Different BNP Peptide Forms Behave Differently on Sacubitril/Valsartan, Helping Predict Which Heart Failure Patients Will Respond | Research

The takeaway

Mature BNP, proBNP, and total BNP respond differently to sacubitril/valsartan treatment because neprilysin only degrades mature BNP, and early changes at 4 weeks can predict treatment responders with about 80% accuracy.

AUC ~0.80 at 4 weeks
Predictive accuracy of natriuretic peptide changes at 4 weeks for identifying sacubitril/valsartan responders at 12 weeks

What the researchers found

In 54 heart failure patients treated with sacubitril/valsartan over 12 weeks:

- Total BNP and BNPcom (commercial assay) did not change overall

- NT-proBNP and proBNP decreased (reflecting hemodynamic improvement)

- Mature BNP modestly increased (because neprilysin inhibition prevents its degradation)

- ANP (A-type natriuretic peptide) greatly increased

Responders (n=31, defined by NT-proBNP <70% of baseline at 12 weeks) showed smaller percentage changes in all natriuretic peptides than non-responders (n=23; all P<0.01). The percentage change in each natriuretic peptide at 4 weeks predicted responder status with AUC of approximately 0.80. Correlations between peptide levels at baseline and during treatment were strong and consistent.

Why it matters

Sacubitril/valsartan is a cornerstone heart failure treatment, but its mechanism of action (neprilysin inhibition) artificially raises mature BNP levels, confusing the BNP tests that cardiologists rely on to monitor treatment response. This study solves that puzzle by showing that different BNP forms respond in opposite directions and that standard BNP tests can still be used — challenging the prevailing belief that BNP monitoring is unreliable on this drug. The ability to predict responders at 4 weeks could help clinicians make faster treatment decisions.

How the study worked

Prospective study of 54 heart failure patients measured at baseline and at 2, 4, 8, and 12 weeks of sacubitril/valsartan treatment. Plasma mature BNP, proBNP, and total BNP were measured using a specialized immunochemiluminescent assay that distinguishes these forms. NT-proBNP, ANP, and conventional BNP (BNPcom) were measured with commercial assays. Responders were defined as NT-proBNP <70% of baseline at 12 weeks. ROC analysis assessed predictive ability of 4-week changes.

What this study cannot tell us

The study included only 54 patients, limiting statistical power for subgroup analyses. The specialized BNP assay distinguishing mature BNP from proBNP is not widely available in clinical laboratories. The responder definition (NT-proBNP <70% of baseline) is somewhat arbitrary. The 12-week follow-up does not address longer-term peptide dynamics or clinical outcomes. The study did not assess whether BNP-guided management changes actually improve patient outcomes.

How to read the evidence

This is a prospective clinical study with serial measurements in 54 patients — moderate-level evidence. The specialized assay methodology is a strength, but the small sample size and single-center design limit generalizability.

When this study was published

Published in 2025, this study addresses an ongoing clinical question that remains highly relevant as sacubitril/valsartan use continues to expand in heart failure management.

The bigger picture

The natriuretic peptide system — particularly BNP and ANP — is one of the most clinically important peptide signaling pathways in cardiovascular medicine. Understanding how pharmaceutical interventions alter the metabolism and measurement of these peptides is essential for their continued use as diagnostic and monitoring tools. This study demonstrates the nuanced biology of peptide processing by neprilysin and has direct implications for how millions of heart failure patients are monitored during treatment.

Questions still open

Should clinical laboratories develop assays that separately measure mature BNP and proBNP for patients on neprilysin inhibitors?
Can the 4-week BNP prediction model be validated in a larger cohort to guide early treatment decisions?
Does the marked ANP increase during sacubitril/valsartan treatment contribute to the drug's clinical benefits?

Common questions

Why do BNP levels seem confusing in patients taking Entresto?

Entresto contains sacubitril, which blocks neprilysin — an enzyme that normally breaks down mature BNP. This causes mature BNP to rise even when the heart is improving. Standard BNP tests measure both mature BNP and proBNP together, so the rise in one and fall in the other can cancel out, making total BNP appear unchanged even when treatment is working.

Can doctors still use BNP tests for patients on Entresto?

Yes — this study challenges the idea that BNP is useless in these patients. While total BNP may not change much, the direction and magnitude of change at 4 weeks can still predict whether the treatment is working. Doctors can use this information to make faster decisions about continuing or adjusting therapy.

Read the original research

Responses of B-type natriuretic peptide (BNP), mature BNP and proBNP to sacubitril/valsartan differs between responders and non-responders.

Open heart, 12(1)

View on PubMed ↗Publisher’s paper ↗

Citation

Nishikimi, Toshio; Nakagawa, Yasuaki; Miyamoto, Shoichi; Kanamori, Takahiko; Inazumi, Hideaki; Yanagisawa, Hiromu; Moriuchi, Kenji; Kinoshita, Hideaki; Tamamura, Yusuke; Takahama, Hiroyuki; Minamino, Naoto; Ono, Koh. (2025). Responses of B-type natriuretic peptide (BNP), mature BNP and proBNP to sacubitril/valsartan differs between responders and non-responders.. Open heart, 12(1). https://doi.org/10.1136/openhrt-2024-002990