From the Guidelines
Yes, Entresto (sacubitril/valsartan) does have a diuretic effect, as evidenced by post-hoc analyses of the PARADIGM-HF trial, which demonstrated decreased loop diuretic requirements with sacubitril/valsartan 1. Entresto works through a dual mechanism of action: sacubitril inhibits neprilysin, which increases levels of natriuretic peptides that promote sodium and water excretion, while valsartan blocks angiotensin II receptors, reducing sodium and water retention. This combination leads to increased urine output and reduced fluid overload in heart failure patients. The diuretic effect is generally mild to moderate compared to traditional diuretics like furosemide or hydrochlorothiazide. Patients taking Entresto may notice increased urination, especially when first starting the medication. This diuretic effect contributes to Entresto's overall benefit in heart failure by reducing cardiac workload through decreased fluid volume. However, many heart failure patients on Entresto still require concurrent treatment with traditional diuretics to achieve optimal fluid balance, particularly those with more severe fluid retention. Key points to consider when prescribing Entresto include:
- Its use is recommended for patients with chronic symptomatic HFrEF NYHA class II or III who tolerate an ACE inhibitor or ARB, as it has been shown to further reduce morbidity and mortality 1
- It should not be administered concomitantly with ACE inhibitors or within 36 hours of the last dose of an ACE inhibitor due to the risk of angioedema 1
- Patients with a history of angioedema should not be administered ARNI therapy due to the concern of recurrence 1
From the FDA Drug Label
In a 7-day valsartan-controlled study in patients with reduced ejection fraction (HFrEF), administration of sacubitril and valsartan resulted in a significant non-sustained increase in natriuresis, increased urine cGMP, and decreased plasma MR-proANP and NT-proBNP compared to valsartan In a 21-day study in HFrEF patients, sacubitril and valsartan significantly increased urine ANP and cGMP and plasma cGMP, and decreased plasma NT-proBNP, aldosterone and endothelin-1.
Diuretic Effect: Entresto (sacubitril/valsartan) may have a mild diuretic effect due to the increase in natriuresis observed in clinical studies 2.
- Key findings:
- Increased urine output (natriuresis)
- Increased urine cGMP
- Decreased plasma NT-proBNP However, this effect is non-sustained and may not be clinically significant in all patients.
From the Research
Diuretic Effect of Entresto (Sacubitril/Valsartan)
- Entresto (sacubitril/valsartan) has been shown to increase endogenous natriuretic peptides, which promote diuresis, natriuresis, and vasodilatation 3
- The inhibition of neprilysin by sacubitril leads to an increase in the levels of natriuretic peptides, resulting in a diuretic effect 3, 4
- A case study reported that sacubitril/valsartan was effective in improving symptoms such as dyspnea and edema, and reducing NT-proBNP levels by increasing endogenous ANP levels in a patient with heart failure and impaired ANP secretion due to long-standing atrial fibrillation 4
- A multicenter retrospective cohort study found that the combination of sacubitril/valsartan and atrial natriuretic peptide increased urinary output in patients with heart failure, suggesting a diuretic effect 5
- The pharmacological mechanisms of sacubitril/valsartan, including the reduction in the degradation of natriuretic peptides, contribute to its diuretic effect 6
Key Findings
- Sacubitril/valsartan increases endogenous natriuretic peptides, leading to a diuretic effect 3, 4
- The combination of sacubitril/valsartan and atrial natriuretic peptide enhances urinary output in patients with heart failure 5
- Sacubitril/valsartan has been shown to improve symptoms such as dyspnea and edema, and reduce NT-proBNP levels in patients with heart failure 4