Skip to main content
Log in

Potential Uses of Sacubitril/Valsartan: Need for Data on Efficacy and Safety

  • Current Opinion
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have been the cornerstone for the treatment of heart failure (HF) with reduced ejection fraction for decades. According to recent and promising studies, sacubitril/valsartan (SV) might be efficient in alternative indications in the area of HF with preserved left ventricular ejection fraction, chronic kidney disease, and so on. This review briefly summarizes these promising therapeutic options regarding SV and the potential limits and pitfalls for its use in routine practice (due to cognitive uncertainties).

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18:891–975.

    Article  PubMed  Google Scholar 

  2. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin–neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.

    Article  CAS  PubMed  Google Scholar 

  3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Colvin MM, et al. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. J Am Coll Cardiol. 2016;68:1476–88.

    Article  PubMed  Google Scholar 

  4. Ruilope LM, Dukat A, Böhm M, Lacourcière Y, Gong J, Lefkowitz MP. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet Lond Engl. 2010;375:1255–66.

    Article  CAS  Google Scholar 

  5. Kario K. The sacubitril/valsartan, a first-in-class, angiotensin receptor neprilysin inhibitor (ARNI): potential uses in hypertension, heart failure, and beyond. Curr Cardiol Rep. 2018;20:5.

    Article  PubMed  Google Scholar 

  6. Williams B, Cockcroft JR, Kario K, Zappe DH, Brunel PC, Wang Q, et al. Effects of sacubitril/valsartan versus olmesartan on central hemodynamics in the elderly with systolic hypertension: the PARAMETER study. Hypertens Dallas Tex. 1979;2017(69):411–20.

    Google Scholar 

  7. Bavishi C, Messerli FH, Kadosh B, Ruilope LM, Kario K. Role of neprilysin inhibitor combinations in hypertension: insights from hypertension and heart failure trials. Eur Heart J. 2015;36:1967–73.

    Article  CAS  PubMed  Google Scholar 

  8. Solomon SD, Zile M, Pieske B, Voors A, Shah A, Kraigher-Krainer E, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: a phase 2 double-blind randomised controlled trial. Lancet Lond Engl. 2012;380:1387–95.

    Article  CAS  Google Scholar 

  9. Wang J-G, Yukisada K, Sibulo A, Hafeez K, Jia Y, Zhang J. Efficacy and safety of sacubitril/valsartan (LCZ696) add-on to amlodipine in Asian patients with systolic hypertension uncontrolled with amlodipine monotherapy. J Hypertens. 2017;35:877–85.

    Article  CAS  PubMed  Google Scholar 

  10. Supasyndh O, Wang J, Hafeez K, Zhang Y, Zhang J, Rakugi H. Efficacy and safety of sacubitril/valsartan (LCZ696) Compared with olmesartan in elderly Asian patients (≥ 65 years) with systolic hypertension. Am J Hypertens. 2017;30:1163–9.

    Article  CAS  PubMed  Google Scholar 

  11. Wang T-D, Tan R-S, Lee H-Y, Ihm S-H, Rhee M-Y, Tomlinson B, et al. Effects of sacubitril/valsartan (LCZ696) on natriuresis, diuresis, blood pressures, and NT-proBNP in salt-sensitive hypertension. Hypertens Dallas Tex. 1979;2017(69):32–41.

    Google Scholar 

  12. Trivedi RK, Polhemus DJ, Li Z, Yoo D, Koiwaya H, Scarborough A, et al. Combined angiotensin receptor-neprilysin inhibitors improve cardiac and vascular function via increased NO bioavailability in heart failure. J Am Heart Assoc. 2018;7:e008268.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schmieder RE, Wagner F, Mayr M, Delles C, Ott C, Keicher C, et al. The effect of sacubitril/valsartan compared to olmesartan on cardiovascular remodelling in subjects with essential hypertension: the results of a randomized, double-blind, active-controlled study. Eur Heart J. 2017;38:3308–17.

    Article  CAS  PubMed  Google Scholar 

  14. Kompa AR, Lu J, Weller TJ, Kelly DJ, Krum H, von Lueder TG, et al. Angiotensin receptor neprilysin inhibition provides superior cardioprotection compared to angiotensin converting enzyme inhibition after experimental myocardial infarction. Int J Cardiol. 2018;258:192–8.

