Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 Mar 15;133(11):1115-24.
doi: 10.1161/CIRCULATIONAHA.115.018622.

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

Scott A Hubers  1 , Nancy J Brown  2
Affiliations
Review

Combined Angiotensin Receptor Antagonism and Neprilysin Inhibition

Scott A Hubers et al. Circulation. .

Abstract

Heart failure affects ≈5.7 million people in the United States alone. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone antagonists have improved mortality in patients with heart failure and reduced ejection fraction, but mortality remains high. In July 2015, the US Food and Drug Administration approved the first of a new class of drugs for the treatment of heart failure: Valsartan/sacubitril (formerly known as LCZ696 and currently marketed by Novartis as Entresto) combines the angiotensin receptor blocker valsartan and the neprilysin inhibitor prodrug sacubitril in a 1:1 ratio in a sodium supramolecular complex. Sacubitril is converted by esterases to LBQ657, which inhibits neprilysin, the enzyme responsible for the degradation of the natriuretic peptides and many other vasoactive peptides. Thus, this combined angiotensin receptor antagonist and neprilysin inhibitor addresses 2 of the pathophysiological mechanisms of heart failure: activation of the renin-angiotensin-aldosterone system and decreased sensitivity to natriuretic peptides. In the Prospective Comparison of ARNI With ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, valsartan/sacubitril significantly reduced mortality and hospitalization for heart failure, as well as blood pressure, compared with enalapril in patients with heart failure, reduced ejection fraction, and an elevated circulating level of brain natriuretic peptide or N-terminal pro-brain natriuretic peptide. Ongoing clinical trials are evaluating the role of valsartan/sacubitril in the treatment of heart failure with preserved ejection fraction and hypertension. We review here the mechanisms of action of valsartan/sacubitril, the pharmacological properties of the drug, and its efficacy and safety in the treatment of heart failure and hypertension.

Keywords: heart failure; natriuretic peptides; pharmacology; prescription drugs.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Effects of valsartan/sacubitril through inhibition of neprilysin (NEP) and blockade of the renin-angiotensin-aldosterone system. Red represents antagonism/inhibition. Ang I indicates angiotensin I; Ang II, angiotensin II; AT1R, angiotensin type 1 receptor; ARB, angiotensin receptor blocker; ACE, angiotensin-converting enzyme; APP, aminopeptidase P; ADM, adrenomedullin; NEPi, neprilysin inhibitor; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; and CNP, C-type natriuretic peptide.
Figure 2
Figure 2
Structure of valsartan/sacubitril using a ball-and-stick model. Carbon atoms are represented in grey; sodium, purple; carboxylate and carbonyl oxygen, red; and water oxygen, green. Hydrogen atoms are not shown. Reproduced with permission from the publisher. Copyright © 2010, the American College of Clinical Pharmacology.
Figure 3
Figure 3
Kaplan-Meier curves from the PARADIGM-HF trial for the primary composite endpoint of cardiovascular death or first hospitalization for heart failure (A), death from cardiovascular causes (B), first hospitalization for heart failure (C), and death from any cause (D). LCZ696 is valsartan/sacubitril. Reproduced with permission from the publisher. Copyright © 2014, Massachusetts Medical Society. All rights reserved.
See this image and copyright information in PMC

Comment in

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB. Heart disease and stroke statistics-2015 update: a report from the American Heart Association. Circulation. 2015;131:e29–e322. - PubMed
    1. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–e239. - PubMed
    1. Gu J, Noe A, Chandra P, Al-Fayoumi S, Ligueros-Saylan M, Sarangapani R, Maahs S, Ksander G, Rigel DF, Jeng AY, Lin TH, Zheng W, Dole WP. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi) J Clin Pharmacol. 2010;50:401–414. - PubMed
    1. Burnier M. Angiotensin II type 1 receptor blockers. Circulation. 2001;103:904–912. - PubMed
    1. Volpe M. Natriuretic peptides and cardio-renal disease. Int J Cardiol. 2014;176:630–639. - PubMed

Publication types

MeSH terms