What is the role of Dapagliflozin (SGLT2 inhibitor) in the treatment of heart failure with reduced ejection fraction?

Dapagliflozin in Heart Failure with Reduced Ejection Fraction: The DAPA-HF Trial

Dapagliflozin 10 mg daily is a cornerstone therapy for all patients with heart failure and reduced ejection fraction (HFrEF), reducing cardiovascular death and heart failure hospitalizations by 26% regardless of diabetes status, and should be initiated immediately—even during hospitalization—as clinical benefits emerge within 2 weeks. 1, 2, 3

Key Trial Results: DAPA-HF

The DAPA-HF trial enrolled 4,744 patients with symptomatic HFrEF (NYHA class II-IV, LVEF ≤40%) and demonstrated:

• Primary composite outcome (cardiovascular death or worsening heart failure): 26% relative risk reduction (HR 0.74,95% CI 0.65-0.85, p<0.0001) 3, 4
• Worsening heart failure events: 30% reduction (HR 0.70,95% CI 0.59-0.83) 3
• Cardiovascular death: 18% reduction (HR 0.82,95% CI 0.69-0.98) 3
• All-cause mortality: 31% reduction 1

Rapid Onset of Benefit

The treatment effect appears remarkably early:

• Statistically significant benefit by day 13-28 after randomization, with sustained separation of event curves thereafter 5, 6
• This rapid benefit supports immediate initiation rather than deferring therapy 1

Universal Benefit Across Patient Populations

Diabetes Status

The benefits are completely independent of diabetes status:

• Patients with diabetes: HR 0.75 (95% CI 0.63-0.90) 1
• Patients without diabetes: HR 0.73 (95% CI 0.60-0.88) 1, 2
• This represents a true cardiovascular benefit unrelated to glucose lowering 1, 7

Background Heart Failure Therapies

Dapagliflozin provides incremental benefit regardless of background medical therapy, including:

• ACE inhibitors/ARBs (at any dose): consistent benefit 1
• Beta-blockers (at any dose): consistent benefit 1
• Mineralocorticoid receptor antagonists: HR 0.80 (95% CI 0.66-0.98) 1
• Angiotensin receptor-neprilysin inhibitors (ARNI): HR 0.90 (95% CI 0.48-1.69) 1
• Triple therapy (ACE/ARB + beta-blocker + MRA): HR 0.74 (95% CI 0.59-0.93) 1

Prior Heart Failure Hospitalization

Patients with recent HF hospitalization derive the greatest absolute benefit:

• No prior hospitalization: 2.1% absolute risk reduction at 2 years 5
• Hospitalization >12 months ago: 4.1% absolute risk reduction 5
• Hospitalization ≤12 months ago: 9.9% absolute risk reduction (HR 0.64,95% CI 0.51-0.80) 5

In-Hospital Initiation: A Critical Opportunity

Dapagliflozin should be initiated during hospitalization for heart failure, not deferred to outpatient follow-up. 1

Rationale for In-Hospital Initiation

• Clinical benefits accrue within days to weeks, making hospitalization an ideal time to start 1
• Strong safety profile with minimal blood pressure effects and no excess kidney adverse events 1
• Deferring initiation leads to never initiating: >75% of eligible patients discharged without medication will not start it within 1 year 1
• Patients are at highest risk immediately post-discharge, when dapagliflozin provides maximum benefit 1, 5

Safety During Hospitalization

• Numerically fewer serious adverse events than placebo 1
• No symptomatic hypotension risk (unlike ACE inhibitors or ARBs) 1
• No adverse renal effects—instead preserves kidney function 1
• Well tolerated in older patients with rare symptomatic side effects 1

Expanded Indications Beyond HFrEF

Heart Failure with Mildly Reduced or Preserved Ejection Fraction (HFmrEF/HFpEF)

The DELIVER trial (6,263 patients with LVEF >40%) demonstrated:

• Primary outcome reduction: 18% (HR 0.82,95% CI 0.73-0.92, p<0.001) 3, 8
• Worsening heart failure events: 21% reduction (HR 0.79,95% CI 0.69-0.91) 3, 8
• Benefits consistent across LVEF spectrum, including LVEF ≥60% 8
• Rapid benefit onset: statistically significant by day 16 6

Recommendation: Dapagliflozin 10 mg daily is recommended for all symptomatic patients with HFmrEF or HFpEF (LVEF >40%) to reduce cardiovascular death and heart failure hospitalizations 1

Chronic Kidney Disease

The DAPA-CKD trial demonstrated benefits in CKD patients (eGFR 25-75 mL/min/1.73m², UACR ≥200 mg/g):

• Primary composite outcome (≥50% eGFR decline, ESKD, CV/renal death): 39% reduction (HR 0.61,95% CI 0.51-0.72) 3
• Hospitalization for heart failure: 49% reduction (HR 0.51,95% CI 0.34-0.76) 3
• Benefits consistent with or without diabetes 2, 3

Practical Implementation

Patient Selection

Initiate dapagliflozin in all patients with:

• HFrEF (LVEF ≤40%) with NYHA class II-IV symptoms 1, 2
• HFmrEF/HFpEF (LVEF >40%) with NYHA class II-IV symptoms 1
• eGFR ≥25 mL/min/1.73m² 3

Dosing

• Standard dose: 10 mg once daily 3, 4
• No titration required—full dose from initiation 1, 2
• No dose adjustment for age, sex, or background therapy 1

Contraindications

• eGFR <20 mL/min/1.73m² (for HF indication; <25 for CKD indication) 2, 3
• History of serious hypersensitivity to dapagliflozin 2
• Polycystic kidney disease or recent immunosuppressive therapy for kidney disease 2

Monitoring

• Renal function: Monitor periodically, especially after initiation 2
• Volume status: Assess for signs of depletion (hypotension occurs in ~5.7%) 2
• Genital mycotic infections (1.5-1.7%) and urinary tract infections (2.3-2.7%) are manageable but should be monitored 2

Important Caveat: Transient eGFR Decline

• A mild, transient decrease in eGFR may occur after initiation but does not indicate kidney injury 2
• Do not discontinue for this expected hemodynamic effect 2
• Long-term kidney function is preserved with continued therapy 1, 3

Comparison with Other SGLT2 Inhibitors

Both dapagliflozin and empagliflozin demonstrate robust benefits in HFrEF:

• Empagliflozin (EMPEROR-Reduced): 25% reduction in CV death/HF hospitalization (HR 0.75,95% CI 0.65-0.86) 1, 7
• Dapagliflozin has additional evidence in HFpEF (DELIVER trial), making it particularly valuable for preserved ejection fraction 7, 8
• Both medications show class effect with consistent benefits 1

Avoiding Common Pitfalls

1. Do not defer initiation to outpatient setting—start during hospitalization when feasible 1
2. Do not withhold due to "borderline" blood pressure—minimal hypotension risk unlike other HF medications 1
3. Do not discontinue for mild eGFR decline—this is expected and does not indicate harm 2
4. Do not restrict to diabetic patients—benefits are independent of diabetes status 1, 4
5. Do not wait for optimization of other HF therapies—benefits are additive regardless of background therapy 1