Postgraduate Medicine

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Non-steroidal mineralocorticoid antagonists

and hyperkalemia monitoring in chronic kidney
disease patients associated with type II diabetes: a
narrative review

Javier Morales & Biff F. Palmer

To cite this article: Javier Morales & Biff F. Palmer (16 Feb 2024): Non-steroidal
mineralocorticoid antagonists and hyperkalemia monitoring in chronic kidney disease
patients associated with type II diabetes: a narrative review, Postgraduate Medicine, DOI:
10.1080/00325481.2024.2316572

To link to this article: https://doi.org/10.1080/00325481.2024.2316572

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POSTGRADUATE MEDICINE
https://doi.org/10.1080/00325481.2024.2316572

REVIEW

Non-steroidal mineralocorticoid antagonists and hyperkalemia monitoring in

chronic kidney disease patients associated with type II diabetes: a narrative review
Javier Moralesa,b and Biff F. Palmerc
a
Medicine, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, Hempstead, NY, USA; bAdvanced Internal Medicine Group, P.C,
East Hills, NY, USA; cDepartment of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, Dallas, TX, USA

ABSTRACT ARTICLE HISTORY

Chronic kidney disease (CKD) is a prevalent complication of Type II diabetes (T2D). The coexistence of CKD Received 7 January 2024
with T2D is comparable to cardiovascular disease (CVD) when the estimated glomerular filtration rate declines Accepted 5 February 2024
below 60 ml/min/1.73 m2. Screening and early detection of people with high risk for CKD would be beneficial
KEYWORDS
in managing CKD progress and the associated complications such as CV complications. Renin-angiotensin-
Chronic kidney disease; type
aldosterone system inhibitors (RAASi) have demonstrated beneficial effects in delaying CKD progression, but II diabetes; urine albumin
they carry the risk of hyperkalemia. Nonsteroidal mineralocorticoid antagonists (nsMRA), such as finerenone, creatinine ratio; finerenone;
exhibit considerable efficacy in their anti-inflammatory, antifibrotic, and renal protective effects with demon­ hyperkalemia
strable reductions in CV complications. In addition, nsMRAs do not cause significant changes in serum
potassium levels compared to traditional steroidal MRA. Ongoing research explores the capacity of the
sodium-glucose transport protein 2 inhibitors (SGLT-2i), combined with nsMRA, to produce synergistic renal
protective effects and reduce the risk of hyperkalemia. Also, a dedicated renal outcomes study (FLOW study)
involving a once-weekly injectable Glucagon-like peptide-1 receptor agonist, semaglutide, was halted early by
the data monitoring committee due to having achieved the predefined efficacy endpoint and considerations
related to renal disease. In CKD patients with T2D on nsMRA, hyperkalemia management requires
a comprehensive approach involving lifestyle adjustments, dietary modifications, regular serum potassium
level monitoring, and potassium binders, if necessary. Withholding or down-titration of nsMRAs with close
monitoring of serum potassium levels may be required in patients with concerning potassium levels. In light of
the current state of knowledge, this review article explores the perspectives and approaches that HCPs may
consider when monitoring and managing hyperkalemia in CKD patients with T2D.

PLAIN LANGUAGE SUMMARY

Chronic Kidney Disease (CKD) is a common and serious problem among people with Type II Diabetes (T2D).
People who have CKD with T2D are at a higher risk for heart disease after normal kidney function declines
below certain levels. Renin-angiotensin-aldosterone system inhibitors are a group of medications that can
help delay CKD progression but may cause a rise in circulating potassium levels. Nonsteroidal mineralocorti­
coid antagonist (nsMRA), such as finerenone, can reduce kidney inflammation and damage, with noted
cardiovascular benefits, and with less effect on serum potassium levels as compared to their steroid-based
counterparts. Researchers are studying whether combining blood sugar medications such as sodium-glucose
transport protein-2 inhibitors (SGLT-2i) and finerenone can help protect the kidneys and heart. They also want
to see if this combination can prevent high potassium levels. This article talks about ways to check and
monitor potassium levels in CKD patients with T2D who may be taking nsMRA. To manage high potassium
levels in people with CKD and T2D, doctors may suggest lifestyle changes, dietary adjustments, potassium-
lowering medication, or adjustment of other medications with close monitoring of potassium levels.

