What are the indications for Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors in non-diabetic Chronic Kidney Disease (CKD)?

Indications of SGLT2 Inhibitors in Nondiabetic CKD

SGLT2 inhibitors are strongly recommended for all adults with chronic kidney disease at risk of progression, regardless of diabetes status, particularly those with eGFR ≥20 mL/min/1.73 m² and albuminuria. 1, 2

Risk Stratification and Indications

SGLT2 inhibitors are indicated for nondiabetic CKD patients based on risk stratification:

1. Very High Risk: Strong recommendation for SGLT2 inhibitors

   • eGFR <30 mL/min/1.73 m² with albuminuria (especially UACR ≥30 mg/g)
   • High certainty evidence for reducing all-cause mortality and kidney failure
   • Moderate certainty for reducing cardiovascular events 1

2. High Risk: Strong recommendation for SGLT2 inhibitors

   • eGFR 30-44 mL/min/1.73 m² with albuminuria
   • Moderate certainty evidence for important reductions in mortality and most cardiovascular/kidney outcomes 1

3. Moderate Risk: Weak recommendation for SGLT2 inhibitors

   • eGFR 45-59 mL/min/1.73 m² with albuminuria (3-30 mg/mmol)
   • Moderate certainty of important reductions in risks of all-cause mortality and non-fatal stroke 1

4. Low Risk: Weak recommendation for SGLT2 inhibitors

   • eGFR ≥60 mL/min/1.73 m² with minimal albuminuria (<3 mg/mmol)
   • Moderate certainty of small but important reductions in risks of all-cause mortality and non-fatal stroke 1

FDA-Approved Indications

Dapagliflozin is specifically FDA-approved:

• "To reduce the risk of sustained eGFR decline, end stage kidney disease, cardiovascular death, and hospitalization for heart failure in adults with chronic kidney disease at risk of progression" 3

Specific Benefits in Nondiabetic CKD

SGLT2 inhibitors in nondiabetic CKD patients provide:

• 48 fewer deaths per 1000 patients (high certainty)
• 58 fewer kidney failure events per 1000 patients (high certainty)
• 25 fewer heart failure hospitalizations per 1000 patients (moderate certainty)
• 32 fewer myocardial infarctions per 1000 patients (moderate certainty)
• 25 fewer strokes per 1000 patients (moderate certainty) 2

Contraindications and Limitations

SGLT2 inhibitors should NOT be initiated in:

• Patients with eGFR <20 mL/min/1.73 m² (though they may be continued if already on therapy until dialysis initiation) 1, 2
• Kidney transplant recipients 1
• Patients requiring or with recent immunosuppressive therapy for kidney disease 1, 3
• Patients with polycystic kidney disease 1, 3

Practical Considerations

1. Initial eGFR Decline: Expect an initial, reversible decline in eGFR (hemodynamic effect) when initiating therapy, which is not a reason to discontinue 2

2. Volume Status:

   • Assess volume status before initiating
   • Consider reducing diuretic doses before starting
   • Monitor for symptoms of volume depletion 2

3. Monitoring:

   • Assess renal function prior to initiation and periodically thereafter
   • Monitor for adverse effects including genital mycotic infections, urinary tract infections, and volume depletion 2

4. Perioperative Management:

   • Withhold SGLT2 inhibitors for at least 3 days before major surgery or procedures associated with prolonged fasting 3

Implementation Challenges

Despite strong evidence and guidelines, SGLT2 inhibitors remain significantly underprescribed in nondiabetic CKD patients, with studies showing <0.1% prescription rates in eligible nondiabetic CKD patients compared to 22% in diabetic CKD patients 4. This highlights the need for improved implementation of guidelines in clinical practice.

Mechanism of Action in Nondiabetic CKD

SGLT2 inhibitors provide renoprotection through multiple mechanisms independent of glucose-lowering effects:

• Reducing intraglomerular pressure
• Decreasing renal tubular workload
• Lowering systemic blood pressure
• Reducing albuminuria
• Decreasing oxidative stress in the kidney 2, 5

SGLT2 inhibitors represent a significant advancement in CKD management, with proven benefits in both diabetic and nondiabetic populations, addressing the previously unmet need for effective treatments that slow disease progression and improve survival in CKD patients 6, 7, 8.