Skip to main content
Log in

The Role of Neprilysin Inhibitors in Cardiovascular Disease

  • Pathophysiology of Myocardial Failure (I Anand and M Patarroyo-Aponte, Section Editors)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Heart failure affects over five million Americans each year and contributes to morbidity, mortality, and high health care costs. Despite the benefits of RAAS and SNS blockers, 5-year survival rates in patients with heart failure remain low, necessitating continued research and new drug targets. LCZ696 (sacubitril/valsartan) is an angiotensin-receptor neprilysin inhibitor recently approved for HFrEF, with dual actions that result in enhancement of natriuretic peptide levels and blockade of angiotensin II activities. This drug shows promise in further improving clinical outcomes in HFrEF and is being studied in patients with HFpEF. In the PARADIGM-HF study, LCZ696 (sacubitril/valsartan) was shown to reduce the composite of cardiovascular mortality and heart failure hospitalizations compared with enalapril in patients with HFrEF taking guideline-directed medical therapies and resulted in prolonged survival. In trials, hypotension occurred more frequently with LCZ696 (sacubitril/valsartan) compared to an ACE inhibitor, warranting careful dose titration. Further clinical experience with LCZ696 (sacubitril/valsartan) will provide additional information on tolerability in a broad range of patients of various demographics.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Explore related subjects

Discover the latest articles, news and stories from top researchers in related subjects.

References

  1. Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics—2013 update: a report from the American Heart Association. Circulation. 2013;127(1):e6–e245.

    Article  PubMed  Google Scholar 

  2. Bahrami H, Kronmal R, Bluemke DA, et al. Differences in the incidence of congestive heart failure by ethnicity: the multi-ethnic study of atheroscleroris. Arch Intern Med. 2008;168(19):2138–45.

    Article  PubMed Central  PubMed  Google Scholar 

  3. Curtis LH, Whellan DJ, Hammill BG, et al. Incidence and prevalence of heart failure in elderly persons, 1994–2003. Arch Intern Med. 2008;168(4):418–24.

    Article  PubMed  Google Scholar 

  4. Lloyd-Jones DM, Larson MG, Leip EP, et al. Lifetime risk for developing congestive heart failure: the Framingham heart study. Circulation. 2002;106(24):3068–72.

    Article  PubMed  Google Scholar 

  5. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3):251–9.

    Article  CAS  PubMed  Google Scholar 

  6. Ranasinghe I, Wang Y, Dharmarajan K, Hsieh AF, Bernheim SM, Krumholz HM. Readmissions after hospitalization for heart failure, acute myocardial infarction, or pneumonia among young and middle-aged adults: a retrospective observational cohort study. PLoS Med. 2014;11(9), e1001737.

    Article  PubMed Central  PubMed  Google Scholar 

  7. Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a community-based population. JAMA. 2004;292(3):344–50.

    Article  CAS  PubMed  Google Scholar 

  8. Levy D, Kenchaiah S, Larson MG, et al. Long-term trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347(18):1397–402.

    Article  PubMed  Google Scholar 

  9. Heidenreich PA, Trogdon JG, Khavjou OA, et al. Forecasting the future of cardiovascular disease in the United States: a policy statement from the American Heart Association. Circulation. 2011;123(8):933–44.

    Article  PubMed  Google Scholar 

  10. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014;370(15):1383–92.

    Article  CAS  PubMed  Google Scholar 

  11. Levin ER, Gardner DG, Sampson WK. Natriuretic peptides. N Engl J Med. 1998;339(5):321–8.

    Article  CAS  PubMed  Google Scholar 

  12. Kuhn M. Molecular physiology of natriuretic peptide signalling. Basic Res Cardiol. 2004;99(2):76–82.

    Article  CAS  PubMed  Google Scholar 

  13. Mangiafico S, Costello-Boerrigter LC, Andersen IA, Cataliotti A, Burnett Jr JC. Neutral endopeptidase inhibition and the natriuretic peptide system: an evolving strategy in cardiovascular therapeutics. Eur Heart J. 2013;34(12):886–893c.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  14. Stingo AJ, Clavell AL, Aarhus LL, Burnett Jr JC. Cardiovascular and renal actions of C-type natriuretic peptide. Am J Physiol. 1992;262(1 Pt 2):H308–312.

    CAS  PubMed  Google Scholar 

  15. Lisy OJ, Jougasaki M, Schirger JA, Chen HH, Barclay PT, Burnett Jr JC. Neutral endopeptidase inhibition potentiates the natriuretic actions of adrenomedullin. Am J Physiol. 1998;275(3 Pt 2):F410–4.

    CAS  PubMed  Google Scholar 

  16. Liu Y, Studzinski C, Beckett T, Murphy MP, Klein RL, Hersh LB. Circulating neprilysin clears brain amyloid. Mol Cell Neurosci. 2010;45(2):101–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Ando S, Rahman MA, Butler GC, Senn BL, Floras JS. Comparison of candoxatril and atrial natriuretic factor in healthy men. Effects on hemodynamics, sympathetic activity, heart rate variability, and endothelin. Hypertension. 1995;26(6 Pt 2):1160–6.

