What are the implications of the Deliver study on the use of dapagliflozin (SGLT2 inhibitor) in patients with heart failure, particularly those with preserved left ventricular ejection fraction (LVEF)?

DELIVER Trial Summary: Dapagliflozin in Heart Failure with Preserved Ejection Fraction

Trial Design and Population

The DELIVER trial was a landmark international, multicenter, randomized, double-blind, placebo-controlled study that enrolled 6,263 patients with heart failure and left ventricular ejection fraction (LVEF) >40% to determine whether dapagliflozin 10 mg daily reduces cardiovascular death, heart failure hospitalization, or urgent heart failure visits. 1

Key Enrollment Criteria

• Patients aged ≥40 years with symptomatic heart failure (NYHA class II-IV) 1
• LVEF >40% with evidence of structural heart disease 1
• Elevated natriuretic peptide levels required for enrollment 2
• Mean baseline LVEF was 54.2 ± 8.8% 2
• Median NT-proBNP was 1,399 pg/mL in patients with atrial fibrillation/flutter and 716 pg/mL in those without 2

Patient Demographics

• Mean age 72 ± 10 years, with 44% women 2
• 45% had type 2 diabetes mellitus 2
• 57% had history of atrial fibrillation or flutter 2
• 75% had NYHA class II symptoms 2
• 10% were enrolled during hospitalization or within 30 days of heart failure hospitalization 1, 3
• 34% had previous myocardial infarction 4

Background Therapy

• 77% were on ACE inhibitors, ARBs, or ARNI 1
• 83% were on beta-blockers 1
• 43% were on mineralocorticoid receptor antagonists 1
• 98% were on diuretics 1

Primary 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) over a median follow-up of 28 months. 5, 1

Component Outcomes

• Hospitalization for heart failure or urgent heart failure visit: 21% reduction (HR 0.79 [95% CI 0.69-0.91]) 1
• Hospitalization for heart failure alone: 23% reduction (HR 0.77 [95% CI 0.67-0.89]) 1
• Cardiovascular death: 12% reduction (HR 0.88 [95% CI 0.74-1.05], not statistically significant) 1
• Urgent heart failure visits: 24% reduction (HR 0.76 [95% CI 0.55-1.07]) 1

Total Events Analysis

When examining total (first and recurrent) heart failure events rather than just time to first event, dapagliflozin demonstrated even greater benefit with a 23% reduction in the rate of total HF events and cardiovascular death (rate ratio 0.77 [95% CI 0.67-0.89]; P < 0.001). 6

Time Course of Benefit

A critical finding was the remarkably rapid onset of clinical benefit—dapagliflozin achieved first nominal statistical significance for the primary endpoint at just 13 days post-randomization (HR 0.45 [95% CI 0.20-0.99]; P = 0.046), with sustained significance from day 15 onwards. 7

• For worsening heart failure events specifically, first and sustained statistical significance was reached by day 16 (HR 0.45 [95% CI 0.21-0.96]; P = 0.04) 7
• Benefits remained consistent at 30 days, 90 days, 6 months, 1 year, 2 years, and final follow-up 7
• The treatment curves separated early and continued to diverge throughout the trial period 1

Special Populations

Recently Hospitalized Patients

Among the 654 patients (10.4%) randomized during heart failure hospitalization or within 30 days of discharge, dapagliflozin reduced the primary outcome by 22% (HR 0.78 [95% CI 0.60-1.03]) compared to 18% in patients without recent hospitalization (HR 0.82 [95% CI 0.72-0.94]; P-interaction = 0.71), demonstrating consistent benefit regardless of hospitalization status. 3

• Recently hospitalized patients had 88% higher risk of the primary outcome after multivariable adjustment (HR 1.88 [95% CI 1.60-2.21]; P < 0.001) 3
• Safety profile was similar in recently hospitalized patients, with no excess volume depletion, diabetic ketoacidosis, or renal events 3

Patients with Previous Myocardial Infarction

In the 3,731 patients (34%) with previous MI, dapagliflozin reduced the primary outcome by 17% (HR 0.83 [95% CI 0.72-0.96]) compared to 24% in those without previous MI (HR 0.76 [95% CI 0.68-0.85]; P-interaction = 0.36), showing consistent efficacy across MI history. 4

Safety Profile

Dapagliflozin demonstrated a favorable safety profile with no increase in serious adverse events compared to placebo. 3

• Symptomatic hypotension occurred in similar rates between groups 5
• No excess kidney adverse events despite use with ACE inhibitors/ARBs/ARNI and MRAs 5
• Genital mycotic infections occurred in 1.5-1.7% of patients 8
• Urinary tract infections occurred in 2.3-2.7% of patients 8
• Risk of diabetic ketoacidosis was significantly lower in non-diabetic populations 8

Clinical Implications and Guideline Recommendations

The American College of Cardiology and American Diabetes Association provide Class I recommendations for SGLT2 inhibitors, including dapagliflozin, in all patients with symptomatic heart failure regardless of ejection fraction or diabetes status. 5, 8

Implementation Strategy

• Initiate dapagliflozin 10 mg once daily during hospitalization in stabilized patients, as deferring initiation results in many eligible patients never receiving the medication within 1 year 5, 8
• No dose titration required, unlike ACE inhibitors, ARBs, or beta-blockers 5
• Can be used with eGFR as low as 25 mL/min/1.73 m² 5, 8
• Contraindicated only if eGFR <25 mL/min/1.73 m² or on dialysis 5
• Continue existing guideline-directed medical therapy, as dapagliflozin provides additive benefit 5

Mechanism Beyond Glucose Lowering

The benefits of dapagliflozin in heart failure appear independent of glucose-lowering effects, representing direct cardiovascular benefit through enhanced diuretic efficacy via natriuresis, improved myocardial energetics through ketone utilization, and reduced cardiac fibrosis. 5, 8