pp 1–10 | Cite as

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

  • Nathalie Esser
  • Sakeneh ZraikaEmail author


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.


GLP-1 Insulin resistance Insulin secretion Neprilysin Obesity Review Type 2 diabetes 



atrial natriuretic peptide


angiotensin II receptor blocker


angiotensin receptor-neprilysin inhibitor


B-type natriuretic peptide


dipeptidyl peptidase-4


glucagon-like peptide-1


islet amyloid polypeptide


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


renin–angiotensin system



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.


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)


  1. 1.
    Roques BP, Noble F, Daugé V et al (1993) Neutral endopeptidase 24.11: structure, inhibition, and experimental and clinical pharmacology. Pharmacol Rev 45(1):87–146PubMedGoogle Scholar
  2. 2.
    Hupe-Sodmann K, McGregor GP, Bridenbaugh R et al (1995) Characterisation of the processing by human neutral endopeptidase 24.11 of GLP-1(7–36) amide and comparison of the substrate specificity of the enzyme for other glucagon-like peptides. Regul Pept 58(3):149–156. CrossRefPubMedGoogle Scholar
  3. 3.
    Plamboeck A, Holst JJ, Carr RD, Deacon CF (2005) Neutral endopeptidase 24.11 and dipeptidyl peptidase IV are both mediators of the degradation of glucagon-like peptide 1 in the anaesthetised pig. Diabetologia 48(9):1882–1890. CrossRefPubMedGoogle Scholar
  4. 4.
    Kenny AJ, Bourne A, Ingram J (1993) Hydrolysis of human and pig brain natriuretic peptides, urodilatin, C-type natriuretic peptide and some C-receptor ligands by endopeptidase-24.11. Biochem J 291(1):83–88. CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    González W, Soleilhac JM, Fournié-Zaluski MC et al (1998) Characterization of neutral endopeptidase in vascular cells, modulation of vasoactive peptide levels. Eur J Pharmacol 345(3):323–331. CrossRefPubMedGoogle Scholar
  6. 6.
    Gafford JT, Skidgel RA, Erdos EG, Hersh LB (1983) Human kidney “enkephalinase”, a neutral metalloendopeptidase that cleaves active peptides. Biochemistry 22(13):3265–3271. CrossRefPubMedGoogle Scholar
  7. 7.
    Orskov C (1992) Glucagon-like peptide-1, a new hormone of the entero-insular axis. Diabetologia 35(8):701–711PubMedGoogle Scholar
  8. 8.
    Mori MA, Sales VM, Motta FL et al (2012) Kinin B1 receptor in adipocytes regulates glucose tolerance and predisposition to obesity. PLoS One 7(9):e44782. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Henriksen EJ, Jacob S, Fogt DL, Dietze GJ (1998) Effect of chronic bradykinin administration on insulin action in an animal model of insulin resistance. Am J Phys 275:R40–R45Google Scholar
  10. 10.
    Moro C (2016) Targeting cardiac natriuretic peptides in the therapy of diabetes and obesity. Expert Opin Ther Targets 20(12):1445–1452. CrossRefPubMedGoogle Scholar
  11. 11.
    Standeven KF, Hess K, Carter AM et al (2011) Neprilysin, obesity and the metabolic syndrome. Int J Obes 35(8):1031–1040. CrossRefGoogle Scholar
  12. 12.
    Willard JR, Barrow BM, Zraika S (2017) Improved glycaemia in high-fat-fed neprilysin-deficient mice is associated with reduced DPP-4 activity and increased active GLP-1 levels. Diabetologia 60(4):701–708. CrossRefPubMedGoogle Scholar
  13. 13.
    Rice GI, Jones AL, Grant PJ et al (2006) Circulating activities of angiotensin-converting enzyme, its homolog, angiotensin-converting enzyme 2, and neprilysin in a family study. Hypertension 48(5):914–920. CrossRefPubMedGoogle Scholar
  14. 14.
    Salazar-Lindo E, Santisteban-Ponce J, Chea-Woo E, Gutierrez M (2000) Racecadotril in the treatment of acute watery diarrhea in children. N Engl J Med 343(7):463–467. CrossRefPubMedGoogle Scholar
  15. 15.
    Jordan J, Stinkens R, Jax T et al (2017) Improved insulin sensitivity with angiotensin receptor neprilysin inhibition in individuals with obesity and hypertension. Clin Pharmacol Ther 101(2):254–263. CrossRefPubMedGoogle Scholar
