Neprilysin inhibition: a new therapeutic option for type 2 diabetes?
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.
KeywordsGLP-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
islet amyloid polypeptide
Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure
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.
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.
- 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. https://doi.org/10.1016/0167-0115(95)00063-H CrossRefPubMedGoogle Scholar
- 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
- 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. https://doi.org/10.1161/01.HYP.0000244543.91937.79 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/S2213-8587(17)30087-6 CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.1038/sj.bjp.0704098 CrossRefPubMedPubMedCentralGoogle Scholar
- 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. https://doi.org/10.1161/01.CIR.0000062646.09566.CC CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1055/s-0029-1225609 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.ejphar.2011.12.003 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1124/dmd.110.034066 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1097/00005344-200302000-00015 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1016/S2213-8587(18)30100-1 CrossRefPubMedGoogle Scholar
- 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. https://doi.org/10.1007/s00125-011-2143-3 CrossRefPubMedPubMedCentralGoogle Scholar
- 57.Feldman AM (2016) Neprilysin inhibition in the time of precision medicine. JACC Heart Fail. pii:S2213–1779(16)30049-XGoogle Scholar
- 58.U.S. Food and Drug Administration (2015) New drug application approval letter. Available from http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/207620Orig1s000ltr.pdf Accessed November 30, 2015