Patients with chronic kidney disease (CKD) and type 2 diabetes have an increased risk of renal and vascular disease (Agarwal et al, 2022). Approximately 1 in 3 people with diabetes progress to CKD (Centers for Disease Control and Prevention, 2023).
Diabetes is the leading cause of CKD worldwide (Li et al, 2017). The use of sodium-glucose transporter 2 inhibitors (SGLT2i), angiotensin-converting enzyme inhibitors (ACEi)/angiotensin II receptor blockers (ARBs) are used in the management of diabetic renal disease; however, despite these therapeutic measures, CKD is still a concern and calls for the discovery of novel therapies. The mineralocorticoid receptor is a nuclear receptor found in a variety of cells and tissues such as the heart, kidney, and fibroblasts. The mineralocorticoid receptor (MR) receptor is activated by the binding of aldosterone and cortisol influencing gene expression, electrolyte and fluid balance, as well as tissue remodeling.
Pathological overactivation of the MR receptor leads to reactive oxygen species, inflammation, and fibrosis in cardiorenal diseases. Spironolactone was one of the first steroidal MR antagonists (MRAs) to be discovered for the treatment of heart failure and diabetic kidney disease which showed immense cardiorenal protection. However, many patients often suffer from gynecomastia and other sexual side effects and hyperkalemia. Despite the growing evidence of MRA use in heart failure, clinical data are limited in patients with CKD. Finerenone and esaxerenone are novel non-steroidal MRAs potentially beneficial for diabetic renal disease and heart failure.
Finerenone is currently used in clinical practice in the US, Canada and UK (Bayer, 2022). Esaxerenone is approved for the treatment of hypertension in Japan (Iwahana et al, 2021). This review will focus only on finerenone. Clinical trials have shown the immense benefits and limited side effects of finerenone compared to spironolactone.
This review aimed to demonstrate the role of finerenone in diabetic kidney disease, including its mechanisms of action, dosing, contraindications, and prospective developments.
Methods
A narrative review was conducted on the potential benefits of finerenone for diabetic kidney disease. Free and paid full-text publications and articles indexed in PUBMED, Science Direct, and Google Scholar were searched from inception using relevant keywords, ‘finerenone’, ‘diabetic kidney disease’, ‘chronic kidney disease’, ‘Kerendia’ and ‘mineralocorticoid receptor antagonist’.
After the search was completed, duplicates were removed. We screened the relevant articles through the titles and abstracts. The inclusion criteria included studies that were: cross-sectional studies, case-control studies, cohort studies, systematic review articles, randomised controlled trials, and meta-analyses; articles published in the English language; participants aged >18 years and older; and scholarly articles. Articles were excluded in cases of unavailability of free full-text articles, case reports, case series, overlap with other articles, rodent studies, and ones with incomplete data.
Indications for finerenone use
Finerenone is used for the treatment of type 2 diabetes, kidney disease and heart failure. Indications for use are GFR >25 mL/min/1.73 m2, serum potassium <4.8 mmol/L, and having been on a maximum tolerated dose of either ACEis or ARBs. Patients diagnosed with heart failure New York Heart Association (NYHA) class II-IV are not eligible for finerenone use (Agarwal et al, 2022a).
Steroidal MRAs vs non-steroidal MRAs
Spironolactone and eplerenone are steroidal MRAs and finerenone is a non-steroidal MRA. Spironolactone and eplerenone are potent and selective for the kidney over the heart. It has multiple active metabolites and a long half-life compared to finerenone, which primarily acts on the kidney (Agarwal et al, 2021). Table 1 shows a comparison between steroidal MRAs and non-steroidal MRAs.
