期刊
DIABETES OBESITY & METABOLISM
卷 24, 期 10, 页码 2017-2026出版社
WILEY
DOI: 10.1111/dom.14789
关键词
clinical trial; drug mechanism; GLP-1; glucagon; glycaemic control
资金
- Det Frie Forskningsrad [1052-00003B]
- Diabetesforeningen
- European Foundation for the Study of Diabetes [NNF21SA0072746]
- Hjerteforeningen [20-R141-A9782-22172]
- Novo Nordisk Fonden [NNF14CC0001, NNF18OC0032330, NNF19OC0055001]
- Novo Nordisk Fonden [NNF18OC0032330, NNF14CC0001] Funding Source: researchfish
In patients with obesity and type 2 diabetes, the use of Sacubitril/valsartan may lower postprandial glucose concentrations by increasing active GLP-1. However, neprilysin inhibition may lead to hyperglucagonemia and worsen glucose tolerance.
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).
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