Background
Diabetes continues to be a growing health care concern worldwide. González-Juanatey (2023) has estimated its prevalence among adults across the globe to rise from 540 million in 2021 to 780 million in 2045.1 Diabetes is also one of the leading causes of chronic kidney disease (CKD), which further exacerbates the negative health effects associated with diabetes. Approximately 40% of individuals with diabetes have stage 1 to 4 CKD, and sequentially, approximately 40% of end-stage CKD cases can be attributed to diabetes.2 Both diabetes and CKD independently result in an increased mortality risk; however, when present concomitantly, the risk of death and development of cardiovascular disease increases 3-fold.3
Typically, CKD management in patients with diabetes has revolved around the control of hypertension and hyperglycemia through angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), and, more recently, sodium-glucose cotransporter 2 (SGLT2) inhibitors.4 Although ACEIs and ARBs are mainstay therapies for renal protection in patients with diabetes, many patients continue to present with cardiovascular and renal complications after initiation of ACEI or ARB therapy. However, SGLT2 inhibitors have recently shown promise in reducing the progression of kidney disease and cardiovascular events.1 Despite the renal protective effects of ACEIs, ARBs, and SGLT2 inhibitors, the risk of CKD progression remains among patients with diabetes, calling for new therapeutic options to be explored.
This narrative review aims to examine the efficacy of finerenone (Kerendia; Bayer HealthCare Pharmaceuticals Inc), a selective nonsteroidal mineralocorticoid antagonist that was recently approved to treat patients with
concomitant CKD and type 2 diabetes (T2D). This review will also compare finerenone with previously existing treatment options on the market and discuss the clinical implications of finerenone within daily practice.
Abstract
Précis
Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has shown benefit in cardiovascular and renal outcomes with lower incidence of hyperkalemia compared with steroidal mineralocorticoid receptor antagonists.
Objectives
This review examines the efficacy and safety of finerenone (Kerendia; Bayer HealthCare Pharmaceuticals Inc) based on the FIDELIO-DKD trial (NCT02540993), FIGARO-DKD trial (NCT02545049), and FIDELITY, a pooled analysis of FIDELIO-DKD and FIGARO-DKD. This review also discusses finerenone’s mechanism of action, pharmacokinetics, dosing, and potential for combination therapy with other standard treatments.
Study Design
This text is a structured literature review conducted in July 2024.
Results
Compared with placebo, finerenone significantly lowered the risk of kidney failure, preserved renal function, and improved cardiovascular outcomes such as heart failure, hospitalization, and cardiovascular death. Although finerenone was associated with an increased risk of hyperkalemia, adverse events were generally manageable.
Conclusions
FIDELIO-DKD, FIGARO-DKD, and FIDELITY collectively demonstrated finerenone’s ability to reduce the progression of chronic kidney disease (CKD) and the incidence of cardiovascular events in patients with CKD and type 2 diabetes (T2D). Finerenone fills a critical gap in CKD management and offers a promising option for improving outcomes in patients with CKD and T2D, supporting its integration into clinical practice.
Data Collection
A literature search was conducted on the PubMed database using medical evidence subject heading terms with the keywords finerenone, diabetes, and chronic kidney disease, accompanied by the conjunction
and. Articles were restricted to the English language. References within articles were also reviewed to provide supporting information. The drug monograph for finerenone was accessed through Wolters Kluwer’s Lexicomp to gather basic information regarding the drug. Additionally, the package insert for finerenone was obtained through a search on the National Institutes of Health’s National Library of Medicine package insert database DailyMed.
Mechanism of Action
The mineralocorticoid receptor (MR) is activated by aldosterone and serves a central role in sustaining homeostasis of Na+ and K+, maintaining extracellular fluid volume, and dictating blood pressure.5 Overactivation of this receptor contributes to fibrosis and inflammation within the kidneys, which leads to a decreased estimated glomerular filtration rate (eGFR) and increased albuminuria among patients, ultimately resulting in rapid CKD progression.1,6 Finerenone, a nonsteroidal selective mineralocorticoid receptor antagonist (MRA), acts by inhibiting MR-mediated sodium reabsorption and MR overactivation in both epithelial and nonepithelial tissues of the kidney. Finerenone is highly selective for the MR and has no relevant affinity for androgen, progesterone, estrogen, and glucocorticoid receptors.6 This selectivity is attributed to its nonsteroidal properties, translating into a reduced risk for hyperkalemia compared with steroidal MRAs such as spironolactone (Aldactone; Pfizer Inc) or eplerenone (Inspra; Pfizer).5
Pharmacokinetics
According to the FDA package insert, finerenone reaches steady-state concentration 2 days after administration of a 20-mg dose.6 Following oral administration, it has an absolute bioavailability of 44% after metabolism.
