DAPA-HF

Dapagliflozin in chronic symptomatic HFrEF with or without diabetes
Dapagliflozin reduced worsening HF and cardiovascular death in HFrEF regardless of diabetes status, establishing SGLT2 inhibition as disease-modifying HF therapy independent of glucose lowering

Study design

  • International, multicenter, randomized, double-blind, placebo-controlled trial
  • 4,744 patients randomized
  • Median follow-up 18.2 months
  • Dapagliflozin added to recommended HFrEF therapy
  • Primary outcome: worsening HF or cardiovascular death
  • Worsening HF defined as hospitalization or urgent HF visit requiring IV therapy

Population

Included
  • Age ≥18 years
  • Chronic symptomatic HFrEF
  • NYHA class II–IV
  • LVEF ≤40%
  • Elevated NT-proBNP
  • Receiving guideline-directed HF therapy
  • 45% had type 2 diabetes
Key exclusions
  • Type 1 diabetes
  • Current or recent SGLT2 inhibitor therapy
  • Symptomatic hypotension
  • SBP <95 mmHg
  • eGFR <30 mL/min/1.73 m²
  • Rapidly progressive or unstable HF

Interventions

Dapagliflozin
  • 10 mg once daily
  • No titration required
  • Added to recommended HFrEF therapy
n = 2,373
Placebo
  • Matching placebo once daily
  • Recommended HFrEF therapy continued
n = 2,371

Primary outcome

Worsening HF or cardiovascular death
16.3% with dapagliflozin vs 21.2% with placebo
HR 0.74, 95% CI 0.65–0.85  |  P < 0.001

Dapagliflozin vs placebo

Worsening HF or cardiovascular death

25% 20% 15% 10% 5% 0%
16.3%
Dapagliflozin
n = 2,373
21.2%
Placebo
n = 2,371
16.3% vs 21.2%  |  HR 0.74  |  ARR 4.9%  |  NNT 21

Benefit emerged early and was consistent regardless of diabetes status

Major outcomes

First worsening HF event

10.0% vs 13.7%
HR 0.70, 95% CI 0.59–0.83

HF hospitalization

9.7% vs 13.4%
HR 0.70, 95% CI 0.59–0.83

Cardiovascular death

9.6% vs 11.5%
HR 0.82, 95% CI 0.69–0.98

All-cause mortality

11.6% vs 13.9%
HR 0.83, 95% CI 0.71–0.97

Secondary outcomes

CV death or HF hospitalization

16.1% vs 20.9%
HR 0.75, 95% CI 0.65–0.85
P < 0.001

Total HF hospitalizations + CV death

567 vs 742 events
Rate ratio 0.75, 95% CI 0.65–0.88
P < 0.001

KCCQ symptoms

Greater symptom improvement at 8 months
P < 0.001

Renal composite

1.2% vs 1.6%
HR 0.71, 95% CI 0.44–1.16
No significant difference

Safety

Volume depletion

7.5% vs 6.8%
No significant difference

Renal adverse events

No significant excess with dapagliflozin

Serious renal adverse events

1.6% vs 2.7%
Less frequent with dapagliflozin

Hypoglycemia

No significant difference

Stopped for adverse event

4.7% vs 4.9%
No significant difference

Diabetes status

Similar benefit with and without type 2 diabetes

Clinical interpretation

  • Dapagliflozin is disease-modifying HFrEF therapy regardless of diabetes status
  • Benefit included fewer HF events, cardiovascular deaths, and deaths from any cause
  • Absolute primary-event reduction was 4.9% over 18.2 months with NNT 21
  • No titration is required: dapagliflozin 10 mg daily was the trial dose
  • SGLT2 inhibition should be viewed as HF therapy rather than primarily glucose-lowering therapy

Limitations

  • Excluded eGFR <30 mL/min/1.73 m² and SBP <95 mmHg
  • Few patients had NYHA class IV HF
  • Less than 5% of participants were Black
  • Baseline sacubitril/valsartan use was relatively low
  • Patients with type 1 diabetes were excluded
  • Trial predates widespread contemporary quadruple HFrEF therapy
McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2019;381:1995–2008. doi:10.1056/NEJMoa1911303. NEJM