 in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a DPP-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: 1) a single dose of sacubitril/valsartan, 2) sitagliptin, 3) sacubitril/valsartan + sitagliptin, 4) control (no treatment), and 5) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.

RESULTS: Postprandial plasma glucose increased by 57% (iAUC 0-240min ) (P=0.0003) and increased peak plasma glucose by 1.7mM [95% CI: 0.6 - 2.9] (P=0.003) after sacubitril/valsartan compared to 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 GIP 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 hyperglucagonemia and this may explain the worsen glucose tolerance observed in this study. This article is protected by copyright. All rights reserved.

Original language	English
Journal	Diabetes, Obesity and Metabolism
Volume	24
Issue number	10
Pages (from-to)	2017-2026
Number of pages	10
ISSN	1462-8902
DOIs	https://doi.org/10.1111/dom.14789
Publication status	Published - 2022

Bibliographical note

Access to Document

10.1111/dom.14789Licence: CC BY-NC

FulltextFinal published version, 1.41 MBLicence: CC BY-NC

Cite this

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. https://doi.org/10.1111/dom.14789

Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes. / Wewer Albrechtsen, Nicolai J; Møller, Andreas; Martinussen, Christoffer; Gluud, Lise L.; Rashu, Elias B.; Richter, Michael M.; Plomgaard, Peter ; Goetze, Jens P.; Kjeldsen, Sasha; Hansen, Lasse Holst; Gustafsson, Finn ; Deacon, Carolyn F ; Holst, Jens J ; Madsbad, Sten; Bojsen-Møller, Kirstine N.

In: Diabetes, Obesity and Metabolism, Vol. 24, No. 10, 2022, p. 2017-2026.

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

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, vol. 24, no. 10, pp. 2017-2026. https://doi.org/10.1111/dom.14789

Wewer Albrechtsen, Nicolai J ; Møller, Andreas ; Martinussen, Christoffer ; Gluud, Lise L. ; Rashu, Elias B. ; Richter, Michael M. ; Plomgaard, Peter ; Goetze, Jens P. ; Kjeldsen, Sasha ; Hansen, Lasse Holst ; Gustafsson, Finn ; Deacon, Carolyn F ; Holst, Jens J ; Madsbad, Sten ; Bojsen-Møller, Kirstine N. / Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes. In: Diabetes, Obesity and Metabolism. 2022 ; Vol. 24, No. 10. pp. 2017-2026.

@article{45d721575c2e45de87de0e8ebac5c961,

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 treatment of heart failure. Recently, a posthoc analysis of a 3-year RCT showed improved glycemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a DPP-4 inhibitor increases active GLP-1 in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a DPP-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: 1) a single dose of sacubitril/valsartan, 2) sitagliptin, 3) sacubitril/valsartan + sitagliptin, 4) control (no treatment), and 5) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.RESULTS: Postprandial plasma glucose increased by 57% (iAUC 0-240min ) (P=0.0003) and increased peak plasma glucose by 1.7mM [95% CI: 0.6 - 2.9] (P=0.003) after sacubitril/valsartan compared to 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 GIP 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 hyperglucagonemia and this may explain the worsen glucose tolerance observed in this study. This article is protected by copyright. All rights reserved.",

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",

doi = "10.1111/dom.14789",

language = "English",

volume = "24",

pages = "2017--2026",

journal = "Diabetes, Obesity and Metabolism",

issn = "1462-8902",

publisher = "Wiley-Blackwell",

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

Y1 - 2022

N2 - AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for treatment of heart failure. Recently, a posthoc analysis of a 3-year RCT showed improved glycemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a DPP-4 inhibitor increases active GLP-1 in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a DPP-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: 1) a single dose of sacubitril/valsartan, 2) sitagliptin, 3) sacubitril/valsartan + sitagliptin, 4) control (no treatment), and 5) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.RESULTS: Postprandial plasma glucose increased by 57% (iAUC 0-240min ) (P=0.0003) and increased peak plasma glucose by 1.7mM [95% CI: 0.6 - 2.9] (P=0.003) after sacubitril/valsartan compared to 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 GIP 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 hyperglucagonemia and this may explain the worsen glucose tolerance observed in this study. This article is protected by copyright. All rights reserved.

AB - AIMS: Sacubitril/valsartan is a neprilysin-inhibitor/angiotensin II receptor blocker used for treatment of heart failure. Recently, a posthoc analysis of a 3-year RCT showed improved glycemic control with sacubitril/valsartan in patients with heart failure and type 2 diabetes. We previously reported that sacubitril/valsartan combined with a DPP-4 inhibitor increases active GLP-1 in healthy individuals. We now hypothesized that administration of sacubitril/valsartan with or without a DPP-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: 1) a single dose of sacubitril/valsartan, 2) sitagliptin, 3) sacubitril/valsartan + sitagliptin, 4) control (no treatment), and 5) valsartan alone. Glucose, gut and pancreatic hormone responses were measured.RESULTS: Postprandial plasma glucose increased by 57% (iAUC 0-240min ) (P=0.0003) and increased peak plasma glucose by 1.7mM [95% CI: 0.6 - 2.9] (P=0.003) after sacubitril/valsartan compared to 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 GIP 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 hyperglucagonemia and this may explain the worsen glucose tolerance observed in this study. This article is protected by copyright. All rights reserved.

U2 - 10.1111/dom.14789

DO - 10.1111/dom.14789

M3 - Journal article

C2 - 35676803

VL - 24

SP - 2017

EP - 2026

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

SN - 1462-8902

IS - 10

ER -