Dapagliflozin Use in FSGS
Dapagliflozin is NOT recommended as first-line treatment for focal segmental glomerulosclerosis (FSGS). The primary treatment for FSGS remains high-dose corticosteroids, with calcineurin inhibitors, mycophenolate, or rituximab reserved for steroid-resistant or steroid-dependent cases 1.
Why Dapagliflozin Is Not First-Line for FSGS
Limited Evidence in FSGS Specifically
The DAPA-CKD trial included only 104 patients with biopsy-confirmed FSGS out of the total study population, representing a small prespecified subgroup analysis 2.
In this FSGS subgroup, dapagliflozin showed a trend toward slowing chronic eGFR decline (difference of 2.0 mL/min/1.73 m²/year compared to placebo), but this difference was not statistically significant 2.
A pilot study in humans with FSGS (n=10) found that 8 weeks of dapagliflozin did not significantly modify GFR, renal plasma flow, or proteinuria 3.
Renal SGLT2 expression is downregulated in FSGS patients, which may explain the limited efficacy of SGLT2 inhibitors in this specific disease 3.
Current Guideline-Directed First-Line Treatment
For primary FSGS, the established first-line therapy is:
Prednisone 1 mg/kg/day (maximum 80 mg) or alternate-day dosing of 2 mg/kg (maximum 120 mg) 1.
Continue high-dose corticosteroids for a minimum of 4 weeks up to 16 weeks as tolerated or until complete remission is achieved 1.
After achieving complete remission, taper corticosteroids slowly over 6 months 1.
When to Use Alternative Agents (Not Dapagliflozin)
For steroid-resistant or steroid-dependent FSGS:
Calcineurin inhibitors (cyclosporine or tacrolimus), rituximab, or mycophenolate are recommended as second-line therapies 4, 1.
Calcineurin inhibitors at doses of 4-6 mg/kg/day have been successful in reducing proteinuria in steroid-resistant cases 5.
Tacrolimus monotherapy can rapidly induce remission of nephrotic syndrome in FSGS, with mean remission achieved after 6.5 months 6.
When Dapagliflozin MAY Be Considered in FSGS
As Adjunctive Therapy in Established CKD
Dapagliflozin can be considered as adjunctive renoprotective therapy when FSGS patients meet broader CKD criteria, but NOT as primary disease-modifying treatment:
For FSGS patients with eGFR ≥20 mL/min/1.73 m² and UACR ≥200 mg/g, SGLT2 inhibitors are recommended for kidney protection as part of comprehensive CKD management 4.
The indication here is based on general CKD progression prevention, not FSGS-specific disease modification 4.
In the DAPA-CKD FSGS subgroup, dapagliflozin caused an initial eGFR dip of -4.5 mL/min/1.73 m² in the first 2 weeks (compared to -0.9 with placebo), followed by slower chronic decline thereafter 2.
Important Caveats
Genetic testing should be considered in early-onset FSGS or those with family history before initiating immunosuppression, as genetic forms may not respond to immunosuppressive therapy 1.
Remission of proteinuria is the most significant predictor of renal survival in FSGS, making disease-specific immunosuppressive therapy the priority 1.
SGLT2 inhibitors should be used on top of maximally tolerated RAS inhibition, not as a replacement for disease-specific therapy 4.
Practical Algorithm for FSGS Treatment
Confirm diagnosis with kidney biopsy showing FSGS pattern 1.
Initiate high-dose corticosteroids (prednisone 1 mg/kg/day, max 80 mg) for 4-16 weeks 1.
If steroid-resistant after 16 weeks, switch to calcineurin inhibitor (cyclosporine 4-6 mg/kg/day or tacrolimus), rituximab, or mycophenolate 4, 1, 5.
Once CKD is established (eGFR <60 and/or UACR ≥200 mg/g), add SGLT2 inhibitor for general renoprotection 4.
Ensure maximally tolerated RAS inhibition throughout treatment 4.
Safety Considerations for SGLT2 Inhibitors in FSGS Context
Monitor for initial eGFR dip of 3-5 mL/min/1.73 m² in first 4 weeks, which is reversible and not an indication to discontinue 4.
Implement sick day rules: hold SGLT2 inhibitors during acute illness with nausea, vomiting, or diarrhea to prevent ketoacidosis 4.
Counsel on genital hygiene to prevent mycotic infections 4.
Reduce diuretic doses in patients at risk for hypovolemia before initiating SGLT2 inhibitors 4.