Are sodium‑glucose cotransporter‑2 (SGLT‑2) inhibitors recommended for patients with heart failure with preserved ejection fraction?

SGLT2 Inhibitors for HFpEF: Recommendation

Yes, SGLT2 inhibitors are recommended for patients with heart failure with preserved ejection fraction (HFpEF), with a Class 2a recommendation from the 2022 AHA/ACC/HFSA guidelines. 1

Strength of Recommendation

For patients with symptomatic HFpEF (LVEF >40%) and elevated natriuretic peptides, SGLT2 inhibitors can be beneficial in decreasing heart failure hospitalizations and cardiovascular mortality. 1

• The recommendation is based primarily on the EMPEROR-Preserved trial (n=5,998), which demonstrated a 21% reduction in the composite endpoint of cardiovascular death or HF hospitalization (HR 0.79,95% CI 0.69-0.90, P<0.001) 1
• This benefit was driven predominantly by a 29% reduction in HF hospitalizations, though cardiovascular death reduction was not statistically significant (HR 0.91,95% CI 0.76-1.0) 1
• No benefit was observed on all-cause mortality 1

Specific SGLT2 Inhibitors with Evidence

Empagliflozin 10 mg daily is the agent with the strongest evidence base for HFpEF, studied in EMPEROR-Preserved 1

Dapagliflozin also has supporting evidence from the DELIVER trial, with consistent benefits across the ejection fraction spectrum 1, 2

Clinical Application Algorithm

Patient Selection Criteria:

• LVEF >40% (includes both HFpEF and HFmrEF) 1
• Symptomatic heart failure (NYHA class II-IV) 1
• Elevated natriuretic peptides as evidence of increased filling pressures 1
• eGFR ≥20 mL/min/1.73 m² (based on subgroup analyses showing safety and efficacy at this threshold) 1

Benefits Apply Regardless Of:

• Diabetes status - benefit is consistent whether or not the patient has type 2 diabetes 1
• Baseline renal function - effective down to eGFR 20 mL/min/1.73 m² 1
• Sex, age, or background medical therapy 1

Magnitude of Benefit

For HF hospitalizations specifically:

• Absolute risk reduction of approximately 3% 3
• Number needed to treat (NNT) of 30-32 patients to prevent one event 4
• Fragility index of 37-46, indicating robust statistical findings 4

Quality of life improvements:

• Mean increase in Kansas City Cardiomyopathy Questionnaire (KCCQ) score of 5-10 points 3, 5
• Functional capacity improvement of 25-30 meters on 6-minute walk test 5

Ejection Fraction Spectrum Considerations

For HFmrEF (LVEF 41-49%): SGLT2 inhibitors receive a Class 2a recommendation with stronger supporting evidence 1

For HFpEF (LVEF ≥50%): The benefit appears consistent, though there may be a signal for slightly lower benefit at LVEF >62.5% 1

• In the subgroup with LVEF 41-49% from EMPEROR-Preserved (n=1,983), empagliflozin reduced the primary composite endpoint with similar magnitude to the overall trial 1

Practical Implementation

Initiation timing:

• Can be started during hospitalization for acute decompensated HF once the patient is stabilized (systolic BP >100 mmHg, no IV vasodilators or inotropes) 1, 2
• Benefits appear within weeks of initiation 1
• Early initiation is preferred as benefits may decline rapidly after discontinuation 2

Unique advantages for implementation:

• No dose titration required - use full therapeutic dose from start 1
• No effect on blood pressure or heart rate - easier to combine with other HF medications 1
• No effect on potassium levels - may actually facilitate use of mineralocorticoid receptor antagonists 1

Safety Profile

Common adverse events:

• Genital mycotic infections: ~2.5% vs 0.5% with placebo 5
• Symptomatic hypotension: 7% vs 5% with placebo 5
• Serious adverse events comparable to placebo (~12% vs 13%) 5

Contraindications and cautions:

• eGFR <20 mL/min/1.73 m² 1
• Patients on dialysis 1
• Volume depletion - consider adjusting diuretic dose 1
• Temporary discontinuation before surgery to avoid ketoacidosis risk 1

Comparison to Other HFpEF Therapies

SGLT2 inhibitors have stronger evidence than:

• Mineralocorticoid receptor antagonists (MRAs): Class 2b recommendation for HFpEF 1
• ARNi (sacubitril-valsartan): Class 2b recommendation for HFpEF 1
• ARBs: Class 2b recommendation 1

Hypertension treatment remains Class 1 for HFpEF patients 1

Current Adoption and Implementation Gap

Despite guideline recommendations, real-world adoption remains suboptimal:

• Only 23.5% of eligible patients were prescribed SGLT2 inhibitors by September 2023, up from 4.2% in 2021 6
• Significant hospital-level variation exists, with 44.8% of hospitals discharging fewer than 10% of eligible patients with an SGLT2 inhibitor 6
• Prescription rates are higher for HFmrEF (18.5%) than HFpEF (13.0%) 6

Bottom Line

Initiate an SGLT2 inhibitor (empagliflozin 10 mg daily or dapagliflozin 10 mg daily) in all patients with symptomatic HFpEF (LVEF >40%) who have elevated natriuretic peptides and eGFR ≥20 mL/min/1.73 m², regardless of diabetes status. 1 The primary benefit is reduction in heart failure hospitalizations, with additional improvements in quality of life and renal function preservation. 1