What is the role of dapagliflozin (SGLT2 inhibitor) in the treatment of heart failure with preserved ejection fraction (HFpEF) based on the DELIVER trial?

DELIVER Trial: Dapagliflozin in Heart Failure with Preserved Ejection Fraction

Dapagliflozin 10 mg once daily significantly reduces cardiovascular death and heart failure hospitalizations in patients with HFpEF (LVEF >40%), with an 18% reduction in the primary composite outcome (HR 0.82,95% CI 0.73-0.92, P=0.0008) and should be initiated in all eligible patients with symptomatic HFpEF. 1

Trial Design and Population

The DELIVER trial was a large, international, randomized, double-blind, placebo-controlled trial that enrolled 6,263 patients with heart failure and LVEF >40% across 350 centers in 20 countries. 1, 2

Key inclusion criteria:

• Symptomatic heart failure (NYHA class II-IV) 1
• LVEF >40% (mean baseline LVEF was 54.2 ± 8.8%) 2
• Elevated natriuretic peptides (median NT-proBNP 1,399 pg/mL in atrial fibrillation patients, 716 pg/mL in those without) 2
• Evidence of structural heart disease 2

Patient characteristics:

• Mean age 72 years, 44% women 3
• 45% had type 2 diabetes 3
• 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 discharge 1, 4

Primary Outcome Results

The primary composite endpoint of cardiovascular death, hospitalization for heart failure, or urgent heart failure visit was significantly reduced:

• Event rate: 7.8 per 100 patient-years with dapagliflozin vs 9.6 with placebo 1
• Hazard ratio: 0.82 (95% CI 0.73-0.92, P=0.0008) 3, 1
• Median follow-up: 2.3 years 3

Individual components of the primary endpoint:

• Hospitalization for heart failure: HR 0.77 (95% CI 0.67-0.89) 3, 1
• Urgent heart failure visits: HR 0.76 (95% CI 0.55-1.07) 1
• Cardiovascular death: HR 0.88 (95% CI 0.74-1.05, not statistically significant) 3, 1

Total Heart Failure Events (First and Recurrent)

Dapagliflozin reduced total heart failure events (first and recurrent hospitalizations plus urgent visits) by 23%:

• 815 total events with dapagliflozin vs 1,057 with placebo 1, 5
• Rate ratio: 0.77 (95% CI 0.67-0.89, P=0.0003) 1, 5

This represents a more substantial benefit than the time-to-first-event analysis alone, as patients with recurrent events had features of more severe heart failure including higher NT-proBNP levels, worse kidney function, and more prior hospitalizations. 5

Time to Clinical Benefit

Clinical benefits emerged rapidly and were sustained:

• First nominal statistical significance for the primary endpoint: 13 days after randomization (HR 0.45,95% CI 0.20-0.99, P=0.046) 6
• Sustained statistical significance from day 15 onwards 6
• For worsening heart failure events alone: significant by day 16 (HR 0.45,95% CI 0.21-0.96, P=0.04) 6
• Benefits remained consistent at 30 days, 90 days, 6 months, 1 year, 2 years, and final follow-up 6

Consistency Across Subgroups

Treatment effects were consistent across all examined subgroups, including:

• Ejection fraction range (benefits consistent across entire LVEF spectrum from >40% to 70%) 1
• Presence or absence of type 2 diabetes (45% had diabetes at baseline) 3, 1
• Age, sex, and race 1
• Baseline NT-proBNP levels 1
• Baseline kidney function (eGFR) 1
• Recent hospitalization status 4

Recently Hospitalized Patients

Dapagliflozin was safe and effective in patients enrolled during or shortly after hospitalization:

• 654 patients (10.4%) were randomized during hospitalization or within 30 days of discharge 4
• Primary outcome reduction: HR 0.78 (95% CI 0.60-1.03) in recently hospitalized vs HR 0.82 (95% CI 0.72-0.94) in others (P-interaction = 0.71) 4
• No increased rates of adverse events including volume depletion, diabetic ketoacidosis, or renal events in recently hospitalized patients 4

Impact on Diuretic Use

Dapagliflozin significantly reduced diuretic requirements over time:

• 32% reduction in new initiation of loop diuretics (HR 0.68,95% CI 0.55-0.84, P<0.001) 7
• Net difference of -6.5% (95% CI -9.4 to -3.6, P<0.001) in sustained loop diuretic dose increases vs decreases 7
• Placebo-corrected treatment effect of -2.5 mg/year reduction in mean loop diuretic dose (95% CI -1.5 to -3.7, P<0.001) 7
• Treatment benefits were consistent regardless of baseline diuretic use: no diuretic (10.9%), non-loop diuretic (12.3%), or loop diuretic (76.8%) with varying doses (P-interaction = 0.64) 7

Quality of Life and Functional Capacity

Dapagliflozin improved symptoms and functional status:

• The PRESERVED-HF trial (separate from DELIVER) showed dapagliflozin significantly improved Kansas City Cardiomyopathy Questionnaire Clinical Summary score by 5.8 points at 12 weeks 3
• 8.2% increase in 6-minute walk distance was observed 3
• This was the first drug trial to demonstrate improvement in exercise capacity and quality of life in HFpEF patients 3

Current Guideline Recommendations

The 2023 ACC Expert Consensus Decision Pathway recommends:

• SGLT2 inhibitors (including dapagliflozin) as guideline-directed medical therapy for HFpEF 3
• Initiation is essential to improve symptoms, functional capacity, and reduce morbidity and mortality 3
• SGLT2 inhibitors received a Class 2a recommendation in the ACC/AHA guidelines 3
• The American College of Cardiology strongly recommends SGLT2 inhibitors for all patients with symptomatic heart failure regardless of ejection fraction or diabetes status 8

Safety Profile

Dapagliflozin demonstrated a favorable safety profile:

• Serious adverse events were similar between dapagliflozin and placebo arms across all diuretic use categories 7
• No excess risk of symptomatic hypotension 8
• Numerically fewer serious adverse events than placebo 8
• Minimal blood pressure effects 8
• Safety considerations include monitoring for euglycemic ketoacidosis, genital and soft tissue infections, and volume depletion, especially when combined with diuretics 8

Clinical Implementation

Practical approach to initiating dapagliflozin in HFpEF:

• Start dapagliflozin 10 mg once daily 3, 1
• Can be initiated during hospitalization in stabilized patients off intravenous heart failure therapies 8, 4
• Continue existing guideline-directed medical therapy (ACE inhibitors, ARBs, beta-blockers, or MRAs) as dapagliflozin provides additive benefit 8
• Benefits are independent of glucose-lowering effects, representing direct cardiovascular benefit 8
• Can be used in patients with eGFR as low as 25 mL/min/1.73 m² 8
• Deferring initiation is associated with high likelihood that eligible patients will never receive the medication within 1 year 8

Mechanism of Benefit

The benefits of dapagliflozin in HFpEF appear to work through mechanisms beyond glycemic control:

• Effects are consistent in patients with and without diabetes 3, 1
• Benefits represent direct cardiovascular effects rather than glucose-lowering alone 8
• The exact mechanism is not fully understood but includes effects on cardiac metabolism, hemodynamics, and neurohormonal pathways 8