How should Entresto (sacubitril/valsartan) and empagliflozin be used and dosed in a patient with heart failure with reduced ejection fraction?

Entresto vs Empagliflozin in Heart Failure with Reduced Ejection Fraction

Both Entresto (sacubitril/valsartan) and empagliflozin should be used together in patients with HFrEF—they are complementary therapies, not alternatives to choose between. This represents the current standard of care based on the most recent guidelines and evidence.

Sequential Implementation Strategy

Start with Empagliflozin First

• Initiate empagliflozin 10 mg daily immediately in all HFrEF patients (LVEF ≤40%) 1, 2
• Requires eGFR >30 mL/min/1.73 m² for dapagliflozin or >60 mL/min/1.73 m² for empagliflozin 3
• Benefits appear within 12 days of initiation 4
• No titration needed—single dose throughout treatment

Then Add or Switch to Entresto

Entresto should replace (not add to) your ACE inhibitor or ARB 5, 6, 2

Starting dose:

• 49/51 mg twice daily for most patients 7
• 24/26 mg twice daily if:
  • Not currently on ACE-I/ARB or on low doses
  • Severe renal impairment (eGFR <30 mL/min/1.73 m²)
  • Moderate hepatic impairment
  • Age ≥75 years with concerns about tolerability 3, 7

Titration schedule:

• Increase dose every 2-4 weeks as tolerated 7
• Target dose: 97/103 mg twice daily 1, 2, 3
• Monitor BP, potassium, and renal function at each step

Critical safety requirement: Wait 36 hours after last ACE inhibitor dose before starting Entresto to avoid angioedema risk 7, 8

Why Both Medications?

Complementary Mechanisms

These drugs work through different pathways:

• Empagliflozin (SGLT2 inhibitor): Reduces sodium reabsorption, improves cardiac metabolism, decreases oxidative stress 1, 9
• Entresto (ARNI): Enhances natriuretic peptides while blocking angiotensin II 5, 7

Mortality and Hospitalization Benefits

Entresto vs. enalapril:

• 20% reduction in cardiovascular death or HF hospitalization (HR 0.80) 5
• 16% reduction in all-cause mortality (HR 0.84) 5
• Benefits consistent regardless of baseline blood pressure (even SBP <122 mmHg) 5

Empagliflozin vs. placebo:

• 25% reduction in cardiovascular death or HF hospitalization 9
• 30% reduction in HF hospitalizations 4
• 35% reduction in hospitalization for HF in EMPA-REG OUTCOME 10

Additive Effects

The 2022 AHA/ACC/HFSA guidelines explicitly recommend both drug classes as foundational therapy for HFrEF 2. The 2025 Canadian guidelines similarly position both as cornerstone treatments 1.

Practical Dosing Considerations

Entresto Dose Achievement in Real-World Practice

Only 15-25% of patients reach target dose (97/103 mg twice daily) in clinical practice 11. Patients more likely to tolerate higher doses have:

• Younger age
• Higher hemoglobin levels
• Better baseline blood pressure (SBP >100 mmHg)
• Better renal function (eGFR >30 mL/min/1.73 m²) 12, 13

However, even lower doses provide benefit—don't withhold Entresto if target dose cannot be achieved 13, 14.

Empagliflozin Simplicity

Empagliflozin requires no titration and has fewer dose-limiting side effects than Entresto 1, 3. This makes it easier to implement quickly.

Monitoring Requirements

For Entresto:

• Blood pressure: Check before each dose increase; hold if SBP <95 mmHg with symptoms 3, 7
• Potassium: Monitor at 2-3 days, then monthly for 3 months; hold if K+ >5.5 mEq/L 3, 7
• Renal function: Check creatinine at each visit; reduce dose if eGFR drops >30% 3, 7

For Empagliflozin:

• Renal function: Ensure eGFR >30 mL/min/1.73 m² before starting 3
• Volume status: Monitor for dehydration, especially with diuretics 1
• Genital mycotic infections: More common in women and diabetics 15

Common Pitfalls to Avoid

1. Waiting to start empagliflozin until "optimizing" other medications—start it immediately alongside beta-blockers 1, 2

2. Adding Entresto to existing ACE-I/ARB instead of replacing—this increases hyperkalemia and renal dysfunction risk 6

3. Starting Entresto too soon after stopping ACE-I—the 36-hour washout prevents life-threatening angioedema 7, 8

4. Abandoning Entresto after one failed titration attempt—even 24/26 mg or 49/51 mg twice daily provides meaningful benefit 13, 14

5. Withholding empagliflozin in non-diabetics—benefits are independent of diabetes status 10, 15, 9

Special Populations

Patients Not on Beta-Blockers

Entresto may provide greater mortality benefit (HR 0.47 vs 0.84) in patients not taking beta-blockers compared to those on beta-blockers 16. However, beta-blockers remain foundational therapy and should be optimized first when possible.

Recent HF Hospitalization

Both medications are safe and effective in recently hospitalized patients 17, 14. Empagliflozin can be started during hospitalization before discharge 1. Entresto can be initiated once hemodynamically stable, typically before discharge or within 30 days 17, 14.

Preserved or Mildly Reduced EF (LVEF 41-60%)

• Empagliflozin: Strong evidence for benefit across entire LVEF spectrum >40% 1, 2
• Entresto: Benefits greatest when LVEF ≤60%; consider in LVEF 41-49% especially if lower end of range 2, 14