title: Combined neprilysin and renin-angiotensin system inhibition for the treatment of heart failure.
abstract: 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.
authors.affiliation: Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, Wisconsin. Electronic address: orly.vardeny@wisc.edu.
authors.forename: Orly
authors.initials: O
authors.lastname: Vardeny
authors.affiliation: Department of Pharmacy, University of Wisconsin School of Pharmacy, Madison, Wisconsin.
authors.forename: Ryan
authors.initials: R
authors.lastname: Miller
authors.affiliation: Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Solomon
mesh_terms: D000613:Aminobutyrates / Q000627:therapeutic use*; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000627:therapeutic use; D015415:Biomarkers / Q000378:metabolism; D001713:Biphenyl Compounds; D002986:Clinical Trials as Topic; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D006333:Heart Failure / Q000188:drug therapy* / Q000401:mortality; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000401:mortality; D020097:Natriuretic Peptide, Brain / Q000378:metabolism; D015260:Neprilysin / Q000037:antagonists & inhibitors*; D010446:Peptide Fragments / Q000378:metabolism; D012084:Renin-Angiotensin System / Q000187:drug effects*; D013777:Tetrazoles / Q000627:therapeutic use*; D000068756:Valsartan
chemical_list: D000613:Aminobutyrates; D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D015415:Biomarkers; D001713:Biphenyl Compounds; D004338:Drug Combinations; D010446:Peptide Fragments; D013777:Tetrazoles; C109794:pro-brain natriuretic peptide (1-76); D020097:Natriuretic Peptide, Brain; D000068756:Valsartan; D015260:Neprilysin; C549068:sacubitril and valsartan sodium hydrate drug combination
keywords: heart failure; natriuretic peptide; neprilysin