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).

• Authors: 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
• Journal: Diabetes, obesity & metabolism (Diabetes Obes Metab) Vol. 24 Issue 10 Pg. 2017-2026 (10 2022) ISSN: 1463-1326 [Electronic] England
• PMID: 35676803 (Publication Type: Clinical Trial, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Chemical References

• Aminobutyrates
• Angiotensin Receptor Antagonists
• Biphenyl Compounds
• Blood Glucose
• Dipeptidyl-Peptidase IV Inhibitors
• Drug Combinations
• Hypoglycemic Agents
• Tetrazoles
• sacubitril
• Valsartan
• Glucagon-Like Peptide 1
• Neprilysin
• Sitagliptin Phosphate

Topics

• Aged
• Aminobutyrates (therapeutic use)
• Angiotensin Receptor Antagonists (therapeutic use)
• Biphenyl Compounds (therapeutic use)
• Blood Glucose (analysis, drug effects)
• Diabetes Mellitus, Type 2 (complications, drug therapy)
• Dipeptidyl-Peptidase IV Inhibitors (therapeutic use)
• Drug Combinations
• Glucagon-Like Peptide 1 (blood)
• Glucose Tolerance Test
• Heart Failure (complications, drug therapy)
• Humans
• Hypoglycemic Agents (therapeutic use)
• Male
• Middle Aged
• Neprilysin (antagonists & inhibitors)
• Sitagliptin Phosphate (therapeutic use)
• Tetrazoles (therapeutic use)
• Valsartan (therapeutic use)