In a patient with chronic kidney disease and albuminuria but a normal urine albumin‑to‑creatinine ratio, is dapagliflozin (Farxiga) still an appropriate treatment option?

Dapagliflozin Remains Appropriate for CKD Despite Normal Albumin-to-Creatinine Ratio

Yes, dapagliflozin (Farxiga) is still an appropriate treatment option for this patient with chronic kidney disease and albuminuria, even when the urine albumin-to-creatinine ratio (UACR) is reported as "normal." The apparent contradiction between "albuminuria" and "normal UACR" requires clinical clarification, but recent evidence demonstrates that SGLT2 inhibitors provide robust kidney and cardiovascular protection across the entire spectrum of albuminuria levels, including patients with UACR below traditional thresholds. 1

Resolving the Clinical Contradiction

• If the patient truly has documented albuminuria on prior testing but current UACR appears normal, this may represent:

  • Laboratory variability in UACR measurement (which can fluctuate significantly day-to-day) 1
  • Successful reduction in albuminuria from prior renin-angiotensin-aldosterone system (RAAS) inhibitor therapy 1
  • Measurement timing issues (first morning void versus random specimen) 1

• The key clinical decision point is whether the patient has chronic kidney disease with eGFR ≥25 mL/min/1.73 m², not the precise UACR level at this single time point. 1

Evidence Supporting Dapagliflozin Use Across All Albuminuria Levels

Guideline Recommendations for Lower Albuminuria

• The American Diabetes Association and KDIGO now recommend SGLT2 inhibitors for patients with CKD and eGFR ≥20 mL/min/1.73 m² with urine albumin ranging from normal to 200 mg/g creatinine (Class I, Level A recommendation). 2

• The American Diabetes Association specifically recommends dapagliflozin 10 mg once daily for patients with CKD to reduce kidney failure, cardiovascular death, and heart failure hospitalization when eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, but emerging evidence supports use at lower UACR levels. 1

Real-World Evidence in Patients with Lower Albuminuria

• A 2024 real-world effectiveness study demonstrated that starting dapagliflozin was associated with slower kidney function decline in patients with CKD and UACR below 200 mg/g compared with not starting treatment. 3

• This protective effect was observed even in a subgroup analysis of patients without type 2 diabetes, suggesting the established benefits of SGLT2 inhibitors extend to patients with lower levels of albuminuria. 3

• The OPTIMISE-CKD observational study (2024) in patients without type 2 diabetes found that dapagliflozin demonstrated similar kidney protection across all UACR levels, including those with normal/mildly elevated UACR (0-29 mg/g), low UACR (30-200 mg/g), and high UACR (>200 mg/g). 4

• After dapagliflozin initiation, an acute eGFR dip of 3 mL/min/1.73 m² was observed (expected and reversible), followed by flat eGFR development in all albuminuria groups. 4

• The eGFR slope for patients with low UACR was 0.79 mL/min/1.73 m² per year, similar to patients with high UACR at 0.40 mL/min/1.73 m² per year, indicating comparable kidney protection. 4

Clinical Decision Algorithm for Initiation

Step 1: Verify Eligibility Criteria

• Check current eGFR: Must be ≥25 mL/min/1.73 m² for cardiovascular/renal protection (or ≥20 mL/min/1.73 m² per most recent 2025 ADA guidelines). 1, 2

• Assess volume status: Correct any volume depletion before initiating, particularly in elderly patients or those on concurrent diuretics. 1, 5

• Exclude contraindications: History of serious hypersensitivity reaction to dapagliflozin, polycystic kidney disease, or recent immunosuppressive therapy for kidney disease. 5

Step 2: Initiate Standard Dosing

• Start dapagliflozin 10 mg orally once daily for cardiovascular and renal protection, regardless of the current UACR level or diabetes status. 1, 5

• No dose titration is required; 10 mg is the fixed dose for all cardiovascular and renal indications. 1

• Continue concurrent RAAS inhibitors (ACE inhibitors or ARBs) without dose adjustment when starting dapagliflozin. 1, 6

Step 3: Adjust Concomitant Medications

• Consider reducing concurrent diuretic doses at initiation to prevent excessive volume depletion, particularly in patients already on loop or thiazide diuretics. 1

• If the patient is on insulin or sulfonylureas, reduce doses by approximately 20% to mitigate hypoglycemia risk and monitor glucose closely for the first 2-4 weeks. 1, 2

