Supplements and Featured Publications
- Hyperkalemia and Its Treatment: Real-World Evidence and Managed Care Considerations Supporting Use of Potassium Binders
Hyperkalemia and Its Treatment: Real-World Evidence and Managed Care Considerations Supporting Use of Potassium Binders
This supplement was supported by AstraZeneca.
ABSTRACT
An estimated 3.7 million adults in the United States have hyperkalemia. It commonly occurs in patients with chronic kidney disease (CKD) and/or heart failure (HF) and as a result of treatment with renin-angiotensin-aldosterone system inhibitors (RAASi), a class of medications recommended by professional guidelines for patients with CKD and those with HF. While lifestyle alterations have been previously recommended to control potassium levels for some patients with hyperkalemia, emerging evidence has shown a concerning pattern of chronicity and recurrence despite counseling to support lifestyle modifications. Real-world health outcomes among patients with hyperkalemia and recurrent episodes thereof have demonstrated higher risks of major adverse cardiovascular events, hospitalization, and mortality relative to patients with normokalemia. Similarly, real-world health economic studies have shown higher rates of health care resource utilization and higher medical costs. Together, these data hightlight the need for strategies that will restore patients’ serum potassium levels to a normal range. Potassium binders are a pharmaceutical class indicated to treat hyperkalemia; sodium zirconium cyclosilicate (SZC), patiromer, and sodium polystyrene sulfonate (SPS) are guideline-recommended for patients with CKD, and the first 2 are considered potentially reasonable for patients with HF. Clinical trials and long-term open-label extensions studying SZC or patiromer support the safety and efficacy of these medications. Controlled clinical evidence supporting SPS’s safety and efficacy is more limited, and its labeling also carries a warning for severe, potentially fatal gastrointestinal adverse events. Based on real-world evidence, use of SZC or patiromer has been associated with reduced medical costs and health care resource utilization, and some patients taking SZC or patiromer have been able to optimize doses of RAASi prescribed for other conditions. From a managed care perspective, proactive potassium control through routine use of potassium binders in patients with hyperkalemia may offer a means to reduce costly acute care while simultaneously supporting optimization of medications for comorbid conditions.
Am J Manag Care. 2026;32(suppl 8):S143-S154.
For author information and disclosures, see end of text.
Introduction
In the United States, an estimated 3.7 million adults have hyperkalemia, with prevalence increasing substantially with declining kidney function.1 The condition is associated with increased mortality risk and substantial health care costs,2,3 yet it remains challenging to manage effectively, particularly in patients who require renin-angiotensin-aldosterone system inhibitors (RAASi) for underlying cardiac or renal disease.2
Hyperkalemia is defined as an elevated concentration of potassium ions (K+) in the blood. Professional societies often demarcate the lower bound of hyperkalemia as 5.0 to 5.5 mmol/L,2,4 and the condition may range from mild to severe, depending on serum K+ concentration and whether patients exhibit echocardiogram (ECG) abnormalities.4 Abnormal K+ concentrations at these levels or higher predispose individuals to potentially lethal cardiac arrhythmias, making hyperkalemia a condition of particular relevance for patients with heart failure (HF) and/or chronic kidney disease (CKD), among whom the condition is common.2,4,5 Other conditions that are commonly comorbid with hyperkalemia include, but are not limited to, hypertension, diabetes, and hyperlipidemia.5
From 2007 through at least 2020, the US age-adjusted mortality rate for cardiac arrest related to hyperkalemia steadily and significantly increased.6 Likewise, hyperkalemia even in the mild to moderate range has been associated with increased predicted probability of mortality among patients with 1 or more comorbid diagnoses of HF, CKD, or diabetes,7 highlighting the importance and urgency of having safe and effective treatments that can rapidly restore normokalemia, particularly among patients with cardiorenal dysfunction. Accordingly, the purpose of this supplement is to review hyperkalemia as a disease state and highlight the interventions available to health care providers to regulate patients’ K+ levels. Special emphasis will be placed on the chronicity and recurrence patterns of hyperkalemia, an examination of its impact on RAASi use and related outcomes among patients with CKD and/or HF, and managed care considerations informed by real-world cost data. It will support the clinical rationale for novel K+ binders as routine therapies for hyperkalemia and recurrent hyperkalemia.
