Cardiorenal benefits of nonsteroidal MRA not modified by HbA1c levels, HbA1c variability, diabetes duration, or insulin use
Effects of finerenone in persons with CKD and T2D are independent of HbA1c at baseline, HbA1c variability, diabetes duration and insulin use at baseline
Introduction and methods
In patients with T2DM, both the level and the variability of HbA1c are associated with an increased risk of adverse cardiorenal outcomes and all-cause mortality [1-4]. In addition, T2DM duration is independently associated with an increased risk of microvascular and macrovascular complications [5-7]. Moreover, insulin-treated T2DM patients tend to have higher rates of CV death and HF hospitalization because of the high level of comorbidities .
Previously, the selective, nonsteroidal MRA finerenone was shown to reduce the risk of adverse cardiorenal outcomes in patients with both T2DM and CKD compared with placebo, as shown by the complementary FIDELIO-DKD and FIGARO-DKD trials and their pooled FIDELITY analysis [9-12]. As excessive aldosterone and associated MR activation lead to the development of T2DM [13,14], finerenone may decrease the progression of this disease.
Aim of the study
Using the FIDELITY dataset, the authors investigated the effect of finerenone on cardiorenal outcomes and diabetes progression and the safety of this agent in patients with T2DM and CKD, stratified by baseline HbA1c levels, continuous HbA1c variability in the first year of treatment, diabetes duration at baseline, and baseline insulin use.
This was a post-hoc analysis of the prespecified pooled FIDELITY dataset, which combined individual patient-level data from 2 multicenter, double-blind, placebo-controlled, phase 3 RCTs (FIDELIO-DKD and FIGARO-DKD). In these trials, a total of 13,026 patients with T2DM and CKD were randomized to finerenone 20 mg (10 mg if eGFR <60 mL/min per 1.73 m2) or placebo. Median follow-up duration of the pooled dataset was 3.0 years (IQR: 2.3–3.8).
Efficacy endpoints were a composite CV outcome (consisting of CV death, nonfatal MI, non-fatal stroke, or HF hospitalization); a composite kidney outcome (kidney failure, sustained eGFR decline ≥57% from baseline for ≥4 weeks, or renal death); and a composite outcome of diabetes progression (new insulin initiation, increase in number of antidiabetic medication classes, HbA1c increase of 1.0% from baseline, new diagnosis of diabetic ketoacidosis, or uncontrolled diabetes).
To assess safety, the incidences of adverse events and treatment-emergent hyperkalemia and hypoglycemia were evaluated.
Composite CV outcome
- In the overall population of the FIDELITY analysis, fewer finerenone-treated patients met the composite CV outcome than placebo-treated patients (4.34 vs. 5.01 per 100 patient-years; HR: 0.86; 95%CI: 0.78–0.95).
- Finerenone reduced the incidence of the composite CV outcome compared with placebo across baseline HbA1c quartiles (≤6.7%; >6.7% to ≤7.5%; >7.5% to ≤8.5%; >8.5%), with no significant interaction among subgroups (P for interaction=0.52).
- Greater HbA1c variability in the first year of treatment was associated with a higher risk of the composite CV outcome (HR: 1.20; 95%CI: 1.07–1.35; P=0.0016), but HbA1c variability did not modify the treatment effect of finerenone on this outcome (P for interaction=0.49).
- Finerenone also reduced the risk of the CV composite outcome compared with placebo across quartiles of diabetes duration at baseline (≤9.1 years; >9.1 to ≤15.1 years; >15.1 to ≤20.2 years; >20.2 years) and baseline insulin use, with no significant interaction among subgroups (P for interaction=0.12 and 0.16, respectively).
Composite kidney outcome
- Overall, the incidence of the composite kidney outcome was lower in the finerenone group than in the placebo group (1.96 vs. 2.55 per 100 patient-years; HR: 0.77; 95%CI: 0.67–0.88; P=0.0002).
- The finerenone treatment effect was not modified by baseline HbA1c level (P for interaction=0.09), HbA1c variability in the first year (P for interaction=0.10), baseline diabetes duration (P for interaction=0.75), or baseline insulin use (P for interaction=0.52).
- Greater HbA1c variability in the first year was also associated with an increased risk of the composite kidney outcome (HR: 1.36; 95%CI: 1.21–1.52; P<0.0001).
Composite diabetes progression outcome
- There was no difference in the occurrence of the composite diabetes progression outcome between the finerenone and placebo groups (63.0% vs. 63.2%; HR: 1.00; 95%CI: 0.95–1.04).
- The incidence of adverse events was similar in the finerenone and placebo groups, irrespective of patient subgroup, and the incidence of serious adverse events leading to study discontinuation was low across subgroups (ranging from 1.6% to 3.0%).
- The incidence of hypoglycemia tended to be lower in the finerenone group than in the placebo group, particularly in patients with higher baseline HbA1c levels, longer diabetes duration, or baseline insulin use.
- Hyperkalemia-related adverse events, including serious adverse events, were more frequently seen in the finerenone group than in the placebo group across all subgroups. The incidences of hyperkalemia-related adverse events leading to discontinuation and serious adverse events leading to hospitalization were low across treatment groups and subgroups.
In this post-hoc analysis of the prespecified pooled FIDELITY dataset, the cardiorenal benefits of finerenone over placebo in T2DM patients with CKD were not modified by baseline HbA1c levels, HbA1c variability in the first year, baseline diabetes duration, or baseline insulin use. Finerenone had no effect on diabetes progression. Of note, HbA1c variability was associated with increased risk of cardiorenal outcomes. Finerenone was well-tolerated across subgroups.
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