Should Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors be held in patients with Heart Failure with Reduced Ejection Fraction (HFrEF) who develop Acute Kidney Injury (AKI) on top of Chronic Kidney Disease (CKD)?

Should SGLT2 Inhibitors Be Held in HFrEF Patients Who Develop AKI on Top of CKD?

SGLT2 inhibitors should generally be continued in patients with HFrEF and CKD who develop AKI manifested by a rise in serum creatinine, unless serious acute kidney injury is suspected or the patient is hemodynamically unstable. 1

Primary Recommendation

• Continue SGLT2 inhibitor therapy during modest eGFR declines, even when eGFR drops >30% from baseline 1
• The expected hemodynamic decline in eGFR with SGLT2 inhibitors is 3-10%, which is not a safety signal and should not prompt discontinuation 1
• SGLT2 inhibitors actually reduce the risk of AKI rather than increase it (RR 0.69,95% CI 0.51-0.93) 2

When to Temporarily Hold SGLT2 Inhibitors

Withhold SGLT2 inhibitors only in specific clinical situations: 1, 3

• Serious acute kidney injury is suspected (not just a modest creatinine rise) 1
• Severe volume depletion or hemodynamic instability requiring aggressive diuresis or vasopressor support 3
• Acute illness with prolonged fasting, surgery, or conditions predisposing to ketoacidosis 1, 4, 3
• Severe infections (urosepsis, pyelonephritis, Fournier's gangrene) 3

Management Algorithm for eGFR Decline

When eGFR declines >30% within a week of SGLT2 inhibitor initiation: 1

1. Ensure euvolemia - adjust diuretic dosage appropriately 1
2. Discontinue nonessential nephrotoxic agents (NSAIDs, aminoglycosides) 1
3. Evaluate alternative etiologies for AKI (obstruction, contrast exposure, other medications) 1
4. Continue SGLT2 inhibitor unless serious AKI is confirmed 1

Evidence Supporting Continuation

• Clinical trial protocols (CREDENCE, DAPA-CKD) specified continuation of SGLT2 inhibitors even when eGFR fell below initiation thresholds 1
• SGLT2 inhibitors reduce discontinuation of RAS blockade by 15%, facilitating use of other guideline-directed therapies 5
• The initial eGFR decline with SGLT2 inhibitors represents beneficial hemodynamic changes (reduced intraglomerular pressure), not kidney injury 1
• No increase in adverse renal events was observed in HFrEF trials 6

Critical Distinction: Expected vs. Pathologic Creatinine Rise

Expected hemodynamic changes (continue SGLT2i): 1

• eGFR decline of 3-10% within first weeks
• Stable decline that plateaus
• Patient remains euvolemic
• No other signs of serious illness

Pathologic AKI requiring evaluation (consider holding): 1

• Rapid, progressive creatinine rise
• Associated with volume depletion, hypotension, or oliguria
• Concurrent nephrotoxic exposures
• Signs of uremia or metabolic acidosis beyond expected SGLT2i effects

When to Resume After Temporary Discontinuation

• Resume SGLT2 inhibitor when the patient is clinically stable and has resumed oral intake 3
• Wait for complete resolution of infection if held for severe UTI or other infection 4
• Reassess volume status and ensure euvolemia before restarting 1, 3

Common Pitfalls to Avoid

• Do not reflexively discontinue SGLT2 inhibitors for every creatinine rise - this deprives patients of proven mortality and morbidity benefits 1
• Do not confuse the expected hemodynamic eGFR decline with true kidney injury 1
• Do not withhold SGLT2 inhibitors based solely on an eGFR threshold - they can be continued even when eGFR falls below 20 mL/min/1.73 m² if already established on therapy 1
• Monitor for ketoacidosis, not just hyperglycemia - SGLT2 inhibitors can cause euglycemic DKA, especially during acute illness 1, 3

Monitoring During AKI Episode

• Check serum creatinine and electrolytes within 1-2 weeks of any significant clinical change 1
• Assess volume status clinically - jugular venous pressure, orthostatic vital signs, mucous membranes 1
• Review medication list for other nephrotoxic agents 1
• Consider blood or urine ketone monitoring if patient has risk factors for ketoacidosis 1

Special Consideration for Severe CKD

• For patients with baseline eGFR 20-30 mL/min/1.73 m², the evidence for continuation during AKI is strongest when albuminuria (UACR ≥200 mg/g) or heart failure is present 1
• The only absolute contraindication is dialysis or ESRD - SGLT2 inhibitors should be discontinued if kidney replacement therapy is initiated 7