Patient Characteristics and Prevalences in the US
Hyperkalemia commonly occurs as a complication of HF, its comorbidities (eg, CKD and diabetes), or as a result of treatment with RAASi.8 In a retrospective analysis of the Truven MarketScan claims and encounters and laboratory databases, the prevalence of hyperkalemia was 3.09% among patients with HF without CKD or dialysis, 6.35% (95% CI, 6.17%-6.54%) among patients with HF and/or CKD, and 9.64% among patients with HF with or without CKD, all of which were elevated relative to the 1.57% (95% CI, 1.54%-1.60%) prevalence rate estimated from the general patient sample.1 Hyperkalemia was found to be prevalent among patients with later-stage CKD with rates increasing stepwise by disease stage (stage 3, 5.00%; stage 4, 22.13%; stage 5, 25.97%) and most prevalent among patients on dialysis (43.49%).1 These findings reflect the essential role of the renal system in maintaining total body K+ homeostasis and the inverse relationship between kidney function and hyperkalemia prevalence.2,9 That nearly half (48.43%) of patients with hyperkalemia had CKD
and/or HF reflects the intricate relationship between hyperkalemia and multiple organ systems.1
Like patients with HF and CKD, patients diagnosed with hyperkalemia tend to be older than patients without hyperkalemia, and both HF and hyperkalemia are more common in men.1,10 In the retrospective analysis, 54.4% of US adults with hyperkalemia were found to be male; this rate was only 43.7% among US adults with no hyperkalemia (P < .001). Adults with hyperkalemia were found to be an average of 10 years older (61.7 vs 51.7 years, P < .001) and to possess a higher burden of hyperkalemia-related comorbidities, including CKD, HF, diabetes, and hypertension, than their counterparts without the condition.1 A similar retrospective analysis using a 5% random sample from the Medicare claims database estimated that approximately 1.1 million US adults 65 years or older experience hyperkalemia annually,11 demonstrating the outsize burden of hyperkalemia among older individuals.
Hyperkalemia Chronicity and Recurrence Burden
While lifestyle alterations are recommended for some patients to reduce their risk of developing hyperkalemia,2 the substantiation for this approach as a preventive strategy is lacking,12 and emerging evidence suggests that recurrence of hyperkalemia is common even with lifestyle alterations. In the REVOLUTIONIZE I study, investigators followed a cohort of patients with stage 3 or 4 CKD who experienced an initial hyperkalemia episode and then received medical nutrition therapy (MNT) counseling; 1503 patients remained uncensored for the study’s full 6-month follow-up period and were included in the analysis of hyperkalemia recurrence.13 Using longitudinal electronic health record (EHR) data to monitor for evidence of hyperkalemia after MNT,13 investigators observed a concerning pattern of recurrence despite the lifestyle intervention. A total of 56% (n = 842) of patients experienced at least 1 recurrence, 58% of those patients (n = 486) experienced a second recurrence, 60% (n = 291) experienced a third, and 70% (n = 204) experienced a fourth or more.13 The mean (SD) number of recurrences was 2.6 (2.2), and the mean (SD) time to recurrence was
45 (46) days.13 Recurrence rates were similar across patient subgroups diagnosed with stage 3b CKD (n = 472; recurrence rate, 54.2%), stage 4 CKD (n = 614; 59.4%), HF concurrent with stage 3 or 4 CKD (n = 861; 56.3%), and patients using RAASi during baseline (n = 681; 53.9%).13 In a similar retrospective cohort study of US veterans (n = 1,493,539), at least 1 hyperkalemia recurrence occurred in 15.7% of patients in the year after an index event.14 Among US-based patients with HF in the multinational, noninterventional Cardiovascular and Renal Treatment in Heart Failure Patients with Hyperkalemia or at High Risk of Hyperkalemia (CARE-HK) registry (n = 832), the proportion of patients who experienced 2 or more hyperkalemia events was 19.6% (n = 163).15
Identified risk factors for hyperkalemia recurrence include, but are not limited to, race and ethnicity,14liver disease,CKD, HF, cancer, rheumatologic disease, and more.16Complementary findings from a population-based analysis of English EHR data support particularly high risk of hyperkalemia recurrence among patients with comorbid diabetes, CKD, HF, or hypertension; patients using mineralocorticoid receptor antagonists (MRAs), angiotensin-converting enzyme inhibitors (ACEis), or angiotensin II receptor blocker (ARBs) at the time of an index episode of hyperkalemia; and patients whose serum K+ levels exceeded 6.0 mmol/L during an index hyperkalemia episode.17Collectively, these data support that hyperkalemia recurrence is common and that the condition has a propensity to become a chronic disease requiring ongoing management in combination with lifestyle modifications. In guidance issued from a panel of 9 European interdisciplinary experts in hyperkalemia (GUARDIAN-HK European Steering Committee), panelists identified that the majority of these most common hyperkalemia risk factors should be considered nonreversible, and they advised exploring alternative K+ management strategies before altering the dose of therapies that are considered disease modifying for these comorbidities.18
