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Diabetologia

pp 1–10 | Cite as

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

  • Nathalie Esser
  • Sakeneh ZraikaEmail author
Review

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 

Abbreviations

ANP

atrial natriuretic peptide

ARB

angiotensin II receptor blocker

ARNi

angiotensin receptor-neprilysin inhibitor

BNP

B-type natriuretic peptide

DPP-4

dipeptidyl peptidase-4

GLP-1

glucagon-like peptide-1

IAPP

islet amyloid polypeptide

PARADIGM-HF

Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure

RAS

renin–angiotensin system

Notes

Acknowledgements

Due to a limit on the number of references allowed, some publications in this field could not be included. However, these additional publications were important in shaping this review; we apologise to those whose work was not cited directly. We thank S.E. Kahn and R.L. Hull (Department of Medicine, University of Washington) for valuable discussions and feedback during the writing of this manuscript.

Contribution statement

SZ and NE conceived the outline for this review. Both authors reviewed and discussed the relevant literature. NE drafted the review, and both authors revised it critically for important intellectual content. Both authors approved the submitted version.

Funding

The authors’ work in this area is supported by the Department of Veterans Affairs, VA Puget Sound Health Care System (Seattle, WA, USA), Seattle Institute for Biomedical and Clinical Research (Seattle, WA, USA) and National Institutes of Health grants R01 DK098506 (SZ), P30 DK017047 (University of Washington Diabetes Research Center, Seattle, WA, USA). NE is supported by the Baillet-Latour Fund and the Belgian American Educational Foundation, the Belgian Association of Diabetes, the French Society of Diabetes, the Horlait-Dapsens Foundation and the Leon Fredericq Foundation.

Duality of interest

SZ receives research support from Novartis Pharmaceuticals Corporation for preclinical studies.

Supplementary material

125_2019_4889_MOESM1_ESM.pptx (277 kb)
Slideset of figures (PPTX 277 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Veterans Affairs Puget Sound Health Care SystemSeattleUSA
  2. 2.Division of Metabolism, Endocrinology and Nutrition, Department of MedicineUniversity of WashingtonSeattleUSA

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