  16. 16.
    Seferovic JP, Claggett B, Seidelmann SB et al (2017) Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol 5(5):333–340. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Nougué H, Pezel T, Picard F et al (2018) Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study. Eur J Heart Fail. CrossRefGoogle Scholar
  18. 18.
    Arbin V, Claperon N, Fournié-Zaluski MC et al (2001) Acute effect of the dual angiotensin-converting enzyme and neutral endopeptidase 24-11 inhibitor mixanpril on insulin sensitivity in obese Zucker rat. Br J Pharmacol 133(4):495–502. CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Chipkin RE, Kreutner W, Billard W (1984) Potentiation of the hypoglycemic effect of insulin by thiorphan, an enkephalinase inhibitor. Eur J Pharmacol 102(1):151–154. CrossRefPubMedGoogle Scholar
  20. 20.
    Wu HT, Chang CK, Cheng KC et al (2010) Increase of plasma insulin by racecadotril, an inhibitor of enkephalinase, in Wistar rats. Horm Metab Res 42(04):261–267. CrossRefPubMedGoogle Scholar
  21. 21.
    Kristensen SL, Preiss D, Jhund PS et al (2016) Risk related to pre-diabetes mellitus and diabetes mellitus in heart failure with reduced ejection fraction. Circ Heart Fail 9:e002560CrossRefGoogle Scholar
  22. 22.
    Vodovar N, Nougué H, Launay JM et al (2017) Sacubitril/valsartan in PARADIGM-HF. Lancet Diabetes Endocrinol 5(7):495–496. CrossRefPubMedGoogle Scholar
  23. 23.
    Esser N, Barrow BM, Choung E et al (2018) Neprilysin inhibition in mouse islets enhances insulin secretion in a GLP-1 receptor dependent manner. Islets 10(5):175–180. CrossRefPubMedGoogle Scholar
  24. 24.
    Zraika S, Koh DS, Barrow BM et al (2013) Neprilysin deficiency protects against fat-induced insulin secretory dysfunction by maintaining calcium influx. Diabetes 62(5):1593–1601. CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Parilla JH, Hull RL, Zraika S (2018) Neprilysin deficiency is associated with expansion of islet β-cell mass in high fat-fed mice. J Histochem Cytochem 66(7):523–530. CrossRefPubMedGoogle Scholar
  26. 26.
    Wang CH, Leung N, Lapointe N et al (2003) Vasopeptidase inhibitor omapatrilat induces profound insulin sensitization and increases myocardial glucose uptake in Zucker fatty rats. Circulation 107(14):1923–1929. CrossRefPubMedGoogle Scholar
  27. 27.
    Northridge D, Alabaster C, Connell JC et al (1989) Effects of UK 69 578: a novel atriopeptidase inhibitor. Lancet 334(8663):591–593. CrossRefGoogle Scholar
  28. 28.
    Campbell DJ, Anastasopoulos F, Duncan AM et al (1998) Effects of neutral endopeptidase inhibition and combined angiotensin converting enzyme and neutral endopeptidase inhibition on angiotensin and bradykinin peptides in rats. J Pharmacol Exp Ther 287(2):567–577PubMedGoogle Scholar
  29. 29.
    Cuenco J, Minnion J, Tan T et al (2017) Degradation paradigm of the gut hormone, pancreatic polypeptide, by hepatic and renal peptidases. Endocrinology 158(6):1755–1765. CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Becker M, Siems W-E, Kluge R et al (2010) New function for an old enzyme: NEP deficient mice develop late-onset obesity. PLoS One 5(9):e12793. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Davidson E, Coppey L, Lu B et al (2009) The roles of streptozotocin neurotoxicity and neutral endopeptidase in murine experimental diabetic neuropathy. Exp Diabetes Res 2009:431980PubMedGoogle Scholar
  32. 32.
    Coppey L, Lu B, Gerard C, Yorek MA (2012) Effect of inhibition of angiotensin-converting enzyme and/or neutral endopeptidase on neuropathy in high-fat-fed C57Bl/6J mice. J Obes 2012:326806CrossRefGoogle Scholar
  33. 33.
    Simonsen L, Pilgaard S, Carr RD et al (2009) Inhibition of neutral endopeptidase 24.11 does not potentiate the improvement in glycemic control obtained with dipeptidyl peptidase-4 inhibition in diabetic Goto–Kakizaki rats. Horm Metab Res 41(11):851–853. CrossRefPubMedGoogle Scholar
