In short Article

Finerenone for type 2 diabetes and chronic kidney disease


Treatment for patients with type 2 diabetes mellitus and chronic kidney or cardiovascular disease has to focus on blocking the renin-angiotensin-aldosterone system (RAAS). In specific cases, the (off-label) addition of a competitive aldosterone receptor antagonist (mineralocorticoid receptor antagonist – MRA) like spironolactone or eplerenone may be considered. Finerenone is a new, non-steroid aldosterone receptor antagonist which is said to theoretically carry a lower risk of hyperkalemia. The results of the registration studies FIDELIO-DKD and FIGARO-DKD show that finerenone reduces the incidence of both renal and cardiovascular complications, compared to placebo. The risk of hyperkalemia does not, however, appear to be relevantly lower than that found with existing MRAs. For now, therefore, there does not appear to be any evidence for the added value of finerenone compared to these older MRAs, which are available as cheaper generic products.

  • The addition of finerenone to a standard treatment in patients with type 2 diabetes mellitus and a chronic kidney disease results in a small reduction of the risk of major renal and cardiovascular complications compared to placebo.
  • Although no direct comparisons are available, older aldosterone receptor antagonists like spironolactone and eplerenone appear to produce a comparable reduction of the risk of major renal and cardiovascular complications.
  • The claimed lower risk of hyperkalemia, compared to older aldosterone receptor antagonists like spironolactone and eplerenone does not appear to have been proven.
  • Treatment with finerenone requires checking serum potassium concentrations.
  • For the time being, finerenone has no place in the treatment of patients with type 2 diabetes mellitus and chronic kidney disease.

The main goal of the treatment of patients with type 2 diabetes mellitus is an optimised glycaemic control. For patients with concomitant chronic kidney disease or cardiovascular disease, the recently revised Dutch College of General Practitioners’ guideline recommends starting treatment with a sodium-dependent glucose co-transporter 2 (SGLT-2) inhibitor, then add metformin, and, where necessary, a glucagon-like peptide (GLP)-1 receptor agonist.1 In addition, the guideline on cardiovascular risk management recommends treating hypertension, if present. The treatment of first choice aims to block the renin-angiotensin-aldosterone system (RAAS).2 This blockade can be achieved with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II antagonist (ARB – angiotensin receptor blocker). Sometimes a competitive aldosterone receptor antagonist (MRA – mineralocorticoid receptor antagonist), like spironolactone or eplerenone, is prescribed to replace an ACE inhibitor or ARB, for instance in case of intolerance. The use of these potassium-sparing diuretics is, however, regarded as off-label for this application in the Netherlands, and doctors are asked to be cautious about prescribing them.3

Since 9 July 2021, finerenone (20 mg daily at an EGFR ≥ 60 mL/min/1.73 m2 or 10 mg daily at an EGFR ≥ 25 and < 60 mL/min/1.73 m2, raised, if possible, to 20 mg daily) has been authorised in the United States for slowing down the progression of chronic kidney diseases and cardiovascular diseases in patients with type 2 diabetes mellitus and concomitant chronic kidney disease. Finerenone is a new, non-steroid aldosterone receptor antagonist, with a higher selectivity for the aldosterone receptor than spironolactone and stronger affinity than eplerenone.3


The American Food and Drug Administration (FDA) based its authorisation of finerenone on the FIDELIO-DKD trial, a randomised placebo-controlled trial to assess the efficacy of finerenone in patients with type 2 diabetes mellitus and chronic kidney disease. This trial found that finerenone reduced the occurrence of a composite primary endpoint including several major complications linked to kidney disease. In addition, it prevented the occurrence of a composite secondary endpoint including several major cardiovascular complications. 

In the meantime another study, the FIGARO-DKD trial, has also been published. This is a comparable trial, in which the primary and secondary endpoints were exchanged and patients with less severe kidney diseases were included. The two trials yielded comparable results.