CONTACT Javier Morales saxodoc@gmail.com Advanced Internal Medicine Group, P.C., 2200 Northern Boulevard, East Hills, New York 11548, USA
© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
The terms on which this article has been published allow the posting of the Accepted Manuscript in a repository by the author(s) or with their consent.
2 J. MORALES AND B. F. PALMER
1. Introduction
The incidence of diabetes mellitus (DM) has been increasing over
recent decades; approximately 537 million diabetic patients were
reported worldwide in 2021, which is expected to increase to
783 million by 2024 [1]. According to the national diabetes
statistics report, the Centers for Disease Control and Prevention
(CDC) stated that around 37.3 million people in the United States
(approximately 11.3% of the country’s population) are affected
by DM; about 90–95% of them have type 2 diabetes (T2D) [2].
Chronic kidney disease (CKD) is considered one of the most
prevalent and severe complications, affecting as many as one
in three diabetic adult patients [3,4]. CKD with T2D associated
with an estimated glomerular filtration rate (eGFR) of <60 ml/
min/1.73m2 is considered a cardiovascular (CV) disease equiva­
lent [5]. Renin-angiotensin-aldosterone system inhibitors (RAASi)
have demonstrated beneficial effects in delaying CKD progres­
sion in CKD patients with T2D. However, hyperkalemia is con­
sidered one of the most prevalent and severe adverse effects in
those patients who are on RAASi [6]. The prevalence of hyperka­
lemia among hospitalized patients was reported at 2.9%, while in
CKD patients, the prevalence of hyperkalemia was reported at
11.5% and 9.1% in patients with heart failure [7]. This review
article critically examines the current body of knowledge to
clarify the perspectives and approaches that healthcare profes­
sionals (HCPs) should contemplate concerning the attentive
monitoring and productive management of hyperkalemia in
the specific subset of CKD in patients with DM. This review article
critically examines the current body of knowledge to clarify the
perspectives and approaches that healthcare professionals
(HCPs) should contemplate concerning the attentive monitoring
and productive management of hyperkalemia in the specific
subset of CKD in patients with DM.
2. Importance of implementing individualized CKD
screening
Although not subjected to randomized controlled trials, there
is abundant indirect evidence supporting the value of com­
munity-based CKD screening, particularly for individuals with
risk factors such as diabetes and hypertension and those with
a family history or other CKD risk factors [8,9]. Also, imple­
menting individualized screening during patient-clinician
encounters based on patient-specific factors and preferences
appears justifiable and cost-effective for individuals at ele­
vated risk of CKD. The American College of Physicians (ACP)
guidelines offer limited guidance regarding the specific
patient groups that should undergo screening [10,11]. The
National Kidney Foundation (NKF), the Renal Physicians
Association (RPA), and the American Diabetes Association
(ADA) endorse selective CKD screening. The ADA advocates
for screening individuals with diabetes, while the NKF and RPA
recommend screening for diabetic and hypertensive people.
Additionally, the NKF and RPA recommend screening for black
Americans, individuals 60 years of age or older, and those with
a family history of kidney disease [4,10,11].
While the eGFR is valuable in monitoring kidney health, the
underutilized urine albumin-to-creatinine ratio (UACR) test
demonstrates higher sensitivity and specificity in detecting early-
stage kidney damage [12–14]. However, when screening for kid­
ney disease, HCPs rely solely on the eGFR. Very often, UACR will be
abnormal even before there is a noted drop in the eGFR.
Therefore, testing for both eGFR and UACR plays critical roles in
comprehensively evaluating kidney health among individuals at
risk for CKD [12,13]. To facilitate the determination of treatment
urgency and the likelihood of kidney failure progression necessi­
tating hemodialysis, Kidney Disease: Improving Global Outcomes
(KDIGO) supports the use of the ‘KDIGO CKD Staging Heat Map’
[6,13]. This tool employs a visual graphical representation integrat­
ing two crucial markers: the eGFR and the UACR. In cases where
UACR ranges from ≥30 to <300 mg/g, it is classified as microalbu­
minuria, which signals the potential onset of early kidney damage.
Alternatively, UACR ≥300 mg/g suggests significant kidney
damage and may require referral to a nephrologist for additional
testing and treatments to address the underlying causes [6,13–15].
3. Medications for chronic kidney disease patients
with type II diabetes
The kidney is the principal regulator of total body potassium
levels [16,17]. Renal excretion eliminates 90% of dietary potas­
sium. The primary mechanism for potassium excretion is secre­
tion in the distal nephron, particularly by the principal cells in
the cortical collecting tubule, which play a pivotal role in
regulating potassium elimination [18,19]. This process of
potassium secretion in the distal convoluted tubule occurs
passively, following an electrochemical gradient. Luminal
flow in the distal nephron, luminal sodium concentration,
and the epithelial sodium channel (ENaC) activity in response
to aldosterone are the factors that potentially lead to hypoka­
lemia or hyperkalemia by either accelerating or reducing renal
potassium secretion. Furthermore, individuals with hyporeni­
nemic hypoaldosteronism are more susceptible to developing
hyperkalemia due to a reduction in renin release from juxta­
glomerular apparatus cells and aldosterone release from the
adrenal gland, which occurs as a consequence of juxtaglomer­
ular apparatus injury [20].
3.1. Renin-angiotensin-aldosterone system inhibitors
(RAASi)
The RAAS activation leads to vasoconstriction, increased
sodium reabsorption, and enhanced aldosterone release [15].
Hypertension and harmful effects on the CV and renal systems
can occur in prolonged uncontrolled RAAS activation. RAASi
have proven beneficial in various conditions, such as CKD with
or without proteinuria and heart failure with reduced ejection
fraction (HFrEF). They reduce mortality, relieve the symptoms,
and delay disease progression; however, using RAASi may be
associated with the risk of hyperkalemia. Nevertheless, the
clinical advantages of RAASi outweigh this risk for most
patients when hyperkalemia is adequately managed with
appropriate follow-up [6,15]. It is of vital importance to recog­
nize the potential for medication combinations that may lead
to hyperkalemia through increased risk of glomerular ische­
mia, reduced luminal flow in the distal nephron, and
decreased sodium concentration (e.g. NSAIDs) [21]. Also,
NSAIDs specifically decrease prostaglandin presence, which is