Finerenone has a plasma protein binding of 92%, primarily binding to serum albumin in vitro. The terminal half-life of finerenone is also relatively short, lasting approximately 2 to 3 hours. Finerenone is primarily metabolized by CYP3A4 (90%) and to a lesser extent by CYP2C8 (10%) into inactive metabolites. Approximately 80% of the administered dose is excreted in urine, and 20% is excreted in feces. No clinically significant differences were observed in patients with renal or mild hepatic impairment (Child-Pugh A). However, in patients with moderate hepatic impairment (Child-Pugh B), the mean area under the curve of finerenone was increased by 38%, indicating a decreased clearance of the drug.6
FIDELIO-DKD Trial
FIDELIO-DKD (NCT02540993) was a phase 3, randomized, double-blind, placebo-controlled, parallel-group, event-driven trial performed in 48 countries and territories in Africa, Asia, Australia, Europe, Latin America, and North America.7 This study aimed to evaluate the effect of finerenone on kidney and cardiovascular outcomes in patients 18 years or older diagnosed with T2D and CKD. CKD was defined as either moderately elevated albuminuria (urine albumin-to-creatinine ratio [UACR] ≥ 30 to < 300 mg/g), an eGFR of 25 or greater to less than 60 mL/min/1.73 m2 and a history of diabetic retinopathy, or severely elevated albuminuria (UACR ≥ 300 to ≤ 5000 mg/g) and an eGFR of 25 or greater to less than 75 mL/min/1.73 m2. Additionally, all patients were required to have a serum potassium level of 4.8 mEq/L or less and to have been on stable treatment with a maximum tolerated dose of an ACEI or an ARB for at least 4 weeks prior to screening.7 Exclusion criteria included patients with known nondiabetic kidney disease, chronic symptomatic heart failure with reduced ejection fraction (HFrEF), a recent history of dialysis for acute kidney failure or a kidney transplant, or uncontrolled hypertension.7
There were 5674 patients who were analyzed in the study (n = 5674), with a 1:1 random assignment to receive finerenone or the placebo. Almost half (n = 2605, 45.9%) of these patients had a history of cardiovascular disease at baseline.7 Randomization was conducted by a computer-generated schedule based on geographical region (North America, Latin America, Europe, Asia, and other), eGFR (25 to < 45, 45 to < 60, or ≥ 60 mL/min/1.73 m2), and albuminuria categories (UACR 30 to < 300 or ≥ 300 mg/g).7 The primary composite outcome included time to first onset of kidney failure, a sustained 40% or greater decrease in eGFR from baseline over at least 4 weeks, or renal death.7 Secondary outcomes included a composite cardiovascular outcome of time to first onset of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or hospitalization for heart failure (HF).7 At baseline, 34.2%, 65.7%, and 4.6% of patients were on an ACEI, ARB, and SGLT2 inhibitor, respectively.
Finerenone decreased the incidence of the primary composite outcome in comparison with placebo (HR, 0.82; 95% CI, 0.73-0.93). Additionally, the composite cardiovascular outcome decreased compared with the placebo (HR, 0.86; 95% CI, 0.75-0.99).7 Any adverse event (AE) occurred at similar rates between the finerenone and placebo groups (87.3% vs 87.5%, respectively). It was found that investigator-reported hyperkalemia occurred at almost double the rate with finerenone vs placebo (18.3% vs 9%, respectively), and discontinuation due to hyperkalemia occurred in 2.3% and 0.9% of patients in the finerenone and placebo arms, respectively.