Study design

As is usual for registration studies, both trials were funded and analysed by the manufacturer. Both trials compared finerenone (20 mg daily at an EGFR ≥ 60 mL/min/1.73 m2 or 10 mg daily at an EGFR ≥ 25 and < 60 mL/min/1.73 m2, raised if possible to 20 mg daily after one month) with placebo. No trials are available that compared finerenone directly with spironolactone or eplerenone for relevant clinical endpoints. The study populations included in those studies of spironolactone and eplerenone that examined the occurrence of relevant clinical endpoints were so different as to exclude reliable indirect comparisons. Hence it is impossible to determine the presence or absence of a potential added value relative to these drugs, which have been available for a long time. Based on the FIDELIO-DKD and FIGARO-DKD trials, there seems to be little reason to assume that finerenone will yield substantially better results. In addition, the study populations assessed in both of these trials were relatively healthy, and it is unclear whether the results are representative of the entire population of patients with type 2 diabetes mellitus. Both trials are discussed in more detail below.

Endpoint: kidney complications (FIDELIO-DKD) 

This randomised, double-blind placebo-controlled trial included 5734 patients. The participants had type 2 diabetes mellitus, mostly with stage 3 or 4 chronic kidney damage (eGFR ≥ 25 and < 60 mL/min/1.73 m2, ≤10% of them with a history of diabetic retinopathy) and usually moderately elevated urinary albumin-to-creatinine ratio (≥90% 30 to 300 mg/g, ≤10% > 300 mg/g). The participants had not had a clinical diagnosis of heart failure with reduced ejection fraction (New York Heart Association class II–IV) nor a serum potassium concentration exceeding 4.8 mmol/L. During a run-in phase, which could last 4 to 16 weeks, potential participants were given the maximum dosage – as recommended by the manufacturer – of an ACE inhibitor or ARB that did not cause unacceptable adverse effects. At a subsequent screening visit, the inclusion and exclusion criteria were checked once more.

Results

The primary endpoint was a composite of kidney failure, a persistent decrease of the eGFR by 40% or more relative to baseline, or death due to renal causes. During a median follow-up of 2.6 years, this primary endpoint occurred in 504 of the 2833 (17.8%) patients in the finerenone group and 600 of the 2841 (21.1%) patients in the placebo group. The hazard ratio was 0.82 (95% confidence interval [CI] 0.73 to 0.93). This corresponds to a number needed to treat (NNT) of 27.

The main secondary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure. This secondary endpoint occurred in 367 of the 2833 (13.0%) patients in the finerenone group and 420 of the 2841 (14.8%) patients in the placebo group. The hazard ratio was 0.86 (95% CI 0.75 to 0.99), and the NNT was 49.

Endpoint: cardiovascular complications (FIGARO-DKD)

This randomised, double-blind placebo-controlled trial included 7437 persons. The participants had type 2 diabetes mellitus with stage 2 to 4 chronic kidney disease (eGFR ≥ 25 and ≤ 90 mL/min/1.73 m2) and a moderately elevated urinary albumin-to-creatinine ratio (≥30 and <300 mg/g), or stage 1 or 2 chronic kidney disease (eGFR ≥ 25 and ≤ 90 mL/min/1.73 m2) and a severely elevated urinary albumin-to-creatinine ratio (≥300 mg/g), ≤10% having a moderately elevated urinary albumin-to-creatinine ratio (≥30 and <300 mg/g) and stage 2 chronic kidney disease (eGFR ≥ 60 and ≤ 90 mL/min/1.73 m2). The participants had not had a clinical diagnosis of heart failure with reduced ejection fraction (New York Heart Association class II–IV) or a serum potassium concentration exceeding 4.8 mmol/L. During a run-in phase, which could last 4 to 16 weeks, potential participants were given the maximum dosage – as recommended by the manufacturer – of RAAS blockade that did not cause unacceptable adverse effects. At a subsequent screening visit, the inclusion and exclusion criteria were checked once more.

Results

The primary endpoint was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure. During a median follow-up of 3.4 years, this primary endpoint occurred in 458 of the 3686 (12.4%) patients in the finerenone group and in 519 of the 3666 (14.2%) patients in the placebo group. The hazard ratio was 0.87 (95% CI 0.76 to 0.98). This corresponds to an NNT of 55.

