The cardiovascular risk associated with type 2 diabetes is exacerbated in chronic kidney disease (CKD). As the urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) exceeds 10 and the estimated glomerular filtration rate (eGFR) decreases below 75 mL/min/1.73 m2, the risks of cardiovascular events and new-onset heart failure increase. The risk for cardiovascular events is higher than that for kidney failure in most patients with CKD, making it important to identify and treat CKD to reduce the substantial burden of cardiovascular disease and heart failure of CKD in patients with type 2 diabetes.
In preclinical models and in patients with CKD in phase 2 studies, finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, improved markers of kidney and cardiovascular damage. In the phase 3 FIDELIO-DKD (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease) trial, finerenone improved kidney outcomes in patients with predominately stage 3 or 4 CKD with severely elevated albuminuria and type 2 diabetes.
The FIGARO-DKD (Finerenone in Reducing Cardiovascular Mortality and morbidity in Diabetic Kidney Disease) trial examined whether finerenone would lead to lower risks of cardiovascular events and death from cardiovascular causes in patients with either stage 2 or 4 CKD and moderately elevated albuminuria or stage 1 or 2 CKD and severely increased albuminuria. Bertram Pitt, MD, and colleagues reported results of FIGARO-DKD online in the New England Journal of Medicine [doi:10.1056/NeJMOA2110956].
FIGARO-DKD was a phase 3, multicenter, randomized, double-blind, placebo-controlled, event-driven clinical trial. Patients with CKD and type 2 diabetes were randomly assigned to receive finerenone or placebo. Eligible patients were adults ≥18 years of age treated with a renin-angiotensin system (RAS) inhibitor at the maximum dose on the manufacturer’s label that did not cause unacceptable side effects. Eligibility criteria included urinary albumin-to-creatinine ratio of 30 to <300 mg/g and an eGFR of 25 to 90 mL/min/1.73 m2 (stage 2 to 4 CKD) or a urinary albumin-to-creatinine ratio of 300 to 5000 mg/g and an eGFR of at least 60 mL/min/1.73 m2 (stage 1 or 2 CKD).
The primary outcome of interest, assessed in a time-to-event analysis, was a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. The first secondary outcome of interest was a composite of kidney failure, a sustained decrease from baseline of at least 40% in eGFR, or death from renal causes. Safety was measured as investigator-reported adverse events.
A total of 19,381 patients from 48 countries underwent screening from September 2015 through October 2018. Of those, 7437 patients underwent randomization. Due to critical violations of Good Clinical Practice, 85 patients were prospectively excluded, resulting in a final analysis cohort of 7352 patients; 3686 in the finerenone group and 3666 in the placebo group.
The two groups were balanced in baseline characteristics and medications, including the dose of RAS inhibitor. At baseline, 8.4% of patients were being treated with a sodium-glucose co-transporter 2 (SGLT2) inhibitor and 7.5% with a glucagon-like peptide-1 (GLP-1) receptor agonist; an additional 15.8% and 11.3% of patients, respectively, initiated treatment during the trial.
At the end of the trial, at a median follow-up of 3.4 years, vital status was ascertained for 99.8% of patients included in the primary analysis (n=7352). The trial was ongoing during the COVID-19 pandemic, resulting in trial disruption for 2096 patients (28.5%; due mostly to missed trial visits). The incidence of premature discontinuation of the trial regimen was balanced between the two groups (27.4% in the finerenone group and 27.7% in the placebo group). The mean daily dose of finerenone was 17.5 mg and the mean daily dose of placebo was 18.2 mg. Adherence to the trial regimen from randomization until receipt of the last dose was 91.5% in the finerenone group and 92.9% in the placebo group.
In the finerenone group, the incidence of the primary outcome was significantly lower than in the placebo group (12.4% [458/3686] vs 14.2% [519/3666]; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.76-0.98; P=.03). The benefit was driven primarily by lower incidence of hospitalization for heart failure; the incidence of hospitalization for heart failure was lower in the finerenone group than in the placebo group (3.2% [117 patients] vs 4.4% [163 patients]; HR, 0.71; 95% CI, 0.56-0.90).
There were no significant differences between the two groups in the incidence of the first secondary outcome of kidney failure, a sustained decrease from baseline of at least 40% in eGFR, or death from renal causes (9.5% [350 patients] in the finerenone group and 10.8% [395 patients] in the placebo group; HR, 0.87; 95% CI, 0.76-1.01). Following adjustment for the competing risk of death, results were consistent. Thirty-two patients in the finerenone group (0.9%) developed end-stage kidney disease compared with 49 patients (1.3%) in the placebo group (HR, 0.64; 95% CI, 0.41-0.995).
The reduction in the urinary albumin-to-creatinine ratio from baseline to month 4 was 32% greater with finerenone compared with placebo (ratio of least-squares mean change from baseline, 0.68; 95% CI, 0.65-0.70). Following adjustment for the competing risk of death, results were similar. The kidney composite outcome of kidney failure occurred in 108 patients in the finerenone group (2.9%) and 139 in the placebo group (3.8%); (HR, 0.77; 95% CI, 0.60-0.99).
There were no substantial differences between the two groups in the incidence of adverse events. The incidence of discontinuation of the trial regimen due to hyperkalemia was higher in the finerenone group than in the placebo group (1.2% vs 0.4%).
The researchers noted that generalizability of the study findings may be restricted because few Black patients underwent randomization.
In conclusion, the authors said, “Among patients with type 2 diabetes and stage 2 to 4 CKD with moderately elevated albuminuria or stage 1 or 2 CKD with severely elevated albuminuria, finerenone therapy improved cardiovascular outcomes as compared with placebo.”
- Researchers reported the results from the FIGARO-DKD trial in patients with type 2 diabetes and CKD.
- The primary outcome—a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure—occurred in 12.4% of patients in the finerenone group and 14.2% of those in the placebo group.
- The kidney composite outcome of kidney failure occurred in 108 patients in the finerenone group (2.9%) and 139 in the placebo group (3.8%); (HR, 0.77; 95% CI, 0.60-0.99).