Entresto Does NOT Cause Hypokalemia—It Causes Hyperkalemia
Entresto (sacubitril/valsartan) is associated with hyperkalemia (elevated potassium), not hypokalemia (low potassium), and this risk is actually LOWER compared to traditional ACE inhibitors like enalapril. 1, 2
Mechanism of Hyperkalemia Risk
- Entresto contains valsartan, an angiotensin receptor blocker (ARB) that blocks angiotensin II-dependent aldosterone release, leading to potassium retention rather than potassium loss 3
- The neprilysin inhibitor component (sacubitril) does not directly affect potassium handling but works synergistically with the ARB component 3
- Like all RAAS inhibitors (ACE inhibitors, ARBs, mineralocorticoid receptor antagonists), Entresto decreases potassium excretion, making hyperkalemia the concern—not hypokalemia 1
Clinical Evidence on Potassium Effects
In the landmark PARADIGM-HF trial, Entresto actually caused LESS hyperkalemia than enalapril:
- Severe hyperkalemia (K+ >6.0 mEq/L) occurred in 2.2 per 100 patient-years with sacubitril/valsartan versus 3.1 per 100 patient-years with enalapril 2
- Overall hyperkalemia rates were comparable between groups, but severe episodes were significantly reduced with Entresto (HR 1.37 for enalapril vs. sacubitril/valsartan, p=0.02) 2
- Hyperkalemia was LESS common with sacubitril/valsartan compared to enalapril in multiple studies 4
Risk Factors for Hyperkalemia with Entresto
Monitor closely in patients with:
- Chronic kidney disease, especially CrCl <30 mL/min 1
- Concurrent use of mineralocorticoid receptor antagonists (spironolactone, eplerenone) 1, 2
- Concurrent potassium supplements or potassium-sparing diuretics 1
- Diabetes mellitus 1
- Advanced age 1
Monitoring Requirements
- Check serum potassium and renal function before initiation 1
- Monitor potassium levels regularly during treatment, especially after dose adjustments 1
- In patients with CrCl <30 mL/min or moderate hepatic impairment, start with reduced dose (24/26 mg twice daily) 1
Important Clinical Distinction
The confusion may arise because:
- Diuretics (like furosemide or thiazides) commonly used WITH Entresto for heart failure DO cause hypokalemia 1
- However, Entresto itself has the opposite effect—it promotes potassium retention 1, 3
- When Entresto is combined with loop diuretics, the potassium-wasting effect of diuretics may partially offset the potassium-retaining effect of Entresto 5
Practical Management
For your patient with mild cardiomyopathy and coronary artery disease:
- Expect hyperkalemia risk, not hypokalemia 1
- Educate patient to avoid potassium supplements, salt substitutes, and high-potassium foods 1
- Avoid NSAIDs which further increase hyperkalemia risk 1
- If using concurrent MRA therapy, the risk of severe hyperkalemia remains lower with Entresto than with traditional ACE inhibitors 2
- Monitor blood pressure as symptomatic hypotension is MORE common with Entresto than hyperkalemia 1, 6