DELIVER Trial Summary: Dapagliflozin in Heart Failure with Preserved/Mildly Reduced Ejection Fraction
The DELIVER trial demonstrated that dapagliflozin 10 mg daily reduces cardiovascular death or worsening heart failure events by 18% in patients with heart failure and ejection fraction >40%, with benefits occurring regardless of diabetes status, background medications, or renal function down to eGFR ≥25 mL/min/1.73 m². 1, 2
Trial Design and Population
DELIVER was an international, multicenter, randomized, double-blind, placebo-controlled trial enrolling 6,263 patients aged ≥40 years with symptomatic heart failure (NYHA class II-IV) and LVEF >40%. 2, 3
Patients required elevated natriuretic peptides (NT-proBNP ≥300 pg/mL or ≥600 pg/mL for those in atrial fibrillation/flutter) and evidence of structural heart disease. 3
The trial included 3,131 patients randomized to dapagliflozin 10 mg daily and 3,132 to placebo, with median follow-up of 28 months (2.3 years). 2, 4
Approximately 10% of patients were randomized during hospitalization for heart failure or within 30 days of discharge. 2
Primary Outcome Results
Dapagliflozin reduced the primary composite endpoint of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit by 18% (HR 0.82 [95% CI 0.73-0.92]; P=0.0008). 1, 2
Event rates were 7.8 per 100 patient-years with dapagliflozin versus 9.6 per 100 patient-years with placebo. 2
All three components of the primary endpoint individually contributed to the treatment effect, with the dapagliflozin and placebo event curves separating early and continuing to diverge throughout the trial period. 2
Component Outcomes
Hospitalization for heart failure or urgent heart failure visit: reduced by 21% (HR 0.79 [95% CI 0.69-0.91]). 2
Hospitalization for heart failure alone: reduced by 23% (HR 0.77 [95% CI 0.67-0.89]). 2
Cardiovascular death: HR 0.88 (95% CI 0.74-1.05), showing a trend toward benefit though not statistically significant as a single component. 2
Urgent heart failure visits: reduced by 24% (HR 0.76 [95% CI 0.55-1.07]). 2
Efficacy Across Subgroups
Diabetes Status
Benefits were consistent across glycemic categories: normoglycemia (HR 0.77 [95% CI 0.57-1.04]), prediabetes (HR 0.87 [95% CI 0.69-1.08]), and type 2 diabetes (HR 0.81 [95% CI 0.69-0.95]; p for interaction=0.82). 4
The heart failure benefits of dapagliflozin were consistent across the continuous HbA1c range (p for interaction=0.85), demonstrating effects independent of glucose-lowering. 1, 4
Of the 6,263 patients, 1,175 had normoglycemia, 1,934 had prediabetes, and 3,150 had type 2 diabetes. 4
Background Medications
At baseline, 77% of patients were on ACE inhibitor/ARB/ARNI, 83% on beta-blocker, 43% on mineralocorticoid receptor antagonist, and 98% on diuretics. 2
Treatment benefits were consistent regardless of whether patients received ≥50% of target doses of background heart failure medications. 5, 6
Diuretic Use
Benefits were consistent across diuretic categories: no diuretic (10.9% of patients), non-loop diuretic (12.3%), and loop diuretic doses of <40 mg, 40 mg, and >40 mg furosemide equivalent (76.8% total on loop diuretics; p for interaction=0.64). 7
Dapagliflozin reduced new initiation of loop diuretics by 32% (HR 0.68 [95% CI 0.55-0.84]; P<0.001). 7
The mean dose of loop diuretic increased over time in the placebo arm, an increase that was significantly attenuated with dapagliflozin (placebo-corrected treatment effect of -2.5 mg/year; 95% CI: -1.5 to -3.7; P<0.001). 7
Previous Myocardial Infarction
In pooled analysis with DAPA-HF, 34% of patients had previous MI, which conferred higher risk of the primary outcome (adjusted HR 1.12 [95% CI 1.02-1.24]). 8
Dapagliflozin reduced the primary outcome similarly in patients with (HR 0.83 [95% CI 0.72-0.96]) and without previous MI (HR 0.76 [95% CI 0.68-0.85]; p for interaction=0.36). 8
Renal Function Considerations
An initial eGFR decline is expected and frequent with dapagliflozin but does not indicate harm. 9
Median eGFR change from baseline to month 1 was -4 mL/min/1.73 m² (-9 to 1) with dapagliflozin versus -1 mL/min/1.73 m² (-6 to 5) with placebo (difference -3; P<0.001). 9
40% of dapagliflozin-treated patients developed an initial eGFR decline >10% versus 25% with placebo (OR 1.9 [95% CI 1.7-2.1]). 9
Critical clinical point: An initial eGFR decline >10% was associated with higher cardiovascular risk in placebo patients (adjusted HR 1.33 [95% CI 1.10-1.62]) but NOT in dapagliflozin-treated patients (adjusted HR 0.90 [95% CI 0.74-1.09]; p for interaction=0.01). 9
Initial eGFR decline >10% was not associated with adverse kidney composite outcomes in dapagliflozin-treated patients (adjusted HR 0.94 [95% CI 0.49-1.82]). 9
These data reinforce that dapagliflozin should not be interrupted or discontinued in response to an initial eGFR decline. 1, 9
Safety Profile
Serious adverse events were similar between dapagliflozin and placebo arms, irrespective of diuretic use or dosing. 7
Volume-related or renal serious adverse events, adverse events leading to discontinuation, hypoglycemia, and amputations were not differentially affected by treatment in any glycemic category. 4
Dapagliflozin has minimal blood pressure effects, with no excess risk of symptomatic hypotension. 1
Safety considerations include monitoring for euglycemic ketoacidosis (though risk is significantly lower in non-diabetic populations), genital mycotic infections (1.5-1.7%), and urinary tract infections (2.3-2.7%). 5
Clinical Implementation
Dapagliflozin 10 mg once daily is the recommended dose with no need for titration or adjustment based on heart failure symptoms. 6
The medication can be initiated in patients with eGFR ≥25 mL/min/1.73 m², and if eGFR falls below 25 mL/min/1.73 m² while on treatment, dapagliflozin can be continued for cardiovascular benefit until dialysis. 6
Dapagliflozin should be initiated during heart failure hospitalization in stabilized patients, as deferring initiation results in many eligible patients never receiving the medication within 1 year. 1
Benefits occur within weeks of initiation and are maintained regardless of age, sex, or background medical therapy. 6
Unlike many heart failure medications, dapagliflozin does not affect blood pressure, heart rate, or potassium levels, making it easier to combine with other guideline-directed medical therapy. 6