Step 4: Monitor Initial Response

• Recheck eGFR within 1-2 weeks after initiation: An acute, reversible eGFR decline of 2-5 mL/min/1.73 m² is expected and should not prompt discontinuation. 1, 4

• If eGFR decreases >30% from baseline AND there are signs of hypovolemia, reduce diuretic doses first before considering dapagliflozin adjustment. 1

• Continue monitoring eGFR at least every 3-6 months if eGFR 25-44 mL/min/1.73 m², or annually if eGFR ≥45 mL/min/1.73 m². 1, 2

Expected Clinical Benefits Regardless of Albuminuria Level

Kidney Protection

• Dapagliflozin produces a 44% relative reduction in kidney-specific composite outcome (sustained eGFR decline ≥50%, end-stage kidney disease, or renal death) in the DAPA-CKD trial. 1

• The drug slows eGFR decline over time, with benefits consistent across all stages of CKD down to eGFR 25 mL/min/1.73 m². 1, 7

• In patients with stage 4 CKD (eGFR <30 mL/min/1.73 m²), dapagliflozin reduced the eGFR slope decline from 3.38 to 2.15 mL/min/1.73 m² per year (p=0.005). 7

Cardiovascular Protection

• Dapagliflozin yields a 29% relative reduction in cardiovascular death or hospitalization for heart failure. 1

• The drug reduces all-cause mortality by 31% (HR 0.69,95% CI 0.53-0.88). 1

• These cardiovascular benefits are consistent regardless of baseline use of other cardiovascular medications including RAAS inhibitors, calcium channel blockers, β-blockers, diuretics, antithrombotics, and lipid-lowering agents. 6

Critical Safety Precautions and Patient Education

Sick Day Management

• Temporarily withhold dapagliflozin during acute illnesses with reduced oral intake, fever, vomiting, or diarrhea to prevent volume depletion and euglycemic diabetic ketoacidosis. 1, 5

• Stop at least 3 days before major surgery or procedures requiring prolonged fasting. 1, 5

• If dapagliflozin must be held temporarily, maintain a low-dose insulin regimen in insulin-requiring patients to prevent hyperglycemia and ketoacidosis. 1

Infection Risk

• Counsel patients that genital mycotic infections occur in approximately 6% of treated individuals versus 1% with placebo; emphasize daily hygiene measures. 1, 2

• Evaluate promptly for signs and symptoms of urinary tract infections (urosepsis and pyelonephritis) and treat if indicated. 5

• Warn about the rare but serious risk of necrotizing fasciitis of the perineum (Fournier's gangrene); assess patients presenting with pain, tenderness, erythema, or swelling in the genital or perineal area along with fever or malaise. 5

Ketoacidosis Monitoring

• Warn about the risk of euglycemic diabetic ketoacidosis and advise immediate medical evaluation for malaise, nausea, vomiting, or abdominal pain even when blood glucose is normal. 1, 5

• This risk is particularly elevated during acute illness, insulin pump malfunctions, or significant reductions in insulin doses. 1

Common Pitfalls to Avoid

• Do not discontinue dapagliflozin when eGFR falls below 45 mL/min/1.73 m²; cardiovascular and renal benefits persist even when glycemic efficacy is lost. 1, 2

• Do not stop the drug because of the expected initial eGFR dip of 2-5 mL/min/1.73 m² in the first 2-4 weeks; this hemodynamic change is reversible and does not indicate harm. 1, 4

• Do not reduce the dose below 10 mg for cardiovascular or renal indications, even if glycemic efficacy wanes at lower eGFR; all outcome trials used the fixed 10 mg dose. 1

• Do not withhold dapagliflozin solely because the current UACR measurement is "normal" if the patient has documented CKD; real-world evidence demonstrates benefit across all albuminuria levels. 3, 4

Integration with Comprehensive CKD Management

• Dapagliflozin should be used alongside RAAS inhibitors (continued unchanged) as part of first-line CKD management. 1, 6

• When combined with mineralocorticoid receptor antagonists (e.g., finerenone), dapagliflozin provides additive renal benefits and may lessen hyperkalemia risk. 1

• SGLT2 inhibition is positioned as foundational therapy for slowing CKD progression and preventing cardiovascular events, irrespective of glycemic status or precise albuminuria level. 1, 4