required for mesangial relaxation. NSAIDS lead to worsened
renal function due to mesangial constriction as well as papil­
lary necrosis with prolonged use [22].
3.2. Glucose-lowering therapies
Glucagon-like peptide-1 receptor agonist (GLP-1RA) and sodium-
glucose transport protein 2 inhibitors (SGLT-2i) have shown effi­
cacy in improving HbA1c levels, reducing body weight and low­
ering systolic blood pressure with the promise of beta cell
preservation in diabetic patients and possibly delaying the devel­
opment of diabetes in individuals at risk [23,24].
3.2.1. Glucagon-like peptide-1 receptor agonist (GLP-1RA)
Several preclinical studies involving long-acting GLP-1 RA have
provided evidence of a renal protective effect. Yin W et al. and
Hendarto et al. demonstrated that GLP-1 RAs decreased albu­
minuria, improved tubulointerstitial lesions, and delayed the
development of diabetic nephropathy by reducing oxidative
stress [25,26].
In the LEADER clinical trial (NCT01179048) (N=9,340 partici­
pants), liraglutide was associated with a 22% risk reduction (hazard
ratio (HR), 0.78; 95%CI, 0.67–0.92) in the composite renal outcomes
compared to placebo [27]. In post hoc analysis from the REWIND
trial (NCT01394952) (N=9,901 participants), dulaglutide showed
a 25% risk reduction in kidney function-related outcomes com­
pared to placebo (HR 0.75, 95%CI 0.62–0.92) [28]. Moreover,
a recent meta-analysis involving 60,080 participants reported
that GLP-1 RA was associated with a 21% risk reduction (HR 0.79
with 95% CI 0.73–0.87) in function – related outcomes [29]. The
previous studies paved the way for an ongoing clinical trial (FLOW
trial (NCT03819153)), which aims to investigate the potential ben­
efits of once-weekly semaglutide on renal outcomes in CKD
patients with T2D [30]. The data monitoring committee stopped
the trial early based on achieving prespecified efficacy endpoints;
however, additional detail will not be provided until after the last
patient and the last visit are completed in February 2024 [31].
3.2.2. Sodium-glucose transport protein 2 inhibitors
(SGLT-2i)
The CREDENCE trial (NCT02065791) and the DAPA-CKD
(NCT03036150) have demonstrated significant renal benefits
of SGLT-2i regarding substantial eGFR declines, kidney failure,
and mortality [32,33]. In the EMPA-KIDNEY trial (NCT03594110)
Table 1. MRAs different eligibility criteria and dose adjustments for serum potassium.
Clinical Trials Exclusion Criteria
RALES [31] Serum creatinine> 221µmol/L (2.5 mg/dL), serum K > 5 mmol/L If K ≥ 5.5 mmol/L, decrease dose to 25 mg every other day (although
EMPHASIS-HF [32] eGFR < 30 mL/min, serum K > 5 mmol/L
TOPCAT [33] eGFR < 30 mL/min, Serum creatinine ≥ 221 µmol/L (2.5 mg/dL), If K ≥ 5.5 mmol/L, reduce drug by 15 mg (no up titration beyond this
serum K ≥ 5.5 mmol/L in past 6 months, serum K ≥ 5 mmol/L
in past 2 weeks
POSTGRADUATE MEDICINE 3
conducted in a diverse group of CKD patients at risk for
disease progression, treatment with empagliflozin was asso­
ciated with a reduced risk of progression of kidney disease or
CV-related mortality compared to placebo [34]. Moreover,
many meta-analyses showed that SGLT-2i was associated
with reduced CKD progression and reduced risk of CV events
[35–38]. The KDIGO 2022 and the ADA standards of care
recommend the initiation of SGLT-2i for patients with T2D
and CKD who have an eGFR ≥ 20 mL/min/1.73 m2 [39].
Furthermore, the updated 2023 ADA standards of care suggest
initiating SGLT-2 inhibitor treatment for patients with T2D and
CKD who have UACR ≥200 mg/g creatinine [40]. However,
