What is the role of SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitors in managing patients with Chronic Kidney Disease (CKD) and type 2 diabetes?

SGLT2 Inhibitors as an Emerging Pillar in CKD Management

SGLT2 inhibitors should be initiated in all adults with CKD regardless of diabetes status, with strong recommendations for high and very high-risk patients (eGFR 30-44 mL/min/1.73 m² with albuminuria ≥200 mg/g, or eGFR <30 mL/min/1.73 m² with albuminuria ≥200 mg/g) to reduce all-cause mortality, cardiovascular death, heart failure hospitalization, and kidney failure. 1

Evidence Base and Mortality Benefits

The 2024 BMJ guideline represents the most comprehensive synthesis of SGLT2 inhibitor evidence in CKD, incorporating 13 trials with 29,614 participants. 1 This guideline demonstrates that among very high-risk patients, SGLT2 inhibitors provide moderate to high certainty evidence for reducing:

• All-cause and cardiovascular mortality 1
• Hospitalization for heart failure 1
• Kidney failure 1
• Non-fatal myocardial infarction and stroke 1

The DAPA-CKD trial specifically showed a 39% reduction in the composite endpoint of sustained eGFR decline, end-stage kidney disease, or renal/cardiovascular death (HR 0.61,95% CI 0.51-0.72), with benefits observed in patients both with and without diabetes. 2, 3

Risk-Stratified Recommendations

The BMJ guideline provides the most actionable framework using KDIGO risk stratification: 1

Strong Recommendations (Must Initiate):

• Very high risk: eGFR <30 mL/min/1.73 m² with ACR ≥200 mg/g 1, 2
• High risk: eGFR 30-44 mL/min/1.73 m² with ACR ≥200 mg/g 1, 2

Weak Recommendations (Should Consider):

• Moderate risk: eGFR 45-59 mL/min/1.73 m² with ACR 30-200 mg/g 1, 2
• Low risk: eGFR ≥60 mL/min/1.73 m² with ACR <30 mg/g 1

Critical point: These recommendations apply to all adults with CKD irrespective of type 2 diabetes status, representing a paradigm shift from diabetes-centric prescribing. 1

Practical Initiation Guidelines

eGFR Thresholds:

• Initiate if eGFR ≥20 mL/min/1.73 m² with ACR ≥200 mg/g or heart failure 2
• Continue therapy even if eGFR falls below 20 mL/min/1.73 m² until dialysis initiation 2, 4
• Do not discontinue solely because eGFR declines below 45 mL/min/1.73 m², as cardiovascular and renal benefits persist even when glycemic efficacy is lost 4

Dosing:

• Fixed dose of 10 mg daily for dapagliflozin or empagliflozin for cardiovascular/renal protection 2, 4
• No titration required 4
• For canagliflozin, can be started down to eGFR 30 mL/min/1.73 m² 1

Baseline Assessment:

• Measure eGFR and urine ACR before initiation 2
• Assess volume status and correct depletion if present 2, 4
• Consider reducing concurrent diuretic doses to prevent excessive volume depletion 4

Expected eGFR Changes and Monitoring

An initial, reversible decrease in eGFR of 3-5 mL/min/1.73 m² is expected within the first 1-4 weeks and is NOT a reason to discontinue therapy. 2, 4 This hemodynamic effect is followed by long-term kidney protection with slower eGFR decline. 2

Monitoring Schedule:

• Recheck eGFR within 1-2 weeks after initiation 4
• Monitor every 3-6 months if eGFR <60 mL/min/1.73 m² 2
• Monitor annually if eGFR ≥60 mL/min/1.73 m² 2

Safety Considerations and Contraindications

When to Withhold Temporarily:

• Prolonged fasting or surgery (hold at least 3 days prior) 2, 4
• Critical medical illness with reduced oral intake 2, 5
• Fever, vomiting, or diarrhea 4
• Active acute kidney injury 5

Absolute Contraindications:

• Polycystic kidney disease 2
• Patients requiring immunosuppressive therapy for kidney disease 2
• Kidney transplant recipients (limited data, increased infection risk) 2

Common Adverse Effects to Monitor:

• Genital mycotic infections (6% vs 1% placebo) 2, 4
• Euglycemic diabetic ketoacidosis (rare but serious, can occur with normal glucose) 4, 6
• Volume depletion (especially in elderly, those on diuretics) 4, 6
• Urinary tract infections 4, 6

Combination Therapy Approach

SGLT2 inhibitors should be used alongside: 2

• RAS inhibitors (ACEi or ARB) for enhanced kidney protection 2
• Nonsteroidal mineralocorticoid receptor antagonists for patients with persistent albuminuria despite SGLT2 inhibitor and RASi therapy 2
• GLP-1 receptor agonists may be considered for additional cardiovascular benefit 7

Common Pitfalls to Avoid

1. Do not withhold SGLT2 inhibitors in non-diabetic CKD patients – benefits are equivalent regardless of diabetes status 1, 2

2. Do not discontinue when eGFR falls below 45 mL/min/1.73 m² – cardiovascular and renal benefits persist at lower eGFR levels 2, 4

3. Do not mistake the initial eGFR dip for treatment failure – this hemodynamic effect predicts better long-term outcomes 4

4. Do not use for glycemic control when eGFR <45 mL/min/1.73 m² – glucose-lowering efficacy is reduced, but continue for cardiovascular/renal protection 4

5. Do not forget to educate patients about sick day rules – hold during acute illness to prevent ketoacidosis and volume depletion 4, 5

Implementation Strategy

The most significant barrier to SGLT2 inhibitor use in CKD is therapeutic inertia, with patients having more severe disease paradoxically less likely to receive treatment. 8 Initiate SGLT2 inhibitors early in the CKD trajectory when eGFR ≥20 mL/min/1.73 m² and ACR ≥200 mg/g, or in the presence of heart failure regardless of albuminuria level. 2