Is Dapagliflozin First-Line for HFpEF?
Yes, dapagliflozin 10 mg daily is now a first-line, core therapy for all patients with heart failure with preserved ejection fraction (HFpEF), alongside diuretics for congestion management. 1, 2
Evidence Supporting First-Line Status
SGLT2 Inhibitors as Core HFpEF Therapy
The American College of Cardiology and European Heart Journal recommend initiating SGLT2 inhibitors (dapagliflozin or empagliflozin) in all patients with HFpEF (LVEF >40%) with NYHA class II-IV symptoms as core treatment. 1, 2
Both dapagliflozin and empagliflozin demonstrate robust benefits across the entire ejection fraction spectrum, with a class effect showing consistent reductions in cardiovascular death and heart failure hospitalizations. 1, 2
Dapagliflozin's Unique Advantages in HFpEF
Dapagliflozin is the only medication proven to improve both clinical outcomes AND functional capacity/quality of life in HFpEF patients. 3
In the DELIVER trial, dapagliflozin reduced the combined risk of cardiovascular death or worsening heart failure by 18% (HR 0.82,95% CI 0.73-0.92, p<0.001) in patients with LVEF >40%. 4, 5
The PRESERVED-HF trial demonstrated that dapagliflozin significantly improved the Kansas City Cardiomyopathy Questionnaire score by 5.8 points and increased 6-minute walk distance by 8.2% at 12 weeks—the first drug trial to achieve this in HFpEF. 3
In contrast, other HFpEF medications showed disappointing results on exercise capacity: spironolactone (mean difference -1 to 0.4 mL/kg/min VO2, p=0.38), sacubitril/valsartan (mean difference in 6MWD 2.5m, p=0.42), and empagliflozin (mean difference in 6MWD 4m, p=0.37). 3
Practical Implementation
Dosing and Initiation
Start dapagliflozin at 10 mg once daily with no titration required and no dose adjustment needed for age, sex, or background therapy. 1
Initiate dapagliflozin during hospitalization for heart failure in stabilized patients, not deferring to outpatient follow-up, as clinical benefits accrue within days to weeks. 1, 6
Statistical significance for reduction in worsening heart failure events was achieved by day 16 after randomization and sustained thereafter. 7
Safety Profile Supporting Early Use
Dapagliflozin requires no dose adjustment or up-titration, does not affect blood pressure, heart rate, or potassium levels, making it ideal for early implementation. 3
The drug has a strong safety profile with minimal blood pressure effects, no excess kidney adverse events, and low risk of hypoglycemia, lower limb amputations, bone fracture, or diabetic ketoacidosis. 3, 1
Benefits are maintained even in patients with eGFR as low as 20 mL/min/1.73 m². 4
Universal Benefit Regardless of Background Therapy
Dapagliflozin provides incremental benefit regardless of background medical therapy, including ACE inhibitors/ARBs, beta-blockers, mineralocorticoid receptor antagonists, and ARNI. 1
In the DAPA-HF trial subanalysis, effectiveness was similar irrespective of whether patients received ≥50% of target doses of background HF medications. 3
Benefits are completely independent of diabetes status, with similar hazard ratios in patients with (HR 0.75,95% CI 0.63-0.90) and without diabetes (HR 0.73,95% CI 0.60-0.88). 1
Comparison with Other HFpEF Therapies
Sacubitril/Valsartan
The FDA granted approval for sacubitril/valsartan in selected HFpEF patients based largely on the PARAGON-HF trial, but this was a less definitive result compared to SGLT2 inhibitor trials. 3
Sacubitril/valsartan showed no significant improvement in exercise capacity (mean difference in 6MWD 2.5m, p=0.42). 3
Spironolactone
Despite promising post hoc analyses from the TOPCAT trial, the FDA issued no final determination on spironolactone use for HFpEF. 3
Spironolactone failed to improve exercise capacity in HFpEF trials. 3
Clinical Context: The Evolution of HFpEF Treatment
Until recently, most HFpEF trials of pharmacological therapy were neutral on their primary outcomes of clinical events (HF hospitalizations and cardiovascular death). 3
The EMPEROR-PRESERVED and DELIVER trials were the first unequivocally positive trials for HFpEF, showing reduction in combined risk of HF hospitalizations or cardiovascular death. 3
Current 2021 HFA/ESC guidelines recommend SGLT2 inhibitors as core treatments suitable for all HFrEF patients, and this recommendation now extends to HFpEF based on DELIVER and EMPEROR-PRESERVED. 3
Key Pitfall to Avoid
- Do not defer SGLT2 inhibitor initiation to outpatient follow-up after heart failure hospitalization. Dapagliflozin safely reduced risk of worsening HF or cardiovascular death similarly in patients with and without recent HF hospitalization, and starting during or shortly after hospitalization is both safe and effective. 6