  34. 34.
    Davidson EP, Coppey LJ, Holmes A, Yorek MA (2012) Effect of inhibition of angiotensin converting enzyme and/or neutral endopeptidase on vascular and neural complications in high fat fed/low dose streptozotocin-diabetic rats. Eur J Pharmacol 677(1-3):180–187. CrossRefPubMedGoogle Scholar
  35. 35.
    Davidson EP, Coppey LJ, Dake B, Yorek MA (2011) Effect of treatment of Sprague Dawley rats with AVE7688, enalapril, or candoxatril on diet-induced obesity. J Obes 2011:686952CrossRefGoogle Scholar
  36. 36.
    Lisy O, Jougasaki M, Schirger JA et al (1998) Neutral endopeptidase inhibition potentiates the natriuretic actions of adrenomedullin. Am J Physiol Ren Physiol 275(3):F410–F414. CrossRefGoogle Scholar
  37. 37.
    Martínez A, Weaver C, López J et al (1996) Regulation of insulin secretion and blood glucose metabolism by adrenomedullin. Endocrinology 137(6):2626–2632. CrossRefPubMedGoogle Scholar
  38. 38.
    Rice GI, Thomas DA, Grant PJ et al (2004) Evaluation of angiotensin-converting enzyme (ACE), its homologue ACE2 and neprilysin in angiotensin peptide metabolism. Biochem J 383(1):45–51. CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Brar GS, Barrow BM, Watson M et al (2017) Neprilysin is required for angiotensin-(1–7)’s ability to enhance insulin secretion via its proteolytic activity to generate angiotensin-(1–2). Diabetes 66(8):2201–2212. CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Windeløv JA, Albrechtsen NJ, Kuhre RE et al (2017) Why is it so difficult to measure glucagon-like peptide-1 in a mouse? Diabetologia 60(10):2066–2075. CrossRefPubMedGoogle Scholar
  41. 41.
    Malm-Erjefält M, Bjørnsdottir I, Vanggaard J et al (2010) Metabolism and excretion of the once-daily human glucagon-like peptide-1 analog liraglutide in healthy male subjects and its in vitro degradation by dipeptidyl peptidase IV and neutral endopeptidase. Drug Metab Dispos 38(11):1944–1953. CrossRefPubMedGoogle Scholar
  42. 42.
    Aguilar-Salinas CA, Arellano SA, Villanueva-Sanchez O et al (2001) Effects of omapatrilat on blood pressure and insulin sensitivity in an animal model of insulin resistance. Blood Press 10(3):164–169. CrossRefPubMedGoogle Scholar
  43. 43.
    Arbin V, Claperon N, Fournié-Zaluski MC et al (2003) Effects of dual angiotensin-converting enzyme and neutral endopeptidase 24-11 chronic inhibition by mixanpril on insulin sensitivity in lean and obese Zucker rats. J Cardiovasc Pharmacol 41(2):254–264. CrossRefPubMedGoogle Scholar
  44. 44.
    Kostis JB, Packer M, Black HR et al (2004) Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens 17(2):103–111. CrossRefPubMedGoogle Scholar
  45. 45.
    Messerli FH, Nussberger J (2000) Vasopeptidase inhibition and angio-oedema. Lancet 356(9230):608–609. CrossRefPubMedGoogle Scholar
  46. 46.
    Malek V, Gaikwad AB (2017) Neprilysin inhibitors: a new hope to halt the diabetic cardiovascular and renal complications? Biomed Pharmacother 90:752–759. CrossRefPubMedGoogle Scholar
  47. 47.
    McMurray JJ, Packer M, Desai AS et al (2014) Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 371(11):993–1004. CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Packer M, Claggett B, Lefkowitz MP et al (2018) Effect of neprilysin inhibition on renal function in patients with type 2 diabetes and chronic heart failure who are receiving target doses of inhibitors of the renin-angiotensin system: a secondary analysis of the PARADIGM-HF trial. Lancet Diabetes Endocrinol 6(7):547–554. CrossRefPubMedGoogle Scholar
  49. 49.
