Activation of GLP-1 receptor signalling by sacubitril/valsartan: Implications for patients with poor glycaemic control

ElsevierVolume 367, 15 November 2022, Pages 81-89International Journal of CardiologyHighlights•

ARNIs used in the treatment of HFrEF improves glycemic control.

Augmentation of neprilysin substrate GLP-1 may be responsible.

Additive glycemic effect may arise from dual neprilysin and DPP-4 inhibition.

Vigilant monitoring of glucose required in co-morbid HF and DM patients.

Abstract

Sacubitril/valsartan is a first-in-class Angiotensin Receptor-Neprilysin inhibitor (ARNi) to be approved for the treatment of heart failure with reduced ejection fraction (HFrEF). The combination tablet has become a mainstay of treatment in the management of heart failure (HF) due to its composite inhibition of the neurohumoral system. There is growing support to show that sacubitril/valsartan may enhance glycaemic control through the augmentation of neprilysin substrates – in particular, glucagon-like peptide 1 (GLP-1). Given that HF and Diabetes Mellitus (DM) frequently coexist, with 44% of patients hospitalised with heart failure also having diabetes as a co-morbidity, it is plausible that sacubitril/valsartan may represent a novel way to address glucose intolerance in HF. However, the role of neprilysin in the degradation of GLP-1 raises important clinical considerations such as the risk of hypoglycaemia and potential drug-drug interactions in patients with and without concurrent DM. We review the current body of research addressing the effect of neprilysin inhibition on GLP-1 receptor signalling and discuss the implications for treatment of HF and DM.

Keywords

Diabetes mellitus

Heart failure

Sacubitril/valsartan

Glycaemic control

AbbreviationsACEi

Angiotensin converting enzyme inhibitors

ARNi

Angiotensin Receptor Neprilysin inhibitor

DPP-4

Dipeptidyl peptidase-4

GLP-1

Glucagon-like peptide 1

GSIS

Glucose stimulated insulin secretion

HFrEF

Heart failure with reduced ejection fraction

PARADIGM-HF

Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor with Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure

RAAS

Renin-Angiotensin-Aldosterone System

T2DM

Type 2 Diabetes Mellitus

Crown Copyright © 2022 Published by Elsevier B.V.

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