What are the considerations for using dapagliflozin (Forxiga) in patients with impaired renal function (raised creatinine)?

Dapagliflozin Use in Patients with Raised Creatinine

Dapagliflozin can and should be initiated in patients with raised creatinine if eGFR ≥25 mL/min/1.73 m² for cardiovascular and renal protection, regardless of the indication (heart failure, chronic kidney disease, or diabetes), though its glucose-lowering efficacy diminishes significantly below eGFR 45 mL/min/1.73 m². 1, 2, 3

eGFR Thresholds for Initiation and Continuation

For cardiovascular and renal protection:

• Initiate dapagliflozin 10 mg daily if eGFR ≥25 mL/min/1.73 m² for heart failure or chronic kidney disease indications 4, 1, 3
• The DAPA-CKD trial demonstrated a 39% reduction in the composite outcome of sustained eGFR decline ≥50%, end-stage kidney disease, or renal/cardiovascular death in patients with eGFR 25-75 mL/min/1.73 m² 5, 1
• Once initiated, continue dapagliflozin even if eGFR falls below 25 mL/min/1.73 m² until dialysis initiation 3, 1

For glycemic control specifically:

• Do not initiate dapagliflozin for glucose-lowering if eGFR <45 mL/min/1.73 m² as the mechanism of action (SGLT2 inhibition in proximal tubules) becomes ineffective 1, 3
• If already on dapagliflozin for diabetes and eGFR falls below 45 mL/min/1.73 m², continue the medication for its cardiovascular/renal benefits but add alternative glucose-lowering agents (GLP-1 agonists or insulin) 1

Expected Changes in Renal Function

Anticipate and do not overreact to an initial eGFR dip:

• A transient, reversible decline in eGFR of 3-5 mL/min/1.73 m² typically occurs within the first 1-4 weeks of dapagliflozin initiation 6, 7
• This acute dip returns toward baseline by week 24 and is followed by long-term renal protection 6, 4
• Patients experiencing an acute eGFR reduction >10% at 2 weeks actually had better long-term renal outcomes with slower eGFR decline (-1.58 vs -2.44 ml/min/1.73 m²/year) compared to those without an initial dip 7
• Do not discontinue dapagliflozin based solely on this expected initial eGFR reduction 4, 7

Monitoring Strategy After Initiation

Assess renal function and volume status systematically:

• Check eGFR and creatinine within 1-2 weeks after initiation 4
• Evaluate volume status before starting and monitor closely for intravascular volume contraction, which may require loop diuretic dose reduction 4, 8
• Continue monitoring at least monthly for the first 3 months, then every 3 months thereafter 4

When to adjust therapy:

• If eGFR decreases >30% from baseline AND there are signs of hypovolemia, reduce diuretic doses first before considering dapagliflozin adjustment 4
• Distinguish between hemodynamic changes (acceptable) versus true tubular injury using urine microscopy if acute kidney injury is suspected 4
• Initial mild worsening of renal function does not predict longer-term adverse outcomes and should not prompt discontinuation 4

Safety Considerations in Renal Impairment

Patients with impaired renal function require specific precautions:

• Higher risk of volume depletion and hypotension, particularly in patients ≥65 years with moderate-to-severe renal impairment 3, 9
• Increased frequency of renal adverse events with age and declining eGFR (29.9% in patients ≥75 years vs 3.5% in <65 years), though most are non-serious transient creatinine elevations 9
• Dapagliflozin reduces the risk of abrupt declines in kidney function (doubling of creatinine: HR 0.68,95% CI 0.49-0.94) 10
• No increased risk of acute kidney injury-related serious adverse events compared to placebo 10

Clinical Pitfalls to Avoid

Common errors in managing dapagliflozin with raised creatinine:

• Do not withhold dapagliflozin solely based on elevated creatinine if eGFR ≥25 mL/min/1.73 m² – the cardiovascular and renal benefits are preserved and actually most pronounced in patients with impaired renal function 5, 1
• Do not confuse the eGFR threshold for glycemic control (≥45 mL/min/1.73 m²) with the threshold for cardiovascular/renal protection (≥25 mL/min/1.73 m²) 1, 3
• Discontinue dapagliflozin at least 3 days before major surgery or prolonged fasting to prevent euglycemic ketoacidosis 1, 2
• In patients with diabetes and moderate renal impairment, be vigilant for hypoglycemia risk, particularly if combined with insulin or sulfonylureas 3

Special Populations

Older patients (≥65 years):

• No dose adjustment needed based on age alone 3
• Monitor more closely for hypotension and volume depletion 3, 9
• Benefits of dapagliflozin are consistent across age groups in heart failure and CKD trials 3

Patients with albuminuria:

• Dapagliflozin is strongly indicated for patients with UACR ≥200 mg/g and eGFR 25-75 mL/min/1.73 m² 1, 5
• The median UACR in DAPA-CKD was 949 mg/g, demonstrating efficacy in patients with substantial proteinuria 1