Real-World Health Outcomes Due to Hyperkalemia
Relative to patients with normokalemia, the impact of hyperkalemia on patients’ overall health may be substantial. At least 2 real-world outcomes studies have detailed the clinical impact of hyperkalemia among patients with CKD.19,20 REVOLUTIONIZE II retrospectively analyzed matched patient cohorts who had stage 3b/4 CKD and hyperkalemia or normokalemia.19 REVOLUTIONIZE III was similar, analyzing matched patient cohorts with stage 3/4 CKD and recurrent hyperkalemia or normokalemia.20
In REVOLUTIONIZE II, patients with hyperkalemia experienced a 32% (95% CI, 23%-40%; P < .001) higher risk of the primary study end point, major adverse cardiovascular events plus (MACE+; defined as all-cause mortality along with nonfatal myocardial infarction, stroke, or hospitalized HF) than matched patients with normokalemia.19 The risk of other adverse outcomes was similarly elevated in patients with hyperkalemia vs patients with normokalemia, including hospitalized arrhythmia (59%; 95% CI, 44%-77%; P < .001) and hospitalized HF (69%; 95% CI, 53%-86%; P < .001).19 Extending and expanding those results, REVOLUTIONIZE III found that the risk of MACE+ in the overall sample of patients with recurrent hyperkalemia was approximately 53% higher than in matched patients with normokalemia (HR, 1.53; 95% CI, 1.43-1.65; P < .001).20 Additionally, patients with recurrent hyperkalemia exhibited a 29% elevated risk of all-cause mortality (HR, 1.29; 95% CI, 1.20-1.38; P < .001), a 94% elevated risk of hospitalized arrhythmia (HR, 1.94; 95% CI, 1.74-2.16; P < .001), and a 72% elevated risk of RAASi discontinuation (HR, 1.72; 95% CI, 1.59-1.85; P < .001).20 Taken together, these data illustrate the clinically meaningful health risks associated with hyperkalemia and recurrent episodes thereof in patients with CKD.
Hyperkalemia is also a health risk for patients with HF. The previously mentioned CARE-HK registry collects data on the clinical characteristics, longitudinal health, and outcomes of patients with HF with active or elevated risk for hyperkalemia who are being treated with RAASi (eg, ACEi, ARB, or angiotensin receptor neprilysin inhibitor [ARNi]) and treated with or eligible for treatment with an MRA.15 Over a median (25th-75th percentile) follow-up period of 12.3 (9.4-18.1) months, 23.1% (n = 192) of US-based patients experienced 1 or more hyperkalemic events and the experience was associated with a 65% greater risk (HR, 1.65; 95% CI, 1.27-2.15; P < .001) of all-cause hospitalization.15 All-cause mortality risk was numerically elevated among patients with HF who experienced hyperkalemia vs those who did not, but this did not reach significance (HR, 1.25; 95% CI, 0.78-1.99; P = .34).15 Of note, patients in the CARE-HK registry were required to be treated with RAASi at enrollment,15 and RAASi use by patients with HF is associated with lower mortality.21 Among US patients in the registry, RAASi/MRA disruptions following any hyperkalemic event were uncommon, occurring in only 5.1% of patients.15 Contrastingly, others have reported RAASi/MRA discontinuation rates of 25% to 33% following a hyperkalemic event, with variation due to the medication type patients were on prior to the event.22,23 Thus, it is possible that the effects of hyperkalemia on mortality in patients with HF were masked in CARE-HK. Indeed, a 2017 analysis of EHR data predicted similar probability of mortality among patients with HF or CKD who had serum K+ values in the hyperkalemic range, and the observed unadjusted mortality rates in this analysis were slightly higher among patients with HF and hyperkalemia compared with patients with CKD and hyperkalemia.7 Coupled with the well-established risk of lethal cardiac arrhythmias due to hyperkalemia,4 the data emphasize the complications hyperkalemia may pose to patients with HF.
Real-World Economic Impact of Hyperkalemia
In addition to its potentially substantial impacts on the general health and well-being of patients with CKD and/or HF, hyperkalemia carries a considerable health economic burden. Based on a matched cohort analysis using data from a 5% random sample of Medicare claims, patients with hyperkalemia incurred significantly higher 1-year all-cause total medical costs than patients without hyperkalemia ($34,362 vs $15,013),11 and results were consistent across patient subgroups. For patients with CKD (n = 26,809 pairs), mean costs were $37,202 vs $17,445; for patients with HF (n = 25,603 pairs), mean costs were $49,244 vs $23,936; and for patients with CKD and/or HF (n = 41,271 pairs), mean costs were $41,416 vs $19,839 (all 2016 US$; P < .001 for all).11 In another study, investigators examined health care resource utilization (HCRU) and medical economic burden between patient subgroups with stage 3/4 CKD and normokalemia, nonrecurrent hyperkalemia, or recurrent hyperkalemia.3 Over 12 months of follow-up, the proportion of patients with recurrent hyperkalemia and any HCRU was 93.5% vs 73.0% for patients with normokalemia; mean 12-month all-cause medical costs, respectively, totaled $34,163 and $15,175 (2022 US$), collectively representing the greatest differences.
