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

Diabetes Obes Metab. 2022 Oct;24(10):2017-2026. doi: 10.1111/dom.14789. Epub 2022 Jul 21.

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: GLP-1; clinical trial; drug mechanism; glucagon; glycaemic control.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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

Associated data

  • ClinicalTrials.gov/NCT03893526