What is the preferred treatment for heart failure with reduced ejection fraction, Entresto (sacubitril/valsartan) or SGLT2 (sodium-glucose cotransporter 2) inhibitors?

Treatment for Heart Failure with Reduced Ejection Fraction: Entresto vs. SGLT2 Inhibitors

For patients with heart failure with reduced ejection fraction (HFrEF), both Entresto (sacubitril/valsartan) and SGLT2 inhibitors should be used as part of quadruple therapy, with neither being preferred over the other as they target different pathophysiological mechanisms and provide complementary benefits. 1, 2

Current Guideline Recommendations

The American College of Cardiology (ACC) recommends four cornerstone drug classes for guideline-directed medical therapy (GDMT) for HFrEF:

1. Renin-angiotensin system inhibitors (preferably ARNI - sacubitril/valsartan)
2. Beta-blockers (carvedilol, metoprolol succinate, or bisoprolol)
3. Mineralocorticoid receptor antagonists (spironolactone or eplerenone)
4. SGLT2 inhibitors (dapagliflozin or empagliflozin)

Entresto (Sacubitril/Valsartan)

• Indicated for HFrEF (EF ≤40%) with NYHA class II-IV symptoms 1
• Preferred over ACE inhibitors or ARBs as the renin-angiotensin system inhibitor of choice 1, 2
• Demonstrated significant mortality benefit in the PARADIGM-HF trial
• Starting dose: 24/26mg BID; Target dose: 97/103mg BID 2
• Contraindications include:
  • Pregnancy
  • History of angioedema
  • Severe hepatic impairment (Child-Pugh C)
  • Concomitant aliskiren use in patients with diabetes 1

SGLT2 Inhibitors

• Indicated for HFrEF (EF ≤40%) with NYHA class II-IV symptoms, with or without diabetes 1
• Dapagliflozin (10mg daily) or empagliflozin (10mg daily) 2
• Contraindications include:
  • eGFR <30 mL/min/1.73 m² for dapagliflozin
  • eGFR <20 mL/min/1.73 m² for empagliflozin
  • Patients on dialysis 1

Comparative Benefits

Entresto (Sacubitril/Valsartan)

• Reduces mortality and hospitalization for heart failure 1
• Improves cardiac remodeling with increased LVEF and decreased LV volumes 1
• Improves diastolic function and quality of life 1
• Reduces burden of ventricular arrhythmias 1

SGLT2 Inhibitors

• Reduce heart failure hospitalizations and cardiovascular death 1, 3
• Provide renal protection 3, 4
• Effective across a broad spectrum of patients regardless of:
  • Diabetic status
  • Renal function (within limits)
  • Acute or chronic settings 3

Implementation Strategy

For optimal management of HFrEF, implement quadruple therapy in this order:

1. Start with beta-blocker (carvedilol, metoprolol succinate, or bisoprolol)
2. Add or switch to Entresto (sacubitril/valsartan) - if patient is on ACEi/ARB, ensure 36-hour washout period if switching from ACEi 1
3. Add mineralocorticoid receptor antagonist (spironolactone or eplerenone)
4. Add SGLT2 inhibitor (dapagliflozin or empagliflozin)

Special Considerations

• Advanced heart failure: In patients with NYHA class IV symptoms, the benefits of sacubitril/valsartan may be less pronounced. A recent trial showed no statistically significant difference between sacubitril/valsartan and valsartan in reducing NT-proBNP levels in patients with advanced heart failure 5

• Renal function:

  • SGLT2 inhibitors can be used with eGFR ≥30 mL/min/1.73m² for dapagliflozin and ≥20 mL/min/1.73m² for empagliflozin 1
  • Entresto requires dose adjustment for moderate hepatic impairment 1

• Hypotension risk:

  • Entresto has higher rates of hypotension (14.0% vs. 9.2% with enalapril) 1
  • Consider adjusting diuretic dose when adding SGLT2 inhibitors to prevent volume depletion 1

Common Pitfalls to Avoid

1. Delaying quadruple therapy: All four drug classes should be initiated as soon as possible, as the combined therapy is estimated to reduce mortality risk by 73% over 2 years compared to no treatment 2

2. Inadequate dose titration: Many patients remain on initial doses rather than target doses. Follow forced-titration strategies to achieve maximum benefits 1

3. Waiting for clinical deterioration: Don't delay adding therapies even if patients appear clinically stable, as these medications prevent sudden death and disease progression 1

4. Skipping ARNI due to cost concerns: If Entresto is not accessible due to coverage issues, an ACEi/ARB should be used instead 1

5. Stopping therapy due to asymptomatic laboratory changes: Minor changes in laboratory values should not prevent uptitration to target doses unless they threaten clinical stability 1

In conclusion, both Entresto and SGLT2 inhibitors are essential components of quadruple therapy for HFrEF, with complementary mechanisms of action and benefits. The optimal approach is to use both medications as part of comprehensive GDMT rather than choosing between them.