What are the considerations for using Farxiga (dapagliflozin) in patients with Chronic Kidney Disease stage 4 (CKD4) and impaired renal function?

Dapagliflozin (Farxiga) in CKD Stage 4: Efficacy, Safety, and Considerations

Dapagliflozin can be used in patients with CKD stage 4 (eGFR 15-29 mL/min/1.73m²) for kidney and cardiovascular benefits, though it should not be initiated when eGFR is below 25 mL/min/1.73m².

Efficacy in CKD Stage 4

Dapagliflozin has demonstrated significant benefits in patients with advanced CKD, including those with stage 4:

• In the DAPA-CKD trial, dapagliflozin reduced the primary composite endpoint (≥50% sustained decline in eGFR, progression to end-stage kidney disease, CV or renal death) by 27% in patients with stage 4 CKD compared to placebo 1
• The eGFR decline was slower with dapagliflozin (2.15 mL/min/1.73m² per year) versus placebo (3.38 mL/min/1.73m² per year) in CKD stage 4 patients 1
• Benefits were consistent regardless of diabetes status, with hazard ratios of 0.64 (95% CI 0.52-0.79) for patients with type 2 diabetes and 0.50 (95% CI 0.35-0.72) for those without diabetes 2

Dosing and Renal Function Considerations

According to FDA labeling and guidelines:

• Dapagliflozin 10 mg daily is the standard dose 3
• Do not initiate dapagliflozin when eGFR is <25 mL/min/1.73m² 4, 3
• For patients already on dapagliflozin, it may be continued for kidney and cardiovascular benefits until dialysis if tolerated 4
• Glucose-lowering efficacy diminishes as eGFR declines, but kidney and cardiovascular benefits are preserved 4

Safety Profile in CKD Stage 4

• The DAPA-CKD trial showed similar rates of serious adverse events between dapagliflozin and placebo groups in stage 4 CKD patients 1
• Patients treated with dapagliflozin or placebo had similar rates of adverse events of interest in CKD stage 4 1
• The safety profile was consistent across the spectrum of frailty, with numerically lower serious adverse events in patients receiving dapagliflozin versus placebo 5

Albuminuria Effects

• Dapagliflozin significantly reduced albuminuria by 29.3% compared to placebo in the overall DAPA-CKD population 6
• Among patients with macroalbuminuria (≥300 mg/g) at baseline, dapagliflozin increased the likelihood of regression in UACR stage (HR 1.81,95% CI 1.60-2.05) 6
• Larger reductions in albuminuria were associated with attenuated eGFR decline during follow-up 6

Clinical Decision Algorithm for Dapagliflozin in CKD Stage 4

1. Assessment of eGFR and Albuminuria:

   • Confirm eGFR is between 15-29 mL/min/1.73m²
   • Measure urinary albumin-to-creatinine ratio (UACR)

2. Initiation Decision:

   • If eGFR ≥25 mL/min/1.73m²: May initiate dapagliflozin 10 mg daily
   • If eGFR <25 mL/min/1.73m²: Do not initiate dapagliflozin

3. Continuation Decision (for patients already on dapagliflozin):

   • May continue dapagliflozin for kidney and cardiovascular benefits until dialysis if tolerated
   • Monitor for adverse effects and tolerability

4. Monitoring Requirements:

   • Regular assessment of kidney function
   • Monitor for genital mycotic infections
   • Assess for volume status and hypotension
   • Watch for signs of diabetic ketoacidosis in patients with diabetes

Important Caveats and Considerations

• Dapagliflozin is not expected to be effective for glycemic control in advanced CKD 4
• Patients should be referred to a nephrologist for management of complex electrolyte disorders and preparation for potential renal replacement therapy 7
• Dapagliflozin benefits are consistent across the spectrum of frailty, suggesting it can be used in frail elderly patients with CKD stage 4 5
• Unlike some other medications, dapagliflozin has shown kidney protective effects even in advanced CKD, making it a valuable option for this population

By following this approach, clinicians can appropriately utilize dapagliflozin in patients with CKD stage 4, maximizing potential benefits while minimizing risks.