    Guan H, Chow KM, Shah R et al (2012) Degradation of islet amyloid polypeptide by neprilysin. Diabetologia 55(11):2989–2998. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Jurgens CA, Toukatly MN, Fligner CL et al (2011) β-cell loss and β-cell apoptosis in human type 2 diabetes are related to islet amyloid deposition. Am J Pathol 178(6):2632–2640. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Zraika S, Aston-Mourney K, Marek P et al (2010) Neprilysin impedes islet amyloid formation by inhibition of fibril formation rather than peptide degradation. J Biol Chem 285(24):18177–18183. CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Aston-Mourney K, Hull RL, Zraika S et al (2011) Exendin-4 increases islet amyloid deposition but offsets the resultant beta cell toxicity in human islet amyloid polypeptide transgenic mouse islets. Diabetologia 54(7):1756–1765. CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Westermark P, Engström U, Johnson KH et al (1990) Islet amyloid polypeptide: pinpointing amino acid residues linked to amyloid fibril formation. Proc Natl Acad Sci 87(13):5036–5040. CrossRefPubMedGoogle Scholar
  54. 54.
    Cannon JA, Shen L, Jhund PS et al (2017) Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction. Eur J Heart Fail 19(1):129–137. CrossRefPubMedGoogle Scholar
  55. 55.
    Iwata N, Tsubuki S, Takaki Y et al (2000) Identification of the major Aβ1–42-degrading catabolic pathway in brain parenchyma: suppression leads to biochemical and pathological deposition. Nat Med 6(2):143–150. CrossRefPubMedGoogle Scholar
  56. 56.
    Campbell DJ (2017) Long-term neprilysin inhibition – implications for ARNIs. Nat Rev Cardiol 14(3):171–186. CrossRefPubMedGoogle Scholar
  57. 57.
    Feldman AM (2016) Neprilysin inhibition in the time of precision medicine. JACC Heart Fail. pii:S2213–1779(16)30049-XGoogle Scholar
  58. 58.
    U.S. Food and Drug Administration (2015) New drug application approval letter. Available from Accessed November 30, 2015
  59. 59.
    Kerr MA, Kenny AJ (1974) The purification and specificity of a neutral endopeptidase from rabbit kidney brush border. Biochem J 137(3):477–488. CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Trebbien R, Klarskov L, Olesen M et al (2004) Neutral endopeptidase 24.11 is important for the degradation of both endogenous and exogenous glucagon in anesthetized pigs. Am J Physiol Endocrinol Metab 287(3):E431–E438. CrossRefPubMedGoogle Scholar
  61. 61.
    Shen R, Milowsky MI, Ozaki N et al (2002) Detection of the p110 beta subunit of phosphatidylinositol 3-kinase complexed with neutral endopeptidase. Anticancer Res 22(5):2533–2538PubMedGoogle Scholar
  62. 62.
    Shipp MA, Tarr GE, Chen CY et al (1991) CD10/neutral endopeptidase 24.11 hydrolyzes bombesin-like peptides and regulates the growth of small cell carcinomas of the lung. Proc Natl Acad Sci U S A 88(23):10662–10666. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Deschodt-Lanckman M, Strosberg AD (1983) In vitro degradation of the C-terminal octapeptide of cholecystokinin by ‘enkephalinase A’. FEBS Lett 152(1):109–113. CrossRefPubMedGoogle Scholar
  64. 64.
    Medeiros MD, Turner AJ (1994) Processing and metabolism of peptide-YY: pivotal roles of dipeptidylpeptidase-IV, aminopeptidase-P, and endopeptidase-24.11. Endocrinology 134(5):2088–2094. CrossRefPubMedGoogle Scholar
  65. 65.
    Skolovsky M, Galron R, Kloog Y et al (1990) Endothelins are more sensitive than sarafotoxins to neutral endopeptidase: possible physiological significance. Proc Natl Acad Sci U S A 87(12):4702–4706. CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Pierart ME, Najdovski T, Appelboom TE, Deschodt-Lanckman MM (1988) Effect of human endopeptidase 24.11 (“enkephalinase”) on IL-1-induced thymocyte proliferation activity. J Immunol 140:3808–3811PubMedGoogle Scholar
  67. 67.
    Sakurada C, Yokosawa H, Ishii S (1990) The degradation of somatostatin by synaptic membrane of rat hippocampus is initiated by endopeptidase-24.11. Peptides 11(2):287–292. CrossRefPubMedGoogle Scholar

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

Personalised recommendations