What are the considerations for using Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, such as canagliflozin (canagliflozin), dapagliflozin (dapagliflozin), or empagliflozin (empagliflozin), in a patient with Chronic Kidney Disease (CKD) Stage V and impaired renal function?

SGLT2 Inhibitors in CKD Stage V

Primary Recommendation

SGLT2 inhibitors should NOT be initiated in patients with CKD Stage V (eGFR <15 mL/min/1.73 m²), but if already established on therapy before reaching Stage V, continuation may be reasonable until dialysis is initiated. 1

Evidence-Based Initiation Thresholds

When to Start SGLT2 Inhibitors

• The KDIGO 2022 guidelines provide a strong recommendation (1A) to initiate SGLT2 inhibitors in patients with eGFR ≥20 mL/min/1.73 m² for cardiovascular and renal protection. 1

• The 2024 BMJ guidelines identify a critical knowledge gap: safety of initiating SGLT2 inhibitors with baseline eGFR <20 mL/min/1.73 m² has not been adequately studied, and current evidence does not apply to this population. 1

• The FDA label for dapagliflozin states that efficacy and safety trials did not enroll patients with eGFR <25 mL/min/1.73 m² or on dialysis. 2

When to Continue SGLT2 Inhibitors

• Once initiated, SGLT2 inhibitors can be continued even if eGFR falls below 20 mL/min/1.73 m², unless not tolerated or kidney replacement therapy is initiated. 1

• The KDOQI 2025 commentary emphasizes that patients enrolled in DAPA-CKD and DELIVER trials were not required to discontinue therapy if eGFR fell below 25 mL/min/1.73 m² or if dialysis was initiated. 1

• The FDA label explicitly states that patients in clinical trials were not required to discontinue dapagliflozin if eGFR fell below 25 mL/min/1.73 m² or dialysis was initiated. 2

Clinical Decision Algorithm for CKD Stage V

If Patient is NOT Currently on SGLT2 Inhibitor:

1. Do NOT initiate SGLT2 inhibitor therapy 1, 2
2. Focus on optimizing RAS inhibition (ACEi/ARB) if tolerated and not contraindicated by hyperkalemia or symptomatic hypotension 1
3. Consider alternative cardioprotective strategies including GLP-1 receptor agonists if diabetes is present and eGFR >30 mL/min/1.73 m² 1

If Patient is Already on SGLT2 Inhibitor:

1. Continue current SGLT2 inhibitor at the same dose (typically 10 mg daily for dapagliflozin, empagliflozin, or canagliflozin) 1, 2
2. Discontinue only if:
   • Dialysis is initiated 1, 2
   • Intolerable side effects develop 1
   • Prolonged fasting, surgery, or critical medical illness occurs (temporary hold) 1, 2

Critical Safety Considerations in Advanced CKD

Volume Depletion Risk

• Assess volume status before each clinical encounter, as patients with eGFR <20 mL/min/1.73 m² are at substantially higher risk for hypovolemia. 1, 2

• Consider reducing thiazide or loop diuretic doses before or concurrent with SGLT2 inhibitor use. 1

• Educate patients about symptoms of volume depletion (lightheadedness, orthostasis, weakness) and instruct them to seek medical attention if these occur. 1

Ketoacidosis Risk

• Withhold SGLT2 inhibitors during prolonged fasting, surgery, or critical medical illness when patients are at greater risk for ketosis. 1, 2

• Educate patients that euglycemic diabetic ketoacidosis can occur even with blood glucose in the 150-250 mg/dL range. 1, 2

• Instruct patients to stop SGLT2 inhibitors immediately during acute illness with reduced oral intake, fever, vomiting, or diarrhea. 3

Expected eGFR Changes

• A reversible decrease in eGFR of 3-5 mL/min/1.73 m² typically occurs within the first 4 weeks of SGLT2 inhibitor initiation, followed by stabilization. 1

• This initial eGFR dip is NOT an indication to discontinue therapy and is actually associated with better long-term renal outcomes. 1, 4

Common Pitfalls to Avoid

Do NOT Discontinue for Wrong Reasons

• Do not stop SGLT2 inhibitors solely because eGFR falls below 20 mL/min/1.73 m² if the patient was already on therapy. 1

• Do not discontinue due to the expected initial eGFR dip of 3-5 mL/min/1.73 m² within the first month. 1, 4

• Do not stop for loss of glycemic efficacy—cardiovascular and renal protective benefits persist even when glucose-lowering effect is minimal. 1, 3

Recognize Absolute Contraindications

• Dialysis initiation is an indication to discontinue SGLT2 inhibitors. 1, 2

• Active acute kidney injury or critical illness requiring hospitalization warrants temporary discontinuation. 1, 5

• Pregnancy is an absolute contraindication, especially during second and third trimesters. 2

Monitoring Requirements in Stage V CKD

• Assess renal function and volume status at each clinical encounter. 1, 2

• Monitor for genital mycotic infections (occur in ~6% of patients on SGLT2 inhibitors vs 1% on placebo). 1, 3

• Evaluate for symptoms of urinary tract infections and treat promptly if indicated. 2

• Check for signs of Fournier's gangrene (necrotizing fasciitis of the perineum) if patients present with genital/perineal pain, erythema, swelling, fever, or malaise. 2

Nuances and Divergent Evidence

The eGFR 20 vs 25 mL/min/1.73 m² Threshold Debate

• KDIGO 2022 uses eGFR ≥20 mL/min/1.73 m² as the initiation threshold 1, while the FDA label and some guidelines use ≥25 mL/min/1.73 m² 2. This reflects the fact that clinical trials enrolled patients down to eGFR 25 mL/min/1.73 m², creating uncertainty about initiation below this level. 1, 2

• The 2024 BMJ guidelines explicitly identify this as a key uncertainty requiring future research. 1

Glycemic Control vs Cardio-Renal Protection

• SGLT2 inhibitors are NOT recommended for glycemic control when eGFR <45 mL/min/1.73 m² due to mechanism of action (reduced glucose filtration). 1, 2

• However, the 10 mg daily dose remains appropriate for cardiovascular and renal protection at any eGFR ≥20 mL/min/1.73 m², regardless of glycemic efficacy. 1, 3