| Parameter | Steroidal MRA (ex. spironolactone and eplerenone) | Non-steroidal MRA (finerenone) |
|---|---|---|
| Method of MR blockage | Spironolactone – potent and selective |
Potent and selective |
| Tissue distribution | Both spironolactone and eplerenone favour the kidneys > heart | Equal distribution in kidneys and heart |
| Active metabolites and half-life | Spironolactone – multiple active metabolites with long half-lives |
No active metabolites, short half-life |
| Blood pressure and proteinuria | Eplerenone – significant blood pressure reduction, but less effect on proteinuria and renal injury improvement | Significant decrease in systolic blood pressure, improvement in fibrosis and inflammation |
Mechanism of action of finerenone
The heart, kidneys, and vascular system all express a transcription factor known as the mineralocorticoid receptor, which is ligand-induced (DeFronzo and Bakris, 2022). The steroidal hormone aldosterone, a component of the renin-angiotensin-aldosterone system (RAAS), promotes a conformational change in the receptor and its movement from the cell's cytoplasm to the nucleus, where it binds to particular hormone response elements and draws in transcriptional cofactors to enable transcription or repression of its target genes (Epstein, 2021).
MR overarousal contributes to the progression of chronic kidney disease by increasing inflammation and fibrosis, which translates into alterations at the renal level, alteration of sodium-potassium ATPase in the distal convoluted tubule causing sodium retention, increased blood pressure, glomerulosclerosis and glomerular hypertrophy, mesangial proliferation, and tubulointerstitial fibrosis (Kolkhof and Barfacker, 2017). Finerenone acts as a bulky passive NS˛MRA and impairs MR signaling at various levels and is designed to protect the kidney and the heart with a more manageable side-effect profile compared with steroidal MRAs which causes undesirable side effects like gynecomastia in males (Kolkhof and Borden, 2012). Both finerenone and spironolactone prevent the phosphorylation and degradation of MR which is aldosterone dependent. However, finerenone delays aldosterone induced nuclear accumulation of MR more effectively than spironolactone, according to an automated assessment of MR subcellular distribution (Amazit et al, 2015).
Chromatin immunoprecipitation experiments reveal that finerenone decreases MR, steroid receptor coactivator-1, and RNA polymerase II binding at the regulatory region of the SCNN1A gene as compared to spironolactone. According to the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (FIDELIO-DKD) study findings, patients with CKD and T2D who received finerenone had a lower risk of experiencing a primary outcome event defined as kidney failure, a sustained decrease of 40% in the estimated glomerular filtration rate from baseline, or death from renal causes than those in the placebocomparison group (21.1 vs 17.8%; HR 0.82; 95% CI 0.73–0.93; p=0.001). Additionally, patients in the finerenone group displayed a lower chance of a significant secondary outcome, such as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for heart failure (Bakris et al, 2020).
Dosing of finerenone
Before initiating finerenone, it is essential to measure serum potassium levels and the estimated glomerular filtration rate (eGFR) in patients. Additionally, patients should receive standard care therapy before starting finerenone.
Serum potassium and eGFR should be remeasured 4 weeks after initiating or up-titrating finerenone to monitor treatment response and assess any potential adverse effects. Prior to administering finerenone, it is important to rule out pregnancy, and breastfeeding should be discontinued due to potential risks to the fetus or the nursing infant.
For patients with renal impairment, hepatic impairment, or those taking concomitant medications, dosage adjustments should be carefully considered to ensure the safe and effective use of finerenone. Close monitoring and appropriate dose modifications are crucial to optimise the treatment outcomes and minimise any potential risks for these patient populations (Agarwal et al, 2022b).
Recommended dose and dosage adjustment
While administering finerenone, the recommended target dose is 20 mg once daily. The initiation of treatment is advised when serum potassium levels are equal to or below 4.8 mmol/L. The starting dose of finerenone depends on the patient's eGFR: 10 mg once-daily for patients with an eGFR ≥25 to <60 mL/min/1.73 m2 and 20 mg once daily for those with an eGFR ≥60 mL/min/1.73 m2 (Agarwal et al, 2022b; Goulooze et al, 2022).
