Safety and efficacy of dapagliflozin in patients with focal segmental glomerulosclerosis: a prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease (DAPA-CKD) trial

Abstract

Background Despite renin-angiotensin-aldosterone-system blockade and immunosuppressive treatment, focal segmental glomerulosclerosis (FSGS) often progresses to kidney failure. The objective of this pre-specified analysis of DAPA-CKD was to assess efficacy and safety of dapagliflozin in a small subgroup participants with FSGS confirmed by kidney biopsy. Methods In DAPA-CKD, patients with estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g (22.6–565 mg/mol) were randomised to dapagliflozin 10mg once-daily or placebo as an adjunct to standard care, and followed for median 2.4 years. The primary composite endpoint was sustained eGFR decline ≥ 50%, end-stage kidney disease (ESKD), or kidney or cardiovascular death. The endpoint of interest for this analysis was eGFR slope (acute effects from baseline to Week 2 and chronic effects from Week 2 to end of treatment). Results Of 104 participants with biopsy-confirmed FSGS, 45 were randomised to dapagliflozin and 59 to placebo. Mean (SD) age was 54.0 (14.3) years, mean eGFR 41.9 (11.5) mL/min/1.73m2 and median (IQR) UACR 1248 (749–2211) mg/g. The primary outcome occurred in 4 (8.9%) and 7 (11.9%) participants randomised to dapagliflozin and placebo, respectively (HR 0.62, 95%CI 0.17–2.17). Dapagliflozin led to a larger acute reduction (SE) in eGFR compared to placebo (−4.5 [95% CI − 5.9-−3.1] vs − 0.9 [−2.1–0.4] mL/min/1.73m2 per 2 wks). Thereafter, mean rates of chronic eGFR decline with dapagliflozin and placebo were − 1.9 (−3.0-−0.9) and − 4.0 (−4.9-−3.0) mL/min/1.73m2/year, respectively (difference 2.0 [95%CI 0.6–3.5] mL/min/1.73m2/year). Adverse events leading to study drug discontinuation were similar in both groups; there were fewer serious adverse events with dapagliflozin. Conclusion Among DAPA-CKD participants with FSGS, dapagliflozin reduced the rate of chronic decline of eGFR compared to placebo, although this difference was not statistically significant.

The Role of Rituximab in Primary Focal Segmental Glomerular Sclerosis of the Adult

“… 27 Novel antiproteinuric drugs are providing further options for treating this insidious disease. 28 , 29 However, immunosuppressive approaches are frequently required in the primary form, where an immune-mediated pathogenesis with a role for B cells is likely. In this context, RTX is an attractive therapeutic option, with a favorable safety profile.…”

Prescribing SGLT2 Inhibitors in Patients With CKD: Expanding Indications and Practical Considerations

“…63,64 For FSGS, a prespecified analysis of DAPA-CKD included 115 individuals with FSGS, of which 105 (90%) were biopsy proven. 65 The primary composite kidney outcome did not reach statistical significance (HR 0.62, 95% CI 0.17-2.17). However, participants treated with dapagliflozin had 26.1% reduction in albuminuria compared with 9.9% in placebo which persisted after a year.…”

Diabetic Proteinuria Revisited: Updated Physiologic Perspectives

“…Thus, with the current clinical data, we cannot unequivocally dissect the independent impact of attenuating proteinuria on renal salvage from renal protection provided by an overall control of metabolic derangements, systemic hypertension and glomerular hypertension and hyperfiltration. Of note, however, the findings of a recent study reporting renoprotective properties of Dapagliflozin unrelated to diabetes in patients with focal segmental glomerulosclerosis (FSGS) strengthen the potential independent impact of reducing proteinuria on the attenuation of progressive diabetic nephropathy [ 126 ]…”