Original and Prespecified Analysis of the FIGARO-DKD Trial Evaluating Heart Failure Outcomes
The FIGARO-DKD study (NCT02545049) was an international, randomized, double-blind, placebo-controlled, multicenter, phase 3 trial. FIGARO-DKD aimed to determine the effect of finerenone in reducing cardiovascular morbidity and mortality, in addition to standard of care, in patients with albuminuric CKD (stage 2-4 with moderately elevated albuminuria or stage 1-2 with severely increased albuminuria) and T2D.8 Eligibility criteria included patients 18 years or older, diagnosed with T2D and albuminuric CKD, treated with a maximum tolerated dose of ACEI or ARB prior to screening, and a serum potassium level of 4.8 mEq/L or less at screening. According to the supplemental document with the FIGARO-DKD trial, patients were excluded if they had chronic symptomatic HFrEF, significant nondiabetic kidney disease, stroke, transient ischemic cerebral attack, acute coronary syndrome, recent history of dialysis for acute kidney failure, a kidney transplant, or uncontrolled hypertension.8
The original study found the primary outcome of a time-to-event analysis of composite death from cardiovascular causes, nonfatal MI, nonfatal stroke, or HF hospitalization occurred at a lower rate in the finerenone group compared with the placebo group (12.4%-14.2%; HR, 0.87; 95% CI,
0.76-0.98).8
In addition to the original analysis mentioned above, there was a prespecified analysis for the FIGARO-DKD trial with separate outcomes. The prespecified analysis used a 1:1 random assignment to receive finerenone or placebo, with 7352 patients included. Of this total, 571 patients had a history of HF at baseline.9 The prespecified outcomes for the analyses were time to new-onset HF, a composite of time to HF-related death or first hypertensive heart failure (HHF), a composite of time to cardiovascular death or HHF, time to first HHF, a composite of time to cardiovascular death or total HHF, a composite of time to HF-related death to total HHF, and time to total HHF. New-onset HF was defined as first HHF in patients without a history of HF at baseline.9
The prespecified analysis of the FIGARO-DKD study found that finerenone significantly decreased new-onset HF compared with placebo (1.9% vs 2.8%; HR, 0.68; 95% CI, 0.50-0.93).9 In the overall population, the incidence of all HF outcomes was significantly lower with finerenone than placebo, including an 18% decreased risk of cardiovascular death or first HHF (HR, 0.82; 95% CI, 0.70-0.95; P = .011), a 29% decreased risk of first HHF (HR, 0.71; 95% CI, 0.56-0.90), and a 30% decreased rate of total HHF (rate ratio, 0.70 [95% CI, 0.52-0.94]).9 Finerenone’s effects were also shown not to be affected by a previous history of HF.
FIDELITY Pooled Analysis
FIDELITY was a pooled analysis of FIDELIO-DKD and FIGARO-DKD, combining the data from 2 phase 3, randomized, double-blind, placebo-controlled, multicenter clinical trials (Table 1).4,8-10 The purpose of the FIDELITY analysis was to perform an individual patient-level prespecified pooled efficacy and safety analysis across a broad spectrum of CKD to provide more robust estimates of safety and efficacy of finerenone compared with placebo (HR, 0.86; 95% CI, 0.78-0.95).10 The composite kidney outcome occurred in 360 (5.5%) patients receiving finerenone and 465 (7.1%) receiving the placebo (HR, 0.77; 95% CI, 0.67-0.88).10 The outcomes regarding safety were relatively similar among treatment arms; however, hyperkalemia leading to permanent treatment discontinuation occurred more often in patients receiving finerenone (1.7%) compared with placebo (0.6%).10
FIDELIO-DKD, FIGARO-DKD, and FIDELITY Study Limitations
These studies were well designed and reliable overall but had limitations worth mentioning. The FIDELIO-DKD study had a limited follow-up time, which, although practical in study design, may not reflect the slow and gradual progression of CKD.7 Additionally, the event rates estimated while calculating power occurred less, which may reduce the power to detect statistical difference in the sample. Further, Black patients were underenrolled in the study (3.5%) in contrast to the overenrollment of White (71.8%) and Asian (19.8%) patients, which is inconsistent with CKD and diabetes mellitus prevalence.11,12 Additionally, some populations of interest (eg, patients with advanced CKD, elevated potassium, or nonalbuminuric CKD) were excluded from enrollment, which limits
generalizability.
The FIGARO-DKD study shared similar concerns about limited follow-up time, exclusions of populations of interest, and reduced event rate.8 Although the FIDELITY pooled analysis provides a larger sample to detect the impact of finerenone on cardiovascular outcomes, there are limitations with this analysis.10 The FIDELITY pooled analysis contains the same concerns as its primary literature data sources (FIDELIO-DKD and FIGARO-DKD). Additionally, the pooled analysis design uses studies with different trial designs, which causes some variability in the subjects selected.