when contemplating the initiation of an SGLT-2i in those
patients, the primary factor to consider is the regulation of
blood pressure. In cases where blood pressure is lower than
the desired range (95–100 mmHg), which may occur in
patients on RAASi and diuretics, it may be prudent to consider
reducing the dosage of diuretics or other antihypertensive
medications to facilitate the introduction of an SGLT-2i, if
appropriate [41].
3.3. Mineralocorticoid antagonists (MRA)
In 1999, the Randomized Aldactone Evaluation Study, RALES,
demonstrated the significant benefits of spironolactone in
reducing the risk of death by 30% in patients with HFrEF
[42]. The trial was stopped early due to the robust results,
including reduced rates of progressive heart failure and sud­
den death. In 2011, EMPHASIS-HF showed that eplerenone,
a more selective version of spironolactone, was associated
with reduced all-cause mortality and hospitalization in these
trials. Despite the demonstrated efficacy and safety of epler­
enone, its use in patients with CKD is limited due to the
associated risk of hyperkalemia and contraindications in
patients with hypertension and T2D with microalbuminuria
[43]. In 2014, The Treatment of Preserved Cardiac Function
Heart Failure with an Aldosterone Antagonist, TOPCAT, trial
showed that spironolactone did not reduce the risk of the
primary outcome in patients with heart failure with preserved
ejection fraction (HFpEF) [44]. All the previously mentioned
trials followed different eligibility criteria and management
protocols for hyperkalemia (Table 1) [45].
Steroidal MRAs (sMRA) have demonstrated their effective­
ness in slowing the progression of kidney disease, reducing
Dose Adjustments for Serum Potassium
investigator encouraged to initially adjust doses of concomitant
medications)
If K ≥ 6.0 mmol/L, withhold study medication
For eGFR ≥ 50 mL/min:
If K ≥ 5.5 mmol/L, decrease dose to 25 mg; If K ≥ 6.0 mmol/L, withhold
dose, re-check K within 72 hours and resume if K < 5.0 mmol/L
For eGFR 30–49 mL/min:
If K ≥ 5.5 mmol/L, withhold dose and re-check within 72 hours and
resume if K < 5.0 mmol/L; If K ≥ 6.0 mmol/L, withhold and recheck
K within 72 hours and resume if K < 5.0 mmol/L.
level for remainder of study) If K ≥ 6.0 mmol/L, permanently
discontinue study drug
4 J. MORALES AND B. F. PALMER
the likelihood of heart failure hospitalization, and improving
overall survival rates among patients with HFrEF [46]. sMRAs
have specific adverse effects, including hyperkalemia, electro­
lyte imbalances, and an increased risk of gynecomastia [47,48].
However, eplerenone demonstrated higher selectivity and
a lower risk of inducing hyperkalemia than spironolactone.
3.3.1. Nonsteroidal mineralocorticoids antagonists
(nsMRA)
nsMRAs are characterized over the sMRA by much better
selectivity for the MR, fitting better in on receptors, fewer off-
target effects, and reduced anti-androgenic side effects [49].
Also, unlike sMRAs, which have active metabolites detectable
in the urine several weeks after discontinuing therapy, nsMRAs
have no active metabolites [50]. Furthermore, nsMRAs have
a significantly shorter half-life [39], significantly mitigating the
risk of hyperkalemia that exhibits an inverse relationship with
the eGFR [51,52].
Finerenone (BAY 94–8862), a nsMRA, exhibits considerable
efficacy in terms of its anti-inflammatory and antifibrotic
effects without causing significant changes in serum potas­
sium levels compared to traditional sMRA [53]. The FIDELIO-
DKD trial (NCT02540993) (N=5743) is a randomized, double-
blinded, phase 3 trial with a 1:1 ratio for participants to receive