The main secondary endpoint was a composite of kidney failure, a persistent decrease of the eGFR by 40% or more relative to baseline, or death due to renal causes. This secondary endpoint occurred in 350 of the 3686 (9.5%) patients in the finerenone group and 395 of the 3666 (10.8%) patients in the placebo group. The hazard ratio was 0.87 (0.76 to 1.01), a non-significant difference.

Switching between the FIDELIO-DKD and FIGARO-DKD trials

The supplementary appendices of both the FIDELIO-DKD and FIGARO-DKD trials describe the option of having patients switch between the two trials during the run-in phase. According to the FIDELIO report, 1552 of the 13,911 patients screened switched to the FIGARO trial, while 1374 patients switched from the FIGARO trial to the FIDELIO trial. However, according to the FIGARO trial, 1376 of the 19,381 patients screened switched to the FIDELIO trial and 1555 actually switched from the FIDELIO to the FIGARO trial. These reported numbers are thus contradictory. Nowhere else in the articles is there any mention of the option of switching between trials, or of the reasons for doing so. Finally, according to the diagram presented in the supplementary appendix, the switches took place before the second screening and randomisation. It is therefore unclear whether those patients who switched were all included, or whether they could still be excluded after their switch, at the second screening. All of this raises doubts about the precise procedure used in the patient recruitment and selection in both trials.


Any adequate estimation of the effect that can be expected of a drug in a clinical setting always needs to take effect modification into account. The term effect modification refers to the phenomenon that differences in effectiveness will arise between patient groups. Hence, in interpreting the results of a drug trial one should always check whether the patient group to which the patient one wishes to treat belongs is included in the trial. This is also known as the representativeness or external validity of a study. In addition, there may be differences in effectiveness between the various subgroups of included patients within a trial. Although the results of subgroup analyses often need to be interpreted with some caution, they can provide an indication of the expected differences between the various patient groups.

FIDELIO versus FIGARO regarding the renal endpoint

The first thing that strikes one in comparing the FIDELIO and FIGARO trials is that the difference regarding the composite renal endpoint in the latter trial was non-significant, unlike in the FIDELIO trial, while the number of included patients was larger. A large part of this discrepancy is explained by the lower degree of severity of the kidney diseases of the patients in FIGARO-DKD. The FIDELIO trial is thus representative of patients with more severe kidney diseases than those in the FIGARO trial.

Subgroup analyses

The supplementary appendices of both trials also present subgroup analyses. The effect on renal outcomes was smaller in patents with a body mass index (BMI) over 30, those using GLP-1 receptor agonists and those using SGLT-2 inhibitors, whereas the effect on cardiovascular endpoints was actually larger in these subgroups. The effects on both the renal and cardiovascular outcomes were also smaller for participants with a history of cardiovascular disease.

In light of the new Dutch guidelines for the treatment of type 2 diabetes mellitus, the possibility of effect modification by SGLT-2 inhibitors and GLP-1 receptor agonists can be especially important.1


One of the main adverse effects of potassium-sparing diuretics, such as the competitive aldosterone receptor antagonists spironolactone and eplerenone, is the occurrence of hyperkalaemia (serum potassium concentration >5.5 mmol/L), which occurs in up to 5.5% of patients.4 A major incentive for the development of new, non-steroid MRAs was that they might reduce the incidence of this adverse effect. In previous (phase 2) studies of finerenone, the risk of hyperkalaemia appeared to be more than halved relative to spironolactone (5.3% versus 12.7%).5 At low dosages of finerenone (<15 mg), the risk was slightly reduced, while at higher dosages (15-20 mg), it was slightly increased relative to eplerenone.5 In the FIDELIO trial, hyperkalaemia was seen in 18.3% of the patients in the finerenone group and 9.0% of the patients in the placebo group. The corresponding figures in the FIGARO trial, which included patients with less severe kidney disease, were 10.8% and 5.3%, respectively.6,7 It should be noted here that both studies only included patients who, after the run-in phase, were using the maximum dosage of RAAS blockade recommended by the manufacturer, and had a serum potassium concentration smaller than or equal to 4.8 mmol/L. This means that they selected specific patients who were at relatively low risk of developing hyperkalaemia. Hence the results cannot be directly applied to other patient groups.

