What are the findings of the DAPA-HF (Dapagliflozin), Emperor Reduced, Emperor Preserved, and Deliver trials on SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in heart failure management?

Summary of Major SGLT2 Inhibitor Trials in Heart Failure Management

SGLT2 inhibitors significantly reduce cardiovascular mortality, heart failure hospitalizations, and improve quality of life across the spectrum of heart failure patients regardless of ejection fraction or diabetes status, as demonstrated in the DAPA-HF, EMPEROR-Reduced, EMPEROR-Preserved, and DELIVER trials. 1

DAPA-HF Trial (Dapagliflozin)

• Enrolled 4,744 patients with heart failure with reduced ejection fraction (HFrEF) ≤40%, NYHA class II-IV, with 45% having type 2 diabetes 1, 2
• Over a median follow-up of 18.2 months, dapagliflozin 10mg daily reduced:
  • Primary composite outcome of worsening heart failure or cardiovascular death by 26% (HR 0.74 [95% CI 0.65-0.85]) 1
  • First worsening heart failure event by 30% (HR 0.70 [95% CI 0.59-0.83]) 1
  • Cardiovascular death by 18% (HR 0.82 [95% CI 0.69-0.98]) 1, 2
• Benefits were consistent regardless of diabetes status 1, 3
• Most patients (94%) were on ACE inhibitors/ARBs/ARNIs, 96% on beta-blockers, and 71% on mineralocorticoid receptor antagonists 2

EMPEROR-Reduced Trial (Empagliflozin)

• Enrolled 3,730 patients with HFrEF ≤40%, NYHA class II-IV, with approximately 50% having type 2 diabetes 1, 4
• Over a median follow-up of 26.2 months, empagliflozin 10mg daily reduced:
  • Primary composite outcome of cardiovascular death or hospitalization for worsening heart failure by 21% (HR 0.79 [95% CI 0.69-0.90]; P < 0.001) 1
  • Benefits were consistent in patients with or without diabetes 1
• Unlike DAPA-HF, no significant cardiovascular mortality benefit was observed with empagliflozin alone, but meta-analysis of both trials showed reduction in cardiovascular death 1, 5
• Serious renal outcomes were less frequent, and the rate of eGFR decline was slower in patients treated with empagliflozin 1, 5

EMPEROR-Preserved Trial (Empagliflozin)

• First successful randomized controlled trial for heart failure with preserved ejection fraction (HFpEF) 6
• Enrolled 5,988 patients with HFpEF (LVEF >40%), randomized to empagliflozin 10mg daily or placebo 6
• Empagliflozin led to:
  • 21% risk reduction in the composite of cardiovascular death or hospitalization for heart failure 6
  • 29% lower risk of hospitalization for heart failure 6
  • Neutral effect on cardiovascular death when analyzed separately 6

DELIVER Trial (Dapagliflozin)

• Enrolled 6,263 patients with heart failure and ejection fraction >40% 1
• Over a median follow-up of 28 months, dapagliflozin reduced:
  • Primary outcome of worsening heart failure (hospitalization or urgent visit) or cardiovascular death by 18% (HR 0.82 [95% CI 0.73-0.92]; P < 0.001) 1
  • Approximately 44% of participants had type 2 diabetes, with consistent results regardless of diabetes status 1

Meta-Analysis of All Trials

• A comprehensive meta-analysis of all five major trials (EMPEROR-Reduced, EMPEROR-Preserved, DAPA-HF, DELIVER, and SOLOIST-WHF) including 21,947 patients showed:
  • Reduced risk for composite of cardiovascular death or hospitalization for heart failure (HR 0.77 [0.72-0.82]) 1, 7
  • Reduced cardiovascular death (HR 0.87 [0.79-0.95]) 7
  • Reduced first hospitalization for heart failure (HR 0.72 [0.67-0.78]) 7
  • Reduced all-cause mortality (HR 0.92 [0.86-0.99]) 7
  • Treatment effects were consistent across all trials and subgroups, including across the spectrum of ejection fraction 7

Clinical Implications

• SGLT2 inhibitors are now strongly recommended for all patients with symptomatic heart failure regardless of ejection fraction or diabetes status 1, 8
• Benefits appear independent of glucose-lowering effects 1
• Safety considerations include monitoring for:
  • Euglycemic ketoacidosis 1, 8
  • Genital and soft tissue infections 1
  • Volume depletion, especially when combined with diuretics 1, 8

Economic Value

• Cost-effectiveness analyses of dapagliflozin found costs per QALY between $60,000 and $90,000, consistent with intermediate value 1
• Results were most sensitive to the magnitude of cardiovascular mortality reduction 1

These landmark trials have established SGLT2 inhibitors as foundational therapy for heart failure across the spectrum of ejection fraction, representing one of the most significant advances in heart failure management in recent years 7.