What is the role of Farxiga (dapagliflozin) in managing a patient with chronic kidney disease (CKD), particularly those with existing cardiovascular disease or at high risk for kidney function decline?

Farxiga (Dapagliflozin) for Chronic Kidney Disease

Dapagliflozin 10 mg once daily should be initiated in all CKD patients with eGFR ≥25 mL/min/1.73 m² and albuminuria (UACR ≥200 mg/g) to reduce kidney failure, cardiovascular death, and heart failure hospitalization, regardless of diabetes status or presence of cardiovascular disease. 1, 2, 3

Primary Indication and Dosing

• Fixed dose of 10 mg orally once daily for all CKD patients meeting criteria—no titration required or recommended 4, 2
• Initiate when eGFR is ≥25 mL/min/1.73 m² with UACR 200-5,000 mg/g 1, 4, 2
• Continue 10 mg daily even if eGFR falls below 25 mL/min/1.73 m² during treatment until dialysis is required 4, 2
• Do NOT initiate if eGFR <25 mL/min/1.73 m² 4, 2

Evidence of Benefit on Mortality and Morbidity

The DAPA-CKD trial provides the strongest evidence for dapagliflozin in CKD, demonstrating dramatic reductions in hard clinical outcomes:

• 39% reduction in the primary composite outcome (≥50% sustained eGFR decline, end-stage kidney disease, or renal/cardiovascular death): HR 0.61 (95% CI 0.51-0.72), p<0.001 1, 5, 2, 3
• 44% reduction in kidney-specific outcomes (same composite minus cardiovascular death): HR 0.56 (95% CI 0.45-0.68), p<0.001 1, 5, 2, 3
• 29% reduction in cardiovascular death or heart failure hospitalization: HR 0.71 (95% CI 0.55-0.92), p=0.009 1, 5, 2, 3
• 31% reduction in all-cause mortality: HR 0.69 (95% CI 0.53-0.88), p=0.004 5, 2, 3

These benefits were consistent regardless of diabetes status—67.5% had type 2 diabetes, 32.5% did not 1, 6

Benefits Independent of Cardiovascular Disease Status

The treatment effect is identical whether patients have established cardiovascular disease or not:

• Primary prevention (no CVD history): HR 0.61 (95% CI 0.48-0.78) 7
• Secondary prevention (with CVD history): HR 0.61 (95% CI 0.47-0.79), p-interaction=0.90 7
• Heart failure hospitalization/CV death composite: HR 0.67 vs 0.70 in primary vs secondary prevention, p-interaction=0.88 7
• All-cause mortality: HR 0.63 vs 0.70 in primary vs secondary prevention, p-interaction=0.71 7

This means you should prescribe dapagliflozin for CKD patients meeting eGFR/albuminuria criteria regardless of their cardiovascular disease history 7.

Benefits Independent of Heart Failure Status

• Patients with baseline heart failure: HR 0.58 (95% CI 0.37-0.91) 8
• Patients without heart failure: HR 0.62 (95% CI 0.51-0.75), p-interaction=0.59 8
• Absolute risk reductions were larger in heart failure patients due to higher baseline risk 8

Critical Distinction: Glycemic Control vs Cardiorenal Protection

This is a common pitfall: Dapagliflozin has TWO separate indications with different eGFR thresholds:

• For glycemic control: Do NOT initiate if eGFR <45 mL/min/1.73 m² (ineffective due to mechanism of action) 4, 2
• For cardiorenal protection: Initiate if eGFR ≥25 mL/min/1.73 m² regardless of glycemic efficacy 4, 2

The glucose-lowering effect diminishes with declining kidney function, but cardiovascular and renal benefits are fully preserved at lower eGFR levels 4. Never discontinue dapagliflozin solely because eGFR falls below 45 mL/min/1.73 m²—the cardiorenal protection persists 4.

Compatibility with Other Cardiovascular Medications

Dapagliflozin's benefits are consistent and additive when combined with standard CKD therapies:

• 98% of DAPA-CKD patients were on renin-angiotensin-aldosterone system inhibitors 9
• Benefits maintained with concurrent use of calcium channel blockers (50.7%), beta-blockers (39.0%), diuretics (43.7%), antithrombotics (47.4%), and lipid-lowering agents 9
• No increase in serious adverse events when combined with these medications 9

Safety Monitoring and Management

Expected Initial eGFR Dip

• Expect a reversible 3-5 mL/min/1.73 m² decrease in eGFR within the first 1-4 weeks 4
• Check eGFR within 1-2 weeks after initiation 4
• Patients with this initial dip actually had better long-term renal outcomes with slower eGFR decline (-1.58 vs -2.44 mL/min/1.73 m²/year) 4
• Do NOT discontinue for this expected hemodynamic effect unless eGFR decreases >30% from baseline AND there are signs of hypovolemia 4

Volume Status Assessment

• Assess volume status before initiation and correct any volume depletion 4
• Consider reducing concurrent diuretic doses to prevent excessive volume depletion 4
• Elderly patients and those on diuretics are at higher risk for intravascular volume contraction 4

Sick Day Management (Critical Safety Issue)

Withhold dapagliflozin during any acute illness:

• Stop immediately during fever, vomiting, diarrhea, or reduced oral intake 4
• Hold at least 3 days before major surgery or procedures with prolonged fasting 4, 2
• Monitor for euglycemic diabetic ketoacidosis (can occur with normal blood glucose) 4
• Check blood or urine ketones if patients develop malaise, nausea, or vomiting 4
• Maintain at least low-dose insulin in insulin-requiring patients even when dapagliflozin is held 4
• Resume only after recovery and normal oral intake is re-established 4

Common Adverse Effects

• Genital mycotic infections: ~6% vs 1% placebo 4, 5
• Urinary tract infections 4
• Rare but serious: Fournier's gangrene (necrotizing fasciitis of perineum)—requires prompt treatment if suspected 4

Clinical Algorithm for CKD Management

Step 1: Confirm CKD diagnosis with eGFR and UACR measurement 1

Step 2: If eGFR ≥25 mL/min/1.73 m² AND UACR ≥200 mg/g → Initiate dapagliflozin 10 mg daily 1, 4, 2

Step 3: Assess volume status and consider reducing diuretic doses if needed 4

Step 4: Check eGFR within 1-2 weeks, expect 3-5 mL/min/1.73 m² dip 4

Step 5: Continue indefinitely unless eGFR falls below 25 mL/min/1.73 m² (then continue until dialysis) or patient develops contraindication 4, 2

Step 6: Educate patient on sick day rules and when to hold medication 4

Limitations of Use

Dapagliflozin is not recommended for CKD treatment in:

• Polycystic kidney disease 2
• Patients requiring or with recent history of immunosuppressive therapy for kidney disease 2
• These patients were excluded from trials and dapagliflozin is not expected to be effective 2