As shown in
RAASi Therapy Interaction
The 2024 Clinical Practice Guideline for the Evaluation and Management of CKD (KDIGO Guideline) recommends that health care providers prescribe the highest approved dose of RAASi (ACEi or ARB) that the patient can tolerate to achieve therapeutic benefits, including decreased risk of mortality, cardiovascular events, and progression to kidney failure.2,24 They further suggest providers prescribe a nonsteroidal MRA to patients with CKD and type 2 diabetes (T2D) who are at high risk of CKD progression or cardiovascular events, noting that this class of medication can be added to RAASi and a sodium-glucose cotransporter 2 inhibitor (SGLT2i).2 Finerenone is currently the only nonsteroidal MRA approved in the US and is indicated in adult patients with CKD associated with T2D to reduce the risk of sustained estimated glomerular filtration rate decline, end-stage kidney disease (ESKD), cardiovascular death, nonfatal myocardial infarction, and hospitalization for HF.25 Spironolactone, a steroidal MRA, may also be of benefit to patients with CKD, with clinical studies having shown its association with reduced proteinuria and blood pressure when added to a conventional regimen of ACEi and/or ARB in patients with and without diabetes.26,27
Similar to the KDIGO Guideline, the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America (AHA/ACC/HFSA) Guideline for the Management of Heart Failure considers RAASi (including ACEi, ARNi, and ARBs) foundational treatments for HF. They are strongly recommended for patients with HF with reduced ejection fraction (HFrEF) and considered reasonable or potentially reasonable in patients with mildly reduced or preserved EF (HFmrEF and HFpEF, respectively) to reduce the risk of mortality and hospitalization for HF.8,24 Steroidal MRAs like spironolactone are also a recommended addition to the treatment regimens of patients with HFrEF,2,8 because they are associated with lower risk of all-cause mortality, HF hospitalization, and sudden cardiac death.8 Likewise, finerenone has a second indication to reduce the risk of cardiovascular death, hospitalization for HF, and urgent HF visits in adult patients with HF and left ventricular EF of 40% or greater.25 A recently published consensus statement supports rapid initiation of finerenone in patients with HF, either concomitantly or in rapid sequence with RAASi and SGLT2is.28
Despite these recommendations, hyperkalemia may result from using RAASi and steroidal or nonsteroidal MRAs,2,8,25-27 compromising optimal treatment rates and adherence and limiting the cardiorenal benefits associated with these therapies.8,26,27 According to the results of a 2017 retrospective analysis of medical and pharmacy claims data for separate and combined cohorts of patients with CKD and/or HF, fewer than half of patients in the exclusive and combined disease cohorts were being treated with RAASi at the time of enrollment. Most of those who were being treated were on a suboptimal dose, and this effect was more pronounced among patients with hyperkalemia. Key results from this analysis are available in
Both the KDIGO Guideline for patients with CKD and the AHA/ACC/HFSA joint guideline for patients with HF advise against RAASi discontinuation to manage hyperkalemia, instead noting that hyperkalemia associated with RAASi use can often be managed through other approaches.2,8 Regardless, real-world evidence from patients with CKD and/or HF who experienced a hyperkalemia event showed that 25% to 33% of US patients discontinued RAASi treatment, either temporarily or long term. MRAs were discontinued at the highest rate (33%, n = 800), followed by ACEis (26%, n = 1721), and ARBs (25%, n = 955).22 The consequences ofRAASi discontinuation may be severe, because patients immediately lose any potential therapeutic benefits; and RAASi reinitiation rates are low, with only 10% to 15% of US patients returning to treatment within 6 months of a discontinuation based on data from the same real-world outcomes study.22 According to a systematic review and meta-analysis, RAASi discontinuation in patients with CKD is associated with higher risk of all-cause mortality (HR, 1.42; 95% CI, 1.23-1.63; P < .001) and elevated risk of cardiovascular events (HR, 1.25; 95% CI, 1.17-1.32; P < .001).30 Supportive evidence from a separate real-world evidence study of patients with CKD and/or HF indicated that patients who discontinued RAASi after an episode of hyperkalemia had an elevated risk of cardiorenal outcomes (defined as HF hospitalization, emergency visit due to HF, or progression to ESKD).23 At 6 months, the risk in patients who discontinued RAASi was 17.5% (95% CI, 16.1%-18.8%) vs 10.6% (95% CI, 9.8%-11.4%) in patients who maintained their RAASi dose or were up-titrated (P < .001).23