    Article  PubMed  Google Scholar 

  15. von Lueder TG, Wang BH, Kompa AR, Huang L, Webb R, Jordaan P, et al. Angiotensin receptor neprilysin inhibitor LCZ696 attenuates cardiac remodeling and dysfunction after myocardial infarction by reducing cardiac fibrosis and hypertrophy. Circ Heart Fail. 2015;8:71–8.

    Article  CAS  Google Scholar 

  16. Ishii M, Kaikita K, Sato K, Sueta D, Fujisue K, Arima Y, et al. Cardioprotective effects of LCZ696 (sacubitril/valsartan) after experimental acute myocardial infarction. JACC Basic Transl Sci. 2017;2:655–68.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456–62.

    Article  CAS  PubMed  Google Scholar 

  18. Yusuf S, Dagenais G, Pogue J, Bosch J, Sleight P. Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:154–60.

    Article  CAS  PubMed  Google Scholar 

  19. Turnbull F, Blood Pressure Lowering Treatment Trialists’ Collaboration. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet Lond Engl. 2003;362:1527–35.

    Article  CAS  Google Scholar 

  20. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–60.

    Article  CAS  PubMed  Google Scholar 

  21. Jing W, Vaziri ND, Nunes A, Suematsu Y, Farzaneh T, Khazaeli M, et al. LCZ696 (sacubitril/valsartan) ameliorates oxidative stress, inflammation, fibrosis and improves renal function beyond angiotensin receptor blockade in CKD. Am J Transl Res. 2017;9:5473–84.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Suematsu Y, Jing W, Nunes A, Kashyap ML, Khazaeli M, Vaziri ND, et al. LCZ696 (sacubitril/valsartan), an angiotensin-receptor neprilysin inhibitor, attenuates cardiac hypertrophy, fibrosis, and vasculopathy in a rat model of chronic kidney disease. J Card Fail. 2018;24:266–75.

    Article  CAS  PubMed  Google Scholar 

  23. Ushijima K, Ando H, Arakawa Y, Aizawa K, Suzuki C, Shimada K, et al. Prevention against renal damage in rats with subtotal nephrectomy by sacubitril/valsartan (LCZ696), a dual-acting angiotensin receptor-neprilysin inhibitor. Pharmacol Res Perspect. 2017;5(4):e00336. https://doi.org/10.1002/prp2.336.

    Article  CAS  PubMed Central  Google Scholar 

  24. UK Harp-Iii Collaborative Group. Randomized multicentre pilot study of sacubitril/valsartan versus irbesartan in patients with chronic kidney disease: United Kingdom Heart and Renal Protection (HARP)- III-rationale, trial design and baseline data. Nephrol Dial Transpl Off Publ Eur Dial Transpl Assoc Eur Ren Assoc. 2017;32:2043–51.

    Google Scholar 

  25. Seferovic JP, Claggett B, Seidelmann SB, Seely EW, Packer M, Zile MR, et al. Effect of sacubitril/valsartan versus enalapril on glycaemic control in patients with heart failure and diabetes: a post-hoc analysis from the PARADIGM-HF trial. Lancet Diabetes Endocrinol. 2017;5:333–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Prasad T, Roksnoer LCW, Zhu P, Verma A, Li Y, Batenburg WW, et al. Beneficial Effects of Combined AT1 Receptor/Neprilysin Inhibition (ARNI) Versus AT1 Receptor Blockade Alone in the Diabetic Eye. Invest Ophthalmol Vis Sci. 2016;57:6722–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Packer M. Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure. Eur J Heart Fail. 2018.

  28. Control Group, Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288–98.

    Article  CAS  Google Scholar 

  29. Schling P, Schäfer T. Human adipose tissue cells keep tight control on the angiotensin II levels in their vicinity. J Biol Chem. 2002;277:48066–75.

