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

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.