Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure

Orly Vardeny, Ryan Miller, Scott D. Solomon

Research output: Contribution to journalReview articlepeer-review

148 Scopus citations


Neprilysin is an enzyme that contributes to the breakdown of the biologically active natriuretic peptides and several other vasoactive compounds. Inhibiting neprilysin has been a therapeutic target for several compounds that have been tested in cardiovascular disease, including ecadotril, candoxatril, omapatrilat, and LCZ696. Although ecadotril, candoxatril, and omapatrilat were initially tested in hypertension and/or heart failure, lack of efficacy and side effects led to discontinuation of their development. LCZ696 (sacubitril valsartan) is a first-in-class angiotensin receptor neprilysin inhibitor that has been developed for use in heart failure. This compound is composed of 2 molecular moieties in a single crystalline complex-the angiotensin receptor blocker valsartan and a neprilysin inhibitor prodrug-and has now been tested in hypertension, in a phase 2 trial in heart failure with preserved ejection fraction, and has demonstrated greater efficacy than enalapril in a phase 3 trial in heart failure with reduced ejection fraction. Its ability to inhibit the renin-angiotensin-aldosterone axis and augment the endogenous natriuretic peptide system provides a distinctive mechanism of action in cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)663-670
Number of pages8
JournalJACC: Heart Failure
Issue number6
StatePublished - 2014

Bibliographical note

Publisher Copyright:
© 2014 American College of Cardiology Foundation.


  • Heart failure
  • Natriuretic peptide
  • Neprilysin


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