Neprilysin inhibition: a new therapeutic option for type 2 diabetes?

Abstract

Neprilysin is a widely expressed peptidase with broad substrate specificity that preferentially hydrolyses oligopeptide substrates, many of which regulate the cardiovascular, nervous and immune systems. Emerging evidence suggests that neprilysin also hydrolyses peptides that play an important role in glucose metabolism. In recent studies in humans, a dual angiotensin receptor-neprilysin inhibitor (ARNi) improved glycaemic control and insulin sensitivity in individuals with type 2 diabetes and/or obesity. Moreover, preclinical studies have also reported that neprilysin inhibition, alone or in combination with renin-angiotensin system blockers, elicits beneficial effects on glucose homeostasis. Since neprilysin inhibitors have been approved for the treatment of heart failure, their repurposing for treating type 2 diabetes would provide a novel therapeutic strategy. In this review, we evaluate existing evidence from preclinical and clinical studies in which neprilysin is deleted/inhibited, we highlight potential mechanisms underlying the beneficial glycaemic effects of neprilysin inhibition, and discuss possible deleterious effects that may limit the efficacy and safety of neprilysin inhibitors in the clinic. We also review the favourable impact neprilysin inhibition can have on diabetic complications, in addition to glucose control. Finally, we conclude that neprilysin inhibitors may be a useful therapeutic option for treating type 2 diabetes; however, their combination with angiotensin II receptor blockers is needed to circumvent deleterious consequences of neprilysin inhibition alone.

Keywords: GLP-1; Insulin resistance; Insulin secretion; Neprilysin; Obesity; Review; Type 2 diabetes.

Fig. 1

Effects of neprilysin inhibition in tissues modulating glucose homeostasis. Neprilysin inhibition improves glucose homeostasis (shaded green) and could induce weight loss (shaded yellow) by increasing levels of several peptides with direct or indirect glucoregulatory properties and anorectic effects. However, neprilysin inhibition may also have detrimental effects in pancreatic islets by increasing levels of substrates that can affect beta cell survival and function or by limiting the ability of angiotensin-(1–7) to promote insulin secretion via its cleavage to angiotensin-(1–2) (shaded pink). The image of the intestine is shaded both yellow and green to indicate that gut incretins impact both glucose homeostasis and body weight. CCK, cholecystokinin; GIP, glucose-dependent insulinotropic peptide; GSIS, glucose-stimulated insulin secretion; PP, pancreatic polypeptide; PYY, peptide YY; VIP, vasoactive intestinal polypeptide. This figure is available as part of a downloadable slideset

Fig. 2

Amino acid sequence of active GLP–1 showing multiple sites of cleavage by neprilysin (blue arrows) vs the only site of cleavage by DPP–4 (green arrow). C-terminal amino acid residues are important for GLP–1 receptor binding, whereas residues 7 and 8 are crucial for GLP–1 receptor activation. The cleavage of GLP–1 by DPP–4 renders the resultant GLP–1(9–36)amide non-insulinotropic, although GLP–1 receptor binding is still possible. GLP–1 cleavage by neprilysin prevents this binding. GLP–1R, glucagon-like peptide-1 receptor; NEP, neprilysin. This figure is available as part of a downloadable slideset