Should dapagliflozin be held in a patient who develops acute kidney injury, and when can it be safely restarted (eGFR ≥ 30 mL/min/1.73 m²), with what alternative glucose‑lowering agents should be used during the AKI?

Dapagliflozin Management During Acute Kidney Injury

Immediate Action: Hold Dapagliflozin During AKI

Dapagliflozin should be immediately discontinued when a patient develops acute kidney injury and held until the AKI resolves and eGFR stabilizes at ≥25 mL/min/1.73 m² (or ≥45 mL/min/1.73 m² if used primarily for glycemic control). 1

Rationale for Holding During AKI

• The Kidney International guidelines explicitly recommend withholding dapagliflozin during acute illness, which includes AKI, to prevent diabetic ketoacidosis and volume depletion 1
• During AKI, patients are at heightened risk of volume depletion and hemodynamic instability, which can be exacerbated by the osmotic diuretic effect of SGLT2 inhibitors 1
• Post-marketing surveillance data identified AKI as a potential adverse event, particularly when SGLT2 inhibitors are combined with RAAS blockers and other nephrotoxic agents or during acute medical events 2
• In the context of AKI, the combination of SGLT2 inhibitors with usual co-medications (particularly RAAS blockers, NSAIDs, or diuretics) significantly increases risk, especially if baseline GFR is already decreased 2

When to Safely Restart Dapagliflozin

Restart Criteria Algorithm

Step 1: Confirm AKI Resolution

• Resume dapagliflozin only after the patient has fully recovered from the acute illness and AKI has resolved 1
• Ensure normal oral intake is re-established before restarting 1
• Verify that volume status is stable and any precipitating factors (sepsis, diarrhea, contrast exposure) have resolved 2

Step 2: Check eGFR Threshold

• For cardiovascular/renal protection: Restart dapagliflozin 10 mg once daily if eGFR ≥25 mL/min/1.73 m² 1, 3
• For glycemic control: Restart only if eGFR ≥45 mL/min/1.73 m², as glucose-lowering efficacy is significantly reduced below this threshold 1
• If eGFR is 25-44 mL/min/1.73 m², dapagliflozin can be restarted at 10 mg daily for cardiovascular and renal protection, but not for glycemic control 1

Step 3: Reassess Concurrent Medications

• Review and potentially reduce diuretic doses before restarting dapagliflozin to prevent excessive volume depletion 1
• Exercise caution if patient remains on RAAS blockers, NSAIDs, or other nephrotoxic agents 2
• Consider proactive dose reduction of concurrent diuretics in patients at high risk for volume depletion 1

Step 4: Monitor Post-Restart

• Check eGFR and creatinine within 1-2 weeks after restarting to assess for the expected transient eGFR dip of 3-5 mL/min/1.73 m² 1, 3
• This initial dip is physiologic and reversible, representing hemodynamic changes rather than kidney injury 4, 5
• Patients experiencing an acute eGFR reduction >10% at 2 weeks actually had better long-term renal outcomes with slower eGFR decline compared to those without an initial dip 4

Alternative Glucose-Lowering Agents During AKI

Primary Alternatives Based on Renal Function

Insulin Therapy (First-Line During AKI)

• Insulin remains effective regardless of kidney function and can be dose-adjusted based on clinical response 1
• Maintain at least low-dose insulin in insulin-requiring individuals even when dapagliflozin is held, as complete insulin cessation increases DKA risk 1
• Do not reduce insulin doses excessively when holding dapagliflozin during illness, as this combination significantly elevates ketoacidosis risk 1

GLP-1 Receptor Agonists (If eGFR >30 mL/min/1.73 m²)

• Liraglutide or semaglutide can be used with eGFR >30 mL/min/1.73 m² and have demonstrated cardiovascular benefits 1
• Preferred agents for patients with eGFR <25 mL/min/1.73 m² according to Mayo Clinic Proceedings 1
• For advanced CKD (eGFR <30 mL/min/1.73 m²), GLP-1 receptor agonists are preferred for glycemic management due to lower hypoglycemia risk 6

DPP-4 Inhibitors (Require Dose Adjustment)

• May require dose adjustment but can be used in advanced CKD 1
• Linagliptin is the only DPP-4 inhibitor that requires no dose adjustment regardless of renal function, with the standard dose remaining 5 mg once daily even in severe renal impairment 1
• Sitagliptin should be reduced to 50 mg once daily if eGFR 30-44 mL/min/1.73 m² 1

Agents to Avoid During AKI

• Metformin: Should be stopped if eGFR falls below 30 mL/min/1.73 m² 1
• Sulfonylureas (e.g., gliclazide): Increase hypoglycemia risk without cardiovascular benefit and should be avoided during AKI 1

Critical Safety Considerations

Volume Status Management

• Assess volume status carefully before restarting, as the diuretic effect of dapagliflozin combined with illness-related fluid losses significantly increases risk of hypovolemia 1
• Patients already on diuretic therapy are at higher risk of volume depletion 1
• Use caution in patients with renal impairment, low systolic blood pressure, those on diuretics, or elderly patients due to risk of intravascular volume contraction 1

Monitoring for Euglycemic DKA

• Monitor for diabetic ketoacidosis even with normal blood glucose levels, as euglycemic DKA is a serious risk during illness in patients taking SGLT2 inhibitors 1
• Check blood or urine ketones if patients develop malaise, nausea, or vomiting 1
• Educate patients on specific triggers that necessitate drug discontinuation, including reduced ability to eat or drink normally 1

Common Pitfall to Avoid

• Do not permanently discontinue dapagliflozin solely because eGFR temporarily dropped during AKI. Once AKI resolves and eGFR stabilizes ≥25 mL/min/1.73 m², dapagliflozin should be restarted for its cardiovascular and renal protective benefits, which persist even when glycemic efficacy is lost 1, 7
• The DAPA-CKD trial demonstrated that dapagliflozin reduces the primary composite outcome by 39% (HR 0.61,95% CI 0.51-0.72) and all-cause mortality by 31% (HR 0.69,95% CI 0.53-0.88) in patients with CKD, benefits that should not be forfeited due to temporary AKI 7