    Article  CAS  PubMed  Google Scholar 

  30. Moro C. Natriuretic peptides and fat metabolism. Curr Opin Clin Nutr Metab Care. 2013;16:645–9.

    Article  CAS  PubMed  Google Scholar 

  31. Engeli S, Stinkens R, Heise T, May M, Goossens GH, Blaak EE, et al. Effect of sacubitril/valsartan on exercise-induced lipid metabolism in patients with obesity and hypertension. Hypertens Dallas Tex. 1979;2018(71):70–7.

    Google Scholar 

  32. Stinkens R, van der Kolk BW, Jordan J, Jax T, Engeli S, Heise T, et al. The effects of angiotensin receptor neprilysin inhibition by sacubitril/valsartan on adipose tissue transcriptome and protein expression in obese hypertensive patients. Sci Rep. 2018;8:3933.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Cannon JA, Shen L, Jhund PS, Kristensen SL, Køber L, Chen F, et al. Dementia-related adverse events in PARADIGM-HF and other trials in heart failure with reduced ejection fraction. Eur J Heart Fail. 2017;19:129–37.

    Article  CAS  PubMed  Google Scholar 

  34. De Vecchis R, Ariano C, Di Biase G, Noutsias M. Cognitive performance of patients with chronic heart failure on sacubitril/valsartan a retrospective cohort study. Herz. 2018. https://doi.org/10.1007/s00059-018-4683-5.

    Article  PubMed  Google Scholar 

  35. Langenickel TH, Tsubouchi C, Ayalasomayajula S, Pal P, Valentin M, Hinder M, et al. The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects. Br J Clin Pharmacol. 2016;81:878–90.

    CAS  Google Scholar 

  36. Iadecola C, Yaffe K, Biller J, Bratzke LC, Faraci FM, Gorelick PB, et al. Impact of hypertension on cognitive function: a scientific statement from the American Heart Association. Hypertension. 2016;68:67–94.

    Article  CAS  Google Scholar 

  37. Böhm M, Young R, Jhund PS, Solomon SD, Gong J, Lefkowitz MP, et al. Systolic blood pressure, cardiovascular outcomes and efficacy and safety of sacubitril/valsartan (LCZ696) in patients with chronic heart failure and reduced ejection fraction: results from PARADIGM-HF. Eur Heart J. 2017;38:1132–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rawal HA, Kocheril AG. Sacubitril/valsartanstive heart failure: cardiogenic shock. Case Rep Cardiol. 2018;2018:8231576.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Li B, Zhao Y, Yin B, Helian M, Wang X, Chen F, et al. Safety of the neprilysin/renin-angiotensin system inhibitor LCZ696. Oncotarget. 2017;8:83323–33.

    PubMed  PubMed Central  Google Scholar 

  40. Desai AS, Vardeny O, Claggett B, McMurray JJV, Packer M, Swedberg K, et al. Reduced risk of hyperkalemia during treatment of heart failure with mineralocorticoid receptor antagonists by use of sacubitril/valsartan compared with enalapril: a secondary analysis of the PARADIGM-HF trial. JAMA Cardiol. 2017;2:79–85.

    Article  PubMed  Google Scholar 

  41. Rodgers JE. Sacubitril/valsartan: the newest addition to the toolbox for guideline-directed medical therapy of heart failure. Am J Med. 2017;130:635–9.

    Article  CAS  PubMed  Google Scholar 

  42. King JB, Shah RU, Bress AP, Nelson RE, Bellows BK. Cost-effectiveness of sacubitril–valsartan combination therapy compared with enalapril for the treatment of heart failure with reduced ejection fraction. JACC Heart Fail. 2016;4:392–402.

    Article  PubMed  Google Scholar 

  43. Ademi Z, Pfeil AM, Hancock E, Trueman D, Haroun RH, Deschaseaux C, et al. Cost-effectiveness of sacubitril/valsartan in chronic heart-failure patients with reduced ejection fraction. Swiss Med Wkly. 2017;147:w14533.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to François Roubille.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Huet, F., Akodad, M., Kalmanovitch, E. et al. Potential Uses of Sacubitril/Valsartan: Need for Data on Efficacy and Safety. Am J Cardiovasc Drugs 19, 1–10 (2019). https://doi.org/10.1007/s40256-018-0306-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-018-0306-z

Navigation