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

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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 languageEnglish
JournalDiabetes, Obesity and Metabolism
Issue number10
Pages (from-to)2017-2026
Number of pages10
Publication statusPublished - 2022

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This article is protected by copyright. All rights reserved.

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