To ensure the appropriate response to treatment and identify any potential adverse effects, serum potassium and eGFR should be re-evaluated after four weeks of initiating or up-titrating finerenone, based on which dosage adjustments may be necessary (Agarwal et al, 2022b). Table 2 shows guidance on the continuation of treatment and dose adjustments, taking into account serum potassium levels. Special considerations are given for patients with renal impairment, hepatic impairment, and those taking concomitant medications; hence such tailored approaches are crucial in optimising the efficacy and safety of finerenone (Agarwal et al, 2022b).
| Serum potassium (mmol/L) | Finerenone dose (after 4 weeks and thereafter) |
|---|---|
| ≤4.8 | Maintain 20 mg once-daily. For patients on 10 mg once daily, increase the dose to 20 mg once-daily if eGFR has not decreased by >30% compared to the prior measurement |
| >4.8–5.5 | Maintain dose |
| >5.5 | Withhold Kerendia. Restart at 10 mg once daily when serum potassium is ≤ 5.0 mmol/L |
Administration
Finerenone is an orally administered medication. It is recommended to be taken once-daily at the same time each day to maintain treatment efficacy. It is essential for patients to avoid consuming grapefruit or grapefruit juice during the course of therapy, as they may interact adversely with the medication. For patients who have difficulty swallowing whole tablets, it can be crushed and mixed with water or soft foods for easier ingestion, ensuring adherence to the prescribed dosage. To prevent any potential complications, it is crucial for patients to adhere to the prescribed maximum daily dose of 20 mg (Goulooze et al, 2022).
Clinical trials
The two clinical trials that have emerged in regards to finerenone are the FIDELIO-DKD trial and the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial. Phase III of these two trials has demonstrated promising results with the use of finerenone in reducing cardiovascular morbidity and mortality, including nonfatal myocardial infarction, nonfatal stroke, or hospitalisation for heart failure compared with placebo.
The FIDELIO-DKD trial examined whether finerenone would reduce the progression of CKD and cardiovascular disease in patients with advanced and type 2 diabetes (Bakris et al, 2020). This was a randomised controlled, double-blind, multi-center study involving 5734 patients with CKD and type 2 diabetes. They were either given finerenone or a placebo. All patients were on the maximum tolerated dose of ACEi/ARBs. Parameters assessed included kidney disease, GFR changes, death from renal causes and cardiac causes compared to placebo. Patients taking finerenone had a lower risk of cardiovascular disease, non-fatal myocardial infarction, non-fatal stroke, and hospitalisation from heart failure.
Results revealed a lower risk of kidney failure or death from renal causes, cardiovascular events, non-fatal myocardial infarction, nonfatal stroke, and hospitalisation from heart failure. Although there was an increase in hyperkalemia in the finerenone groups compared to placebo, non-fatal hyperkalemia was reported. Moreover, there was no significant change in glycated hemoglobin and weight. These results indicate that finerenone is an effective therapy for the treatment of kidney disease and cardiovascular protection in patients with type 2 diabetes (Pitt et al, 2021).
The FIGARO-DKD trial investigated less advanced CKD. The study included 7352 patients with type 2 diabetes and kidney disease. They hypothesised that treatment with finerenone would reduce the risk of mortality and morbidity from cardiovascular disease, among patients with stage II and IV CKD and moderately elevated albuminuria and stage I or II CKD with severely increased albuminuria. Results demonstrated a decrease in cardiovascular mortality, non-fatal myocardial infarction, stroke, and hospitalisations for heart failure. There were no significant changes in HbA1c and body weight in the placebo and finerenone groups (Filippatos et al, 2022).
Benefits of finerenone in diabetic kidney disease
In Canada and the US, finerenone is currently indicated as an adjunct to standard-of-care therapy in adults with chronic kidney disease (CKD) and type 2 diabetes (T2D) to reduce the risk of end-stage kidney disease, sustained eGFR decline, cardiovascular death, non-fatal myocardial infarction, and hospitalisation for heart failure (Bayer, 2022).
In randomised, double-blind, placebo-controlled, multicenter phase III studies in adults with CKD and T2D (FIDELIO-DKD and FIGARO-DKD), the placebo-corrected relative reduction in urinary albumin-to-creatinine ratio (UACR) in patients randomised to finerenone at Month 4 was 31% and 32%, respectively and UACR remained reduced throughout both studies for at least 48 months. A randomised, double-blind, placebo-controlled study in adults with CKD and T2D was conducted, which demonstrated that the placebo-corrected relative reduction in UACR at Day 90 was 25% and 38% in patients treated with finerenone 10 mg and 20 mg once daily, respectively (Bayer, 2022).
