What is the role of Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors in the treatment of Chronic Kidney Disease (CKD)?

Role of SGLT2 Inhibitors in Chronic Kidney Disease Treatment

SGLT2 inhibitors are strongly recommended for all adults with chronic kidney disease at risk of progression, particularly those with eGFR ≥20 mL/min/1.73 m² and albuminuria, as they significantly reduce CKD progression, cardiovascular events, and mortality. 1

Mechanism and Benefits

SGLT2 inhibitors provide renoprotection through multiple mechanisms:

• Reduce intraglomerular pressure via tubuloglomerular feedback
• Decrease renal tubular glucose reabsorption
• Lower systemic blood pressure
• Reduce albuminuria
• Decrease oxidative stress in the kidney by >50%
• Reduce NLRP3 inflammasome activity
• Decrease overhydration in CKD patients 1, 2

Evidence-Based Recommendations by CKD Risk Category

Very High Risk Patients

• Strong recommendation for SGLT2 inhibitors 1
• Benefits (per 1000 patients):
  • 48 fewer deaths (high certainty)
  • 58 fewer kidney failure events (high certainty)
  • 25 fewer heart failure hospitalizations (moderate certainty)
  • 32 fewer myocardial infarctions (moderate certainty)
  • 25 fewer strokes (moderate certainty)

High Risk Patients

• SGLT2 inhibitors reduce:
  • All-cause mortality (24 fewer per 1000)
  • Cardiovascular mortality (6 fewer per 1000)
  • Non-fatal MI (21 fewer per 1000)
  • Non-fatal stroke (21 fewer per 1000) 1

Moderate to Low Risk Patients

• Weak recommendation for SGLT2 inhibitors
• Still provides mortality benefit and stroke reduction 1

Specific Indications and Usage Guidelines

1. For diabetic kidney disease:

   • Recommended for patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g creatinine (Grade A recommendation) 1
   • Also recommended for patients with eGFR ≥20 mL/min/1.73 m² and normal to moderately elevated albuminuria (<200 mg/g creatinine) (Grade B recommendation) 1

2. For non-diabetic CKD:

   • Effective in patients with or without diabetes (based on DAPA-CKD trial) 1, 3
   • 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 CKD at risk of progression 4

Practical Prescribing Considerations

1. eGFR thresholds:

   • Can be initiated at eGFR ≥20 mL/min/1.73 m² 1
   • Not recommended for glycemic control in patients with eGFR <45 mL/min/1.73 m² (though still beneficial for kidney protection) 4
   • Safety of initiating at eGFR <20 mL/min/1.73 m² remains uncertain 1

2. Monitoring:

   • Assess renal function prior to initiation and periodically thereafter
   • Expect an initial acute decline in eGFR that is hemodynamic and typically reversible 5
   • Do not discontinue for mild to moderate increases in serum creatinine (≤30%) in the absence of volume depletion 1

3. Dosing:

   • For CKD and heart failure indications: 10 mg daily for dapagliflozin 4
   • Start with the lowest dosage used in clinical trials 5

4. Contraindications/Limitations:

   • Not recommended for CKD in polycystic kidney disease
   • Not recommended for patients requiring or with recent immunosuppressive therapy for kidney disease 4

Combination Therapy Considerations

• SGLT2 inhibitors can be used alongside:
  • ACE inhibitors or ARBs (standard of care)
  • GLP-1 receptor agonists (for additional cardiovascular risk reduction)
  • Nonsteroidal mineralocorticoid receptor antagonists (if eGFR ≥25 mL/min/1.73 m²) 1, 5

Adverse Effects to Monitor

• Volume depletion (assess and correct volume status before initiating)
• Diabetic ketoacidosis (consider ketone monitoring in at-risk patients)
• Genital mycotic infections
• Urinary tract infections
• Hypoglycemia (when used with insulin or insulin secretagogues)
• Temporary discontinuation before major surgery 4, 6

Clinical Pearl

While SGLT2 inhibitors were initially developed for glycemic control in diabetes, their kidney protective effects are independent of glucose-lowering and extend to non-diabetic CKD patients. This represents a paradigm shift in CKD management, providing the first new class of medications in decades that significantly slows CKD progression and reduces mortality 3, 7.