What is the role of SGLT2 (sodium-glucose cotransporter 2) inhibitors, such as canagliflozin (canagliflozin) or dapagliflozin (dapagliflozin), in treating patients with non-diabetic kidney disease, specifically those with chronic kidney disease (CKD) and comorbidities like hypertension or cardiovascular disease?

SGLT2 Inhibitors in Non-Diabetic Chronic Kidney Disease

SGLT2 inhibitors are strongly recommended for adults with non-diabetic CKD who have eGFR ≥20 mL/min/1.73 m² and either albuminuria (ACR ≥200 mg/g) or heart failure, as they reduce kidney failure, cardiovascular death, and all-cause mortality regardless of diabetes status. 1

Risk-Stratified Recommendations

The 2024 BMJ guideline provides clear, risk-stratified recommendations for all adults with CKD, explicitly including those without diabetes 1:

• Very High Risk (eGFR <30 mL/min/1.73 m² with ACR ≥200 mg/g): Strong recommendation to administer SGLT2 inhibitors 1, 2
• High Risk (eGFR 30-44 mL/min/1.73 m² with ACR ≥200 mg/g): Strong recommendation to administer SGLT2 inhibitors 1, 2
• Moderate Risk (eGFR 45-59 mL/min/1.73 m² with ACR 30-200 mg/g): Weak recommendation in favor 1, 2
• Low Risk: Weak recommendation in favor 1

Specific Clinical Benefits in Non-Diabetic CKD

The evidence demonstrates substantial benefits independent of diabetes status 1, 3:

• Kidney protection: 39% reduction in composite kidney outcomes (≥50% sustained eGFR decline, ESKD, or renal death) 4, 5
• Mortality reduction: 52% reduction in all-cause mortality in non-diabetic CKD patients 4
• Cardiovascular protection: 21% reduction in cardiovascular death or heart failure hospitalization 4
• Absolute benefit: 58 fewer kidney failure events per 1000 very high-risk patients over 5 years 4

Initiation Criteria and Practical Algorithm

Step 1: Identify eligible patients 1, 2:

• eGFR ≥20 mL/min/1.73 m² AND
• Either ACR ≥200 mg/g (≥20 mg/mmol) OR heart failure (regardless of albuminuria level)

Step 2: Select appropriate agent 4, 6:

• Dapagliflozin 10 mg daily: FDA-approved for CKD with eGFR ≥25 mL/min/1.73 m² 6
• Empagliflozin or dapagliflozin: Preferred if concurrent heart failure 4
• Canagliflozin, dapagliflozin, or empagliflozin: All three demonstrate consistent efficacy 4

Step 3: Initiate on background therapy 4:

• Start SGLT2 inhibitor on top of ACE inhibitor or ARB (if already prescribed) 4
• Do not delay SGLT2 inhibitor initiation waiting for ACE/ARB optimization 2

Critical Monitoring Expectations

Expect an initial reversible eGFR decline of 3-5 mL/min/1.73 m² within the first 4 weeks 4, 2. This is:

• A hemodynamic effect, not kidney injury 7
• Not a reason to discontinue therapy 2
• Associated with long-term kidney protection 7

Continue SGLT2 inhibitors even if eGFR falls below 20 mL/min/1.73 m² during treatment 2, 6. Once initiated, maintain therapy until dialysis initiation or intolerance develops 4, 6.

Safety Considerations and Contraindications

Absolute contraindications 6:

• Polycystic kidney disease (not expected to be effective) 6
• Patients requiring or with recent immunosuppressive therapy for kidney disease 6
• Type 1 diabetes mellitus (for glycemic control indication) 6

Temporary discontinuation required 2:

• Prolonged fasting, surgery, or critical illness (increased ketosis risk) 2
• Implement "sick day protocols" to hold during acute illness 4

Common adverse effects 8, 2:

• Genital mycotic infections (6% vs 1% placebo): counsel on proper hygiene 8
• Volume depletion: consider proactive diuretic dose reduction in high-risk patients 4

Combination Therapy Strategy

SGLT2 inhibitors provide additive benefits when combined with other nephroprotective agents 2, 9:

• With RAS inhibitors: Enhanced kidney protection demonstrated 2
• With nonsteroidal MRAs (finerenone): Consider for persistent albuminuria despite SGLT2 inhibitor and RAS inhibitor 2
• With GLP-1 receptor agonists: May reduce residual cardiovascular risk in diabetic patients 9

Common Pitfalls to Avoid

1. Do not withhold SGLT2 inhibitors from non-diabetic CKD patients based on outdated diabetes-only indications 1
2. Do not discontinue for initial eGFR dip of 3-5 mL/min/1.73 m² 4, 2
3. Do not stop therapy when eGFR falls below initiation threshold during treatment 2, 6
4. Do not delay initiation in patients meeting criteria, as benefits accrue over time 1
5. Do not use for glycemic control alone when eGFR <45 mL/min/1.73 m² (ineffective for glucose lowering) 6

Populations Where Evidence is Limited

The following groups were excluded from major trials and require individualized assessment 2, 6:

• Kidney transplant recipients (potential increased infection risk) 2
• Patients on dialysis (no efficacy data) 6
• Severe hepatic impairment (safety not established) 6