Non-steroidal mineralocorticoid antagonists and hyperkalemia monitoring in chronic kidney disease patients associated with type II diabetes: a narrative review

ABSTRACT

Chronic kidney disease (CKD) is a prevalent complication of Type II diabetes (T2D). The coexistence of CKD with T2D is comparable to cardiovascular disease (CVD) when the estimated glomerular filtration rate declines below 60 ml/min/1.73 m². Screening and early detection of people with high risk for CKD would be beneficial in managing CKD progress and the associated complications such as CV complications. Renin-angiotensin-aldosterone system inhibitors (RAASi) have demonstrated beneficial effects in delaying CKD progression, but they carry the risk of hyperkalemia. Nonsteroidal mineralocorticoid antagonists (nsMRA), such as finerenone, exhibit considerable efficacy in their anti-inflammatory, antifibrotic, and renal protective effects with demonstrable 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 mineralocorticoid 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.

Graphical Abstract

KEYWORDS:

• Chronic kidney disease
• type II diabetes
• urine albumin creatinine ratio
• finerenone
• hyperkalemia

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 equivalent [5]. Renin-angiotensin-aldosterone system inhibitors (RAASi) have demonstrated beneficial effects in delaying CKD progression in CKD patients with T2D. However, hyperkalemia is considered one of the most prevalent and severe adverse effects in those patients who are on RAASi [6]. The prevalence of hyperkalemia 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 professionals (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 community-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, implementing individualized screening during patient-clinician encounters based on patient-specific factors and preferences appears justifiable and cost-effective for individuals at elevated 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 kidney 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 necessitating 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 integrating two crucial markers: the eGFR and the UACR. In cases where UACR ranges from ≥30 to <300 mg/g, it is classified as microalbuminuria, 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 potassium. The primary mechanism for potassium excretion is secretion 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 hypokalemia or hyperkalemia by either accelerating or reducing renal potassium secretion. Furthermore, individuals with hyporeninemic hypoaldosteronism are more susceptible to developing hyperkalemia due to a reduction in renin release from juxtaglomerular apparatus cells and aldosterone release from the adrenal gland, which occurs as a consequence of juxtaglomerular 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 recognize the potential for medication combinations that may lead to hyperkalemia through increased risk of glomerular ischemia, 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 papillary 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 efficacy in improving HbA1c levels, reducing body weight and lowering systolic blood pressure with the promise of beta cell preservation in diabetic patients and possibly delaying the development 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 albuminuria, 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 participants), 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 compared 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 benefits 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) conducted in a diverse group of CKD patients at risk for disease progression, treatment with empagliflozin was associated 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 sudden 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 eplerenone, 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].

Table 1. MRAs different eligibility criteria and dose adjustments for serum potassium.

Clinical Trials	Exclusion Criteria	Dose Adjustments for Serum Potassium
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 investigator encouraged to initially adjust doses of concomitant medications) If K ≥ 6.0 mmol/L, withhold study medication
EMPHASIS-HF [32]	eGFR < 30 mL/min, serum K > 5 mmol/L	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.
TOPCAT [33]	eGFR < 30 mL/min, Serum creatinine ≥ 221 µmol/L (2.5 mg/dL), serum K ≥ 5.5 mmol/L in past 6 months, serum K ≥ 5 mmol/L in past 2 weeks	If K ≥ 5.5 mmol/L, reduce drug by 15 mg (no up titration beyond this level for remainder of study) If K ≥ 6.0 mmol/L, permanently discontinue study drug

Steroidal MRAs (sMRA) have demonstrated their effectiveness in slowing the progression of kidney disease, reducing the likelihood of heart failure hospitalization, and improving overall survival rates among patients with HFrEF [46]. sMRAs have specific adverse effects, including hyperkalemia, electrolyte 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 potassium 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 advantages 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 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, hyperkalemia is a serum potassium concentration of ≥5.5 mmol/ [39,61]. However, the Canadian Cardiovascular Society has hyperkalemia 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), moderate (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 involving sMRA for mild to moderate hyperkalemia [42–44].

Figure 1. Potassium management algorithm of the FIDELIO-DKD study protocol [42].

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 content of different foods to make informed dietary choices. The nutritional recommendations should focus on maintaining 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 electrocardiograms (EKG), as needed [68]. The frequency of monitoring serum potassium levels depends on various factors, including the severity of kidney disease, comorbidities, and concurrent medication use. According to the FIDELIO-DKD trial protocol, potassium 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 managing serum potassium levels and provided a quantitative framework 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 communication with HCPs and adhering to the recommended monitoring and treatment plan are essential in effectively managing hyperkalemia 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 myocardial function, bicarbonate to correct acid-base imbalances and promote intracellular potassium shifting, or potassium-binders utilization [70]. Dialysis decreases the body’s potassium levels and may be required in severe cases (serum potassium levels >6.5 mmol/L) and hyperkalemia with evidence of myocardial irritability or EKG changes as they are considered medical emergencies [70].

Utilizing loop diuretics and thiazide diuretics have potential adverse effects, including the exacerbation of prerenal azotemia, 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 unnecessarily prolonged use of diuretics can paradoxically precipitate 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 combination 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 cyclosilicate (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 recommends 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 patiromer 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 frequency of laboratory investigations. Medicaid-managed care populations have demonstrated increased healthcare utilization and costs associated with hyperkalemia [82]. The study highlights that patients with cardiorenal comorbidities already impose significant costs on Medicaid plans, further amplified by a hyperkalemia diagnosis. These findings emphasize the importance 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 perspectives 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 management in CKD patients with T2D. Based on the clinical perspectives of the authors and HCPs, the following elements will elucidate essential strategies in the management of hyperkalemia 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 appropriate 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 therapy, 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 measured 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 adhering to the recommended monitoring and treatment plan is essential for effectively managing hyperkalemia while optimizing 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 demonstrates 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 necessitates 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 hyperkalemia risk, which is lower than the demonstrated risk associated 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 outcomes in CKD patients with T2D. Raising HCPs’ and PCCs’ awareness with continuous education on CKD management is crucial.

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.

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.

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 guidelines for Good Publication Practice (GPP 2023).

Additional information

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.