What is the recommended use of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in patients with Chronic Kidney Disease (CKD) without diabetes?

Recommended Use of SGLT2 Inhibitors in CKD Without Diabetes

SGLT2 inhibitors are strongly recommended for adults with chronic kidney disease without diabetes who have eGFR ≥20 mL/min/1.73 m² and urine albumin-to-creatinine ratio (ACR) ≥200 mg/g, or heart failure, regardless of albuminuria level. 1

Indications and Benefits

• SGLT2 inhibitors are indicated to reduce the risk of sustained eGFR decline, end-stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with CKD at risk of progression, regardless of diabetes status 2
• For patients with CKD without diabetes, SGLT2 inhibitors provide significant kidney protection and cardiovascular benefits, similar to those observed in patients with diabetes 1
• The benefits extend beyond glycemic control, suggesting mechanisms related to reduction in glomerular hypertension through tubuloglomerular feedback 3

Risk Stratification and Recommendations

Based on risk of CKD progression and complications:

1. Very High Risk (eGFR <30 mL/min/1.73 m² with ACR ≥200 mg/g): Strong recommendation for SGLT2 inhibitor therapy 1
2. High Risk (eGFR 30-44 mL/min/1.73 m² with ACR ≥200 mg/g): Strong recommendation for SGLT2 inhibitor therapy 1
3. Moderate Risk (eGFR 45-59 mL/min/1.73 m² with ACR 30-200 mg/g): Weak recommendation for SGLT2 inhibitor therapy 1
4. Low Risk (eGFR ≥60 mL/min/1.73 m² with ACR <30 mg/g): Weak recommendation for SGLT2 inhibitor therapy 1

Specific Recommendations by GFR and Albuminuria

• eGFR ≥20 mL/min/1.73 m² with ACR ≥200 mg/g: Strongly recommended to use SGLT2 inhibitors 1
• eGFR 20-45 mL/min/1.73 m² with ACR <200 mg/g: Suggested to use SGLT2 inhibitors (weaker recommendation) 1
• Heart failure patients with CKD: Strongly recommended regardless of albuminuria level 1

Practical Considerations for Initiation and Monitoring

• Baseline assessment should include measurement of eGFR and urine ACR before starting SGLT2 inhibitor therapy 4
• Monitor eGFR every 3-6 months if <60 mL/min/1.73 m², and annually if ≥60 mL/min/1.73 m² 4
• An initial, reversible decrease in eGFR (typically 3-5 mL/min/1.73 m²) is expected and not a reason to discontinue therapy 1
• 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
• Consider reducing diuretic doses if the patient is also on diuretic therapy to prevent volume depletion 1, 4

Safety Considerations

• Temporarily withhold SGLT2 inhibitors during times of prolonged fasting, surgery, or critical medical illness when patients may be at greater risk for ketosis 1
• Monitor for genital mycotic infections and educate patients about symptoms of volume depletion 4
• SGLT2 inhibitors have not been adequately studied in kidney transplant recipients and are not recommended for patients with polycystic kidney disease 1, 2

Combination Therapy

• SGLT2 inhibitors can be used alongside RAS inhibitors (ACEi or ARB) for enhanced kidney protection 1
• Consider adding a nonsteroidal mineralocorticoid receptor antagonist (MRA) with proven kidney or cardiovascular benefit for patients with persistent albuminuria despite SGLT2 inhibitor and RASi therapy 1

Evidence from Key Trials

• The DAPA-CKD trial demonstrated significant benefits of dapagliflozin in patients with CKD with and without diabetes, showing a 39% reduction in the primary composite endpoint of sustained decline in eGFR, end-stage kidney disease, or death 1, 5
• SGLT2 inhibitors have shown benefits in reducing the risk of CKD progression and cardiovascular events in patients without diabetes, similar to those observed in patients with diabetes 1, 6
• Short-term studies in non-diabetic CKD patients show that while SGLT2 inhibitors may not significantly affect proteinuria over a 6-week period, they do induce an acute and reversible decline in measured GFR and reduction in bodyweight 7

Limitations and Contraindications

• Not recommended for patients with eGFR <20 mL/min/1.73 m² for initial therapy 1
• Not recommended for patients with polycystic kidney disease or those requiring immunosuppressive therapy for kidney disease 2
• Not recommended for kidney transplant recipients due to limited data and potential increased risk of infections 1

SGLT2 inhibitors represent a significant advancement in CKD management, offering kidney and cardiovascular protection for patients with CKD regardless of diabetes status, with the strongest evidence supporting their use in patients with albuminuria ≥200 mg/g and eGFR ≥20 mL/min/1.73 m².