Finerenone usage on DKD was evaluated on two large randomized, double-blind, multicenter (48 countries), phase 3 placebo-controlled trials – Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) and Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD). These trials were designed similarly to combine their results on FInerenone in CKD and type 2 diabetes: combined FIDELIO-DKD and FIGARO-DKD Trial program analysis (FIDELITY) – a retrospective prespecified pooled analysis, endorsing their individual results and achieving statistical power to conclude on the efficacy of finerenone on the joined population.12–14

The two aimed at determining the efficacy and safety of finerenone compared to placebo on patients with T2D and CKD on top of an optimized therapeutic regimen, but on different outcomes: FIDELIO-DKD on renal outcomes and FIGARO-DKD on CV outcomes. Patients included were adults (≥18 years old), on a maximum tolerated dose of RAAS inhibitor, had T2D and a serum potassium ≤4.8mmol/L. It excluded patients with non-DKD; uncontrolled cardiovascular risk factors; pregnant and breastfeeding women; concomitant therapy that could interact with nsMRA and other comorbidities. A key difference on the pair was CKD definition: FIDELIO-DKD included patients with overall worse kidney function and more renal damage than FIGARO-DKD, with an overlapping, nonetheless. Patients on the intervention group received finerenone on an initial dose dependent on basal kidney function – 10mg/od to eGFR 25 to <60mL/min/1.73m2 or 20mg/od to eGFR≥60mL/min/1.73m2 – titrated to 20mg/od depending on serum potassium and eGFR. Patients on the control group received a placebo pill/od. Total study duration was longer on FIGARO-DKD, to be able to detect CV outcomes – 3.4 years vs 2.6 years. Statistical analysis included 5674 participants for FIDELIO-DKD and 7352 patients for FIGARO-DKD. In terms of efficacy, on FIDELIO-DKD, the primary outcome, a renal outcome, was a composite of kidney failure, a sustained ≥40% decrease in eGFR and renal death. The results showed a hazard ratio (HR) of 0.82 ([95%CI] 0.73–0.93) on the finerenone group vs the placebo group, consistent across pre-stated subgroups and statistically significant. On FIGARO-DKD, the primary outcome, a CV outcome, was a composite of time to CV death, non-fatal myocardial infarction (MI), non-fatal stroke and hospitalization for heart failure (HHF). The results showed a statistically significant lower incidence on finerenone group, with a hazard ratio (HR) of 0.87 ([95%CI] 0.76–0.98). The single outcome in which the reduction was more significant was HHF (HR 0.71 [95%CI] 0.56–0.90). There was no significant heterogeneity across prespecified groups. FIDELIO-DKD assessed the FIGARO-DKD's CV primary outcome as a secondary outcome, and the results were consistent with a HR of 0.86 ([95% CI] 0.75–0.99) on the finerenone group vs the placebo group. Of note, the incidence of individual outcomes was smaller in finerenone, but nonfatal stroke had an akin incidence on both groups. FIGARO-DKD assessed the FIDELIO-DKD's renal primary outcome and shown a lower incidence in the finerenone group versus placebo, although not statistically significant. Furthermore, both trials considered another key secondary outcome, a composite kidney outcome, composed of three items: first onset of kidney failure, sustained decrease from baseline of at least 57% in eGFR for a period of at least 4 weeks or death from renal causes. The results from FIDELIO-DKD showed a lower incidence on the finerenone group, with a HR of 0.76 ([95% CI] 0.65–0.90). The results from FIGARO-DKD pointed to a HR of 0.77 ([95% CI] 0.60–0.99), providing evidence on the efficacy of finerenone in lowering this composite outcome. Lastly, other outcomes measured on both trials were change in mean SBP and change in the UACR. In both FIDELIO-DKD and FIGARO-DKD there was a reduction in SBP. The researchers claim that this lowering effect on BP is not known to have an impact on hard clinical outcomes, showing that the benefits of finerenone are not necessarily related to its hypotensive effect. It also does not seem to be an inconvenience to use this drug on patients with low BP. The change in the UACR from baseline to month four in FIDELIO-DKD was 31% greater with finerenone than with placebo, and on the end of the trial the UACR was sustained lower on the finerenone's group. This same outcome on FIGARO-DKD showed results coincident with FIDELIO-DKD. Finerenone's safety was determined based on the adverse events reported. The results were similar, with a ratio of serious adverse events of about 30% on the finerenone groups on both studies, mainly hyperkalemia related. FIDELIO-DKD had a slightly bigger proportion of hyperkalemia-related adverse events, probably due to including patients with overall worse kidney function. Despite that, the incidence of hyperkalemia-related discontinuation was not concerning neither for FIDELIO-DKD – finerenone 2.3% and placebo 0.9% – nor for FIGARO-DKD – finerenone 1.2% and placebo 0.4% – and only a small percent of patients from FIGARO-DKD required hospitalization – 0.6% on finerenone and 0.1% on placebo.12,13 The incidence of severe hyperkalemia (>6mmol/L) was only 4.5% with finerenone versus 1.4% with placebo. No fatal events were reported. The studies’ protocol allowed the patients to maintain a normal diet and supplementation, not advising on specific measures to restrain potassium intake. The extent to which the results from these studies can be applied on real world are influenced by some limitations, as it did not include patients with non-albuminuric CKD, non-diabetic CKD and only a small percent of patients reported identifying themselves as black. Also, the study excluded pregnant women, children and teenagers, and ESKD patients, limiting the application of these results. 12,13

