Acute effects on glucose tolerance by neprilysin inhibition in patients with type 2 diabetes
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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
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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.
N1 - This article is protected by copyright. All rights reserved.
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 -
ID: 311120927