In the FIDELIO-DKD study, finerenone significantly reduced the primary composite kidney outcome and the key secondary cardiovascular composite outcome compared with placebo in patients with CKD and T2D without affecting HbA1c levels. These subgroup analyses demonstrated that the benefits of finerenone in patients with CKD and T2D were consistent irrespective of HbA1c level or insulin use at baseline. Efficacy outcomes included kidney (kidney failure, sustained decrease of 40% in eGFR from baseline, or renal death) and cardiovascular (cardiovascular death, non-fatal myocardial infarction, nonfatal stroke, or hospitalisation for heart failure) composite endpoints (Rossing et al, 2022).
A systematic review by Singh et al (2022) studied the efficacy and safety of finerenone in CKD with or without T2D and concluded that in short-term studies involving patients with CKD and reduced ejection heart failure, with or without T2D, finerenone 20 mg appears to have a better renal outcome compared with spironolactone and a better mortality outcome compared with eplerenone, with significantly lesser hyperkalemia compared to both spironolactone and finerenone.
In long-term studies in patients with CKD and T2D, finerenone 10/20 mg significantly reduced the progression of renal disease and reduced CV endpoints (especially heart failure hospitalisation) compared to placebo. Finerenone has no effect on HbA1c, body weight, and sexual side effects, including gynecomastia, and has only a modest effect on blood pressure. However, hyperkalemia leading to drug withdrawal was significantly higher with finerenone compared to placebo (Singh et al, 2022).
Concomitant use of finerenone with RAS/SGLT2 inhibitors
In T2DM, SGLT2i and finerenone have been demonstrated to have beneficial effects on cardiovascular and renal outcomes in recent clinical trials. Due to the complementarity of their respective mechanisms, finerenone and SGLT2i have some overlapping and distinct pathophysiological pathways that, when combined, may have a beneficial effect on both cardiovascular and renal function.
Although the specific mechanism of action has not yet been fully clarified, it is thought that SGLT2i may be connected to the hemodynamic effect and the reduction of proteinuria. Finerenone works primarily by preventing the excessive activation of the mineralocorticoid receptor, which lowers oxidative stress, inhibits fibrosis, and improves endothelial function, slowing the progression of kidney disease.
The combination of SGLT2i and finerenone is theoretically supported by the complementary roles played by their various mechanisms. Additional information on whether finerenone and SGLT2i together have more cardiovascular and renal protective benefits than either medicine alone may come from the CONFIDENCE research (Green et al, 2023).
CONFIDENCE is a randomised controlled, double-blind, three-armed, parallel-group, Phase 2 study in 807 adults with CKD and T2DM. If the CONFIDENCE research finds an additive effect on UACR, it may mean that early intervention with finerenone and SGLT2i treatment slows the progression of renal disease and, as a result, may result in long-term decreases in morbidity and mortality for individuals with CKD and T2DM (Green et al, 2023). With three therapeutic agent classes (glucose lowering [SGLT2is, GLP1RAs], RAS inhibition [ACEis/ARBs], and MR inhibition [MRAs]) with complementary mechanisms of action, it may be possible to provide a more intensive and potentially disease-modifying treatment approach, which may reduce the ongoing risk of CV events (MI, stroke, or hospitalisations for HF) and CKD progression observed with current SOC therapies (Chaudhuri et al, 2022).
Side effects of finerenone
Despite its potential to lower cardiovascular and all-cause mortality, finerenone can lead to side effects like hyperkalemia. In long-term studies, finerenone outperformed the placebo in terms of causing hyperkalemia, which resulted in medication withdrawal. Regular potassium testing and hyperkalemia management techniques used in FIDELIO-DKD reduced the effects of hyperkalemia and provided support for the use of finerenone in clinical settings (Rossing et al, 2022).
