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

Neprilysinis a widely expressed peptidase with broad substrate specificity that preferentially hydrolyses oligopeptidesubstrates, many of which regulate the cardiovascular, nervous and immune systems. Emerging evidence suggests that neprilysinalso hydrolyses peptides that play an important role in glucose metabolism. In recent studies in humans, a dual angiotensin receptor– neprilysininhibitor (ARNi) improved glycaemic control and insulin sensitivity in individuals with type 2 diabetes and/or obesity. Moreover, preclinical studies have also reported that neprilysininhibition, alone or in combination with renin–angiotensin systemblockers, elicits beneficial effects on glucose homeostasis. Since neprilysininhibitors have been approved for the treatment of heart failure, their repurposingfor treating type 2 diabetes would provide a novel therapeutic strategy. In this review, we evaluate existing evidence from preclinical and clinical studies in which neprilysinis deleted/inhibited, we highlight potential mechanisms underlying the beneficial glycaemic effects of neprilysininhibition, and discuss possible deleterious effects that may limit the efficacy and safety of neprilysininhibitors in the clinic. We also review the favourable impact neprilysininhibition can have on diabetic complications, in addition to glucose control. Finally, we conclude that neprilysininhibitors 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 neprilysininhibition alone.