The consequences of RAASi dose reduction are similar to those of full discontinuation. In the first of the previously mentioned real-world evidence studies among patients with CKD and/or HF, a sizable proportion (23%-30%) of the patient cohort who reinitiated RAASi after a prior discontinuation did so at a dose more than 25% lower than their prior dose before the hyperkalemia episode.22 At 6 months after an episode of hyperkalemia, the risk of cardiorenal outcomes among patients whose RAASi dose was down-titrated was 18.2% (95% CI, 15.1%-21.3%), similar to that in patients who discontinued RAASi and significantly higher than in patients on a maintained or up-titrated RAASi dose following a hyperkalemic event (P < .001).23 Specific to patients with HF, the propensity to down-titrate RAASi in response to hyperkalemia appears substantially lower based on results from the CARE-HK in HF registry. Within 30 days of any hyperkalemic event, only 0.7% (n = 2) of US patients in this registry were being treated with a down-titrated RAASi dose.15 However, 79% (n = 657) of patients in this study were maintained on a suboptimal RAASi dose regimen both during the 24-month retrospective baseline and the prospective follow-up,15 perhaps suggesting that providers had limited ability to lower medication doses rather than discontinue treatment. Recall that the clinical outcomes from the CARE-HK in HF registry study indicated a significantly higher risk of all-cause hospitalization among patients who experienced 1 or more hyperkalemic episodes compared with patients who experienced no hyperkalemic episodes.15 Coupled with data supporting high rates of suboptimal RAASi dosing and the real-world evidence from patients with CKD and/or HF, these data suggest that RAASi dose reductions are associated with adverse outcomes similar to those observed with RAASi discontinuation.
Recognizing the clinical complexity of recurrent hyperkalemia, the GUARDIAN-HK European Steering Committee recently convened to develop consensus recommendations for its prevention and management. The panel recommends that chronic conditions such as CKD, HF, and T2D, along with the RAASi therapies these patients require, should be considered nonreversible risk factors for recurrence and that every acute hyperkalemic episode should be viewed as an opportunity to optimize RAASi therapy rather than reduce it. The panel advises proactive initiation of K+ binders to maintain patients on guideline-directed RAASi doses, with the expectation that K+-lowering treatment will be required indefinitely in patients with nonreversible risk factors.18
Current and Emerging Treatment Options
To promote better clinical outcomes among patients with hyperkalemia and, ostensibly, to enable RAASi use among patients with hyperkalemia-associated comorbidities such as CKD and/or HF, management strategies must extend beyond acute correction to address the risk of recurrence. Acute interventions that might be used to temporarily stabilize patients presenting to an emergency department include intravenous calcium salts, insulin, b-adrenergic agonists, and sodium bicarbonate.4 However, these approaches fail to address the underlying cause of hyperkalemia, because they do not remove excess K+ from the body. As evident from REVOLUTIONIZE I data,13 hyperkalemia commonly recurs, necessitating strategies that promote K+ excretion or removal. Loop diuretics, K+ binders, and dialysis are the only means for this, with loop diuretics being a common acute treatment, particularly for patients with volume overload.4 However, the renal K+ excretion effect of K+-wasting diuretics may dissipate with chronic use.9
The KDIGO Guideline describes a tiered approach for overall hyperkalemia management in patients with CKD,2 reflecting the need for durable K+ control. Initial recommended interventions aim to address modifiable contributors to bodily K+ levels through reducing dietary K+ intake and adjusting non-RAASi medications,2 but the evidence supporting these as preventive or avoidant approaches is limited.12 As a result, second-line pharmacologic intervention with diuretics and K+ binders may be necessary.2 Among pharmaceutical interventions, K+ binders represent a key strategy for sustained K+ removal. Three agents—patiromer, sodium zirconium cyclosilicate (SZC), and sodium polystyrene sulfonate (SPS)—are currently available and recommended by the KDIGO Guideline for patients with CKD.2 They differ by therapeutic mechanism, onset of K+ lowering effects, and safety profile.