Pharmacokinetics, metabolism and interactions

Orally administered finerenone is rapidly taken up, reaching its a peak plasma concentration at 30 to 60 minutes after intake, and reaching a stable plasma concentration after two doses. It has a 44% absolute bioavailability as a result of the first-pass effect in the liver, and has a half-life of 2 to 3 hours. Finerenone is mainly metabolised by CYP3A4 (90%) and to a lesser degree by CYP2C8 (10%). Eighty percent of it is cleared via the urine. Its pharmacokinetics is not influenced in a clinically relevant way by age, sex, ethnicity, kidney function or mild to moderate liver function impairments (Child-Pugh classes A and B).8

In view of its conversion via CYP3A4, the plasma concentration of finerenone will increase with concomitant use of CYP3A4 inhibitors. Concomitant use of strong to moderately strong CYP3A4 inhibitors like itraconazole, erythromycin, verapamil and grapefruit or grapefruit juice should thus be avoided. If patients concomitantly use weak CYP3A4 inhibitors, such as amiodarone, their serum potassium concentration and the plasma concentration of finerenone must both be monitored, and the dosage must, if necessary, be adjusted to this. Concomitant use of strong to moderately strong CYP3A4-inducing agents, like rifampicin and efavirenz, must be avoided.8

Details of the studies discussed

FIDELIO-DKD6
Study name: Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) trial
Design: randomised, double-blind, placebo-controlled trial in 48 countries
Inclusion criteria: 18 years or older, type 2 diabetes mellitus with predominantly stage 3 or 4 chronic kidney disease (eGFR ≥ 25 and < 60 mL/min/1.73 m2, with ≤10% having a history of diabetic retinopathy) and a usually moderately elevated urinary albumin-creatinine ratio (≥90% 30 to 300 mg/g; ≤10% ≥300 mg/g) and using the maximum dosage of RAAS blockade recommended by the manufacturer
Main exclusion criteria: heart failure with reduced ejection fraction, serum potassium concentration >4.8 mmol/L
Intervention: two interventions were compared with placebo. Participants with an eGFR ≥ 25 and < 60 mL/min/1.73 m2 received 10 mg finerenone once a day, orally and if the serum potassium concentration was still ≤4.8 mmol/L after one month, the dosage could be raised to 20 mg daily. Participants with an eGFR ≥ 60 mL/min/1.73 m2 received 20 mg finerenone once a day, orally

Primary endpoint(s) and duration: a composite endpoint consisting of kidney failure, persistent reduction of the eGFR by ≥40% relative to baseline, or death due to renal causes. Median follow-up was 2.6 years
Intended number of patients and power: an ‘event-driven sample size’ calculation showed that 1068 patients with a primary endpoint were required to show a 20% risk reduction in the finerenone group at 90% power
Randomisation: 1:1 ratio, stratified for region, eGFR category and albuminuria category
Blinding: patients and researchers were blinded for the treatments 
Population analysed: intention-to-treat (60 randomised patients excluded due to ‘critical’ violations of Good Clinical Practice; 33 from the finerenone group and 27 from the placebo group)
Number of patients included: 5734 (2866 finerenone group + 2868 placebo group)
Trial registration: clinicaltrials.gov: NCT02540993
Funding: Bayer
Analyses conducted by: Bayer
Conflicts of interest: 10 of the 11 authors

