Outcomes with Finerenone in Participants with Stage 4 CKD and Type 2 Diabetes: A FIDELITY Subgroup Analysis

Abstract

Background: Patients with stage 4 CKD and type 2 diabetes have limited treatment options to reduce their persistent cardiovascular and kidney risk. In Finerenone in Chronic Kidney Disease and Type 2 Diabetes (FIDELITY), a prespecified pooled analysis of Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD), finerenone improved heart-kidney outcomes in participants with CKD and type 2 diabetes.

Methods: This FIDELITY subgroup analysis investigated the effects of finerenone in participants with stage 4 CKD (eGFR <30 ml/min per 1.73 m 2 ). Efficacy outcomes included a cardiovascular composite (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and a kidney composite (kidney failure, sustained ≥57% decrease in eGFR from baseline, or kidney disease death).

Results: Of 13,023 participants, 890 (7%) had stage 4 CKD. The hazard ratio for risk of cardiovascular composite outcome with finerenone versus placebo was 0.78 (95% confidence interval, 0.57 to 1.07). The kidney composite outcome proportional hazards assumption was not met for the overall study period, with a protective effect only shown up to 2 years, after which the direction of association was inconsistent, and an observed loss of precision over time incurred on finerenone versus placebo risk differences. Nonetheless, albuminuria and rate of eGFR decline were consistently reduced with finerenone versus placebo. Adverse events were balanced between treatment arms. Hyperkalemia was the most common adverse event reported (stage 4 CKD: 26% and 13% for finerenone versus placebo, respectively); however, the incidence of hyperkalemia leading to permanent discontinuation was low (stage 4 CKD: 3% and 2% for finerenone versus placebo, respectively).

Conclusions: The cardiovascular benefits and safety profile of finerenone in participants with stage 4 CKD were consistent with the overall FIDELITY population; this was also the case for albuminuria and the rate of eGFR decline. The effects on the composite kidney outcome were not consistent over time.

Trial registration: ClinicalTrials.gov NCT02540993 NCT02545049.

Graphical abstract

Figure 1

Kidney and cardiovascular outcomes according to CKD stage at baseline. ^aTime to first onset of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. ^bTime to first onset of kidney failure, sustained ≥57% decrease in eGFR from baseline over ≥4 weeks, or kidney disease death. ^cNot calculated because the proportional hazards assumption was not met. CI, confidence interval; HR, hazard ratio; NC, not calculated; PY, person-years.

Figure 2

Cardiovascular and kidney composite outcomes in participants with stage 4 CKD. Aalen–Johansen estimates of (A) time to onset of the cardiovascular composite outcome in participants with stage 4 CKD and (B) time to onset of the kidney composite outcome in participants with stage 4 CKD. ^aNot calculated because the proportional hazards assumption was not met.

Figure 3

Finerenone versus placebo risk differences over time in participants with stage 4 CKD at baseline based on Aalen–Johansen estimates for time to onset of kidney failure, a sustained decrease of eGFR ≥57% from baseline over ≥4 weeks, or kidney disease death.

Figure 4

Markers of kidney function over time in participants with stage 4 CKD. (A) Mixed-model analysis of eGFR over time (LS mean change in eGFR from baseline by visit) in participants with stage 4 CKD at baseline. (B) Effect on albuminuria over time in participants with stage 4 CKD at baseline. ^aTotal slope assessed as annualized LS mean change in eGFR from baseline to the permanent discontinuation or end-of-study visit based on the ANCOVA model. ^bChronic slope assessed as annualized LS mean change in eGFR from month 4 to the permanent discontinuation or end-of-study visit based on ANCOVA model. ^cP < 0.001. ^dP = 0.0012. ANCOVA, analysis of covariance; BL, baseline; LS, least squares; NS, not significant; UACR, urine albumin-to-creatinine ratio.