Guideline recommendations for patients with HF consider only patiromer or SZC as potentially reasonable, and the guidance highlights that these therapies’ FDA approvals include an indication for patients receiving RAASi.8 Although SPS was the first K+ binder approved for the treatment of hyperkalemia and has been used for decades,34 it is not supported by robust randomized clinical trial data.42 Moreover, in 2009, the FDA required the addition of a warning on the SPS product label that serious, often fatal gastrointestinal (GI) injury has been associated with use of this medication in its premixed suspension formulation containing 70% sorbitol; persistent case reports of GI injury associated with SPS as a solo agent have also been noted.43 Accordingly, its prescription has fallen out of favor.44
As one of the only means to remove excess K+ from the body,4 K+ binders play a central role in the long-term management of hyperkalemia. Within this medication class, SZC reduces K+ levels the fastest and can restore patients to normokalemia within 24 to 48 hours.2
Clinical Evidence Review of K+ Binders
Sodium Zirconium Cyclosilicate
The KDIGO Guideline for patients with CKD recommends SZC for the management of hyperkalemia, and the ACC/AHA/HFSA joint guideline for patients with HF considers its effectiveness unknown.2,8 Its mechanism of action involves capturing K+ ions in exchange for hydrogen and sodium ions, enabling fecal excretion of excess K+.38 The safety and efficacy of SZC have been evaluated across 3 pivotal trials: a randomized, placebo-controlled phase 3 trial (study 1; NCT01737697),39 a randomized, placebo-controlled phase 3 trial with an open-label correction phase (study 2; NCT02088073),35 and a long-term open-label, single-arm study (study 3; NCT02163499).45 Together, these trials established the safety and efficacy of SZC across a broad range of patients with hyperkalemia. Disease-specific efficacy in patients with HFrEF was subsequently evaluated in the REALIZE-K trial (NCT04676646),46 and efficacy among patients on dialysis was the subject of the DIALIZE trial (NCT03303521).32
Within study 1 (n = 753; mean baseline serum K+, 5.3 mmol/L) and study 2 (n = 258; mean baseline serum K+, 5.6 mmol/L), SZC consistently reduced serum K+ to normokalemic levels during a 48-hour initial treatment phase. In study 1, absolute mean reductions in serum K+ at 48 hours were 0.46 mmol/L (95% CI, −0.53 to −0.39 mmol/L), 0.54 mmol/L (95% CI, −0.62 to −0.47 mmol/L), and 0.73 mmol/L (95% CI, −0.82 to −0.65 mmol/L) for the doses 2.5 g, 5 g, and 10 g, respectively, vs 0.25 mmol/L (95% CI, −0.32 to −0.19 mmol/L) for placebo (P < .001 for all comparisons vs placebo).39 In study 2, mean serum K+ level fell from baseline hyperkalemia to a normokalemic level of 4.6 mmol/L following treatment with 10 g of SZC given 3 times daily.35,38
Both trials then entered a maintenance phase during which SZC demonstrated a sustained ability to maintain normal K+ levels. In study 1, the 5- and 10-g once-daily doses were superior to placebo over 12 days (P = .008 and P < .001, respectively), and patients who switched from SZC to placebo experienced recurrences of hyperkalemia.39 In the monthlong maintenance phase of study 2, significantly greater proportions of patients receiving 5, 10, and 15 g of SZC once daily maintained normal serum K+ levels (80%, 90%, and 94%, respectively) compared with placebo (46%; P < .001 for each dose vs placebo).35,38
An 11-month open-label extension of study 2 supports durable K+ control with ongoing SZC treatment. The unadjusted proportion of SZC-treated patients who achieved serum K+ levels less than or equal to 5.1 mmol/L was 88.3% (95% CI, 81.2%–93.5% [P < .001] vs the expected 50%).47 Additionally, the study 2 open-label extension included 78.3% of patients who remained on a stable RAASi dose, 8.4% who increased their RAASi dose, 3.6% who added another RAASi medication, 2.4% who switched RAASi, and 3.6% who discontinued RAASi.47 The durability of K+ control associated with SZC was further confirmed in study 3 (n = 746), in which, over 12 months of long-term follow-up, 88% of patients achieved a mean serum K+ level less than or equal to 5.1 mmol/L, 99% achieved less than or equal to 5.5 mmol/L, and 99% maintained K+ levels within the normal range (3.5-5.5 mmol/L).45 A prespecified exploratory analysis additionally found that among patients on RAASi at enrollment (n = 483), 74% maintained their RAASi dose, 13% were able to increase their dose, 14% required a dose reduction, and 11% discontinued RAASi. Among patients not on RAASi at enrollment (n = 263), 14% initiated this medication class while receiving SZC.45
In patients with HFrEF, the REALIZE-K trial demonstrated that a significantly higher proportion of patients receiving SZC achieved the composite primary end point—defined as maintaining normal K+ levels while continuing spironolactone at 25 mg/day or higher without rescue therapy for hyperkalemia—compared with placebo (71.2% vs 35.7%; odds ratio [OR], 4.45; 95% CI, 2.89-6.86; P < .001).46 This finding suggests SZC may support adherence to guideline-directed MRA therapy in patients with HFrEF. In patients on dialysis, a greater proportion of those treated with SZC than treated with placebo maintained normokalemia in between dialysis sessions (41.2% vs 1.0%; OR, 68.8; 95% CI, 10.9-2810.9; P < .001); similarly, throughout the study evaluation period, the mean predialysis serum K+ level was lower in patients treated with SZC than in patients treated with placebo,32 demonstrating efficacy in patients with severe renal dysfunction.