FIDELITY, the analysis joining the results from FIDELIO-DKD and FIGARO-DKD assessed two primary outcomes: the composite CV outcome (time to CV death, non-fatal MI, non-fatal stroke and HHF) and the composite renal outcome (kidney failure, renal death and a sustained ≥57% decrease in eGFR from baseline over ≥4weeks). The CV primary outcome was statistically significant, with a HR of 0.86 ([95% CI] 0.78–0.95), with a relative risk reduction on the primary CV outcome of 14%. The great reduction in single outcome was observed in the HHF, with a HR of 0.78 ([95%CI] 0.66–0.92) on finerenone versus placebo, meaning a relative risk reduction of 22%. The renal primary outcome was also statistically significant, with a 5.5% rate of events happening with finerenone versus 7.1% with placebo, proving a HR of 0.77 ([95%CI] 0.67–0.88) and a relative risk reduction of 23% with finerenone. Particularly, the relative risk of ESKD was reduced by 20%, the risk of kidney failure by 16%, and sustained decrease in eGFR to <15mL/min/1.73m2 by 19%, shedding light on the beneficial effects of finerenone on dreadful complications associated with CKD. Concerning other important results, the change in mean SBP at 4 months was −3.2mmHg on finerenone versus +0.5mmHg on placebo. The change in UACR from baseline to month four was 32% lower in finerenone than with placebo. Regarding safety outcomes, FIDELITY concluded that finerenone is safe. Despite a greater incidence of hyperkalemia related adverse events (14% on Finerenone vs. 6.9% on placebo), there was only a small incidence of permanent discontinuation (1.7% on finerenone vs. 0.6% on placebo), a modest incidence of hyperkalemia related hospitalization (0.9% on finerenone vs. 0.2% on placebo), and no fatal events. Concluding, this meta-analysis proved the clinical benefit of using finerenone on a vast spectrum of CKD in patients with T2D.14

One FIDELITY sub-analysis also assessed the same cardiovascular composite and kidney composite outcome on patients who were under concomitant therapy with SGLT2 inhibitors and finerenone. This analysis showed benefit for both composite outcomes, kidney and cardiovascular, irrespective of the SGL2i use.15 Furthermore, a network meta-analysis pooled data from 8 randomized controlled trials using SGLT2 inhibitors and finerenone and showed potential CV benefits with combination therapy.16 For better understanding of these positive outcomes the “COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with CKD and type 2 diabetes using a UACR Endpoint study” (CONFIDENCE – NCT05254002) is an ongoing phase 2 study aiming to demonstrate the superiority of combination therapy with finerenone and empagliflozin on reducing UACR when compared to monotherapy with either one of them on patients with T2D and CKD (KDIGO stage G2–G3 and UACR 300–5000mg/g). The primary outcomes assessed will be the relative change in UACR and mean ratio of change in UACR. Results are due February 2025.

“The Effects of Finerenone on Vascular Stiffness and Cardiorenal Biomarkers in Type 2 Diabetes and Chronic Kidney Disease” (FIVE-STAR – NCT05887817) trial aspires to deepen the knowledge on the mechanisms underlying the benefits of finerenone observed on both FIDELIO-DKD and FIGARO-DKD. Patients with T2D and CKD will be randomized to either finerenone or placebo for 24 weeks. The primary endpoint will be the change from baseline to 24 weeks after treatment initiation on cardio ankle vascular index (CAVI), which will be the parameter to assess vascular stiffness. Results are due to July 2026.

“The A Prospective, Interventional, Multicenter, Phase IV, Open-label, Single Arm Study to Assess the Safety and Effectiveness of Finerenone in Participants From India With Chronic Kidney Disease Associated With Type 2 Diabetes” (NCT05705271) is a phase 4 trial evaluating the long-term effects, mainly safety wise, of finerenone use on a population with CKD and T2D from India, estimated to be completed by July 2025.

