Finerenone improves cardiovascular outcomes in patients with Type 2 Diabetes and CKD

Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, improves cardiovascular events (MI, stroke, HF) in Type 2 Diabetes and Chronic Kidney Disease (CKD) patients. 

Some risk factors for cardiovascular diseases (CVD), such as high blood glucose, blood pressure, serum cholesterol, and BMI, are also associated with CKD and type 2 diabetes. Thus, among patients with diabetes, those with kidney disease have exceptionally high rates of cardiovascular disease (CVD), leading to a 3-fold increase in all-cause mortality and a 16-year loss in life expectancy, which is exceptionally high compared to patients who have diabetes alone (approximately two-fold increase in mortality and 10-year loss in life expectancy) or CKD alone (approximately 2 fold increase in mortality and 6-year loss in life expectancy). Newer diabetic treatments such as SGLT-2 inhibitors showed only moderate benefits on major CV events, and glucagon-like peptide 1 (GLP-1) analogs were not sufficiently tested in CV outcomes trials. Preclinical investigations have shown that plasma aldosterone concentrations and mineralocorticoid receptor (MR) overactivation are associated with a higher CV risk by exerting harmful effects to the heart, kidney, brain, and peripheral vasculature.

 Currently marketed MR antagonists have significant adverse effects such as gynecomastia and hyperkalemia, limiting their use. Finerenone is a novel nonsteroidal, selective mineralocorticoid receptor (MR) antagonist with greater MR selectivity and affinity than currently marketed MR antagonists, thus, reaching the heart and renal tissue in equal concentration and causing a low incidence of hyperkalemia. 

In brief, the FIGARO-DKD trial is an international, multicenter, phase 3, randomized, placebo-controlled, double-blind, event-driven clinical trial, in which 7,437 adults (≥18 years old) patients with Type 2 Diabetes and Stage 1-4 CKD treated with either ACE-R or ACB at the maximum dose and having serum potassium level of 4.8mmol/L or less at the time of screening were randomized from September 2015 through October 2018. Patients were randomly assigned in a 1:1 ratio to receive either oral finerenone or placebo. Patients with screening eGFR of between 25 and 60 were started with finerenone 10mg once daily, and others with eGFR>60 were started with finerenone 20mg once daily. For post-screening 1-month onward, the target dose of finerenone or placebo was 20mg once daily, provided that the serum potassium level was no more than 4.8mmol/L and that eGFR was stable. Downgrading the finerenone dose from 20mg to 10mg once daily was allowed for any safety reason during the trial. Trial drugs were withheld if serum K level exceeded 5.5mmol/L and were restarted when serum K level decreased to 5.9mmol/L or less. The primary endpoint was a composite of death from cardiovascular events and nonfatal MI, stroke, or HF events. Secondary outcomes were 1). Composite of the first occurrence of kidney failure, a sustained decrease of 40% in eGFR from baseline for at least four weeks, or death from renal causes, 2). Hospitalization for any cause, death from any cause, and the change in the urinary albumin-to-creatinine ratio from baseline to month 4. Cox proportional hazard models were used to provide treatment effects in terms of hazard ratios (HRs). All p values are for 2-sided tests with p<0.05 considered statistical significance.

This trial shows that the incidence of primary outcome was significantly lower in the finerenone group (458 out of 3686 patients, 12.4%) compared to the placebo group (519 out of 3666 patients, 14.2%) (HR 0.87; 95% CI: 0.76-0.98, p=0.03). The Number Needed to Treat (NNT) with finerenone to prevent one primary outcome event was 47 (95% CI: 26 to 226). There is no significant difference between treatment and control groups for secondary outcomes. 31.4% of the patients in the finerenone group had a serious adverse event, compared with 33.2% in the placebo group. Although however, hyperkalemia incidence was double with finerenone than in placebo (10.8% and 5.3%, respectively), none of these incidences resulted in death. At month-1, a between-group serum potassium level difference of 0.16mmol/L was seen and mainly remained stable after that. Gynecomastia and AKI incidents were balanced between finerenone and placebo groups. 

FIGARO-DKD trial showed that finerenone significantly lowers the risk of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure compared to placebo in patients with Type 2 Diabetes and Stage 1-4 CKD. This trial shows that finerenone use improves cardiovascular events outcomes in patients with less advanced CKD (stage 1 and 2 CKD). This trial also shows a lower incidence of AKI and gynecomastia. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, is a better alternative to steroidal mineralocorticoid antagonist and an attractive therapeutic option in improving cardiovascular outcomes in patients with Type 2 Diabetes and CKD. 

Practice Pearls:

1. Chronic Kidney Disease (CKD) exacerbates cardiovascular events risk (MI, stroke, HF) in patients with Type 2 Diabetes.
2. Currently marketed steroidal mineralocorticoid receptor antagonists, e.g., spironolactone and eplerenone, decrease CV events risk and sudden death in patients with HFrEF and impaired kidney function. However, they have substantial side effects such as gynecomastia and hyperkalemia, causing early treatment termination.
3. ARTS study shows that finerenone 10mg daily dose has significantly lower incidence (4.5%) of hyperkalemia than with spironolactone 25 to 50mg daily dose (11.1%). 

 

1. Pitt, Bertram et al. “Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes.” The New England journal of medicine, 10.1056/NEJMoa2110956. 28 Aug. 2021, doi:10.1056/NEJMoa2110956
2. Ruilope, Luis M et al. “Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial.” American journal of nephrology vol. 50,5 (2019): 345-356. doi:10.1159/000503712

Kandarp Mehta, MS, PharmD Candidate, University of Colorado Anschutz Medical Campus, Skaggs School of Pharmacy and Pharmaceutical Sciences