Which SGLT2 (Sodium-Glucose Linked Transporter 2) inhibitor to add?

Which SGLT2 Inhibitor to Add

For patients with type 2 diabetes and cardiovascular disease or CKD, empagliflozin, canagliflozin, or dapagliflozin are all appropriate choices, with selection based primarily on eGFR and specific patient characteristics rather than superiority of one agent over another. 1

Selection Algorithm Based on Renal Function

eGFR ≥45 mL/min/1.73 m²

• All three agents are appropriate: empagliflozin 10 mg daily, canagliflozin 100 mg daily, or dapagliflozin 10 mg daily 1, 2
• No dose adjustment required in this range 1
• Choice can be based on formulary availability, cost, or patient preference 1

eGFR 30-44 mL/min/1.73 m²

• Prefer canagliflozin 100 mg daily or dapagliflozin 10 mg daily 1, 2
• Empagliflozin should not be initiated in this range per FDA labeling, though it may be continued if eGFR falls after initiation 1, 3
• The KDIGO guidelines emphasize that cardiovascular and renal benefits persist at these lower eGFR levels despite reduced glucose-lowering efficacy 1, 2

eGFR <30 mL/min/1.73 m²

• Do not initiate any SGLT2 inhibitor 1
• However, if already established on therapy, continuation is reasonable unless dialysis is initiated 1, 2

Evidence for Cardiovascular Benefit

All three agents have demonstrated cardiovascular benefits in major outcomes trials, with no clear superiority of one over another 1:

• Empagliflozin (EMPA-REG OUTCOME): Reduced MACE (HR 0.86), CV death (HR 0.62), and HF hospitalization (HR 0.65) in 7,020 patients 1
• Canagliflozin (CANVAS): Reduced MACE (HR 0.86) and HF hospitalization (HR 0.67) in 10,142 patients 1
• Dapagliflozin (DECLARE-TIMI 58): Reduced HF hospitalization/CV death composite (HR 0.83) in 17,160 patients 1

Practical Implementation

Dosing Strategy

• Start at the lowest available dose for cardiovascular risk reduction—no dose titration is needed for CV benefit 1
• Empagliflozin: 10 mg daily 1
• Canagliflozin: 100 mg daily (do not exceed this dose if eGFR 45-59) 1
• Dapagliflozin: 10 mg daily 1

Pre-Initiation Assessment

• Confirm eGFR ≥30 mL/min/1.73 m² (or ≥45 for empagliflozin) 1
• Assess volume status and consider reducing diuretic doses if patient is on thiazides or loop diuretics 1, 4
• If patient is on sulfonylureas or insulin and meeting glycemic targets, reduce those doses by 50% to prevent hypoglycemia 4

Monitoring After Initiation

• Expect a reversible eGFR decrease of up to 30% within 4 weeks—this represents hemodynamic changes from reduced glomerular hyperfiltration, not kidney injury, and is not an indication to discontinue 1, 2
• Continue therapy even if eGFR subsequently falls below initiation threshold, as cardiovascular and renal benefits persist 1, 2
• Monitor for volume depletion, especially in elderly patients or those on diuretics 1
• Educate patients about genital mycotic infections and euglycemic diabetic ketoacidosis risk 4, 5

Special Considerations

Canagliflozin-Specific Concerns

• Canagliflozin has been associated with increased risk of lower-extremity amputation and bone fractures in some studies 6, 5
• This may influence selection in patients with peripheral artery disease or osteoporosis 5

Combination with Other Agents

• SGLT2 inhibitors should be combined with metformin (if eGFR ≥30) as foundational therapy 1
• Can be safely added to RAS inhibitors without dose adjustment 2
• The cardiovascular benefits are independent of glucose-lowering effects 1, 5

When to Withhold Temporarily

• During prolonged fasting, surgery, or critical medical illness when patients are at greater risk for ketosis 1