What is the use of dapagliflozin (SGLT2 inhibitor) in non-diabetic patients with heart failure with reduced ejection fraction (HFrEF) or chronic kidney disease (CKD)?

Dapagliflozin Use in Non-Diabetic Patients with HFrEF or CKD

Dapagliflozin is strongly recommended for non-diabetic patients with heart failure with reduced ejection fraction (HFrEF) or chronic kidney disease (CKD) due to its proven benefits in reducing mortality, hospitalizations, and disease progression. 1, 2

Indications for Non-Diabetic Patients

• Dapagliflozin (10 mg daily) is FDA-approved to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure visits in adults with heart failure, regardless of diabetes status 1
• Dapagliflozin is indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression, with or without diabetes 1
• These indications are supported by multiple large randomized controlled trials showing consistent benefits in non-diabetic populations 2

Benefits in Non-Diabetic HFrEF Patients

• In the DAPA-HF trial, dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 27% in non-diabetic patients with HFrEF (HR 0.73 [95% CI 0.60-0.88]) 2, 3
• The benefits were consistent regardless of baseline glycemic status, including in patients with completely normal glycated hemoglobin levels <5.7% 3
• Dapagliflozin significantly improved exercise capacity in non-diabetic HFrEF patients, with a 3.1 mL/kg/min increase in peak oxygen uptake after 6 months of treatment 4
• Treatment resulted in a 24% reduction in NYHA class III patients, indicating significant symptomatic improvement 4

Benefits in Non-Diabetic CKD Patients

• In the DAPA-CKD trial, dapagliflozin reduced the primary composite outcome (sustained decline in eGFR of ≥50%, end-stage kidney disease, or death from renal or cardiovascular causes) by 39% (HR 0.61 [95% CI 0.51-0.72]) 2
• The renal-specific composite outcome (excluding cardiovascular death) was reduced by 44% (HR 0.56 [95% CI 0.45-0.68]) 2
• All-cause mortality was reduced by 31% (HR 0.69 [95% CI 0.53-0.88]) in CKD patients regardless of diabetes status 5
• The benefits were consistent across the spectrum of baseline kidney function (eGFR ≥25 mL/min/1.73 m²) 6

Dosing and Monitoring for Non-Diabetic Patients

• The recommended dose is 10 mg orally once daily for heart failure and CKD indications 1
• Assess renal function prior to initiation and periodically thereafter 1
• Correct volume depletion before initiating therapy to minimize risk of hypotension 1
• Withhold dapagliflozin for at least 3 days prior to major surgery or procedures requiring prolonged fasting 1

Safety Considerations in Non-Diabetic Patients

• Volume depletion was reported in 7.3% of non-diabetic patients on dapagliflozin versus 6.1% on placebo in the DAPA-HF trial 3
• Renal adverse events were actually lower in non-diabetic patients on dapagliflozin (4.8%) compared to placebo (6.0%) 3
• Hypotension may occur in approximately 5.7% of patients, especially those with volume depletion 7
• While diabetic ketoacidosis is a concern in diabetic patients, this risk is significantly lower in non-diabetic populations 2
• Genital mycotic infections (1.5-1.7%) and urinary tract infections (2.3-2.7%) can occur but are generally manageable 7

Clinical Implementation Algorithm

1. Identify eligible non-diabetic patients:

   • HFrEF patients (LVEF ≤40%) with NYHA class II-IV symptoms 2, 3
   • CKD patients with eGFR 25-75 mL/min/1.73 m² and UACR ≥200 mg/g 2

2. Assess contraindications:

   • History of serious hypersensitivity to dapagliflozin 1
   • Polycystic kidney disease 1
   • Recent immunosuppressive therapy for kidney disease 1

3. Baseline evaluation:

   • Measure eGFR, electrolytes, and volume status 1
   • Correct volume depletion if present 1

4. Initiate dapagliflozin 10 mg once daily 1

5. Monitor:

   • Renal function periodically 1
   • Signs of volume depletion (hypotension, dizziness) 7
   • Symptoms of heart failure or kidney disease progression 2

Conclusion

Dapagliflozin provides significant cardiorenal benefits in non-diabetic patients with HFrEF or CKD, with consistent risk reductions in heart failure hospitalizations, kidney disease progression, and mortality. The safety profile is favorable in non-diabetic populations, with lower risks of metabolic complications compared to diabetic patients.