Neprilysin inhibition to treat heart failure: a tale of science, serendipity, and second chances

McMurray, John J.V.

doi:10.1002/ejhf.250

Cited by 117 publications

(93 citation statements)

References 62 publications

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“…Sacubitril is a prodrug and is metabolised to sacubitrilat (LBQ 657), which then inhibits NEP 23. With the mean elimination half-lives of sacubitril, sacubitrilat and valsartan being 1.4, 11.5 and 9.9 hours, respectively,23 sacubitril/valsartan is suitable for once daily administration, although it is used as a two times per day preparation in HF to ensure a sustained and uninterrupted effect on both NPS and RAAS 25…”

Section: Pharmacology Of Sacubitril/valsartanmentioning

confidence: 99%

Sacubitril/valsartan: beyond natriuretic peptides

Singh

Burrell

Cherif

et al. 2017

Heart

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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 potentially beneficial physiological effects.The angiotensin receptor-neprilysin inhibitor (ARNI), sacubitril/valsartan, simultaneously augments the natriuretic peptide system (NPS) by inhibiting the enzyme neprilysin (NEP) and inhibits the renin-angiotensin-aldosterone system 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. Secondly, 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 'auto-inhibition' 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 auto-inhibition 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.

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Section: Pharmacology Of Sacubitril/valsartanmentioning

confidence: 99%

Sacubitril/valsartan: beyond natriuretic peptides

Singh

Burrell

Cherif

et al. 2017

Heart

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“…Indeed, the P value achieved for the primary endpoint was equivalent to at least four trials with a P value <0.05. 32 On this basis, it would appear unethical to conduct a similar study to confirm the PARADIGM-HF findings.…”

Section: Limitations Of the Evidence For Angiotensin Receptor-neprilymentioning

confidence: 99%

Should Angiotensin Receptor Neprilysin Inhibitors Replace Angiotensin-converting Enzyme Inhibitors in Heart Failure With a Reduced Ejection Fraction?

Hayman

Atherton

2016

Cardiac Failure Review

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Heart failure (HF) is associated with significant morbidity and mortality and confers a major economic burden.1 Large randomised controlled trials (RCTs) have demonstrated that inhibition of the renin-angiotensinaldosterone and sympathetic nervous systems improve outcomes in patients with HF and a reduced left ventricular ejection fraction (HFrEF) (see Figure 1), [2][3][4][5][6][7][8][9] with clinical guidelines recommending angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers and mineralocorticoid receptor antagonists in all patients with symptomatic HFrEF unless contraindicated. [10][11][12] However, despite the considerable therapeutic gains made in the field of HFrEF, outcomes remain poor especially in patients with persisting left ventricular systolic dysfunction. Evidence for Angiotensin-converting Enzyme Inhibitors in Heart FailureThe ACEIs was the first class of drug shown to improve survival rates and reduce HF hospitalisation rates in patients with mild, moderate or severely symptomatic HF.2,3 A meta-analysis of RCTs evaluating ACEI in patients with HF reported substantial reductions in total mortality rates (hazard ratio 13-15 On the basis of these studies, ACEI are given the highest level of evidence in HF clinical guidelines, 11,12 with recent registries and real-world studies reporting prescription rates >90 % for ACEI/ARB therapy in eligible patients with HF. 16,17 Rationale for Neprilysin Inhibition in Heart FailureNeprilysin is an enzyme that catalyses the degradation of a number of vasoactive compounds, including natriuretic peptides. Natriuretic peptides have multiple actions that could have a favourable effect on HF disease progression including vasodilation, natriuresis and diuresis;18 thus the promotion of natriuretic peptides through exogenous administration or inhibition of neprilysin are attractive therapeutic options. Intravenous nesiritide, a synthetic B-type natriuretic peptide (BNP), was shown to reduce the rates of dyspnoea and pulmonary capillary wedge pressure compared with placebo in the Vasodilation in the Management of Acute Congestive HF (VMAC) study; however, there was no difference in symptom improvement compared with nitroglycerin.19 Furthermore, nesiritide had no effect on death or rehospitalisation rates in the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) study, and is therefore not recommended for routine use. 20The first orally available neprilysin inhibitor, candoxatril, although displaying a dose-dependent increase in atrial natriuretic peptide levels accompanied by natriuresis and haemodynamic benefits in the setting of HF in short-term studies, 21,22 was associated with increases in levels of angiotensin II and endothelin, which likely offsets the favourable haemodynamic effects in the absence of renin-angiotensin system inhibition. 23,24 Another neprilysin inhibitor, ecadotril, failed to show benefit in a dose-ranging study with a trend towards increased mortality rates. KeywordsAngiotensin-converting en...

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“…29 Interest in this class of agents appears to have stalled in the early to mid-2000s and there is surprisingly little information in the public domain about forthcoming neprilysin inhibitors.…”

Section: Other Neprilysin Inhibitors In Developmentmentioning

confidence: 99%