Can patients with chronic kidney disease stage 4 be treated with dapagliflozin (Farxiga)?

Dapagliflozin (Farxiga) in CKD Stage 4: Evidence-Based Recommendation

Yes, patients with CKD stage 4 can and should take dapagliflozin 10 mg daily for cardiovascular and renal protection when eGFR is ≥25 mL/min/1.73 m², but it should not be initiated if eGFR is <25 mL/min/1.73 m².

Defining CKD Stage 4 and Initiation Thresholds

• CKD stage 4 is defined as eGFR 15–29 mL/min/1.73 m², which means only the upper portion of stage 4 (eGFR 25–29 mL/min/1.73 m²) qualifies for dapagliflozin initiation 1.
• The FDA label explicitly states that dapagliflozin 10 mg once daily is recommended for patients with eGFR ≥25 mL/min/1.73 m² to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure 1.
• The 2022 KDIGO guidelines recommend initiating SGLT2 inhibitors when eGFR is ≥20 mL/min/1.73 m² and continuing them until dialysis or transplantation is initiated 2.

Critical Distinction: Glycemic Control vs. Cardiorenal Protection

• Dapagliflozin is NOT recommended for glycemic control when eGFR <45 mL/min/1.73 m² because it is likely ineffective due to its mechanism of action, which requires adequate renal glucose filtration 3, 1.
• However, the cardiovascular and renal protective benefits are preserved at lower eGFR levels, independent of glucose-lowering effects 2, 3.
• The standard dose remains 10 mg once daily for cardiorenal protection in CKD stage 4 patients with eGFR ≥25 mL/min/1.73 m²—no dose adjustment is required 4, 1.

Landmark Trial Evidence Supporting Use in Advanced CKD

• The DAPA-CKD trial enrolled 4,304 participants with eGFR 25–75 mL/min/1.73 m² and UACR 200–5,000 mg/g; 15% had baseline eGFR <30 mL/min/1.73 m² (CKD stage 4) 5, 6.
• Dapagliflozin reduced the primary composite outcome (≥50% sustained eGFR decline, end-stage kidney disease, or renal/cardiovascular death) by 39% (HR 0.61,95% CI 0.51–0.72) 5.
• The kidney-specific composite outcome was reduced by 44% (HR 0.56,95% CI 0.45–0.68) 1, 5.
• Cardiovascular death or hospitalization for heart failure decreased by 29% (HR 0.71,95% CI 0.55–0.92) 1, 5.
• All-cause mortality was reduced by 31% (HR 0.69,95% CI 0.53–0.88) 5.
• These benefits were consistent regardless of diabetes status—68% had type 2 diabetes and 32% did not 7, 5.

Pre-Initiation Assessment for CKD Stage 4 Patients

• Confirm eGFR is ≥25 mL/min/1.73 m² before starting dapagliflozin 3, 1.
• Assess and correct volume depletion before initiation; consider reducing concurrent diuretic doses in elderly patients or those on loop/thiazide diuretics 3, 4.
• Continue ACE inhibitors or ARBs unchanged—97% of DAPA-CKD participants were on renin-angiotensin system blockers, and the combination provided additive renal protection 6, 8.

Expected eGFR Changes and Monitoring

• An acute, reversible eGFR dip of 2–5 mL/min/1.73 m² typically occurs within the first 2–4 weeks; this hemodynamic change should not prompt discontinuation 3.
• Re-measure eGFR 1–2 weeks after initiation to document the expected dip, then monitor periodically 3, 4.
• After the initial dip, eGFR stabilizes and the long-term decline is slower compared with placebo 3.

Continuation Below the Initiation Threshold

• If eGFR falls below 25 mL/min/1.73 m² during treatment, patients may continue dapagliflozin 10 mg daily until dialysis or transplantation is initiated 2, 1.
• The 2022 KDIGO guidelines advocate continuing SGLT2 inhibitors as long as tolerated, even if eGFR falls below 20 mL/min/1.73 m², until kidney replacement therapy begins 2.

Safety Precautions Specific to CKD Stage 4

• Temporarily withhold dapagliflozin during acute illness with reduced oral intake, fever, vomiting, or diarrhea, and stop at least 3 days before major surgery or procedures requiring prolonged fasting 3, 1.
• Genital mycotic infections occur in approximately 6% of patients versus 1% with placebo; counsel patients on daily hygiene 3, 4.
• Warn about euglycemic diabetic ketoacidosis and advise immediate medical evaluation for malaise, nausea, vomiting, or abdominal pain even when blood glucose is normal 3.
• Volume depletion risk is higher in elderly patients and those on concurrent diuretics; monitor volume status closely 3, 4.

Common Pitfalls to Avoid in CKD Stage 4

• Do not discontinue dapagliflozin solely because eGFR falls below 45 mL/min/1.73 m²; cardiovascular and renal benefits persist despite loss of glycemic efficacy 2, 3.
• Do not stop dapagliflozin in response to the expected early eGFR dip; the change is hemodynamic and reversible, not indicative of kidney injury 3.
• Do not reduce the dose below 10 mg for cardiovascular or renal indications; all outcome trials used the fixed 10 mg dose 3.
• Do not withhold ACE inhibitors or ARBs when starting dapagliflozin—the combination is safe and provides additive renal protection 8.

Integration with Other CKD Therapies

• Dapagliflozin should be used alongside ACE inhibitors or ARBs as part of foundational CKD management 2, 8.
• When combined with mineralocorticoid receptor antagonists, dapagliflozin provides additive renal benefits and may lessen hyperkalemia risk 2.
• SGLT2 inhibition is positioned as foundational therapy for slowing CKD progression and preventing cardiovascular events, irrespective of glycemic status 2.

Efficacy Across Albuminuria Levels

• While DAPA-CKD enrolled patients with UACR 200–5,000 mg/g (median 949 mg/g), real-world evidence demonstrates similar kidney protection across all albuminuria levels, including those with UACR <200 mg/g 9.
• The strongest evidence for benefit exists in patients with UACR ≥200 mg/g, but efficacy extends to lower albuminuria levels 3, 9.