Potassium management with finerenone: Practical aspects

Abstract Introduction Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, has favourable effects on cardiorenal outcomes in patients with mild‐to‐severe chronic kidney disease with increased albuminuria and type 2 diabetes. Methods Two large, randomized trials have evaluated the effects of finerenone on clinical outcomes. The first trial (FIDELIO‐DKD) investigated renal outcomes, and the second (FIGARO‐DKD) cardiovascular outcomes. Results Patients in the two studies had a high intrinsic risk of hyperkalemia due to type 2 diabetes, treatment with optimized doses of an inhibitor of the renin‐angiotensin system, and, in some patients, their advanced chronic kidney disease. This was reflected in the incidence of hyperkalemia in the placebo group during the trials. Patients on finerenone had a significantly higher incidence of hyperkalemia compared with patients on placebo, but treatment discontinuation due to hyperkalemia was low, and no patients experienced death attributable to hyperkalemia. Structured routine potassium monitoring with temporary treatment interruption and dose reduction, as used in the two trials, should ensure the safe use of finerenone to protect the kidneys and cardiovascular system of patients with albuminuric chronic kidney disease and type 2 diabetes. Conclusions The aim of this document is to highlight the routine potassium management required when using finerenone and to provide practical recommendations.


| INTRODUC TI ON
Finerenone is a novel nonsteroidal selective antagonist of the mineralocorticoid receptor (MR), which is activated by aldosterone and cortisol. 1 Furthermore, finerenone has high potency and selectivity for the MR. Finerenone blocks MR-mediated sodium reabsorption and MR overactivation as well as modifies tissue remodelling by exerting anti-inflammatory, antifibrotic, and antiproliferative effects on both the kidney and the heart. 2,3 The FInerenone in reducing kiDnEy faiLure and dIsease prOgression in Diabetic Kidney Disease (FIDELIO-DKD) 4 and FInerenone in reducinG cArdiovascular moRtality and mOrbidity in Diabetic Kidney Disease (FIGARO-DKD) 5 phase III trials evaluated the effect of the novel mineralocorticoid receptor antagonist (MRA) finerenone. These trials investigated the efficacy and safety of finerenone, on top of maximum tolerated labelled dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), on kidney and cardiovascular outcomes in patients with mild-to-severe chronic kidney disease (CKD) and type 2 diabetes (T2D). The FIDELIO-DKD trial was designed to demonstrate a treatment effect of finerenone on kidney end-points, whereas the FIGARO-DKD trial was designed to demonstrate an effect on a composite cardiovascular primary end-point.
Both trials included a broad range of patients with CKD and T2D. 4,5 The FIDELITY analysis with the complementary FIDELIO-DKD and FIGARO-DKD trials performed a pooled analysis of efficacy and safety at the individual patient level across a broad spectrum of CKD to provide more robust estimates of the safety and efficacy of finerenone compared with placebo. 6 In its inherent mode of action as an MRA, finerenone may elevate serum potassium concentrations, particularly in patients with advanced CKD receiving the maximum tolerated dose of an inhibitor of the renin-angiotensin system (RAS). Both studies showed increased serum potassium concentrations and hyperkalemia rates with finerenone treatment compared with placebo, with a maximum difference in mean serum potassium between groups of 0.16 mmol/L in FIDELIO-DKD and 0.23 mmol/L in FIGARO-DKD. The increase in risk of hyperkalemia leading to permanent treatment discontinuation (1.7% for finerenone and 0.6% for placebo) was small. [4][5][6] In this article, we aim to highlight aspects of potassium management with finerenone that were applied in the two trials and that are of particular relevance to clinical practice. We believe that a simple strategy for the management of hyperkalemia is important among clinicians, when several renoprotective drugs (e.g., RAS blockers, finerenone) may cause increases in potassium concentrations. Consequently, there is a high risk of drug discontinuation, with an increased risk of progression towards end-stage kidney disease (ESKD). This discontinuation can be avoided by applying simple protocols for potassium management. In this regard, we spotlight the fact that changes in patient's serum potassium concentrations were predictable and manageable with routine potassium monitoring throughout the entire finerenone trial program. This reliable routine may thereby serve as a basis for potassium management with finerenone in clinical practice.

