What is the effect of neprilysin on potassium levels?

From the Guidelines

Neprilysin inhibitors, such as sacubitril, can indirectly affect potassium levels by increasing natriuretic peptides, which lead to increased sodium and water excretion while preserving potassium, but may also increase the risk of hyperkalemia when combined with angiotensin receptor blockers, particularly in patients with kidney dysfunction or those taking other medications that increase potassium 1.

Key Points

• Neprilysin is an enzyme that breaks down natriuretic peptides, which are hormones involved in regulating blood pressure and fluid balance.
• Inhibition of neprilysin can increase natriuretic peptides, leading to increased sodium and water excretion while preserving potassium.
• The combination of neprilysin inhibitors with angiotensin receptor blockers, such as sacubitril-valsartan, may increase the risk of hyperkalemia in some patients, particularly those with kidney dysfunction or those taking other medications that increase potassium 1.
• Patients taking neprilysin inhibitors should have their potassium levels monitored regularly, especially when starting treatment or adjusting dosage.

Clinical Implications

• The occurrence of hyperkalemia and the composite outcome of decline in renal function favored sacubitril-valsartan in the PARAGON-HF trial, but it was associated with a higher incidence of hypotension and angioedema 1.
• A benefit of sacubitril-valsartan compared with valsartan was observed in patients with LVEF below the median (45%–57%; rate ratio, 0.78; 95% CI, 0.64–0.95), and in women (rate ratio, 0.73; 95% CI, 0.59–0.90) 1.
• Regular monitoring of potassium levels is crucial in patients taking neprilysin inhibitors, especially when combined with angiotensin receptor blockers, to minimize the risk of hyperkalemia and its associated complications.

From the Research

Neprilysin Effect on Potassium

• The effect of neprilysin on potassium levels is not directly addressed in the provided studies, but its impact can be inferred through its role in the renin-angiotensin-aldosterone system (RAAS) and its interaction with other RAAS inhibitors 2, 3, 4, 5, 6.
• RAAS inhibitors, which include angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, aldosterone receptor antagonists, and direct renin inhibitors, can increase the risk of hyperkalemia (serum potassium >5.5 mmol/L) 3.
• The incidence of hyperkalemia with RAAS inhibitor monotherapy is low (< or =2%) in patients with hypertension without risk factors for hyperkalemia, but rates are higher with dual RAAS inhibition (approximately 5%) 3.
• Patients with heart failure or chronic kidney disease are at greater risk of hyperkalemia with RAAS inhibitors than those without these conditions, but the absolute changes in serum potassium are generally small and unlikely to be clinically significant 3.
• Neprilysin inhibitors, such as sacubitril, which is combined with valsartan in the drug sacubitril/valsartan, may have a similar effect on potassium levels as other RAAS inhibitors, but this is not explicitly stated in the provided studies 2, 4, 5, 6.

Mechanism of Neprilysin Inhibition

• Neprilysin is a neutral endopeptidase that breaks down vasoactive peptides, including natriuretic peptides, which have a role in regulating blood pressure and electrolyte balance 2, 4, 5.
• Inhibition of neprilysin, combined with angiotensin receptor blockade, may have a beneficial effect on blood pressure and cardiovascular outcomes, but its specific effect on potassium levels is not well understood 2, 4, 5, 6.

Clinical Implications

• The use of neprilysin inhibitors, such as sacubitril/valsartan, in patients with heart failure or hypertension requires careful monitoring of electrolyte levels, including potassium, due to the potential risk of hyperkalemia 3, 4, 5.
• Further studies are needed to fully understand the effect of neprilysin inhibition on potassium levels and to determine the clinical implications of this effect 5, 6.