ASCVD history does not modify nonsteroidal MRA’s cardiorenal effects in T2DM and CKD
Finerenone efficacy in patients with chronic kidney disease, type 2 diabetes and atherosclerotic cardiovascular diseaseLiterature - Filippatos G, Anker SD, Pitt B, et al. - Eur Heart J Cardiovasc Pharmacother. 2022 Oct 17;pvac054 [Online ahead of print]. doi: 10.1093/ehjcvp/pvac054
Introduction and methods
In patients with T2DM, the risk of ASCVD is up to 4 times higher than that in people without this disease [1,2]. In addition, CV complications are one the most frequent causes of death in patients with both T2DM and CKD , and those with ASCVD on top of CKD and T2DM have the highest risk of all-cause mortality . However, data on effective prevention or reduction of CV events in patients with T2DM and CKD are limited.
Previously, 2 phase 3 trials, FIDELIO-DKD and FIGARO-DKD , showed improved CV and kidney outcomes with the selective, nonsteroidal MRA finerenone compared with placebo in patients with T2DM and CKD [5-7]. It turned out that nearly half of the patients in these studies had a history of ASCVD .
Aim of the study
By performing a pooled analysis of the FIDELIO-DKD and FIGARO-DKD trials, the authors sought to investigate whether the cardiorenal protective effects of finerenone versus placebo are modified by a baseline history of ASCVD in patients with T2DM and CKD.
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 20 mg (10 mg if eGFR <60 mL/min per 1.73 m2) or placebo [5,7]. In the FIDELIO-DKD trial, T2DM patients with more advanced CKD compared with the FIGARO-DKD trial were included, while the latter included T2DM patients with earlier CKD stages but at high CVD risk. Key exclusion criteria included HFrEF with persistent NYHA class II–IV HF symptoms and hospitalization for worsening HF ≤30 days prior to screening.
To evaluate outcomes across a broad spectrum of CKD, individual patient-level data from these trials were pooled in the prespecified FIDELITY (The FInerenone in chronic kidney diseasE and type 2 diabetes: Combined FIDELIO-DKD and FIGARO-DKD Trial programme analysis) database . The median follow-up duration of the pooled data set was 3 years.
For the current FIDELITY subgroup analysis, prespecified subgroups were categorized by the presence or absence of ASCVD at baseline (defined as investigator-reported medical history of CAD, previous ischemic stroke, peripheral artery disease , or carotid endarterectomy). Of the 13,026 patients included in the FIDELITY analysis, 5935 (45.6%) had a history of ASCVD.
Efficacy outcomes included a primary composite CV outcome (time to first event of CV death, nonfatal MI, nonfatal stroke, or HF hospitalization); a composite outcome of time to CV death or HF hospitalization; a composite kidney outcome (time to first event of kidney failure, sustained eGFR decrease ≥57% ≥4 weeks from baseline, or kidney-related death); and all-cause mortality. Safety was assessed as the occurrence of investigator-reported treatment-emergent adverse events.
Effect of finerenone on CV and kidney outcomes and all-cause mortality by history of ASCVD
- In the overall study population, finerenone reduced the risk of the primary composite CV outcome compared with placebo (HR: 0.86; 95%CI: 0.78–0.95; P=0.0018). This treatment effect was not modified by history of ASCVD: The HR was 0.83 (95%CI: 0.74–0.94) for patients with history of ASCVD and 0.91 (95%CI 0.78–1.06) for those without a history of ASCVD (P for interaction=0.38).
- The risk of the composite outcome of CV death or HF hospitalization was also lower in the finerenone group compared with the placebo group (HR: 0.83; 95%CI: 0.74–0.93; P=0.0018). There was no effect modification by history of ASCVD (HR for patients with ASCVD: 0.82; 95%CI: 0.71–0.94 vs. HR for patients without ASCVD: 0.86; 95%CI: 0.71–1.04; P for interaction=0.68).
- The risk of the composite kidney outcome was reduced with finerenone compared with placebo (HR: 0.77; 95%CI: 0.67–0.88; P=0.0002), with no effect modification by history of ASCVD (HR for patients with ASCVD: 0.71; 95%CI: 0.57–0.88 vs. HR for patients without ASCVD: 0.81; 95%CI: 0.68–0.97; P for interaction=0.33).
- The risk of all-cause mortality was numerically but not statistically significantly lower in patients treated with finerenone compared with placebo-treated patients (2.8 vs. 3.1 per 100 patient-years; HR: 0.89; 95%CI: 0.79–1.01; P=0.051). History of ASCVD did not alter the effect of finerenone (HR for patients with ASCVD: 0.85; 95%CI: 0.74–0.99 vs. HR for patients without ASCVD: 0.95; 95%CI: 0.79–1.14; P for interaction=0.38).
Safety outcomes by history of ASCVD
- Serious treatment-emergent adverse events were more common in patients with a history of ASCVD than in those without such a history, irrespective of whether they were treated with finerenone (34.4% vs. 29.4%) or placebo (36.8% vs. 31.1%).
- Similar to the overall results, the frequency of hyperkalemia was higher with finerenone compared with placebo in patients with a history of ASCVD (16.7% vs. 8.9%) and those without a history of ASCVD (14.3% vs. 8.1%).
- The incidence of finerenone-related hyperkalemia leading to hospitalization was 1.2% in the group of patients with a history of ASCVD (0.49 per 100 patient-years) and 0.7% in patients without prior ASCVD (0.27 per 100 patient-years).
- Few patients discontinued finerenone because of a serious treatment-emergent adverse event (0.2% of patients with ASCVD history vs. 0.1% of patients without ASCVD history).
A prespecified FIDELITY subgroup analysis showed that treatment with finerenone reduced the risk of CV events and CKD progression but not all-cause mortality, irrespective of history of ASCVD, in T2DM patients across a broad spectrum of CKD. The safety profile of finerenone in the 2 patient subgroups was largely similar.
According to the authors, “results from the present analyses suggest that the protection conferred by finerenone against HF is independent of a history of ASCVD, [...], indicating that finerenone addresses some of the underlying pathogenetic mechanisms that lead to HF in patients with T2D[M] and CKD, even in the absence of overt ASCVD.”