| Definition of hyperkalemia
Hyperkalemia can be classified as acute (as occurring in an emergent setting), chronic, or recurrent, depending on the onset and number of hyperkalemia episodes that have occurred. 7 The decision of whether emergency therapy is warranted is largely based on subjective clinical judgement. The lack of robust and evidence-based treatment guidelines for the management of hyperkalemia in the emergency department poses a challenge for treatment. 8 Although the European Society of Cardiology (ESC), 9 Kidney Disease: Improving Global Outcomes (KDIGO), 10 and other organizations, such as the American College of Cardiology (ACC), American Heart Association (AHA), and Hearth Failure Society of America (HFSA) 11 have issued guidelines, the concentration of potassium that is labelled as hyperkalemia varies. Serum potassium concentrations of 5.0, 11 5.5, 12 or 6.0 mmol/L 13 are commonly used cutoffs for the definition of hyperkalemia.
The KDIGO controversies' conference report defines the severity of hyperkalemia by both serum potassium concentration and ECG changes. 10 The most common ECG change is peaked T waves, followed by QRS prolongation. Hyperkalemia is classified as mild, moderate, or severe based on potassium concentration and the presence or absence of ECG changes. Serum potassium concentrations ≥5.0-  17 While lower eGFR was a strong risk factor for hyperkalemia, higher albuminuria was a weaker risk factor. 17 Furthermore, medications such as potassium-sparing diuretics, MRAs, ACE inhibitors, ARBs, direct renin antagonists, β-blockers, nonsteroidal anti-inflammatory drugs, heparin, and penicillin are associated with hyperkalemia. 18 Potassium supplements and potassium-based salt substitutes may also be a cause of hyperkalemia, especially in patients with underlying CKD or concomitant use of hyperkalemiainducing drugs. 19 3 | FINERENONE CLINIC AL OUTCOME S
Patients were required to have persistent high albuminuria (UACR ≥30 but <300 mg/g) with an eGFR ≥25 to ≤60 ml/min/1.73 m 2 and a history of diabetic retinopathy or severe albuminuria (UACR ≥300 but <5000 mg/g) and an eGFR ≥25 to ≤75 ml/min/1.73 m 2.4 All patients were treated with RAS blockade at the maximum tolerated dose.
The median follow-up time was 2.6 years. At screening, 640/7114 (9.0%) patients had serum potassium concentrations >4.8 mmol/L and dropped out of the screening. At baseline, the mean serum potassium concentration was 4.37 ± 0.46 mmol/L in the finerenone group and 4.38 ± 0.46 mmol/L in the placebo group. 20 Hyperkalemia was a treatment-emergent, investigator-reported adverse event.
Hyperkalemia was considered serious if it resulted in death, was lifethreatening, required inpatient hospitalization, caused persistent or significant disability or incapacity, or was judged by the investigator to be a serious or important medical event (Table 1). 4 In patients with CKD and T2D, treatment with finerenone resulted in lower risks of CKD progression and cardiovascular events than placebo.

| FIGARO-DKD
The FIGARO-DKD trial included 7437 patients with T2D and CKD. 5 Patients were required to have persistent high albuminuria (UACR ≥30 but <300 mg/g) with an eGFR ≥25 to ≤90 ml/min/1.73 m 2 and a history of diabetic retinopathy or severe albuminuria (UACR ≥300 but <5000 mg/g) and an eGFR of at least 60 ml/min/1.73 m 2 . All patients were treated with RAS blockade at the maximum tolerated dose. The median follow-up time was 3.4 years. 5 Patients were required to have a serum potassium concentration of 4.8 mmol/L or less at the time of screening. As in FIDELIO-DKD, hyperkalemia was a treatment-emergent, investigator-reported adverse event (Table 2).
In patients with T2D and stage 2 to 4 CKD with moderately increased albuminuria or stage 1 or 2 CKD with severely increased albuminuria, finerenone improved cardiovascular outcomes compared with placebo.

| FIDELITY
FIDELITY, a pooled-analysis of more than 13,000 patients from the FIGARO-DKD and FIDELIO-DKD phase III trials, demonstrated cardiovascular and kidney benefits of finerenone in patients with CKD and T2D. 6 In the FIDELITY analysis, finerenone reduced the risk for the composite cardiovascular end-point, i.e., time to cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure, by 14% compared with placebo (HR:0.86 [95% CI: 0.78-0.95]; p = .0018). The risk of composite kidney event, i.e., time to the first episode of kidney failure, sustained decrease in eGFR by ≥57% from baseline over a period of ≥4 weeks, or death from kidney failure, was 23% lower with finerenone compared with placebo (HR: 0.77 [95% CI: 0.67-0.88]; p = 0.0002). A kidney-related event occurred in 360 (5.5%) patients on finerenone and 465 (7.1%) on placebo. 6 Although overall incidence of hyperkalemia was low, low eGFR was associated with higher incidence of hyperkalemia leading to discontinuation or hospitalization (Table 3).