finerenone or a placebo alongside the regular standard of care
[54]. Participants were CKD patients with T2D, on treatment
with the maximum tolerated dose of an angiotensin-
converting enzyme inhibitor (ACEi) or angiotensin receptor
blocker (ARB) for at least four weeks before the screening
visit and with serum potassium level below 4.8 mmol/L [54].
Finerenone showed a 23% risk reduction (HR 0.77,
95% CI 0.67–0.88) of the kidney composite endpoint of
a 57% decline in eGFR, kidney failure, or death from kidney
failure. In addition, the FIGARO-DKD clinical trial that focused
on CV events as a primary endpoint demonstrated that the
administration of finerenone can yield considerable CV advan­
tages for individuals diagnosed with CKD with T2D [55,56].
Finerenone showed a 14% risk reduction (HR: 0.86; 95% CI:
0.78–0.95) of the CV composite outcome of CV death, nonfatal
myocardial infarction, and nonfatal stroke or hospitalization
for heart failure.
Many trials involving dual RAASi reported higher potassium
rates. In the VA NEPHRON-D trial (NCT00494815), patients
Figure 1. Potassium management algorithm of the FIDELIO-DKD study protocol [42].
experienced severe hyperkalemia in 4.4% of the losartan group
compared to 9.9% in the losartan plus lisinopril group [57]. As
a result, it has been duly noted that using an ACEi with an ARB
dramatically increases hyperkalemia risk, and thus, such practices
should not be exercised. Post hoc subgroup analyses of clinical
studies indicated that combining finerenone and SGLT-2i in
therapy may have additional beneficial renal protective effects
and decrease hyperkalemia occurrence [58,59]. The CONFIDENCE
trial (NCT05254002) is the first Phase 2 study investigating the
efficacy and safety of a combination treatment of empagliflozin
and finerenone compared to either one of these medications
used on a back-bone of maximally treated RAAS inhibition in
CKD patients with T2D [60]. The study’s primary objective is to
demonstrate whether initiating this dual therapy is superior in
reducing UACR compared to treatment with either empagliflozin
or finerenone alone in CKD patients with T2D.
4. Hyperkalemia monitoring and management in
patients on nsMRA
Hyperkalemia classification varies from society to society, and
according to the guidelines stipulated by the European
Resuscitation Council and the UK Renal Association, hyperkale­
mia is a serum potassium concentration of ≥5.5 mmol/ [39,61].
However, the Canadian Cardiovascular Society has hyperkale­
mia cutoff points of mild (5.0–5.5 mEq/L), moderate (5.6–5.9
mEq/L)) and severe ˃5.9 mEq/L) to define hyperkalemia [62].
While the Renal Association Clinical Practice Guidelines classify
hyperkalemia as mild (5.5–5.9 mEq/L), moderate (6–6.4 mEq/L)
and severe (˃6.5 mEq/L) [63]. However, Clase et al. suggest
classifying hyperkalemia based on mild (5–5.9 mEq/L), moder­
ate (6–6.4 mEq/L)) and severe ≥6.5 mEq/L) and the presence or
absence of ECG changes as a conclusion from the KDIGO-2018
[64]. The FIDELIO-DKD study protocol has developed
a potassium management algorithm that adheres to existing
guidelines [21,54]. This algorithm can potentially provide
a valuable framework for implementation in clinical practice
(Figure 1). However, for fair balance, it is important to note
that no protocols exist for sMRA, such as spironolactone or
eplerenone. No protocols had been prespecified in trials invol­
ving sMRA for mild to moderate hyperkalemia [42–44].
Conservative measures can involve dietary modifications,
such as reducing the consumption of high-potassium foods.

