What level of estimated glomerular filtration rate (eGFR) is required for SGLT2 (sodium-glucose cotransporter 2) inhibitors to be effective in decreasing the progression of kidney disease?

SGLT2 Inhibitors for Kidney Disease: Optimal eGFR Thresholds

SGLT2 inhibitors are recommended for patients with type 2 diabetes and chronic kidney disease with an eGFR ≥20 mL/min/1.73 m² to reduce CKD progression and cardiovascular events, regardless of albuminuria status. 1

Efficacy Across Different eGFR Levels

SGLT2 inhibitors demonstrate varying degrees of effectiveness based on kidney function:

• eGFR ≥20 mL/min/1.73 m²: Optimal range for both renal and cardiovascular protection

  • Recommended for all patients with type 2 diabetes and CKD in this range 1
  • Effective regardless of albuminuria levels (normal to >200 mg/g creatinine) 1

• eGFR <20 mL/min/1.73 m²:

  • Not recommended for initiation due to reduced efficacy 1
  • If already on canagliflozin or dapagliflozin, continuation may still provide kidney and cardiovascular benefits 1

Evidence Supporting the 20 mL/min/1.73 m² Threshold

The 20 mL/min/1.73 m² threshold is based on several landmark trials:

• CREDENCE trial: Enrolled patients with eGFR >30 mL/min/1.73 m² and UACR >300 mg/g 1
• DAPA-CKD trial: Enrolled patients with eGFR >25 mL/min/1.73 m² and UACR >200 mg/g 1
• EMPEROR heart failure trials: Showed efficacy at eGFR levels >20 mL/min/1.73 m² 1

Subgroup analyses from these trials demonstrated that SGLT2 inhibitors remain safe and effective at eGFR levels as low as 20 mL/min/1.73 m² 1.

Mechanism of Action and eGFR Considerations

SGLT2 inhibitors work by:

1. Blocking glucose reabsorption in the proximal tubule
2. Reducing glomerular hyperfiltration
3. Decreasing albuminuria

As eGFR declines, the glucose-lowering effect diminishes, but the renal and cardiovascular protective effects persist even at lower eGFR levels 2. This explains why these medications remain beneficial for kidney protection even when their glycemic effect is reduced.

Initial eGFR Response and Long-term Benefits

When starting SGLT2 inhibitors, an initial decrease in eGFR of 3-5 mL/min/1.73 m² is common and expected 1. This "eGFR dip" typically:

• Occurs within the first few weeks of treatment
• Returns to baseline over subsequent weeks
• Does not indicate harm and should not prompt discontinuation
• May actually be associated with long-term kidney protection

Recent Evidence on Advanced CKD

The most recent evidence from 2025 suggests that SGLT2 inhibitors may retain their kidney and cardiovascular protective effects even in patients with advanced CKD (eGFR <30 mL/min/1.73 m²), with no additional safety concerns 3. This supports the current threshold of ≥20 mL/min/1.73 m² and suggests potential benefit even in more advanced kidney disease.

Special Considerations

• Older patients: Benefits of SGLT2 inhibitors on renal outcomes apply to patients aged ≥75 years with diabetic kidney disease 4
• Albuminuria: SGLT2 inhibitors are particularly beneficial in patients with albuminuria ≥200 mg/g creatinine but also show benefits with lower or normal albumin levels 1
• Monitoring: Regular monitoring of kidney function is recommended, but mild-to-moderate decreases in eGFR (≤30%) should not prompt discontinuation 1

Practical Recommendations

1. Initiate SGLT2 inhibitors in patients with type 2 diabetes and CKD with eGFR ≥20 mL/min/1.73 m²
2. Do not discontinue for mild-to-moderate decreases in eGFR after initiation
3. Consider continuation even if eGFR falls below the initiation threshold
4. Prioritize SGLT2 inhibitors in patients with albuminuria, but recognize benefits exist regardless of albuminuria status

Common Pitfalls to Avoid

1. Not initiating SGLT2 inhibitors in eligible patients due to concerns about the initial eGFR dip
2. Discontinuing therapy prematurely when observing the expected initial eGFR decline
3. Focusing solely on glycemic effects rather than kidney and cardiovascular protection
4. Overlooking benefits in older patients or those with lower levels of albuminuria

By following these evidence-based recommendations, clinicians can optimize the use of SGLT2 inhibitors to reduce CKD progression and cardiovascular events in patients with type 2 diabetes and kidney disease.