“The Feasibility of Remote Clinical Trial Conduct in Patients With Diabetes and Elevated Albuminuria, Individual Responses to Empagliflozin, and Whether Suboptimal Treatment Responses Can be Overcome by the Addition or Switch With Finerenone” (Optimize@Home, NCT06094920) is a phase 4 trial with multiple goals. Firstly, it will assess the feasibility of conducting a remote clinical trial on a small population of adults with T2D and albuminuria. Secondly, it is going to assess the individual response to empagliflozin, part of the intervention treatment, in UACR, SBP, eGFR and plasma glucose. Lastly, it will evaluate the impact of either adding or replacing empagliflozin with finerenone on patients with refractory albuminuria. Results are due to October 2024.

A recent prospective, single center, open label randomized clinical trial gave insight on benefits of combination therapy with finerenone and dapagliflozin in reducing albuminuria in a population with non-DKD. A population of twenty non-DKD patients aged between 18–80 years old, UACR of 150–2000mg/g and an eGFR in-between 25 and 45mL/min/1.73m2, on maximum tolerated dose of RAAS inhibitor for at least four weeks, was gathered and studied. Patients were excluded based on presence of comorbidities, such as diabetes, autosomal dominant polycystic kidney disease, HFrEF (left ventricular ejection fraction<40%), poorly controlled hypertension (SBP>160mmHg and DBP>100mmHg), hyperkalemia (>4.5mmol/L) or hyponatremia, previous renal transplantation, conditions requiring immunosuppressants use, and patients on other SGLT2 inhibitors. They were randomized on a 1:1 manner to two arms: the FINEDAPA arm and the DAPAFINE arm. The differences between these groups laid in which medicine was started first: FINEDAPA had a 4-week monotherapy regimen with finerenone 20mg od, while DAPAFINE had the same period with dapagliflozin 10mg od. Following week 4, patients were treated with the combination therapy (finerenone 20mg od+dapagliflozin 10mg od), for a period of 4 weeks, completing a total trial duration of 8 weeks. There was no lost to follow up and there were no significant differences in baseline characteristics among participants. The primary endpoint was the relative change in UACR from baseline to end of treatment and it showed a notable change of −36% [95%CI: −46% to −24%]. When data from the first 4 weeks of treatment is analyzed, it depicts a greater reduction in UACR with finerenone compared to dapagliflozin [−24% ([95% CI] −36 to −11%) vs −8% ([95% CI] −22 to 9%)]. Secondary endpoints showed a significant difference on mean eGFR (mGFR) from baseline to end of treatment, of −3mL/min/1.73m2 with finerenone, −2mL/min/1.73m2 with dapagliflozin and −7mL/min/1.73m2 [95% CI −8 to −5] with combination therapy. These results are indicative that both SGLT2 inhibitors and nsMRAs can cause a reduction in mGFR, at least on the short term. Regarding safety, only three patients developed hyperkalemia (>5.0mmol/L). The raise in serum potassium was more noticeable when finerenone was added to dapagliflozin (DAPAFINE arm), which is incongruent with a theory that states that SGLT2 inhibitors may counteract the hyperkalemia related to nsMRA use. Both events were self-limiting. There were no reports of acute kidney injury. Only one adverse event, from the DAPAFINE arm, was considered serious. These results could be limited, considering the small sample size, short follow up period, absence of a placebo group, and the continuity between single and combination therapy.17

Larger studies to validate finerenone on a population with non-DKD are being developed. The “A Trial to Learn How Well Finerenone Works and How Safe it is in Adult Participants With Non-diabetic Chronic Kidney Disease (FIND-CKD)” (NCT05047263) is a randomized double-blind, placebo-controlled, multicenter (24 countries) phase 3 trial researching the efficacy and safety of finerenone on top of an optimized therapeutic regimen on the evolution of non-DKD. The investigators estimate to gather a population of about 1580 adults (≥18 years old) with eGFR 25–90mL/min/1.73m2 and UACR 200–3500mg/g on an optimized treatment regimen with RAAS inhibitor for at least 4 months and a serum potassium≤4.8mmol/L. Patients are excluded based on the presence of T1D, T2D, or HbA1c≥6.5%; other nephropathies (polycystic kidney disease and any kidney disease requiring immunosuppressants in the 6 months before screening); and the presence of symptomatic HFrEF. Patients will be randomly attributed to two arms receiving either finerenone (10 or 20mg) or placebo daily, for an estimated period of 32 months, comprising 50 weeks total of study duration. The primary outcome is the mean rate of change as measured by total slope of eGFR, from baseline to month thirty-two. Secondary outcomes include the time to a composite kidney and CV outcome (a compound of kidney failure, sustained eGFR decline of ≥57%, HHF or CV death); and the time to both the kidney composite outcome (kidney failure, sustained eGFR decline of ≥57%) and the CV composite outcome (heart failure hospitalization or CV death), on their own. The trial is estimated to end in January 2026.

Finerenone is also currently being investigated for CKD and T1D on a phase 3 trial (NCT05901831), for CKD on pediatric age on two phase 3 trials (NCT05196035 and NCT05457283), and on kidney transplant recipients (NCT06059664).