FIGARO-DKD7
Study name: Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial
Design: randomised, double-blind, placebo-controlled trial in 48 countries
Inclusion criteria: 18 years or older, type 2 diabetes mellitus with stage 2 to 4 chronic kidney disease (eGFR ≥ 25 and ≤ 90 mL/min/1.73 m2) and a moderately elevated urinary albumin-creatinine ratio (≥30 and <300 mg/g), or stage 1 or 2 chronic kidney disease (eGFR ≥ 25 and ≤ 90 mL/min/1.73 m2) and a severely elevated urinary albumin-creatinine ratio (≥300 mg/g); ≤10% having a moderately elevated urinary albumin-creatinine ratio (≥30 and < 300 mg/g) and stage 2 chronic kidney disease (eGFR ≥ 60 and ≤ 90 mL/min/1.73 m2), all using the maximum dosage of RAAS blockade recommended by the manufacturer
Main exclusion criteria: heart failure with reduced ejection fraction, serum potassium concentration >4.8 mmol/L
Intervention: two interventions were compared with placebo. Participants with an eGFR ≥25 and <60 mL/min/1.73 m2 received 10 mg finerenone once a day, orally and if the serum potassium concentration was still 4.8 mmol/L after one month, the dosage could be raised to 20 mg daily. Participants with an eGFR ≥ 60 mL/min/1.73 m2 received 20 mg finerenone once a day, orally
Primary endpoint(s) and duration: death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke or hospitalisation due to heart failure. Median follow-up was 3.4 years
Intended number of patients and power: an ‘event-driven sample size’ calculation showed that 976 patients with a primary endpoint were required to show a 20% risk reduction in the finerenone group at 90% power
Randomisation: 1:1 ratio, stratified for region, eGFR category and albuminuria category
Blinding: patients and researchers were blinded for the treatments
Population analysed: intention-to-treat (85 randomised patients excluded due to ‘critical’ violations of Good Clinical Practice; 37 from the finerenone group and 48 from the placebo group)
Number of patients included: 7437 (3723 finerenone group + 3714 placebo group)
Trial registration: clinicaltrials.gov: NCT02545049
Funding: Bayer
Analyses conducted by: Bayer
Conflict of interest: 11 of the 11 authors 

  1. Nederlands Huisartsen Genootschap, Utrecht, 2021. Available from: https://richtlijnen.nhg.org/standaarden/diabetes-mellitus-type-2#volledige-tekst-richtlijnen-beleid. Accessed 14-12-2021.
  2. Nederlands Huisartsen Genootschap, Utrecht, 2021. Available from: https://richtlijnen.nhg.org/standaarden/cardiovasculair-risicomanagement#volledige-tekst-richtlijnen-beleid. Accessed 14-12-2021.
  3. Horizonscan geneesmiddelen, Zorginstituut Nederland, Diemen, 2021. Available from: https://www.horizonscangeneesmiddelen.nl/geneesmiddelen/finerenon-stofwisseling-en-endocrinologie-diabetes/versie3. Accessed 16-11-2021.
  4. Capelli I, Gasperoni L, Ruggeri M, Donati G, Baraldi O, Sorrenti G, et al. New mineralocorticoid receptor antagonists: update on their use in chronic kidney disease and heart failure. J Nephrol. 2020 Feb;33(1):37-48. doi: 10.1007/s40620-019-00600-7. 
  5. Ruilope LM, Tamargo J. Renin-angiotensin system blockade: Finerenone. Nephrol Ther. 2017 Apr;13 Suppl 1:S47-S53. doi: 10.1016/j.nephro.2017.02.003. 
  6. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. FIDELIO-DKD Investigators. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. N Engl J Med. 2020 Dec 3;383(23):2219-2229. doi: 10.1056/NEJMoa2025845. 
  7. Pitt B, Filippatos G, Agarwal R, Anker SD, Bakris GL, Rossing P, et al. FIGARO-DKD Investigators. Cardiovascular Events with Finerenone in Kidney Disease and Type 2 Diabetes. N Engl J Med. 2021 Dec 9;385(24):2252-2263. doi: 10.1056/NEJMoa2110956.
  8. Frampton JE. Finerenone: First Approval. Drugs. 2021 Oct;81(15):1787-1794. doi: 10.1007/s40265-021-01599-7. 

Authors

  • Rutger A. Middelburg