Cardiovascular events with finerenone in kidney disease and type 2 diabetes

Chronic kidney disease (CKD) is one of the most frequent complications of type 2 diabetes (T2D), and is also an independent risk factor of cardiovascular disease. Finerenone has proved effective in the treatment of patients with CKD in Phase II studies. The Phase III programme covers two studies: the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial, in which finerenone improved kidney outcomes in patients with predominantly stage 3 or 4 CKD with severely elevated albuminuria and T2D, and the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial.

The aim of this study was to investigate whether the addition of oral finerenone to standard daily therapy would reduce the risks of cardiovascular events and death from cardiovascular causes among patients with either stage 2 to 4 CKD and moderately elevated albuminuria, or stage 1 or 2 CKD and severely increased albuminuria.

Finerenone is the first investigational non-steroidal, selective mineralocorticoid receptor antagonist to demonstrate renal and cardiovascular benefits in patients with CKD and T2D across a broad range of disease severity. These benefits are primarily due to a reduction in hospitalisation for heart failure (HF). This study also supports the use of therapies to improve cardiorenal outcomes in patients with less-advanced CKD, which until now had little clinical trial evidence to support it.

The FIGARO-DKD study has demonstrated the cardiovascular benefits of finerenone, highlighting its potential to be a valuable tool in the treatment armamentarium for a vulnerable patient group.

The FIGARO-DKD study (NCT02545049) was a Phase III, multicentre, randomised clinical trial. The trial comprised run-in, screening, and double-blind treatment periods. During the run-in period, renin–angiotensin system (RAS) inhibitor therapy was adjusted upward to a maximum labelled dose that did not cause unacceptable side effects. Patients who met the eligibility criteria at the end of the run-in were randomly assigned (1:1) to receive oral finerenone or placebo. Patients with an estimated glomerular filtration rate (eGFR) of 25-60 ml/min/1.73 m2 at the screening visit received an initial dose of 10 mg once daily, and those with an eGFR of ≥60 at the screening visit received an initial dose of 20 mg once daily. An increase in the dose from 10 to 20 mg once daily was encouraged after 1 month, provided the serum potassium level was ≤4.8 mmol/L and the eGFR was stable. Trial visits occurred at month 1, month 4, and then every 4 months.

Composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalisation for HF.

• Composite of the first occurrence of kidney failure, a sustained decrease from baseline of at least 40% in the eGFR for at least 4 weeks, or death from renal causes.
• All-cause mortality
• All-cause hospitalisation
• Change in urinary albumin-to-creatine ratio (UCAR) from baseline to month 4
• Composite of onset of kidney failure, a sustained decrease in eGFR of ≥ 57% from baseline over at least 4 weeks or renal death

• ≥18 years of age
• T2D
• CKD with persistent moderately elevated albuminuria (UACR  ≥30-<300 mg/g) and eGFR  ≥25-≤90 ml/min/1.73 m2; or persistent severely elevated albuminuria (UACR 300-5000 mg/g) an eGFR ≥60 ml/min/1.73 m2
• Pretreated with either angiotensin-converting enzyme inhibitor or angiotensin receptor blocker at maximal tolerated labelled dose
• Serum potassium ≤4.8 mmol/L

• Confirmed significant non-diabetic renal disease, including clinically relevant renal artery stenosis
• Uncontrolled arterial hypertension
• Clinical diagnosis of chronic HF with reduced ejection fraction and persistent symptoms (New York Heart Association (NYHA) class II – IV) at run in visit

• At a median follow-up of 3.4 years, 7334 of the 7352 enrolled patients were included in the primary analysis
• The incidence of the primary composite outcome was significantly lower in the finerenone group than in the placebo group (12.4% vs. 14.2%; hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.76-0.98; p=0.03)
• The incidence of hospitalisation for HF was lower in the finerenone group than in the placebo group (3.2% vs. 4.4%; HR, 0.71; 95% CI, 0.56–0.90)
• The number of patients who needed to be treated with finerenone to prevent one primary outcome event was 47 (95% CI, 26–226) after 3.5 years
• The effect of finerenone therapy on the primary outcome was consistent across prespecified subgroups
• There was no significant between-group difference in the incidence of the first secondary composite outcome
• Adverse events and serious adverse events of pneumonia were less common with finerenone than with placebo (3.9% vs. 5.6% and 2.0% vs. 3.1%, respectively), as were adverse events related to Covid-19 (2.3% vs.3.2%).
• Finerenone treatment was associated with a greater increase in the serum potassium level from baseline than that observed with placebo

Among patients with T2D and CKD (stage 2 to 4 with moderately elevated albuminuria or stage 1 or 2 with severely elevated albuminuria), those receiving finerenone had a lower risk of the primary composite outcome of death from cardiovascular causes, nonfatal MI, nonfatal stroke, or hospitalisation for HF than those receiving placebo. This difference was driven mostly by a lower incidence of hospitalisation for HF in the finerenone group. These differences were clinically meaningful and add to findings from FIDELIO-DKD, including patients with less severe CKD. During the course of this study, the recommended care for patients with CKD and T2D evolved to include sodium-glucose co-transporter-2 (SGLT2) inhibitors or glucagon-like peptide-1 receptor agonists (GLP-1 RA)s. Finerenone therapy was shown to be beneficial both independent of and in combination with the use of either an SGLT2 inhibitor or a GLP-1 RA. It is possible that a combined therapeutic approach could be used routinely, and this warrants further investigation.

• The study was disrupted by the COVID-19 pandemic; however, only 10 patients were lost to follow-up
• Although the study included a large population of patients with CKD and T2D, the generalisability of the findings may be restricted because few black patients underwent randomisation