Neprilysin (NEP) is a membrane-bound neutral endopeptidase that degrades a variety of bioactive peptides. The substrates include natriuretic peptides (NPs), which are important regulating mediators for cardiovascular and renal biology.

Inhibition of NEP activity and exogenous NP administration thus have emerged as potential therapeutic strategies for treating cardiorenal diseases. More recently, B-type natriuretic peptide (BNP) or N-terminal-proBNP (NT-proBNP), 3'-5' cyclic guanosine monophosphate (cGMP), and soluble NEP as biomarkers have also been investigated in heart failure (HF) trials and their predictive value are beginning to be recognized.

The biological functions of NEP and NPs are discussed. Enhancing NPs through NEP inhibition combined with renin-angiotensin-aldosterone system (RAAS) antagonism has proved to be successful in HF treatment, although future surveillance studies will be required.

Direct NP enhancement through peptide delivery may have fewer potentially hazardous effects compared to NEP inhibition. Strategies of combined inhibition on NEP with other cardiorenal pathophysiological pathways are promising.

Biomarkers for HF

Finally, monitoring BNP/NT-proBNP/cGMP concentrations during NEP inhibition treatment may provide supplemental benefits to conventional biomarkers, and the identification of soluble NEP as a novel biomarker for HF needs further investigation.

In this review, the biology of NEP is summarized, with a focus on NP regulation. The degradation of NPs by NEP provides the rationale for NEP inhibition as a strategy for cardiorenal disease treatment.

The researchers also describe the current therapeutic strategies of NEP inhibition and NP therapeutics in cardiorenal diseases. Moreover, the discovery of its circulating form, soluble NEP, as a biomarker is also discussed.

NEP inhibition and NP therapeutics have grown as promising strategies for HF treatment. The success of LCZ696 (Entresto) supports the rationale that NEP inhibition with RAAS inhibition has more beneficial effects and reduces the risks caused by NEP inhibition alone.

However, NEP inhibition generates off-target effects which warrant close surveillance. Another strategy, the use of NEP-resistant NPs, may be more specific. BNP and NT-proBNP are gold-standard diagnostic biomarkers for HF.

More and more evidence supports the conclusion that the “BNP paradox” is caused by inaccurate assay measurement, in which plasma BNP is overestimated by proBNP immunoreactivity (BNP deficiency, reduced BNP availability).

Importantly, during ARNi treatment, BNP and cGMP were increased in parallel with a reduction of NT-proBNP, which supports the use of BNP, NT-proBNP, and cGMP as a triad of biomarkers to be used with ARNis to guide treatment.