AEs and Precautions
As previously mentioned, nonsteroidal MRAs such as finerenone are associated with a lower risk of hyperkalemia than steroidal MRAs such as spironolactone and eplerenone.5 However, this does not translate to a complete risk elimination, as hyperkalemia may still occur in some patients taking finerenone. The FDA package insert states that 1% or more of patients on finerenone may experience hyperkalemia, hypotension, and hyponatremia.6
In the FIDELITY study, AEs associated with a higher frequency of hyperkalemia with finerenone (14%) vs placebo (6.9%) were more frequent; however, none of these events were fatal, and the hyperkalemia resolved upon discontinuation. Wanner et al’s secondary analysis of FIDELIO-DKD and FIGARO-DKD recommends dose reduction and treatment interruption rather than phosphate binders for kidney protection.13 A small proportion of these events led to permanent treatment discontinuation (1.7% for finerenone [incidence rate, 0.66 per 100 patient-years] and 0.6% for the placebo [incidence rate, 0.22 per 100 patient-years], respectively) or hospitalization (finerenone, 0.9%; placebo, 0.2%).10 Although the risk for AEs is relatively low, patients with diminished kidney function should have their potassium levels routinely monitored throughout treatment.
Dosing and Administration
As depicted in Table 2, the starting dose of finerenone is 10 mg to 20 mg once daily, depending on eGFR and serum potassium thresholds. A starting dose of 20 mg once daily is initiated if the patient’s eGFR is 60 mL/min/1.73 m2 or greater; 10 mg once daily for an eGFR of 25 or greater to less than 60 mL/min/1.73 m2; and initiation of therapy is not recommended if the patient’s eGFR is less than 25 mL/min/1.73 m2.6 The target maintenance dose of finerenone is 20 mg once daily. Additionally, if the patient is started on the 10-mg once-daily dose, the dose can be increased to 20 mg once daily if the patient’s serum potassium is 4.8 mEq/L or less.6 If the patient’s serum potassium is greater than 4.8 to 5.5 mEq/L, it is recommended to maintain the patient on the 10-mg once daily dose. However, if the patient has a serum potassium level greater than 5.5, regardless of the initiation dose, withhold finerenone until potassium levels are at 5.0 mEq/L or less.6 According to the package insert, no dose adjustment is necessary for hepatic impairment.6,14
Cost
As of June 2024, the average wholesale price (AWP) of finerenone was $26.36 per tablet for either the 10- or 20-mg strength.14 The AWP is a reference price that estimates the average price to purchase the medication from the manufacturer.14 Further information regarding insurance coverage and pharmaceutical manufacturer patient assistance programs is yet to be released.
Relevance to Patient Care and Clinical Practice
Treatment for patients with diabetes and CKD includes ACEIs, ARBs, and SGLT2 inhibitors, which provide benefit by acting on hemodynamic factors and improving glycemic control; however, these drug classes do not act on the MR.2 Overactivation of the MR receptor in the context of diabetes plays a key role in developing CKD, and this pathway must be targeted to prevent further inflammation and fibrosis of renal tissue.5 Furthermore, research is currently being conducted to examine the potential synergistic relationship among these drug classes of
treatment options.
The CONFIDENCE trial (NCT05254002) is an ongoing study that explores the combination effect of finerenone and empagliflozin (Jardiance; Boehringer Ingelheim and Eli Lilly and Company) in patients with concomitant CKD and T2D, as it aims to investigate whether dual therapy is superior to monotherapy of either agent alone in reducing cardiovascular events.15 The findings of this study are yet to be determined; however, the results may pave the way for the possibility of dual-therapy or even triple-therapy options in the future. Additionally, a study analyzing the effect of finerenone and dapagliflozin (Farxiga; AstraZeneca and Bristol Myers Squibb) in patients with nondiabetic CKD showed that the combination was safe and reduced albuminuria compared with finerenone alone by 24% (P < .001) over 8 weeks.16
These studies also have potential implications for finerenone’s place in therapy for patients with CKD and T2D. Per the 2024 Kidney Disease: Improving Global Outcomes guideline for CKD, finerenone is listed as an add-on therapy for patients already optimized on ACEI or ARB therapy.17 Finerenone has a reduced risk of hyperkalemia compared with spironolactone and may be preferred in patients at particularly high risk, but excluding these patients from the enrollment makes this assertion difficult without further study.7,8 FIDELITY supports the data from both studies regarding cardiovascular outcomes as primary therapy; however, use in combination with an SGLT2 inhibitor is still under investigation in the CONFIDENCE trial.10
Conclusion
Despite the current standard of treatment involving ACEIs, ARBs, and SGLT2 inhibitors, a significant risk of cardiovascular events remains among patients with CKD and T2D. Finerenone, a novel nonsteroidal MRA, demonstrates that it could significantly reduce the risk of cardiovascular and renal outcomes. For example, finerenone was capable of reducing the time to first onset of cardiovascular death, nonfatal MI, nonfatal stroke, and hospitalization due to HF, while also minimizing the risk of AEs such as hyperkalemia.7 With its proven efficacy and relative safety, the future of its application toward clinical use is promising and expected to grow within the coming years.
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