Long-term neprilysin inhibition - implications for ARNIs

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Biochemistry

Background:

• Neprilysin regulates bioactive peptides, impacting cardiovascular homeostasis.
• LCZ696 (valsartan/sacubitril) is a novel dual-acting angiotensin-receptor-neprilysin inhibitor.
• LCZ696 is approved for heart failure with reduced ejection fraction, marking the first chronic neprilysin inhibition therapy.

Purpose of the Study:

• To review neprilysin function and potential consequences of chronic neprilysin inhibition.
• To highlight potential beneficial and adverse effects of neprilysin inhibitor therapy.
• To emphasize the need for vigilance in using neprilysin inhibitor therapy.

Main Methods:

• Review of existing literature on neprilysin function and neprilysin inhibitor therapy.
• Analysis of data from clinical trials, including the PARADIGM-HF study.
• Examination of preclinical evidence regarding potential adverse effects.

Main Results:

• LCZ696 demonstrated superior efficacy over enalapril in heart failure with reduced ejection fraction.
• LCZ696 reduced blood pressure more effectively than valsartan alone in hypertensive patients.
• Potential adverse effects of chronic neprilysin inhibition include angio-oedema, inflammation, and effects on neurodegenerative diseases, though human relevance is often unclear.

Conclusions:

• Chronic neprilysin inhibition, as with LCZ696, presents a new therapeutic avenue but necessitates careful monitoring for potential adverse events.
• Further research is needed to clarify the human relevance of adverse effects observed in animal models.
• Vigilance is crucial when utilizing neprilysin inhibitor therapies due to their broad impact on peptide metabolism.