However, implementing this approach presents challenges,
as many potassium-containing foods are also considered
heart-healthy [65]. Excessive potassium intake, particularly
in CKD, can lead to hyperkalemia, posing severe health risks
[64,66,67]. While reducing the intake of potassium-rich
foods may have beneficial effects, it is essential to note
that foods like vegetables, fruit juices, and processed
foods provide important nutrients like fiber, vitamins, and
antioxidants, which may be crucial for heart health.
Therefore, patients should be aware of the potassium con­
tent of different foods to make informed dietary choices.
The nutritional recommendations should focus on maintain­
ing a balance that supports overall health while managing
the risks associated with cardiac and renal conditions
[66,67].
4.1. Hyperkalemia monitoring in patients on nsMRA
The diagnosis and monitoring of hyperkalemia patients with
CKD with T2D typically involve a comprehensive approach
through clinical evaluations, laboratory tests, and electrocardio­
grams (EKG), as needed [68]. The frequency of monitoring serum
potassium levels depends on various factors, including the
severity of kidney disease, comorbidities, and concurrent med­
ication use. According to the FIDELIO-DKD trial protocol, potas­
sium levels should be monitored four weeks after initiating
nsMRA (finerenone), with subsequent titration of finerenone
dosage based on serum potassium levels [21,54,69]. The study
demonstrated the efficacy of finerenone dose titration in mana­
ging serum potassium levels and provided a quantitative frame­
work to guide its safe clinical use [21]. As deemed necessary,
periodic evaluations should be conducted multiple times
per year, along with appropriate interventions. For clinically
stable patients without hyperkalemia symptoms, measuring
potassium levels during HbA1c assessments every 90 days is
advisable. This approach enables comprehensive monitoring of
glycemic control and serum potassium levels and assessing
electrolyte balance [21,54]. Maintaining consistent communica­
tion with HCPs and adhering to the recommended monitoring
and treatment plan are essential in effectively managing hyper­
kalemia while optimizing the benefits of finerenone therapy.
4.2. Hyperkalemia management in patients on nsMRA
Treating hyperkalemia involves addressing the root cause,
making dietary and lifestyle recommendations, adjusting any
medications contributing to a potassium imbalance, and
administering medications to reduce serum potassium levels
as needed. Extreme medical emergencies may include glucose
administration with insulin to facilitate intracellular potassium
movement, intravenous calcium gluconate to stabilize myo­
cardial function, bicarbonate to correct acid-base imbalances
and promote intracellular potassium shifting, or potassium-
binders utilization [70]. Dialysis decreases the body’s potas­
sium levels and may be required in severe cases (serum
potassium levels >6.5 mmol/L) and hyperkalemia with evi­
dence of myocardial irritability or EKG changes as they are
considered medical emergencies [70].
POSTGRADUATE MEDICINE 5
Utilizing loop diuretics and thiazide diuretics have potential
adverse effects, including the exacerbation of prerenal azote­
mia, contraction metabolic alkalosis, and hypomagnesemia
that limit their use to lower serum potassium levels [71].
Guidelines discourage suboptimal dosing or discontinuation
of RAASi drugs, including finerenone, in managing CKD. In
such patients, oral potassium-binding drugs may prove helpful
in enabling the use of RAASi and nsMRA at the recommended
doses [39,54,72]. It is crucial to note that high doses or unne­
cessarily prolonged use of diuretics can paradoxically precipi­
tate hyperkalemia, mainly in patients with bilateral
renovascular disease or critical aortic stenosis or when used
while the patient is on a high dose of ACEi/ARB or in combi­
nation with SGLT-2i [71].
4.2.1. Potassium binders to maintain CKD patients on
RAASi
Many studies showed a notable increase in the rates of RAASi
discontinuation among patients with hyperkalemia levels ≥
6.0 mmol/L [73,74]. Epstein et al. observed that 47% of