Hyperkalemia events were observed in 18.3% of patients taking Kerendia compared to 9.0% of patients taking a placebo in the FIDELIO-DKD study, which included patients with CKD (mean eGFR 44.3 ml/min/1.73 m2) and T2D. In the FIGARO-DKD study, which included patients with CKD and T2D (mean eGFR: 67.8 ml/min/1.73 m2), hyperkalemia episodes were documented in 10.8% of Kerendia-treated patients vs 5.3% of individuals receiving a placebo.
The majority of hyperkalemia episodes in participants receiving Kerendia were mild to moderate in both studies. In the FIDELIO-DKD study, hospitalisation for hyperkalemia was 1.4% for the Kerendia group vs 0.3% in the placebo group, and 0.6% for the Kerendia group vs <0.1% in the placebo group in the FIGARO-DKD study.
Patients on Kerendia more frequently experienced asymptomatic hyperuricemia. In the FIGARO-DKD study, Kerendia caused a temporary rise from baseline in mean serum uric acid, reaching up to 0.3 mg/dL compared to the placebo group, although this rise gradually subsided. There were no documented treatment interruptions because of hyperuricemia (Bayer, 2022).
HbA1c, body weight, and adverse sexual effects, such as gynecomastia, are unaffected by finerenone, while blood pressure is the only factor that is significantly affected (Rossing et al, 2022). Hypotension episodes were observed in 4.8% of Kerendia-treated (finerenone-treated) patients and 3.4% of placebo-treated individuals in the FIDELIO-DKD study. Hypotension events were observed in 4.5% of participants receiving Kerendia compared to 2.7% of patients getting a placebo in the FIGARO-DKD study.
Patients taking Kerendia experienced hypotension episodes that were often mild to moderate in severity, infrequently requiring medication cessation, and largely resolving. Dizziness, syncope, or falls – events linked to hypotension – were not more frequent in patients taking Kerendia than in those taking a placebo. At the end of the first month in patients receiving Kerendia, the mean systolic blood pressure dropped by 3 mmHg, and the mean diastolic blood pressure dropped by 1–2 mmHg.
The following side events (independent of cause) were noted in the pooled FIDELIO-DKD and FIGARO-DKD investigations with a frequency of less than 1% and at a higher frequency in the Kerendia arm compared to placebo: Drug hypersensitivity (0.2% Kerendia vs 0.1% placebo). Patients receiving Kerendia therapy had a higher percentage of glomerular filtration rate decline than those receiving a placebo.
In both investigations, GFR-reduced occurrences were infrequently associated with hospitalisation or a permanent Kerendia cessation. In the FIDELIO-DKD research, a drop in mean hemoglobin levels was shown in patients receiving Kerendia treatment in the first 4 months, with a maximum difference between Kerendia treatment and placebo of less than 0.15 g/dL, which levelled out by Month 28. For finerenone hematocrit, a comparable impact was seen, with a maximum difference of less than 0.45% at Month 4.
Compared to 6.7% of patients getting a placebo, anemia episodes were observed in 7.4% of patients receiving Kerendia. Anemia incidents were observed in 5.9% of patients receiving Kerendia compared to 5.6% of those receiving a placebo in the FIGARO-DKD study (Bayer, 2022).
Contraindications to finerenone
Finerenone is contraindicated with the concomitant use of CYP3A4 inhibitors such as itraconazole, clarithromycin, ritonavir, cobicistat, and nefazodone. Concomitant use of finerenone with fluvoxamine 100 mg BID can lead to hyperkalemia and must be carefully monitored. Patients are advised to avoid taking rifampin, carbamazepine, phenytoin, St John's Wort and phenobarbital while on finerenone as it can lead to accelerated degradation of finerenone, resulting in decreased therapeutic effect. Another contraindication to finerenone is Addison's disease. Breastfeeding and hypersensitivity to finerenone are contraindications as well (Bayer, 2022).