| P OTA SS I UM MANAG EMENT AND P OTA SS I UM CON CENTR ATI ON S IN FIDELIO -DKD and FIG ARO -DKD
In the FIDELIO-DKD and the FIGARO-DKD trials, hyperkalemia was reported using thresholds of >5.5 mmol/L for mild hyperkalemia and >6.0 to <6.5 mmol/L for moderate hyperkalemia, in accordance with the latest KDIGO guidance based on the protocol. 10 The earliest time point after which serum potassium was measured in both trials was 1 month after treatment initiation.
The second scheduled assessment of serum potassium was at the fourth month after treatment initiation and at 4-month intervals thereafter. 4,5 The frequency of potassium monitoring in both trials was consistent with that recommended in the KDIGO guidelines for patients with CKD (3-4 times per year for patients with UACR TA B L E 1 FIDELIO-DKD clinical outcomes 4 year for patients with UACR 30-300 mg/g and eGFR 15-59 ml/min per 1.73 m 2 ). 10 In both trials, the risk of hyperkalemia from finerenone (14.0%) versus placebo (6.9%) was more than doubled. [4][5][6] This occurred despite the fact that potassium-increasing drugs other than ACE inhibitors and ARBs were prohibited and subjects with baseline potassium concentrations >4.8 mmol/L were excluded from the trials. 4,5 Finerenone had a predictable impact on serum potassium con-

| Practical considerations to minimize the risk of hyperkalemia with finerenone
Patients at the highest risk of hyperkalemia are those with low eGFR and high baseline serum potassium concentrations. More frequent serum potassium monitoring may be required for higher-risk patients, including those using medications that impair potassium excretion or increase serum potassium concentrations. 16 Trigger events for hyperkalemia may include a potassium-rich diet, acute sickness (e.g., acute kidney injury, volume depletion, GI problems, and infection), new comedications such as nonsteroidal anti-inflammatory drugs (NSAIDS), and surgery. 4,5,24 Finerenone is a CYP3A4 substrate. Concomitant use with a CYP3A4 inhibitor increases finerenone exposure, which may increase the risk of adverse reactions. 25 The concomitant use of finerenone with itraconazole, clarithromycin, and other strong CYP3A4 inhibitors (e.g., ketoconazole, ritonavir, nelfinavir, cobicistat, telithromycin, or nefazodone) is contraindicated. Concomitant intake of grapefruit or grapefruit juice should be avoided. 26

| Practical considerations for dietary intake
If serum potassium is elevated with normal acid-base balance, dietary modification is recommended to reduce potassium intake from foods of lower nutritional value after other non-nutritional causes such as medications have been considered and treated, if medically appropriate. 28 Many fresh fruits, and vegetables such as bananas, oranges, melon, honeydew, apricots, and grapefruit are rich in potassium. 29 Some dried fruits such as prunes, raisins, and dates are also rich in potassium. In addition, potassium is also found in many beverages such as fruit juices and coconut water. Meat, fish, and dairy foods often contribute more dietary potassium than fruits and vegetables, so consideration of the dietary pattern or a whole-diet plan is required for optimal management. 28 If hyperkalemia does occur, patients should avoid salt substitutes and receive nutritional counselling to reduce excessive potassium intake. 7,29 In a study comparing high consumption of fruits and vegetables against sodium bicarbonate and control conditions, fruit and vegetable consumption was as effective as sodium bicarbonate in reducing acidosis and slowing the decline in eGFR without increasing serum potassium. 30 In addition, high fruit and vegetable consumption was superior to sodium bicarbonate in lowering body weight, systolic blood pressure, and low-density lipoprotein (LDL) cholesterol. 30 It is important to note that dietary modifications are now recommended only to treat hyperkalemia and not as a preventative measure. 28

ACK N OWLED G EM ENTS
The authors would like to thank Martin Miszon, Sciarc GmbH, for his editorial and writing support of the manuscript.

FU N D I N G I N FO R M ATI O N
The publication has been funded by an unrestricted Educational Grant from Bayer AG.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.