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.