Are SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors more effective in Heart Failure with Reduced Ejection Fraction (HFrEF) versus Heart Failure with Preserved Ejection Fraction (HFpEF)?

SGLT2 Inhibitors: Comparable Efficacy in HFrEF and HFpEF

SGLT2 inhibitors provide robust cardiovascular benefits in both HFrEF and HFpEF, with similar relative risk reductions for the composite outcome of cardiovascular death or heart failure hospitalization (approximately 20-26% reduction), though the absolute benefit for reducing cardiovascular death alone is clearly established only in HFrEF. 1, 2

Comparative Efficacy by Heart Failure Phenotype

HFrEF (LVEF ≤40%)

• SGLT2 inhibitors are Class I, Level A recommendations for all patients with HFrEF to reduce cardiovascular death and heart failure hospitalizations 1, 2
• Dapagliflozin reduced the composite outcome of worsening heart failure or cardiovascular death by 26% (HR 0.74,95% CI 0.65-0.85) in the DAPA-HF trial 2
• Empagliflozin reduced the same composite outcome by 25% (HR 0.75,95% CI 0.65-0.86) in EMPEROR-Reduced 2
• Cardiovascular death alone was reduced by 18% in HFrEF patients 2
• First worsening heart failure events were reduced by 30% 2

HFpEF (LVEF >40%)

• SGLT2 inhibitors are Class 2a, Level B-R recommendations for patients with HFpEF to decrease heart failure hospitalizations and cardiovascular mortality 1, 3
• Empagliflozin reduced the composite outcome by 21% (HR 0.79) in EMPEROR-Preserved 4
• Dapagliflozin reduced the composite outcome by 18% in the DELIVER trial 2, 5
• Cardiovascular death alone showed no significant reduction (HR 0.88,95% CI 0.77-1.00) in HFpEF 6
• The benefit was primarily driven by a 29% reduction in heart failure hospitalizations rather than mortality 4

HFmrEF (LVEF 41-49%)

• SGLT2 inhibitors receive Class 2a recommendations for this intermediate phenotype 1, 3
• Benefits appear consistent across the entire ejection fraction spectrum, including patients with LVEF 50-60% (HR 0.64,95% CI 0.54-0.76) and >60% (HR 0.84,95% CI 0.71-0.98) 5

Key Differences in Clinical Outcomes

Mortality Benefit

The most important distinction is that SGLT2 inhibitors definitively reduce cardiovascular death in HFrEF but not in HFpEF 2, 6. In HFpEF, the benefit is almost entirely from reducing heart failure hospitalizations 4, 6.

Hospitalization Reduction

Both phenotypes show robust reductions in heart failure hospitalizations (27-39% across trials), with consistent class effects 2, 6, 5.

Quality of Life

SGLT2 inhibitors improve Kansas City Cardiomyopathy Questionnaire (KCCQ) scores in both HFrEF and HFpEF, with mean improvement of 1.33 points (95% CI 1.31-1.35) compared to baseline 5.

Clinical Implementation Algorithm

Step 1: Identify Eligible Patients

• HFrEF (LVEF ≤40%): All patients with NYHA class II-IV symptoms 2
• HFpEF (LVEF >40%): Symptomatic patients (NYHA class II-IV) with frequent symptoms or recent hospitalizations 1, 6
• Both phenotypes: Benefits are independent of diabetes status 1, 2

Step 2: Check for Contraindications

• eGFR <20 mL/min/1.73m² is the primary contraindication 2
• Dapagliflozin has been shown effective with eGFR as low as 20-30 mL/min/1.73m² 2
• History of serious hypersensitivity to SGLT2 inhibitors 2

Step 3: Initiate Therapy

• Dapagliflozin 10 mg daily or empagliflozin 10 mg daily are the evidence-based options 2
• No dose titration required, unlike other heart failure medications 1, 2
• Can be initiated during hospitalization in stabilized patients (no increase in IV diuretics for 6 hours, no IV vasodilators or inotropes for 24 hours) 1
• Early initiation is critical: empagliflozin showed 58% relative risk reduction at just 12 days after initiation 1

Step 4: Monitor

• Mild, transient decrease in eGFR may occur but does not indicate kidney injury and should not prompt discontinuation 2
• Monitor for volume depletion (hypotension occurs in approximately 5.7% of patients) 2
• Genital mycotic infections (1.5-1.7%) and urinary tract infections (2.3-2.7%) are manageable adverse effects 2

Common Pitfalls to Avoid

Deferring Initiation

Patients not prescribed SGLT2 inhibitors at hospital discharge have a >75% chance they will not be initiated within the next year 1. Current data show only 15.7% of eligible HFrEF patients receive SGLT2 inhibitors at discharge, despite 94.8% being eligible 7.

Restricting to Diabetic Patients

SGLT2 inhibitors provide equivalent benefits regardless of diabetes status 1, 2. In DAPA-HF, non-diabetic patients experienced a 27% risk reduction (HR 0.73,95% CI 0.60-0.88) 2.

Withholding Due to Mild Renal Dysfunction

Benefits extend to patients with eGFR 25-75 mL/min/1.73m², and the medication should not be withheld based on mild renal impairment 2.

Using Ertugliflozin

Ertugliflozin lacks dedicated heart failure outcome trials and should not be used, as evidence is specific to dapagliflozin and empagliflozin 2.

Strength of Evidence Comparison

The evidence quality is highest for HFrEF (Class I, Level A) based on DAPA-HF and EMPEROR-Reduced trials 1, 2. For HFpEF, the evidence is strong but slightly lower (Class 2a, Level B-R) based on EMPEROR-Preserved and DELIVER trials 1, 4. The consistent benefit across the ejection fraction spectrum in pooled analyses supports broad application 5.