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 prespecified analysis of the dapagliflozin and prevention of adverse outcomes in chronic kidney disease trial (DAPA-CKD) was to assess efficacy and safety of dapagliflozin in a small subgroup of participants with FSGS confirmed by kidney biopsy.

Methods: In DAPA-CKD, patients with an estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73 m2 and urinary albumin:creatinine ratio (UACR) 200-5000 mg/g (22.6-565 mg/mol) were randomized to dapagliflozin 10 mg 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, 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 randomized to dapagliflozin and 59 to placebo. Mean (standard deviation) age was 54.0 (14.3) years, mean eGFR 41.9 (11.5) mL/min/1.73 m2 and median (interquartile range) UACR 1248 (749-2211) mg/g. The primary outcome occurred in 4 (8.9%) and 7 (11.9%) participants randomized to dapagliflozin and placebo, respectively [hazard ratio 0.62, 95% confidence interval (95% CI) 0.17, 2.17]. Dapagliflozin led to a larger acute reduction (standard error) in eGFR compared with placebo (-4.5, 95% CI -5.9 to -3.1 versus -0.9, -2.1 to 0.4 mL/min/1.73 m2/2 weeks). 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/1.73 m2/year, respectively (difference 2.0, 95% CI 0.6 to 3.5, mL/min/1.73 m2/year). Adverse events leading to study drug discontinuation were similar in both groups; there were fewer serious adverse events with dapagliflozin.

Conclusions: Among DAPA-CKD participants with FSGS, dapagliflozin reduced the rate of chronic decline of eGFR compared with placebo, although this difference was not statistically significant.

Keywords: DAPA-CKD; dapagliflozin; eGFR slope; focal segmental glomerulosclerosis.

Figure 1:

Forest plot for the primary composite endpoint, kidney-disease specific composite endpoint and a post hoc exploratory composite endpoint of ≥40% eGFR decline, onset of ESKD or death from kidney or cardiovascular causes in the overall DAPA-CKD population and in patients with glomerulonephritis and those with FSGS. *Includes those with biopsy-confirmed FSGS (n = 104) and those classed as FSGS but without biopsy confirmation (n = 11). Primary composite outcome, sustained ≥50% decline in eGFR, onset of ESKD, or death from a kidney or cardiovascular cause; kidney-specific composite outcome, sustained ≥50% decline in eGFR, onset of ESKD or death from a kidney cause.

Figure 2:

eGFR trajectory over time in patients with focal segmental glomerulosclerosis.

Figure 3:

Relationship between percentage change in UACR from baseline to Week 2 and subsequent chronic eGFR slope* in patients with FSGS in the dapagliflozin and placebo groups combined. *Chronic eGFR slope is calculated from Week 2 to end of treatment and expressed as mL/min/1.73 m²/year. The solid line represents the chronic eGFR slope in the overall FSGS population at different values of acute UACR change. The shaded area represents the 95% CI. The distribution of % change in UACR from baseline to Week 2 in the dapagliflozin and placebo group is shown in the histogram, with the bars for the treatment groups superimposed on one another.