Obesity does not influence beneficial effects of nonsteroidal MRA in CKD and T2D
The impact of obesity on cardiovascular and kidney outcomes in patients with chronic kidney disease and type 2 diabetes treated with finerenone: Post hoc analysis of the FIDELITY study
Introduction and methods
Patients with obesity have an increased risk of developing CKD, CVD, T2D, and hypertension compared with people with a health body weight [1,2]. The FIDELITY (FInerenone in chronic kiDney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analYsis) prespecified pooled analysis previously showed the selective, nonsteroidal MRA finerenone reduced the risks of CV outcomes and kidney disease progression in patients with CKD and T2D compared with placebo . However, data on the influence of obesity on the response to MRAs in this patient population are limited.
Aim of the study
In a post-hoc analysis of the FIDELITY dataset, the authors assessed whether the CV and renal benefits of finerenone in the overall FIDELITY population were consistent in patients with CKD and T2D with and without obesity.
The FIDELITY dataset is a prespecified, individual patient-level data pooled analysis of 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 [3-5]. In these multicenter, double-blind, placebo-controlled, phase 3 RCTs, a total of 13,026 patients with T2D and CKD were randomized to oral finerenone (10 or 20 mg once daily based on eGFR at the screening visit) or placebo. Median follow-up duration was 3.0 years (IQR: 2.3–3.8).
In this post-hoc analysis, 12.986 participants were stratified into 2 groups by their waist circumference (WC)—which represents the degree of visceral obesity—: low-risk (n=1198; 9.2%) or high-risk to very high–risk (n=11.788; 90.8%).
Efficacy endpoints included, among others: (1) composite CV outcome, consisting of time to first event of CV death, nonfatal MI, nonfatal stroke, or hospitalization for HF; (2) composite renal outcome, consisting of time to first event of kidney failure, sustained eGFR decline ≥57% from baseline, or kidney disease death; and (3) results from an additional analysis of covariance on annualized eGFR slopes.
Safety outcomes included the incidence of investigator-reported adverse events and other safety events such as a change in systolic blood pressure.
- In the low-risk WC group, the incidence of the composite CV endpoint was similar for patients treated with finerenone and placebo-treated patients (3.9 vs. 3.7 per 100 patient-years; HR: 1.03; 95%CI: 0.72–1.47).
- In the high-/very high–risk WC group, finerenone reduced the event rate compared with placebo (4.4 vs. 5.2 per 100 patient-years; HR: 0.85; 95%CI: 0.77-0.93), but there was no significant heterogeneity between the 2 WC groups (P for interaction=0.26).
- There was also no significant interaction between WC groups by sex (P for interaction=0.64).
- The rate of the composite renal endpoint was similar for finerenone-treated and placebo-treated patients in the low-risk WC group (3.0 vs. 3.4 per 100 patient-years; HR: 0.98; 95%CI: 0.66–1.46), whereas it was reduced with finerenone versus placebo in the high-/very high–risk WC group (1.9 vs. 2.5 per 100 patient-years; HR: 0.75; 95%CI: 0.65-0.87; P for interaction=0.34).
- In addition, no significant interaction between WC groups by sex was observed for the renal endpoint (P for interaction=0.34).
- In the low-risk WC group, the annualized least-squares (LS) mean change in eGFR slope from 4 months to end of treatment (44 months) (i.e., chronic eGFR slope) was similar for finerenone-treated and placebo-treated patients (difference: 0.1 mL/min per 1.73 m² per year; 95%CI: −0.9 to 1.0; P=0.89), as was the annualized LS mean change in eGFR slope from baseline to end of treatment (i.e., total eGFR slope) (difference: −0.9 mL/min per 1.73 m² per year; 95%CI: −2.3 to 0.6; P=0 .21).
- In the high-/very high–risk WC group, finerenone attenuated the chronic eGFR slope compared with placebo (difference in LS means: 1.3 mL/min per 1.73 m² per year; 95%CI: 0.9-1.7; P<0.0001) but not the total eGFR slope (difference in LS means: 0.2 mL/min per 1.73 m² per year; 95%CI: −0.2 to 0.5; P=0.34).
- The incidences of any adverse event (~87%) and any serious adverse event (~32%) were similar across the 2 treatment groups, irrespective of WC group.
- In the low-risk WC group, the risk of treatment-emergent events related to hyperkalemia was higher in patients treated with finerenone (17.6%) compared with placebo (10.2%) and also higher than in the high-/very high–risk WC group (13.7% for finerenone vs. 6.6% for placebo).
- However, the risk of hyperkalemia adverse events leading to study drug discontinuation was low across all groups (range: 0.5%–1.7%), as was the risk of serious hyperkalemia adverse events (range: 0.2%–1.1%).
This post-hoc analysis of the FIDELITY dataset showed that visceral obesity did not significantly modify the effects of finerenone versus placebo on reducing the risk of CV events and kidney disease progression in patients with CKD and T2D. Although finerenone appeared to have greater cardiorenal benefits in the high-/very high–risk WC group, there was no significant heterogeneity between the 2 WC groups, which the authors believe may be due to the small sample size of the low-risk WC group. The safety profile of finerenone was similar in both WC groups, and the drug was generally well tolerated.