Hyperkalemia is a relative contraindication to finerenone use. If serum potassium is >4.8 to 5.0 mmol/L, finerenone may be considered with potassium monitoring within the first 4 weeks. Initiation of finerenone is not recommended in patients with serum potassium >5.0 mmol/L. In addition, patients with severe renal impairment and hepatic impairment have to be carefully monitored with finerenone use (Bayer, 2022). Finerenone treatment is not recommended in patients with a GFR of <25 mL/min/1.73 m2 due to a lack of clinical data.
Insurance and availability of finerenone
In Canada, Kerendia is regulated as a prescription drug and after review, the CADTH Canadian Drug Expert Committee (CDEC) recommends that finerenone be reimbursed as an adjunct to standard of care therapy in adults with chronic kidney disease (CKD) and type 2 diabetes (T2D) to reduce the risk of end-stage kidney disease (ESKD), a sustained decrease in estimated glomerular filtration rate (eGFR), cardiovascular death, non-fatal myocardial infarction, and hospitalisation for heart failure only if the conditions laid down are met.
These conditions include the following (Canadian Agency for Drugs and Technologies in Health, 2024):
In the US, Kerendia is available only as a brand-name drug, as a generic version is not yet available. Patients who have Medicare Part D coverage may be eligible to apply for the Part D Extra Help Subsidy. Once accepted into the programme, they may receive reduced premiums and lower prescription costs. Patient Assistance and Copay Programs for Kerendia include the Bayer US Patient Assistance Foundation Free Drug Program.
The eligibility requirements for this programme include the patient having no prescription coverage for needed medication, a medically appropriate condition/diagnosis, and residency in the US or Puerto Rico. Eligibility is determined on a case-by-case basis (Drugs.com, 2024). In 2022, the European Medicines Agency (EMA) authorised the use of finerenone in the EU under additional monitoring to treat chronic kidney disease in adults with type 2 diabetes (EMA, 2023).
Prospective studies
Analysis of data from studies pertaining to the mechanism of action of finerenone suggests that it could prove to be beneficial in patients suffering from habitual, accidental, or chronic over-ingestion of licorice as a part of self-medication or herbal supplements.
Future studies may also investigate whether the effects of overproduction of aldosterone at their end organs could be negated by a mineralocorticoid antagonist like finerenone in cases like primary hyperaldosteronism and adrenal carcinoma, in patients who are surgically unfit, or in the interim prior to surgery.
In cases of unilateral renal artery stenosis where the contralateral adrenal gland hypertrophies, to produce excess aldosterone, this drug could prove beneficial. Extensive studies and clinical trials would be needed to back up the effect, potency, and adverse effects of finerenone in the above-mentioned conditions.
Conclusion
The use of mineralocorticoid receptor antagonists is essential in the management of chronic kidney disease to reduce the risk of mortality and morbidity linked to the progression of the disease and future cardiovascular complications. A non-steroidal MRA labeled finerenone is more effective than traditional steroidal MRAs at reducing CKD-related fibrosis and inflammation.
Proteinuria and GFR are improved by finerenone when used alone or in conjunction with SGLT2 inhibitors. Patients who are >65 years old, with an estimated GFR >25 mL/min/1.73 m2, serum potassium ≤4.8 mmol/L, and have been on a maximum tolerable dose of either ACEi or ARBs are eligible to receive finerenone for the treatment of type 2 diabetes, kidney disease, and heart failure.
For patients with an eGFR less than 60 mL/min/1.73 m2, the suggested daily dosage is 20 mg once per day. Pregnancy should be ruled out before finerenone is administered, and breastfeeding should be discontinued due to potential dangers to the fetus or the nursing infant.
When compared to the placebo, patients receiving finerenone had a lower risk of mortality from CV causes, nonfatal MI, nonfatal stroke, and hospitalisation for heart failure. The main adverse effect, hyperkalemia, calls for regular observation.
Finerenone has no impact on HbA1c, body weight, or sexual adverse effects, including gynecomastia. Nonetheless, further research is required to determine the precise role of finerenone, either alone or in conjunction with other medications, in slowing the progression of CKD and the potential consequences that accompany it.