What is the best SGLT2 (sodium-glucose cotransporter 2) inhibitor for a patient with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), and what are the available options worldwide?

SGLT2 Inhibitors for Type 2 Diabetes with Chronic Kidney Disease

Available SGLT2 Inhibitors Worldwide

The three SGLT2 inhibitors with proven kidney and cardiovascular benefits in patients with type 2 diabetes and CKD are canagliflozin, dapagliflozin, and empagliflozin. 1, 2

Complete List of SGLT2 Inhibitors:

• Canagliflozin - 100 mg daily dose for CKD patients 2
• Dapagliflozin - 10 mg daily dose for CKD patients 2, 3
• Empagliflozin - 10 mg daily dose for CKD patients 2, 4
• Ertugliflozin - available but less evidence for kidney outcomes 5
• Sotagliflozin - available but less evidence for kidney outcomes 5
• Ipragliflozin, Tofogliflozin - available primarily in Japan 6

Best Choice for Your Patient with T2DM and CKD

For a patient with type 2 diabetes and CKD, initiate dapagliflozin 10 mg daily if eGFR ≥20 mL/min/1.73 m², as it has the strongest evidence from the DAPA-CKD trial specifically designed for kidney outcomes in both diabetic and non-diabetic CKD patients. 1

Why Dapagliflozin is the Preferred Choice:

• Dapagliflozin demonstrated a 39% risk reduction in the primary kidney endpoint (≥50% eGFR decline, ESKD, or renal/CV death) in the DAPA-CKD trial, which specifically enrolled CKD patients with eGFR 25-75 mL/min/1.73 m² and albuminuria ≥200 mg/g 1

• The DAPA-CKD trial showed a 56% risk reduction for the composite of sustained eGFR decline ≥50%, ESKD, or death from renal causes (HR 0.56,95% CI 0.45-0.68) 1

• Dapagliflozin reduced all-cause mortality by 31% (HR 0.69,95% CI 0.53-0.88) in CKD patients, with benefits consistent regardless of diabetes status 1, 7

Alternative Options Based on Specific Circumstances:

• Canagliflozin 100 mg daily - Use if patient has higher baseline eGFR (30-90 mL/min/1.73 m²) and severe albuminuria (ACR 300-5000 mg/g), as the CREDENCE trial showed 30% risk reduction in primary kidney outcomes and 32% reduction in ESKD development 1, 8

• Empagliflozin 10 mg daily - Consider if patient has established heart failure with reduced ejection fraction (LVEF ≤40%), as it has Class 1 recommendation for reducing CV death and HF hospitalization 2, 9

Initiation Criteria and Dosing Algorithm

When to Start SGLT2 Inhibitors:

Initiate SGLT2 inhibitor when eGFR ≥20 mL/min/1.73 m², regardless of current HbA1c or glycemic control needs, as benefits are independent of glucose-lowering effects. 1, 2

• High priority initiation: Patients with albuminuria ≥200 mg/g (≥20 mg/mmol) 2, 9
• Standard initiation: Patients with eGFR 20-90 mL/min/1.73 m² and any degree of albuminuria ≥30 mg/g 1, 2
• Continue therapy: Once started, continue SGLT2 inhibitor even if eGFR falls below 20 mL/min/1.73 m² until dialysis or transplantation 2, 9

Dosing Specifics:

• Dapagliflozin: 10 mg once daily for kidney/cardiovascular protection (5 mg can be used initially for glycemic control only, then increase to 10 mg) 3
• Canagliflozin: 100 mg once daily for CKD patients 2
• Empagliflozin: 10 mg once daily 2

Pre-Initiation Assessment and Risk Mitigation

Before Starting SGLT2 Inhibitor:

• Assess volume status and correct volume depletion before initiating, particularly in patients on loop diuretics 1, 2
• Check baseline eGFR and albuminuria (spot urine ACR) 1, 2
• Evaluate hypoglycemia risk if patient is on insulin or sulfonylureas - reduce doses of these agents proactively 1, 2
• Consider reducing diuretic dose in patients at high risk for volume depletion 1, 2

Key Monitoring Strategies:

• Counsel on genital hygiene to prevent mycotic infections (6% vs 1% placebo risk) 1, 9
• Educate about diabetic ketoacidosis signs/symptoms, particularly during illness 1
• Institute sick day protocol: withhold SGLT2 inhibitor during acute illness, dehydration, or prolonged fasting 1
• Withhold at least 3 days before major surgery or procedures with prolonged fasting 3
• Monitor blood or urine ketones in high-risk situations 1

Critical Pitfalls to Avoid

• Do NOT withhold SGLT2 inhibitors based on HbA1c being at goal - the kidney and cardiovascular benefits are independent of glucose-lowering effects 1, 2

• Do NOT discontinue when eGFR falls below 20 mL/min/1.73 m² if already initiated - continue until dialysis or transplant 2, 9

• Do NOT assume SGLT2 inhibitors replace metformin - they can be used together when eGFR ≥30 mL/min/1.73 m² (metformin dose reduced to 1000 mg daily for eGFR 30-44) 1, 2

• Do NOT initiate in patients with normal albuminuria (<30 mg/g) and no CKD unless they have established heart failure or cardiovascular disease 9

• Do NOT use in patients with polycystic kidney disease or those requiring immunosuppressive therapy for kidney disease - SGLT2 inhibitors are not expected to be effective in these populations 3

Combination Therapy Considerations

• SGLT2 inhibitors can and should be combined with RAS inhibitors (ACE inhibitors or ARBs) - over 99% of CREDENCE participants were on background RAS blockade 1

• SGLT2 inhibitors can be combined with nonsteroidal mineralocorticoid receptor antagonists (finerenone) with additive cardiovascular benefits 9

• Add GLP-1 receptor agonist if glycemic targets not met with metformin and SGLT2 inhibitor, or if additional weight loss needed 2