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Sacubitril/valsartan: beyond natriuretic peptides
  1. Jagdeep S S Singh1,
  2. Louise M Burrell2,
  3. Myriam Cherif3,
  4. Iain B Squire4,
  5. Andrew L Clark5,
  6. Chim C Lang1
  1. 1 Division of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK
  2. 2 Department of Medicine, Austin Health, The University of Melbourne, Victoria, Australia
  3. 3 Novartis Pharmaceuticals, Frimley Business Park, Frimley, Surrey, UK
  4. 4 Department of Cardiovascular Sciences, University of Leicester and Leicester NIHR Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, UK
  5. 5 Department of Academic Cardiology, University of Hull, Daisy Building, Castle Hill Hospital, Castle Road, Cottingham, UK
  1. Correspondence to Professor Chim C Lang, Division of Molecular and Clinical Medicine, University of Dundee, Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, United Kingdom; c.c.lang{at}


Natriuretic peptides, especially B-type natriuretic peptide (BNP), have primarily been regarded as biomarkers in heart failure (HF). However, they are also possible therapeutic agents due to their potentially beneficial physiological effects. The angiotensin receptor–neprilysin inhibitor, sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin–angiotensin–aldosterone system (RAAS) by blocking the angiotensin II receptor. It has been shown to improve mortality and hospitalisation outcomes in patients with HF due to left ventricular systolic dysfunction. The key advantage of sacubitril/valsartan has been perceived to be its ability to augment BNP, while its other effects have largely been overlooked. This review highlights the important effects of sacubitril/valsartan, beyond just the augmentation of BNP. First we discuss how NPS physiology differs between healthy individuals and those with HF by looking at mechanisms like the overwhelming effects of RAAS on the NPS, natriuretic peptide receptor desensitisation and absolute natriuretic deficiency. Second, this review explores other hormones that are augmented by sacubitril/valsartan such as bradykinin, substance P and adrenomedullin that may contribute to the efficacy of sacubitril/valsartan in HF. We also discuss concerns that sacubitril/valsartan may interfere with amyloid-β homeostasis with potential implications on Alzheimer’s disease and macular degeneration. Finally, we explore the concept of ‘autoinhibition’ which is a recently described observation that humans have innate NEP inhibitory capability when natriuretic peptide levels rise above a threshold. There is speculation that autoinhibition may provide a surge of natriuretic and other vasoactive peptides to rapidly reverse decompensation. We contend that by pre-emptively inhibiting NEP, sacubitril/valsartan is inducing this surge earlier during decompensation, resulting in the better outcomes observed.

  • Sacubitril/valsartan
  • angiotensin receptor-neprilysin inhibitor
  • natriuretic peptides
  • B-type natriuretic peptide
  • mechanism of action
  • bradykinin
  • Alzheimer’s disease

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  • Contributors All authors co-developed the hypothesis and drafted the manuscript.

  • Competing interests LMB has received consulting fees from Novartis Pharmaceuticals outside the submitted work and lecture fees from AstraZeneca. MC is an employee of Novartis Pharmaceuticals UK Ltd. IBS reports grants and personal fees from Novartis Pharmaceuticals, outside the submitted work, in advisory boards and educational events. ALC has received financial support for travel to meetings from Servier and accepted personal fees from Novartis Pharmaceuticals outside the submitted work. CCL received research support, lecture fees and consulting fees from Astra Zeneca, other from Bayer, research support and consulting fees from Novartis Pharmaceuticals and other from Servier, lecture fees from Merck Sharp & Dohme and research support from Pfizer and Sanofi outside the submitted work.

  • Provenance and peer review Not commissioned; externally peer reviewed.