SZC was generally well tolerated across clinical trials. Edema was the most commonly reported adverse event (AE) in placebo-controlled trials, occurring in 4.4%, 5.9%, and 16.1% of patients receiving 5, 10, and 15 g of SZC, respectively, compared with 2.4% for placebo. Edema was most often mild to moderate in severity; however, prescribers are advised to monitor for this reaction, particularly in patients with HF or renal disease who require sodium restriction. Dietary modifications or diuretic use may help mitigate edema risk in appropriate patients. Additional AEs included GI discomfort, constipation (observed primarily in patients of Asian descent), and hypokalemia, all of which were generally manageable with dose adjustment or discontinuation.38
Patiromer
Patiromer is also recommended by the KDIGO Guideline for the management of hyperkalemia in patients with CKD,2 and its effectiveness in patients with HF is considered unknown according to the AHA/ACA/HFSA joint guideline.8 It is indicated to treat hyperkalemia in adults and pediatric patients aged at least 12 years.40 Like SZC, patiromer increases fecal K+ excretion, but as a calcium-K+ exchange polymer instead of SZC’s sodium/hydrogen ion exchange mechanism.38,40 Clinical trials investigating the safety and efficacy of patiromer in various populations include the phase 2 trials PEARL-HF (NCT00868439),48 AMETHYST-DN (NCT01371747),49 and EMERALD (NCT03087058)50 and the phase 3 trials OPAL-HK (NCT01810939)41 and DIAMOND (NCT03888066).51 Across these studies, patiromer consistently demonstrated clinically meaningful reductions in serum K+ concentrations, with treatment effects observed as early as 48 hours and sustained with continued therapy.41,49 In addition to lowering K+, patients who maintained patiromer therapy experienced reduced risk of hyperkalemic events and maintained normokalemia over both short- and long-term follow-up, while discontinuation was associated with increases in serum K+ levels.41,49,51 These effects translated into clinically relevant benefits, including enabling continuation and optimization of RAASi therapy and reducing the need for dose reduction or discontinuation due to hyperkalemia.48,51 Consistent efficacy was observed across diverse patient populations, including pediatric patients aged 12 to 17 years.40 Evidence for a K+-lowering effect of patiromer in patients receiving dialysis is limited in clinical trials, although its efficacy in this population has been documented in a real-world, retrospective study of EHR data.36
Regarding safety, the main AEs experienced by adults in the safety and efficacy clinical trials (n = 666) were constipation (7.2%), hypomagnesemia (5.3%), diarrhea (4.8%), nausea (2.3%), abdominal discomfort (2.0%), and flatulence (2.0%). Pediatric patients demonstrated a similar AE experience.40
Patiromer and SZC have been deemed safe and effective to treat hyperkalemia in adults.38,40 However, randomized, controlled comparative effectiveness studies have not yet been conducted. As described in the KDIGO Guideline, SZC may lower K+ levels more rapidly than patiromer, and recommendations suggest SZC may be administered within 2 hours of other oral medications, whereas those for patiromer suggest at least 3 hours separation.2 The approved dosing schedule for SZC allows more flexibility in the acute stage of hyperkalemia management than patiromer,38,40 and the safety information for each medication details the possibility of GI AEs.2,38,40 Edema is an additional AE that has been associated with SZC, and higher doses were associated with greater prevalence of edema in clinical trials.38 Thus, the choice between these agents depends on patient-specific factors including age, severity of hyperkalemia, concomitant medications, insurance coverage, and comorbidities.