patients with CKD, HF, T2D, and hypertension discontinued
RAASi when experiencing hyperkalemia ≥ 5.5 mmol/L while
receiving the maximum RAASi dose [75]. In the context of
managing hyperkalemia related to RAASi therapy in CKD
patients, it is essential to consider alternative strategies
beyond discontinuing or reducing the dosage of RAASi. In
cases of hyperkalemia, potassium binders offer a potential
strategy to maintain RAASi therapy. These binders, such as
patiromer sorbitex calcium and sodium zirconium cyclosili­
cate (SZC), have demonstrated efficacy in clinical trials and
have received approval in the US and Europe [76–78]. The
National Institute for Health and Care Excellence recom­
mends SZC and patiromer as adjunctive treatments for
acute life-threatening hyperkalemia, expanding their role
beyond standard care. The European Society of Cardiology
also advocates using potassium binders, specifically patiro­
mer and SZC, in managing hyperkalemia associated with
RAASi therapy. These findings suggest that potassium binders
could be valuable tools in managing hyperkalemia, allowing
for the continuation of RAASi therapy in patients with CKD.
5. The burden on health economics and social
disparities
Hyperkalemia contributes to a notable proportion of hospital
admissions, ranging from 1.1% to 10.0% [79]. As previously
mentioned, the prevalence of hyperkalemia among hospitalized
patients was reported at 2.9%. In contrast, in CKD patients, the
prevalence of hyperkalemia was reported at 11.5% and 9.1% in
patients with heart failure and reached up to 13% if the patient
had diabetes, CKD, and CV complications [7,80,81]. Follow-up for
hyperkalemia in CKD patients and T2D exhibits considerable
variation, influenced by insurance type, coverage, and benefits,
which impact access to HCPs, medication coverage, and fre­
quency of laboratory investigations. Medicaid-managed care
populations have demonstrated increased healthcare utilization
and costs associated with hyperkalemia [82]. The study high­
lights that patients with cardiorenal comorbidities already
6 J. MORALES AND B. F. PALMER
impose significant costs on Medicaid plans, further amplified by
a hyperkalemia diagnosis. These findings emphasize the impor­
tance of proactive measures for close monitoring and managing
hyperkalemia in this population. In 2014, the Agency for
Healthcare Research and Quality estimated that the health
expenditure for patients admitted with hyperkalemia was
$1.2 billion, with an average stay of 3.3 days [40,82].
6. Primary care clinicians and healthcare
professionals’ perspectives (a call to action)
6.1. Hyperkalemia monitoring and management at the
primary care units
Primary care units serve as the initial point of contact for most
patients worldwide who are in the early stage of CKD and are
seeking healthcare services [83]. To gather diverse perspec­
tives and opinions on CKD management, it is crucial to involve
primary care clinicians (PCCs) and HCPs. However, there are
limitations regarding understanding PCCs’ challenges and
opportunities for enhancing CKD management due to limited
published data. Additional prospective studies are required to
assess the PCCs’ perspectives that build upon the connections
between ordering practices and clinical outcomes.
6.2. Approaches for HCPs and PCCs to manage
hyperkalemia
The Optum Clinformatics Data Mart database showed that less
than 50% of the US patients with T2D identified between
January 2008 and December 2016 underwent screening for
albuminuria [12].
The following approaches should help HCPs and the PCCs,
especially in regions where specialist services may not be
readily available for hyperkalemia monitoring and manage­
ment in CKD patients with T2D. Based on the clinical perspec­
tives of the authors and HCPs, the following elements will
elucidate essential strategies in the management of hyperka­
lemia in patients with CKD and T2D. Regular monitoring and
proper control of hyperkalemia are crucial, often spanning
multiple years [84,85]. Implementing lifestyle adjustments,
dietary modifications, and potassium binders in the appropri­
ate clinical situation might help normalize potassium levels in
