Neprilysin inhibitors (NEPi) are a class of medication used in cardiovascular health that modulates the body’s natural regulatory systems. These agents target a specific enzyme responsible for breaking down substances beneficial for the heart and blood vessels. By preventing this breakdown, neprilysin inhibitors enhance the protective actions of endogenous hormones that regulate blood pressure and fluid balance. This therapeutic approach, focusing on dual-action neurohormonal modulation, has shifted the treatment strategy for certain heart conditions.
The Function of Neprilysin
Neprilysin, also known as neutral endopeptidase (NEP), is an enzyme widely distributed throughout the body, including the kidneys, lungs, and heart. Its natural role is to cleave and degrade a variety of small, biologically active peptides. Among its primary targets are the natriuretic peptides, specifically atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP).
These protective hormones are released by the heart in response to strain or volume overload. They promote the excretion of salt and water (natriuresis and diuresis), cause blood vessel widening (vasodilation), and suppress the effects of stress hormones. Neprilysin degrades these peptides, limiting their beneficial duration in the circulation.
The enzyme also breaks down other vasoactive peptides, including bradykinin, which encourages vasodilation. However, neprilysin also degrades substances that cause blood vessel constriction, such as angiotensin I and angiotensin II. In heart failure, neprilysin activity can be elevated, leading to the rapid destruction of the heart’s protective peptides.
Mechanism of Action: Boosting Protective Peptides
The therapeutic strategy of using a neprilysin inhibitor is to block the enzyme, increasing the concentration of beneficial peptides like ANP and BNP. The accumulation of these peptides enhances their positive effects, leading to natriuresis, diuresis, and vasodilation. This collective action reduces the fluid volume and pressure load on the failing heart. It also suppresses detrimental processes like cardiac fibrosis and hypertrophy.
A challenge arises because neprilysin also breaks down the vasoconstrictive hormone angiotensin II. When neprilysin is inhibited alone, the concentration of angiotensin II increases, potentially counteracting the beneficial effects and causing a rise in blood pressure. Therefore, neprilysin inhibitors are never given by themselves.
The solution is to combine the neprilysin inhibitor (NEPi), such as sacubitril, with an Angiotensin Receptor Blocker (ARB), such as valsartan. This combination drug, known as an Angiotensin Receptor-Neprilysin Inhibitor (ARNI), provides a dual mechanism of action. The NEPi component boosts the protective natriuretic peptides. Simultaneously, the ARB component blocks the receptors for the harmful effects of increased angiotensin II. This synergistic approach maximizes the beneficial effects while suppressing the negative effects of the renin-angiotensin-aldosterone system (RAAS) activation.
Clinical Use in Heart Failure Management
The dual-acting Angiotensin Receptor-Neprilysin Inhibitor (ARNI) has become a standard therapy for patients diagnosed with Heart Failure with Reduced Ejection Fraction (HFrEF). HFrEF means the left ventricle’s pumping action is compromised. The medication addresses the underlying neurohormonal activation that drives disease progression.
Clinical trials show that this therapy improves patient outcomes compared to previous standard treatments. It reduces the risk of cardiovascular death and lowers the rate of heart failure hospitalizations. These improvements result from the drug’s ability to favorably remodel the heart structure, known as reverse remodeling, by reducing strain and fibrosis.
The medication is often recommended as a first-line therapy for HFrEF patients, or as a replacement for an ACE inhibitor or ARB in symptomatic patients. Therapy initiation is not limited to stable, chronic patients. It can also be started safely in the hospital after a patient has been stabilized following an acute heart failure episode. Starting treatment early is associated with a lower risk of adverse clinical outcomes and greater improvement in the heart’s pumping function.
Monitoring and Potential Side Effects
While neprilysin inhibitor therapy offers benefits, it necessitates careful patient monitoring due to potential side effects. The most common adverse effect is symptomatic hypotension, or low blood pressure, due to the drug’s potent vasodilatory and diuretic effects. Patients often experience dizziness or lightheadedness, particularly when starting the medication or following a dose increase.
A more serious, though rare, side effect is angioedema, involving rapid swelling of the face, tongue, lips, or throat. This risk is heightened because the neprilysin inhibitor component prevents the breakdown of bradykinin, a substance contributing to angioedema. For this reason, these inhibitors must never be used concurrently with an Angiotensin-Converting Enzyme (ACE) inhibitor, which also prevents bradykinin breakdown.
When transitioning a patient from an ACE inhibitor to an ARNI, a mandatory 36-hour “washout” period is required to minimize angioedema risk. Close monitoring of blood chemistry is also necessary, including checking serum creatinine for kidney function and potassium levels. The therapy can sometimes lead to hyperkalemia (high potassium) or a temporary decline in renal function, requiring dose adjustments.