    Article  CAS  PubMed  Google Scholar 

  18. McDowell G, Nicholls DP. The therapeutic potential of candoxatril, a neutral endopeptidase inhibitor, in humans. Cardiovasc Drug Rev. 2000;18(4):259–70.

    Article  CAS  Google Scholar 

  19. Cleland JG, Swedberg K. Lack of efficacy of neutral endopeptidase inhibitor ecadotril in heart failure. The international ecadotril multi-centre dose-ranging study investigators. Lancet. 1998;35(9116):1657–8.

    Article  Google Scholar 

  20. Packer M, Califf RM, Konstam MA, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106(8):920–6.

    Article  CAS  PubMed  Google Scholar 

  21. Kostis JB, Packer M, Black HR, Schmieder R, Henry D, Levy E. Omapatrilat and enalapril in patients with hypertension: the Omapatrilat Cardiovascular Treatment vs. Enalapril (OCTAVE) trial. Am J Hypertens. 2004;17(2):103–11.

    Article  CAS  PubMed  Google Scholar 

  22. Blumberg AL, Denny SE, Marshall GR, Needleman P. Blood vessel-hormone interactions: angiotensin, bradykinin, and prostaglandins. Am J Physiol. 1977;232(3):H305–310.

    CAS  PubMed  Google Scholar 

  23. Cruden NL, Fox KA, Ludlam CA, Johnston NR, Newby DE. Neutral endopeptidase inhibition augments vascular actions of bradykinin in patients treated with angiotensin-converting enzyme inhibition. Hypertension. 2004;44(6):913–8.

    Article  CAS  PubMed  Google Scholar 

  24. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor. (ARNi). J Clin Pharmacol. 2010;50(4):401–14.

    Article  CAS  PubMed  Google Scholar 

  25. Ayalasomayajula S, Jordaan P, Pal P, et al. Assessment of drug interaction potential between LCZ696 and warfarin. Hypertension. 2013;62:A448.

    Google Scholar 

  26. Ayalasomayajula S, Jordaan P, Pal P, et al. Assessment of pharmacokinetic drug interaction between LCZ696 and digoxin. Hypertension. 2013;62:A449.

    Google Scholar 

  27. Mendonza A, Mizuki A, Langenickel T, et al. Assessment of pharmacokinetic drug interaction between LCZ696 and metformin. Hypertension. 2013;62:A456.

    Google Scholar 

  28. Hsiu-Ling H, Greeley M, Pal P, et al. Assessment of pharmacokinetic drug–drug interaction between LCZ696 and carvedilol. Hypertension. 2013;62:A457.

    Article  Google Scholar 

  29. Kalliokoski A, Niemi M. Impact of OATP transporters on pharmacokinetics. Br J Pharmacol. 2009;158(3):693–705.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. McMurray J, Packer M, Desai A, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371(11):993–1004.

    Article  PubMed  Google Scholar 

  31. Packer M, McMurray J, Akshay S, et al. Angiotensin receptor neprilysin inhibition compared with enalapril on the risk of clinical progression in surviving patients with heart failure. Circulation. 2015;131(1):54–61.

    Article  CAS  PubMed  Google Scholar 

  32. Desai AS, McMurray JJ, Packer M, et al. Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients. Eur Heart J. 2015. doi:10.1093/eurheartj/ehv186.

    Google Scholar 

  33. Jhund PS, Fu M, Bayram E, et al. Efficacy and safety of LCZ696 (sacubitril-valsartan) according to age: insights from PARADIGM-HF. Eur Heart J. 2015.

  34. Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet. 2012;380(9851):1387–95.

    Article  CAS  PubMed  Google Scholar 

  35. Product Information: ENTRESTO(TM) oral tablets, sacubitril valsartan oral tablets. Novartis Pharmaceuticals Corporation (per Manufacturer), East Hanover, NJ, 2015.

  36. Gan L, Langenickel T, Petruck J, et al. Effects of age and sex on the pharmacokinetics of LCZ696, an angiotensin receptor neprilysin inhibitor. J Clin Pharmacol. 2015. doi:10.1002/jcph.571.

    Google Scholar 

  37. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the prospective comparison and ARNI with ACEI to determine impact on global mortality and morbidity in heart failure trial. Eur J Heart Fail. 2013;15(9):1062–73.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Sondhi D, Lippmann M, Murali G. Airway compromise due to angiotensin-converting enzyme inhibitor-induced angioedema: clinical experience at a large community teaching hospital. Chest. 2004;126(2):400–4.

    Article  CAS  PubMed  Google Scholar 

  39. Gibbs CR, Lip GY, Beevers DG. Angioedema due to ACE inhibitors: increased risk in patients of Afrigin origin. Br J Clin Pharmacol. 1999;48(6):861–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Orly Vardeny.

Ethics declarations

Conflict of Interest

Jared Mills declares that he has no competing interests.

Orly Vardeny has received consulting honoraria from Novartis.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

This article is part of the Topical Collection on Pathophysiology of Myocardial Failure

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mills, J., Vardeny, O. The Role of Neprilysin Inhibitors in Cardiovascular Disease. Curr Heart Fail Rep 12, 389–394 (2015). https://doi.org/10.1007/s11897-015-0270-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11897-015-0270-8

Keywords

Navigation