CV benefits and safety with nonsteroidal MRA in stage 4 CKD

Introduction and methods

Background

In an effort to optimize treatment for patients with both T2DM and CKD, several drugs are being investigated. However, treatment options are limited for T2DM patients with stage 4 CKD, a population that is also understudied. The FIDELIO-DKD trial recently demonstrated that the selective, nonsteroidal MRA finerenone reduced the risk of the primary composite renal outcome in T2DM patients with a mean eGFR of 44.3 mL/min per 1.73 m²2 and median urine albumin-to-creatinine ratio (UACR) of 852 mg/g [1], whereas the FIGARO-DKD trial showed finerenone reduced the risk of the primary composite CV outcome in patients with less advanced CKD [2]. The data of these 2 trials were pooled in the FIDELITY dataset.

Aim of the study

In an exploratory subgroup analysis of the FIDELITY dataset, the authors evaluated the efficacy and safety of finerenone versus placebo in patients with T2DM and stage 4 CKD.

Methods

This was a subgroup analysis of FIDELITY (Finerenone in Chronic Kidney Disease and Type 2 Diabetes: Combined FIDELIO-DKD and FIGARO-DKD trial programme analysis), a prespecified, individual participant data pooled analysis of the FIDELIO-DKD and FIGARO-DKD trials (n=13,026) with a median follow-up duration of 3.0 years [3]. The FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease) trials were multicenter, double-blind, placebo-controlled, phase 3 RCTs in which patients with T2DM and CKD were randomized to finerenone (10 or 20 mg once daily based on eGFR at the screening visit) or placebo.

For this subgroup analysis, participants were categorized by CKD stage at baseline: stage 4 (eGFR <30 mL/min per 1.73 m²) (n=890; 7%) or stages 1–3 (eGFR ≥30 mL/min per 1.73 m²) (n=12,133; 93%).

Outcomes

To assess efficacy, CV and renal endpoints were employed. The CV endpoint was a composite outcome of time to CV death, nonfatal MI, nonfatal stroke, or hospitalization for HF. The renal endpoint was a composite outcome of time to kidney failure, sustained eGFR decrease ≥57% from baseline for ≥4 weeks, or kidney disease death. Kidney failure was defined as end-stage renal disease (i.e., initiation of long-term dialysis (for ≥90 days) or kidney transplantation) or sustained eGFR decrease <15 mL/min per 1.73 m² for ≥4 weeks. Other efficacy endpoints were the individual components of the composite CV and renal endpoints and changes in eGFR and UACR over time.

Safety outcomes included investigator-reported adverse events and changes in systolic blood pressure and serum potassium over time.

Main results

CV outcomes

• In T2DM patients with stage 4 CKD, the composite CV endpoint occurred in 75 of 440 patients (17.0%) in the finerenone group and in 92 of 450 (20.4%) in the placebo group (HR: 0.78; 95%CI: 0.57–1.07 ). In T2DM patients with stages 1–3 CKD, this rate was 749/6078 (12.3%) and 846/6055 (14.0%), respectively (HR: 0.87; 95%CI: 0.79–0.96) (P for interaction=0.67).
• Cumulative incidence analyses in patients with stage 4 CKD showed that the CV benefits of finerenone over placebo became apparent during the first year of follow-up.
• The estimated HRs of each component of the composite CV endpoint for finerenone versus placebo were similar or more favorable in patients with stage 4 CKD compared with those with stages 1–3 CKD, except for HF hospitalization, which showed a less favorable effect in patients with stage 4 CKD, although there was no statistically significant evidence of heterogeneity in the effects of finerenone versus placebo (all P for interaction≥0.18).

Renal outcomes

• The composite renal endpoint occurred in 94/440 stage 4 CKD patients (21.4%) who were treated with finerenone and in 92/450 (20.4%) taking placebo. The incidence in patients with stages 1–3 CKD was 266/6078 (4.4%) and 373/6055 (6.2%), respectively (HR: 0.71; 95%CI: 0.60–0.83).
• In the group of patients with stage 4 CKD, the proportional hazards assumption was not met according to the Cox proportional hazards model that included a treatment×log(time) interaction (P for interaction<0.01). At 2-year follow-up, the HR for the effect of finerenone versus placebo on the composite renal endpoint in this subgroup was 0.63 (95%CI: 0.42–0.95; P=0.026).
• Cumulative incidence analyses in stage 4 CKD patients indicated a slower accumulation of first renal events with finerenone versus placebo during the first 2 years of follow-up (between-group risk difference at 1 year: −2%; 95%CI: −5% to 0%; between-group difference at 2 years: −5%; 95%CI: −10% to −1%). However, subsequent renal events accumulated more rapidly in the finerenone group, with between-group differences of 3% (95%CI: −4% to 9%) at 3 years and 5% (95%CI: −4% to 14%) at 4 years.
• Of the individual renal endpoint components, the proportional hazards assumption was only met in stage 4 CKD patients for end-stage renal disease and sustained eGFR decrease ≥57% (both P for interaction≥0.23). All patients with stage 4 CKD who met the composite renal endpoint experienced a kidney failure event, and no kidney disease death was observed in this subgroup.
• In patients with stage 4 CKD, finerenone reduced the annualized least-squares (LS) mean change in eGFR from 4 months to end of treatment (44 months) (i.e., chronic eGFR slope) compared with placebo (−1.8 vs. −3.2 mL/min per 1.73 m² per year; difference: 1.39 mL/min per 1.73 m² ; 95%CI: 0.48–2.30; P=0.04). The annualized LS mean change in eGFR slope from baseline to end of treatment (i.e., total eGFR slope) was numerically lower, albeit not significantly, in patients on finerenone versus placebo (−0.7 vs. −1.6 mL/min per 1.73 m² per year; difference: 0.84 mL/min per 1.73 m²; 95%CI: 0.02–1.67; P=0.22).
• At 4 months, finerenone reduced the LS mean UACR by 31% compared with placebo in stage 4 CKD patients (LS mean treatment ratio: 0.69; 95%CI: 0.63–0.77; P<0.001). The lower UACR in the finerenone group versus placebo group was maintained for up to 24 months.

Safety outcomes

• The incidence of adverse events was similar for the finerenone and placebo groups among patients with stage 4 CKD.
• The most common investigator-reported adverse event in stage 4 CKD patients was hyperkalemia, which was more frequently observed among those taking finerenone compared with placebo (26% vs. 13%). However, the incidences of hyperkalemia leading to permanent discontinuation (3% vs. 2%) or hospitalization (3% vs. 1%) were low.

Conclusion

References

Find this article online at Clin J Am Soc Nephrol.