patients using MRAs that are associated with a greater degree
of hyperkalemia or even using nsMRA [51]. The decision to
initiate nsMRS (finerenone) therapy should be guided by the
individual’s eGFR [54]. Four weeks after initiating nsMRA ther­
apy, potassium levels should be monitored according to the
FIDELIO-DKD trial protocol and 2022 KDIGO guidelines with
subsequent titration to the highest effective dose if the mea­
sured potassium levels permit. [6, 55] Based on the published
trials, such guidance was unavailable while using MRA [42–44].
Also, no dedicated study protocol has been listed to guide
potassium management when using those agents. Once
a patient achieves stability on finerenone, the frequency of
potassium monitoring may be reduced. It may coincide with
the assessment of HbA1c levels, which is typically performed
every 90 days for most patients. In more severe cases of
hyperkalemia or when patients exhibit symptoms related to
elevated potassium levels, temporary interruption or down-
titration of nsMRA therapy may be necessary [21,54].
Following such adjustments, HCPs should closely monitor
their patient’s potassium levels and overall clinical status.
Maintaining consistent communication with HCPs and adher­
ing to the recommended monitoring and treatment plan is
essential for effectively managing hyperkalemia while optimiz­
ing the benefits of nsMRA, such as finerenone therapy.
7. Conclusion
The nsMRA demonstrates renal preservation with reduced
risks in the progression of CKD and benefits in CV outcomes,
including risk reduction of hospitalization for heart failure in
CKD patients with T2D. Hyperkalemia is a significant concern
in such patients, and the FIDELIO-DKD trial protocol demon­
strates that potassium should be monitored four weeks after
finerenone initiation, with upward titration based on serum
potassium levels. Once stable, it is reasonable to assess
potassium levels concurrently with HbA1c measurements,
with more frequent monitoring during concurrent medical
therapy utilization. The management of hyperkalemia neces­
sitates a comprehensive approach encompassing lifestyle
modifications, dietary adjustments, regular serum potassium
levels monitoring, and the potential use of potassium binders
such as SZC and patiromer might help avoid down titration
or drug stoppage in CKD patients of T2D. Using nsMRA, such
as finerenone, has shown promising results regarding hyper­
kalemia risk, which is lower than the demonstrated risk asso­
ciated with sMRA, such as spironolactone and eplerenone.
Studies to understand the combination effect mechanisms of
nsMRA and SGLT-2i could lead to personalized treatments
and new therapeutic targets. Prospective studies are needed
to link PCCs’ laboratory ordering practices with clinical out­
comes in CKD patients with T2D. Raising HCPs’ and PCCs’
awareness with continuous education on CKD management
is crucial.
Funding
Bayer US, LLC. funded the article processing charges for this article. Bayer
US, LLC. also funded ILM Consulting Services, LLC. for medical writing
support and publication management.
Declaration of financial/other relationships
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties. Peer
reviewers on this manuscript have received an honorarium from IPGM
for their review work but have no other relevant financial relationships to
disclose.
Acknowledgments
The authors would like to acknowledge the medical writing support
provided by Mahmoud Azqul of ILM Consulting Services, LLC., which
was funded by Bayer US, LLC. The authors would also like to acknowledge
the editorial support, visualization and graphical abstract development

provided by Aqsa Dar of ILM Consulting Services, LLC., which was also
funded by Bayer US, LLC. ILM’s services complied with international guide­
lines for Good Publication Practice (GPP 2023).
Author contributions
All authors contributed to the writing and reviewing of each draft and
reviewing and approving the final draft for submission. Javier Morales:
Conceptualization, Writing – review & editing. Biff F. Palmer:
Conceptualization, Writing – review & editing.
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