Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study

Abstract

Aim This study aimed at evaluating the effects of sacubitril/valsartan on neprilysin (NEP), and the metabolism of natriuretic peptides in heart failure (HF) and providing additional mechanistic information on the mode of action of the drug. Methods and results We enrolled 73 chronic HF patients who were switched from angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. In addition to clinical and echocardiographic assessment, plasma biomarkers were measured at baseline, day 30 and day 90 after initiation of treatment. Sacubitril/valsartan led to decrease in New York Heart Association class and improvement of echocardiographic parameters, as well as a dose‐dependent decrease in soluble NEP (sNEP) activity, while sNEP concentration remained unchanged. Neprilysin inhibition translated into an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon‐like peptide 1, the latter translating into a decrease in fructosamine. Cardiac troponin and soluble ST2 levels, biomarkers of HF severity unrelated to NEP metabolism also decreased. While there was a ∼4‐fold increase in ANP, we observed no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in N‐terminal proBNP (NT‐proBNP) concentrations. Finally, we found a progressive increase in the relationship between BNP and NT‐proBNP, which strongly correlated with an increase in T71 proBNP glycosylation (R2 = 0.94). Conclusion Sacubitril/valsartan rapidly and strongly reduced sNEP activity, leading to an increase in levels of NEP substrates. These data suggest a pleiotropic favourable impact of sacubitril/valsartan on the metabolism of HF patients with ANP rather than BNP as major effectors amongst natriuretic peptides.

Sacubitril‐Valsartan in a routine community population: attention to volume status critical to achieving target dose

“…Furthermore, within this data set, TD was linked to responder status, further supporting efforts to achieve maximum dose. Our data, while not reporting on clinical end points, indicate a similar community response in terms of natriuretic peptide and ST2 reduction, to that observed in PARADIGM‐HF, and extend the clinical trial observations by demonstrating an increase in LVEF over time with this therapy . We also noted that those responding to therapy tended to be younger and had better renal function.…”

“…The clinical importance of these data is that they reinforce the positive observations from the clinical trial data, and the emerging real world data, and indicate that the majority of the cohort of community patients can tolerate the agent and benefit from the compound, in terms of either a reduction in NT‐proBNP or an improvement in LVEF. More importantly, these data support the importance of achieving maximum dose and link this to a reduction in diuretic use, establishing clinical volume assessment as a critical feature in using this agent.…”

“…Our data, while not reporting on clinical end points, indicate a similar community response in terms of natriuretic peptide and ST2 reduction, to that observed in PARADIGM-HF, and extend the clinical trial observations by demonstrating an increase in LVEF over time with this therapy. 1,17,33 We also noted that those responding to therapy tended to be younger and had better renal function. These data might indicate that earlier intervention with sacubitril-valsartan in the natural history of HF-rEF might be the most effective strategy in terms of improving the chances of a beneficial response.…”

“…However, there has been a lower rate of achievement of the target dose (TD), with the majority of studies reaching TD in less than 50% the patients, including a large cohort in Germany . To our knowledge, only one study to date had reported success in titration to TD in greater than 50% of the cases . Given that achieving maximum dose seems to have an impact on outcome, a fuller understanding is needed of the success and difficulties of titration of this agent in community HF‐rEF.…”

Sacubitril/valsartan and B‐type natriuretic peptide value: recalculating route

“…Finally, it has recently been demonstrated that sacubitril/valsartan increases the levels of glycosylated proBNP, which is especially resistant to cleavage into BNP and NT-proBNP. 10 Therefore, we would expect lower BNP levels under sacubitril/valsartan treatment, 11 although showing cross-reactivity with proBNP, may hide those results.…”