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  • Review Article
  • Published:

Long-term neprilysin inhibition — implications for ARNIs

Nature Reviews Cardiology volume 14, pages 171–186 (2017)Cite this article

Subjects

This article has been updated

Key Points

  • The approval of LCZ696 for the treatment of heart failure with reduced ejection fraction is the first for chronic neprilysin inhibitor therapy

  • Neprilysin contributes to the formation and degradation of many bioactive peptides and, therefore, chronic neprilysin inhibitor therapy has not only potential benefits but also potential adverse effects

  • By inhibiting the degradation of bradykinin and other inflammatory peptides, neprilysin inhibitor therapy might promote angio-oedema, bronchoconstriction, and inflammation, and might promote cancer by inhibiting the degradation of mitogenic peptides

  • Neprilysin might have a role in metabolizing amyloid-β peptides and by inhibiting amyloid-β degradation, neprilysin inhibition might predispose to diseases related to amyloid-β deposition such as Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy

  • Neprilysin inhibition might also predispose to late-onset sensorimotor axonal polyneuropathy

  • Evidence suggesting potential adverse consequences of chronic neprilysin inhibition come mostly from animal models and whether this evidence applies to humans is unknown; nevertheless, we need to be vigilant in the use of chronic neprilysin inhibitor therapy

Abstract

Neprilysin has a major role in both the generation and degradation of bioactive peptides. LCZ696 (valsartan/sacubitril, Entresto), the first of the new ARNI (dual-acting angiotensin-receptor–neprilysin inhibitor) drug class, contains equimolar amounts of valsartan, an angiotensin-receptor blocker, and sacubitril, a prodrug for the neprilysin inhibitor LBQ657. LCZ696 reduced blood pressure more than valsartan alone in patients with hypertension. In the PARADIGM-HF study, LCZ696 was superior to the angiotensin-converting enzyme inhibitor enalapril for the treatment of heart failure with reduced ejection fraction, and LCZ696 was approved by the FDA for this purpose in 2015. This approval was the first for chronic neprilysin inhibition. The many peptides metabolized by neprilysin suggest many potential consequences of chronic neprilysin inhibitor therapy, both beneficial and adverse. Moreover, LBQ657 might inhibit enzymes other than neprilysin. Chronic neprilysin inhibition might have an effect on angio-oedema, bronchial reactivity, inflammation, and cancer, and might predispose to polyneuropathy. Additionally, inhibition of neprilysin metabolism of amyloid-β peptides might have an effect on Alzheimer disease, age-related macular degeneration, and cerebral amyloid angiopathy. Much of the evidence for possible adverse consequences of chronic neprilysin inhibition comes from studies in animal models, and the relevance of this evidence to humans is unknown. This Review summarizes current knowledge of neprilysin function and possible consequences of chronic neprilysin inhibition that indicate a need for vigilance in the use of neprilysin inhibitor therapy.

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Figure 1: Effect of neprilysin inhibition on natriuretic peptides.
Figure 2: Effect of neprilysin inhibition on the kallikrein–kinin system.
Figure 3: Action of ARNIs on the renin–angiotensin–aldosterone system.

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  • 02 February 2017

    In the version of this article initially published online, reference 203 was incorrect. The error has been corrected for the HTML, PDF, and print versions of the article.

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Acknowledgements

St Vincent's Institute of Medical Research is supported in part by the Victorian Government's Operational Infrastructure Support Program.

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    Duncan J. Campbell

  2. University of Melbourne, Parkville, Melbourne, 3010, Victoria, Australia

    Duncan J. Campbell

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D.J.C. has consulted for, and received financial and material support from, Novartis.

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Campbell, D. Long-term neprilysin inhibition — implications for ARNIs. Nat Rev Cardiol 14, 171–186 (2017). https://doi.org/10.1038/nrcardio.2016.200

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