How does Dapagliflozin work in heart failure as part of quadruple therapy, including an Angiotensin-Converting Enzyme inhibitor (ACEi) or Angiotensin Receptor Blocker (ARB), a beta-blocker, and a Mineralocorticoid Receptor Antagonist (MRA)?

How Dapagliflozin Works in Heart Failure as Quadruple Therapy

Direct Answer

Dapagliflozin should be added to existing quadruple therapy (ACEi/ARB/ARNI + beta-blocker + MRA) in all patients with symptomatic heart failure regardless of ejection fraction or diabetes status, as it provides incremental mortality and morbidity benefit beyond optimized background therapy. 1, 2

Mechanism of Action in Heart Failure

Dapagliflozin works through multiple complementary mechanisms that are independent of glucose-lowering effects:

Renal and Hemodynamic Effects

• Inhibits proximal tubular sodium-glucose reabsorption, leading to glucosuria and natriuresis that enhances diuretic efficacy when combined with loop diuretics 3
• Triggers tubuloglomerular feedback through increased distal tubule sodium delivery, causing afferent arteriolar vasoconstriction that prevents glomerular hyperfiltration and provides long-term kidney protection 3
• Promotes decongestion more effectively than standard diuretics alone, facilitating fluid removal in acute and chronic heart failure 4

Metabolic and Cardiac Effects

• Shifts cardiac metabolism toward ketone utilization, which requires less oxygen than glucose or fatty acid metabolism, directly improving myocardial energetics 3
• Reduces cardiac fibrosis and adverse remodeling through mechanisms that complement the effects of RAAS inhibitors and beta-blockers 3

Evidence for Incremental Benefit Beyond Triple/Quadruple Therapy

Heart Failure with Reduced Ejection Fraction (HFrEF)

In DAPA-HF, 94% of patients were already on ACEi/ARB/ARNI, 96% on beta-blockers, and 71% on MRAs at baseline, yet dapagliflozin still reduced the primary composite endpoint of cardiovascular death or worsening heart failure by 26% (HR 0.74,95% CI 0.65-0.85, p<0.0001). 5

• Cardiovascular death was reduced by 18% (HR 0.82,95% CI 0.69-0.98) 5
• Heart failure hospitalizations were reduced by 30% (HR 0.70,95% CI 0.59-0.83) 5
• All-cause mortality was reduced by 31% in patients with HFrEF 6
• Benefits were identical in patients with and without diabetes (HR 0.75 vs 0.73, respectively) 1, 2

Heart Failure with Mildly Reduced or Preserved Ejection Fraction (HFmrEF/HFpEF)

In DELIVER, 77% of patients were on ACEi/ARB/ARNI, 83% on beta-blockers, and 43% on MRAs, yet dapagliflozin reduced the primary endpoint by 18% (HR 0.82,95% CI 0.73-0.92, p=0.0008). 5, 7

• Worsening heart failure events were reduced by 21% (HR 0.79,95% CI 0.69-0.91) 5
• Benefits were consistent across the entire ejection fraction spectrum, including patients with LVEF ≥60% 7
• Dapagliflozin is the only medication proven to improve both clinical outcomes and functional capacity/quality of life in HFpEF patients 1

Clinical Implementation as Fourth Pillar of Therapy

Guideline Recommendations

The 2022 ACC/AHA/HFSA guidelines recommend SGLT2 inhibitors (Class I recommendation) for all patients with symptomatic HFrEF (LVEF ≤40%) in addition to ACEi/ARB/ARNI, beta-blockers, and MRAs. 3

The 2024 ESC guidelines recommend dapagliflozin or empagliflozin (Class I recommendation) for patients with HFmrEF or HFpEF (LVEF >40%) to reduce cardiovascular death and heart failure hospitalizations. 3

Dosing and Initiation

• Standard dose is 10 mg once daily with no titration required 1, 2
• No dose adjustment needed for age, sex, or background therapy 1
• Can be initiated in patients with eGFR as low as 25 mL/min/1.73 m² 2
• Should be started during hospitalization in stabilized patients, not deferred to outpatient follow-up, as deferring is associated with high likelihood patients will never receive the medication within 1 year 2

Safety Profile with Quadruple Therapy

Dapagliflozin has minimal blood pressure effects, particularly in patients with lower baseline blood pressure (95-110 mmHg), where the average BP decrease is only 1.5 mmHg and diminishes to <1 mmHg after 4 months. 3

• Symptomatic hypotension occurred in only 0.3% of dapagliflozin patients vs 0.5% of placebo patients in DAPA-HF 3
• No excess kidney adverse events despite use with ACEi/ARB/ARNI and MRAs 1, 2
• Low risk of hypoglycemia, amputations, fractures, or diabetic ketoacidosis 1
• Preserves kidney function rather than causing adverse renal effects, reducing composite renal outcomes by 39-44% 2, 5

Severe Heart Failure Populations

Among patients with severe heart failure (NYHA III/IV, recent hospitalization, KCCQ <75), dapagliflozin reduced cardiovascular death or worsening heart failure consistently across all ejection fractions (3-way interaction p=0.52) with an acceptable safety profile. 8

• Severe heart failure patients had 85% higher event rates than non-severe patients (adjusted HR 1.85,95% CI 1.60-2.12) 8
• Treatment benefit was maintained regardless of severe HF status (interaction p=0.48) 8

Critical Implementation Points

When to Add Dapagliflozin

Initiate immediately once ACEi/ARB/ARNI and beta-blocker are started, without waiting for MRA optimization or target doses of other medications. 1, 2

• Clinical benefits accrue within days to weeks of initiation 1
• The STRONG-HF trial demonstrated safety and efficacy of rapid uptitration of all four GDMT components within 2 weeks in patients with eGFR ≥30 mL/min/1.73 m² 3

Contraindications and Cautions

• Avoid in patients with eGFR <25 mL/min/1.73 m² or on dialysis 5
• Monitor for euglycemic ketoacidosis, particularly in patients with very low carbohydrate intake or prolonged fasting 2
• Monitor for genital and soft tissue infections 2
• Use caution when combined with high-dose loop diuretics due to enhanced natriuresis 3

Continuation of Existing Therapy

Do not discontinue or reduce doses of ACEi/ARB/ARNI, beta-blockers, or MRAs when adding dapagliflozin, as the benefits are additive, not substitutive. 2