Nonsteroidal MRA reduces kidney and CV risks in patients with CKD and T2DM with or without CVD

AHA 2020 The nonsteroidal MRA finerenone, evaluated in the FIDELIO-DKD trial, reduced the risk on renal and CV outcome compared to placebo in CKD and T2DM patients with or without a history of CVD.

Presented at the AHA Scientific Sessions 2020 by Gerasimos Filippatos (Athens, Greece)

Introduction and methods

Patients with T2DM and CKD have a threefold higher risk of CV death compared to patients with T2DM alone. Overactivation of the mineralocorticoid receptor (MR) in these patients, drives inflammation and fibrosis formation, which can lead to damage of the heart, kidneys and peripheral vasculature and is associated with increased CV risk. The nonsteroidal MR antagonist (MRA) finerenone inhibits inflammation and reduces fibrosis in animal models.

The FIDELIO-DKD trial was designed to evaluated the effect of finerenone on renal and CV outcomes in patients with CKD and diabetes. This substudy analyzed the effect of finerenone on renal and CV outcomes as well as the individual components in patients with CKD and T2DM with or without ASCVD.

The FIDELIO-DKD trial was a randomized, double-blind placebo-controlled trial included 5734 patients (≥18 years) with T2DM, eGFR ≥25-<75 ml/min/1.73 m², moderate to severe albuminuria, potassium serum levels ≤4.8 mmol/L, treated with a maximally tolerated and optimized dose of ACE inhibitor or ARB for ≥4 weeks, that were randomized (1:1) to finerenone (10 mg when eGFR levels were 25-<60 ml/min/1.73 m² or 20 mg with eGFR levels >60 ml/min/1.73 m²) or placebo. Patients’ CV and diabetes therapies were fully optimized during a run-in period (4-16 weeks), prior to randomization. Primary kidney outcome was a composite of time to kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death. Secondary CV outcome included time to CV death, nonfatal MI, nonfatal stroke, or HF hospitalization. Median follow-up was 2.6 years (IQR 2.0-3.4 years).

Main results

• Patients treated with finerenone had a decreased risk on kidney failure, sustained ≥40% decrease in eGFR from baseline, or renal death compared to patients receiving placebo (HR=0.82, 95% CI: 0.73-0.93, P=0.0014).
• Finerenone also reduced the risk of CV death, nonfatal MI, nonfatal stroke, or HF hospitalization compared to placebo (HR=0.83, 95% CI: 0.75-0.99, P=0.034), irrespective of history of CVD (with CVD: HR 0.85, 95% CI: 0.71-1.02 vs. without CVD: HR 0.86, 95% CI: 0.68-1.08, Pinteraction=0.85).
• Patients receiving finerenone had a decreased risk of the individual endpoints of CV mortality, hospitalization for HF, or nonfatal MI, compared to those treated with a placebo. However, finerenone had no effect on nonfatal stroke (HR=1.03, 95% CI: 0.76-1.38).
• Overall, treatment-emergent adverse events were similar between the two groups. Hyperkalemia-related treatment emergent adverse events though occurred more frequent in the finerenone group compared to placebo group (18.3% vs. 9.0%, respectively). Hyperkalemia resulted in increased hospitalization in patients treated with finerenone (1.4%) compared to patients receiving placebo (0.3%) as well as permanent discontinuation of the study drug (2.3% in the finerenone group vs. 0.9% in the placebo group).

Conclusion

The FIDELIO-DKD trial showed that the nonsteroidal MRA finerenone had a significant positive effect on kidney and CV outcomes compared to placebo in patients with CKD and T2DM, irrespective of CVD history.

Discussion

Until today, adequate RAAS blockage was limited because of rising potassium levels, said the discussant Christoph Wanner (Würzberg, Germany). He continued: ‘We have learned not to exclude those with impaired kidney function and high CV risk from large clinical trials. And we see good safety outcomes’. With the newest drug interventions (SGLT2i and MRA-finerenone), he said, a shift away from glucose management and towards organ protection has been made. So, finerenone is both a cardiovascular and kidney protective treatment in individuals with T2DM and is a valid option where SGLT2i are not preferred or they can be used as combination therapy. He concluded: ‘My feeling is, is that we have entered a new era of effective treatments for diabetic kidney disease. Nothing has happened in 20 years and these new data provide a good perspective for the FIGARO-DKD trial 2021, a cardiovascular outcome trial’.

- Our reporting is based on the information during AHA Scientific Sessions 2020 -

The findings of this study were simultaneously published in Circulation