What is the percentage reduction in urine protein-to-creatinine ratio (UPCR) in patients with IgA nephropathy treated with Sodium-Glucose Linked Transporter 2 (SGLT2) inhibitors, such as empagliflozin (Empagliflozin) or canagliflozin (Canagliflozin), over what period of time, and does the presence of Renin-Angiotensin System (RAS) inhibitors affect this outcome?

SGLT2 Inhibitors and UPCR Reduction in IgA Nephropathy

The available evidence does not provide specific quantifiable data on SGLT2 inhibitor effects on UPCR in IgA nephropathy patients, as the major SGLT2 inhibitor trials (CREDENCE, DAPA-CKD, EMPA-KIDNEY) primarily enrolled diabetic kidney disease patients and did not specifically report IgA nephropathy subgroup outcomes for proteinuria reduction.

Current Evidence Limitations

The guideline evidence focuses predominantly on diabetic kidney disease populations:

• CREDENCE trial (canagliflozin) enrolled 4,401 adults with type 2 diabetes and demonstrated a 27% reduction in progression of albuminuria and 30% reduction in the primary composite renal outcome over 2.6 years 1
• DAPA-CKD trial (dapagliflozin) included only 67.5% diabetic patients (one-third had CKD without diabetes), with median baseline UACR of 949 mg/g, showing 39% risk reduction for kidney composite outcomes 1
• EMPA-KIDNEY trial (empagliflozin) enrolled participants with significant kidney disease but did not specifically report IgA nephropathy outcomes 1

Critical gap: None of these landmark trials specifically reported UPCR reduction percentages or timeframes for IgA nephropathy patients as a distinct subgroup 1.

Emerging Real-World Evidence in IgA Nephropathy

The most relevant recent data comes from a 2024 observational study:

• 31% of enrolled patients had IgA nephropathy (alongside 29% diabetic/hypertensive CKD) 2
• Patients received primarily dapagliflozin 10 mg (88%) with median baseline eGFR 46 mL/min/1.73 m² and albuminuria 1,911 mg/g creatinine 2
• However, this study reported overhydration and protease activity outcomes, not specific UPCR percentage reductions 2

A 2025 real-world study provides indirect evidence:

• 23 IgA nephropathy patients on maximum tolerated RAS inhibitors AND SGLT2 inhibitors showed median baseline UPCR of 1.5 g/g 3
• When sparsentan was added to this dual therapy, UPCR decreased to 0.85 g/g at 2 weeks and 0.60 g/g at 14 weeks (62% relative reduction) 3
• This demonstrates that patients already on SGLT2 inhibitors still had significant residual proteinuria, suggesting SGLT2 inhibitors alone may not achieve optimal UPCR targets in IgA nephropathy 3

Impact of Concurrent RAS Inhibitor Use

All major SGLT2 inhibitor trials required background RAS inhibition:

• CREDENCE had >99% of participants on ACE inhibitor or ARB therapy at maximal tolerated doses 1
• The renal benefits (30% reduction in primary composite outcome) were achieved on top of optimized RAS blockade 1

There are no trials examining SGLT2 inhibitors in IgA nephropathy patients NOT on RAS inhibitors, making direct comparison impossible 1.

Clinical Context for IgA Nephropathy

Current guidelines for IgA nephropathy do not specifically address SGLT2 inhibitors:

• KDIGO 2021 guidelines focus on corticosteroids (34% proteinuria reduction at 9 months with budesonide) and supportive care with RAS blockade 1
• Target proteinuria reduction in IgA nephropathy is ≥50% by 6 months, with goal UPCR <0.5-0.7 g/g by 12 months 1
• Proteinuria reduction ≥30% at 9-12 months is validated as a surrogate endpoint for long-term renal outcomes in Japanese IgA nephropathy patients 4

Practical Algorithmic Approach

Given the evidence gaps, the following approach is recommended:

1. Initiate maximal tolerated RAS inhibition first (ACE inhibitor or ARB) as this remains the foundation of therapy for IgA nephropathy with proteinuria >0.5-1 g/day 1

2. Add SGLT2 inhibitor if eGFR ≥30 mL/min/1.73 m² based on extrapolation from diabetic CKD data showing 27-40% reduction in albuminuria progression and 30-39% reduction in composite renal outcomes over 2-4 years 1

3. Monitor UPCR at 3-month intervals, expecting gradual reduction over 6-12 months rather than rapid response 1, 5, 4

4. If UPCR remains >1 g/g after 3-6 months of optimized supportive therapy (RAS inhibitor + SGLT2 inhibitor), consider additional immunosuppression per KDIGO guidelines 1

Critical Caveats

• The specific percentage UPCR reduction from SGLT2 inhibitors in IgA nephropathy is unknown and cannot be reliably extrapolated from diabetic kidney disease trials 1
• Real-world evidence suggests patients on both RAS inhibitors and SGLT2 inhibitors may still have substantial residual proteinuria (median 1.5 g/g) requiring additional therapy 3
• Time to maximal proteinuria reduction is likely 6-12 months, consistent with the gradual mechanism of action through hemodynamic and tubular effects 1, 5
• The absence of trials comparing SGLT2 inhibitors with versus without RAS inhibitors in IgA nephropathy means the independent contribution of SGLT2 inhibitors cannot be quantified 1, 3