Augmentation of glucagon‐like peptide‐1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure

Augmentation of glucagon‐like peptide‐1 (GLP‐1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP‐1 and long‐acting GLP‐1 receptor analogues are degraded not only by dipeptidyl peptidase‐4, but also by neprilysin. This observation raises the possibilities that endogenous GLP‐1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin‐based drugs may experience important drug–drug interactions. Specifically, potentiation of GLP‐1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long‐acting GLP‐1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP‐1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP‐1 analogues, the action of neprilysin to enhance the effects of GLP‐1 may be particularly relevant in the brain, where augmentation of GLP‐1 and other endogenous peptides may act to inhibit amyloid‐induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP‐1 and GLP‐1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP‐1 and long‐acting GLP‐1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes.