What is the role of Farxiga (dapagliflozin) in treating albuminuria in an adult patient with a history of diabetes or hypertension?

Farxiga (Dapagliflozin) for Albuminuria

Dapagliflozin should be initiated in adult patients with albuminuria (≥200 mg/g) and chronic kidney disease (eGFR 25-75 mL/min/1.73 m²), regardless of diabetes status, as it significantly reduces albuminuria by approximately 29-38% and slows kidney disease progression. 1, 2

Evidence-Based Indications

For Patients WITH Type 2 Diabetes:

• Dapagliflozin reduces albuminuria by 35% in diabetic patients with CKD when added to ACE inhibitor or ARB therapy 2
• The DAPA-CKD trial demonstrated a 56% reduction in the composite kidney outcome (≥50% sustained decline in eGFR, ESKD, or renal death) 1
• Dapagliflozin reduced the risk of new or worsening nephropathy by 36% in cardiovascular outcomes trials 1
• The DELIGHT trial showed dapagliflozin alone reduced albuminuria by 21%, and when combined with saxagliptin reduced it by 38% at 24 weeks 3

For Patients WITHOUT Type 2 Diabetes:

• Dapagliflozin reduces albuminuria by 15% in non-diabetic CKD patients 2
• In DAPA-CKD, 32.5% of participants had CKD without diabetes, and benefits were consistent across both groups 1
• The protective effect appears partially independent of albuminuria reduction, suggesting additional renoprotective mechanisms 2

Specific Patient Selection Criteria

Initiate dapagliflozin when:

• UACR ≥200 mg/g (22.6 mg/mmol) and eGFR 25-75 mL/min/1.73 m² 1, 2
• Patient is already on maximally tolerated ACE inhibitor or ARB therapy (>99% of CREDENCE and DAPA-CKD participants were on RAS blockade) 1
• For glycemic control in diabetes: eGFR ≥45 mL/min/1.73 m² without established CVD, or eGFR ≥25 mL/min/1.73 m² with established CVD or CKD 4

Continue dapagliflozin even if:

• eGFR falls below 25 mL/min/1.73 m² after initiation (patients were not required to discontinue in DAPA-CKD) 4
• Dialysis is initiated after enrollment 4

Expected Albuminuria Response

Magnitude and Timeline:

• Geometric mean UACR reduction of 29.3% overall compared to placebo 2
• Greater relative reduction in patients with diabetes (35%) versus without diabetes (15%), though absolute benefits similar 2
• Albuminuria reduction evident early and sustained throughout treatment 3, 2

Clinical Significance:

• Larger reductions in UACR at day 14 are associated with slower subsequent eGFR decline (β per log unit UACR change -3.06 mL/min/1.73 m²/year) 2
• Dapagliflozin increased likelihood of regression from macroalbuminuria to microalbuminuria/normoalbuminuria (HR 1.81) 2
• Decreased risk of progression to severe albuminuria (≥3000 mg/g) by 59% (HR 0.41) 2

Managing the Initial eGFR Dip

Expected Hemodynamic Changes:

• An initial, transient eGFR decrease of 3-5 mL/min/1.73 m² within 2-4 weeks is expected and represents reduced intraglomerular pressure, not kidney injury 5
• In DAPA-CKD, 49.4% of dapagliflozin-treated patients experienced >10% acute eGFR reduction versus 23.7% on placebo 6

Management Algorithm:

• Continue dapagliflozin if creatinine increase is <30% from baseline with stable volume status 5
• Do not discontinue for initial eGFR dip, as patients with >10% acute reduction actually had slower long-term eGFR decline (-1.58 vs -2.44 mL/min/1.73 m²/year) 6
• Use BUN:creatinine ratio to differentiate hemodynamic changes (ratio <10:1) from volume depletion 5
• Check urine microscopy if concerned about tubular injury (excellent negative predictive value) 5

Long-term Renal Protection:

• Despite initial eGFR dip, dapagliflozin reduces risk of doubling serum creatinine by 44% long-term 5
• Rates of serious adverse events unrelated to acute eGFR change magnitude 6

Cardiovascular and Mortality Benefits

Beyond Albuminuria Reduction:

• 31% reduction in cardiovascular death or heart failure hospitalization in CREDENCE 1
• 29% reduction in composite of cardiovascular death or hospitalization for heart failure in DAPA-CKD 1
• All-cause mortality decreased in dapagliflozin group 1

Safety Considerations

Common Adverse Events:

• Genital mycotic infections (particularly in women) are most common 7, 8
• Low risk of hypoglycemia when used alone or with metformin 7, 8
• Diabetic ketoacidosis is rare but more common than placebo; educate patients on risk factors 1, 8

Monitoring Requirements:

• Monitor serum creatinine and potassium when initiating, especially if on ACE inhibitor/ARB 1
• Assess volume status, particularly in elderly patients (higher risk of hypotension) 4
• Continue monitoring UACR to assess treatment response 1

Integration with Guideline-Recommended Therapy

First-Line Foundation:

• ACE inhibitors or ARBs remain first-line for hypertension with albuminuria 1
• Optimize blood pressure to <130/80 mmHg in most patients with CKD 1
• Optimize glycemic control (HbA1c targets individualized) 1

Add Dapagliflozin as Second-Line:

• SGLT2 inhibitors like dapagliflozin should be added to RAS blockade for additional renoprotection 1
• The 2024 ADA guidelines position SGLT2 inhibitors prominently in the treatment algorithm for CKD with albuminuria 1
• Consider adding finerenone (nonsteroidal MRA) for further risk reduction in appropriate patients 1

Common Pitfalls to Avoid

• Do not discontinue dapagliflozin for initial eGFR dip if <30% increase in creatinine and patient is euvolemic 5, 6
• Do not withhold dapagliflozin in non-diabetic CKD patients; benefits extend beyond glycemic control 2
• Do not delay initiation waiting for "optimal" blood pressure control; benefits are additive to RAS blockade 1
• Do not use combination ACE inhibitor + ARB therapy (associated with harm); use SGLT2 inhibitor as add-on instead 1
• Do not restrict protein excessively; maintain 0.8 g/kg/day 1