Which drug is most helpful for patients with heart failure with recovered or preserved ejection fraction (HFpEF)?

SGLT2 Inhibitors Are First-Line for HFpEF and HFmrEF

SGLT2 inhibitors (empagliflozin or dapagliflozin) are the most helpful medications for patients with heart failure with recovered or preserved ejection fraction, with the strongest evidence for reducing heart failure hospitalizations and cardiovascular events across the entire spectrum of preserved ejection fraction. 1

Primary Recommendation: SGLT2 Inhibitors

The 2022 AHA/ACC/HFSA guidelines give SGLT2 inhibitors a Class 2a recommendation (moderate strength) for both HFmrEF (LVEF 41-49%) and HFpEF (LVEF ≥50%), making them the only medication class with consistent benefit across all preserved ejection fraction phenotypes. 1

Evidence Base for SGLT2 Inhibitors

• Empagliflozin reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 21% in EMPEROR-Preserved (LVEF >40%), driven primarily by a 29% reduction in heart failure hospitalizations. 1, 2

• Dapagliflozin demonstrated a hazard ratio of 0.82 (95% CI 0.73-0.92, P=0.0008) for cardiovascular death, hospitalization, or urgent heart failure visit in the DELIVER trial. 3

• The benefit of SGLT2 inhibitors is consistent regardless of diabetes status, making them universally applicable. 1, 2

Important Nuance on Ejection Fraction Spectrum

• SGLT2 inhibitors show consistent benefit across the entire LVEF spectrum in HFpEF, though there may be slightly attenuated effects at very high ejection fractions (>62.5% or >65%). 1, 2

• Dapagliflozin maintained benefit across all LVEF ranges, while empagliflozin showed some signal for reduced benefit above LVEF 65%. 1, 2

Secondary Medications: Conditional Recommendations

For HFmrEF (LVEF 41-49%)

Patients with HFmrEF, particularly those with LVEF on the lower end of this spectrum (41-45%), may benefit from the full HFrEF medication regimen including ACE inhibitors/ARBs/ARNI, beta-blockers, and mineralocorticoid receptor antagonists (MRAs). 1

• Beta-blockers showed mortality benefit in a meta-analysis of 575 patients with LVEF 40-49% in sinus rhythm (BBmeta-HF analysis). 1

• Sacubitril-valsartan (ARNI) demonstrated benefit in PARAGON-HF subgroup analysis for patients with LVEF 45-57%, with rate ratio 0.78 (95% CI 0.64-0.95). 1

• Spironolactone reduced the primary composite endpoint in TOPCAT subgroup analysis of 520 patients with LVEF 44-49%, primarily through cardiovascular mortality reduction. 1

For HFpEF (LVEF ≥50%)

Beyond SGLT2 inhibitors, evidence for other medications in true HFpEF is weak or absent. 1

• The 2012 ESC guidelines explicitly state that no treatment has been convincingly shown to reduce morbidity and mortality in HFpEF, with negative trials including CHARM-Preserved (candesartan), PEP-CHF (perindopril), and I-PRESERVE (irbesartan). 1

• Finerenone, a non-steroidal MRA, recently showed promise in FINEARTS-HF with 31% risk reduction when combined with SGLT2 inhibitors, though this represents emerging rather than established therapy. 4, 5, 6

Practical Implementation Algorithm

Step 1: Initiate SGLT2 Inhibitor

• Start dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily. 3
• Can be initiated during hospitalization in stabilized patients. 3
• Provides additive benefit to existing therapies. 3

Step 2: Assess LVEF Range

• If LVEF 41-45%: Add beta-blocker (evidence-based for HFrEF), ARNI/ACEi/ARB, and MRA as tolerated. 1
• If LVEF 46-49%: Consider beta-blocker, ARNI/ACEi/ARB, and MRA based on individual factors (hypertension, prior HFrEF). 1
• If LVEF ≥50%: SGLT2 inhibitor remains primary disease-modifying therapy; other agents lack robust evidence. 1

Step 3: Symptomatic Management

• Use loop diuretics (furosemide) at the lowest effective dose for fluid retention. 1
• Uptitrate diuretic dose before adding combination diuresis. 1
• For refractory edema, add thiazide/thiazide-like diuretic (metolazone) with close monitoring of renal function and electrolytes. 1

Critical Pitfalls to Avoid

Do not withhold SGLT2 inhibitors based on absence of diabetes—the benefit is independent of glycemic status. 1, 2

Do not assume all HFpEF medications work equally—only SGLT2 inhibitors have consistent Class 2a guideline support across the preserved EF spectrum. 1

Do not over-diurese patients with HFpEF, as this can reduce cardiac output and worsen symptoms while preventing use of disease-modifying therapies. 1

Repeat LVEF assessment is essential, as patients with "recovered" EF (previously reduced, now improved) should continue HFrEF guideline-directed medical therapy to prevent recrudescence. 1

Emerging Therapies

GLP-1 receptor agonists (semaglutide, tirzepatide) show promise specifically for obese HFpEF phenotype, with impact on heart failure hospitalizations and quality of life, though not yet guideline-recommended. 7, 6, 8

The combination of SGLT2 inhibitor plus non-steroidal MRA (finerenone) is projected to provide 3.6 additional years free from cardiovascular death or heart failure events in a 65-year-old patient with HFmrEF/HFpEF. 5