Sodium Polystyrene Sulfonate
As the oldest of the K+ binders recommended by KDIGO,2 SPS, indicated for the treatment of hyperkalemia, is in a different position regarding its supporting safety and efficacy data, because it was initially approved in 1958 before modern FDA requirements for controlled clinical trials were introduced to support drug safety and efficacy.34,37 One such trial was conducted in 2015 among outpatients with mild hyperkalemia and CKD (n = 33).37 The results of this single-center randomized controlled trial, obtained after an average of 6.9 days, showed that patients treated with SPS exhibited a mean (SD) decrease of 1.25 (0.56) mmol/L from baseline serum K+ levels (5.26 [0.22] mmol/L); among patients treated with placebo, the mean (SD) decrease from baseline (5.23 [0.22] mmol/L) was 0.21 (0.29) mmol/L, a between-group difference of –1.04 mmol/L (95% CI, –1.37 to –0.71 mmol/L; P < .001).37 Nausea, vomiting, constipation, and diarrhea were all reported as AEs, but without significant differences between patients randomly assigned to the SPS or placebo arms.37
Notably, the KDIGO Guideline comparative chart of K+ binders highlights that SPS has been associated with potentially serious GI events including intestinal necrosis, bleeding, ischemia, colitis, and perforation.2 Indeed, the SPS prescribing information carries a warning for potentially fatal intestinal necrosis, particularly in its premixed formulation containing 70% sorbitol.34 Accordingly, the newer agents, SZC and patiromer, may be more favorable, because they appear safe long term and may facilitate the use of RAASi
and/or MRAs.2
Real World Evidence From Patients Taking K+ Binders
Sodium Zirconium Cyclosilicate
Three studies—RECOGNIZE II, GALVANIZE, and OPTIMIZE I—offer complementary real-world evidence detailing clinical and economic outcomes among diverse cardiorenal patient populations with hyperkalemia who have been treated with SZC for variable durations.
The RECOGNIZE II study evaluated the economic impact of long-term outpatient SZC use compared with no SZC use.52 Overall hyperkalemia-related medical costs were 49.5% lower among patients receiving SZC compared with those who were not ($3798 vs $7527; mean reduction, $3728; 95% CI, $1840-$5617). This effect was primarily a result of 57.2% reduced inpatient costs ($2476 vs $5785; mean reduction, $3309; 95% CI, $1606-$5013), while costs for ED and outpatient visits were similar between groups.52 All-cause medical and pharmacy costs were also reduced by 21.0% among SZC users compared with patients not using SZC, with significant differences observed for overall ($20,722 vs $26,214; mean reduction, $5492; 95% CI, $541-$9444; P < .01) and inpatient ($6201 vs $11,716; mean reduction, $5516; 95% CI, $2919-$8113; P < .001) cost categories.52 Together, these real-world findings suggest that sustained SZC use may be associated with meaningful reductions in health care utilization and costs among patients with hyperkalemia, particularly those with underlying cardiorenal disease.
Complementing these cost data, the GALVANIZE study assessed real-world HCRU among patients with hyperkalemia, stratified by duration of SZC therapy.53 Patients were categorized as short-term SZC users (≤ 30 days of therapy) or long-term users (> 90 days),53 with analyses conducted on matched patient cohorts with cardiorenal dysfunction (defined as CKD, ESKD, or HF) plus a subgroup analysis specific to patients with HF.53 Results of these analyses are presented in
Whereas GALVANIZE and RECOGNIZE II compared their utilization and cost data between patient groups who had used SZC for various durations, the OPTIMIZE I study was a retrospective, observational, noncomparative study that characterized real-world patterns of RAASi optimization after patients began taking SZC.54 The study included patients (n = 589) who began taking SZC while on RAASi, and it described RAASi modifications thereafter.54 After initiating SZC, most (77.4%; n = 456) patients were able to optimize their RAASi dose, including 69.6% (n = 410) who maintained the same dose and 7.8% (n = 46) who up-titrated.54 Conversely, only 17.3% (n = 102) discontinued RAASi, and even fewer (5.3%; n = 31) down-titrated their dose after beginning SZC.54 With the understanding that RAASi are recommended by both the KDIGO Guideline for patients with CKD and the joint guideline for patients with HF,2,8 these data that support RAASi optimization through initiating SZC indicate the potential benefit of this K+ binder for patients whose comorbidities call for therapy that would otherwise increase their risk of hyperkalemia.
Patiromer
Similar patterns have been observed in real-world studies evaluating patiromer, which have consistently demonstrated reductions in HCRU and overall medical costs despite increased pharmacy expenditures associated with K+ binder therapy. In a retrospective analysis comparing longer-term vs shorter-term patiromer exposure, longer-term use was associated with significantly lower mean medical costs ($42,000 vs $54,311; difference, −$12,311; P < .0001), driven largely by reductions in inpatient and ESKD-related services, while prescription costs were modestly higher among longer-term users. These findings were accompanied by modest reductions in total medical encounters, including fewer inpatient admissions (4 vs 6 admissions; P < .0001) and fewer ESKD service encounters (1.5 vs 2.9 encounters; P < .0001), suggesting decreased high-cost HCRU with sustained patiromer therapy.55
Consistent with these findings, another matched-cohort analysis comparing patiromer exposure with no K+ binder reported lower rates of inpatient admission or ED encounters at 6 months among patients treated with patiromer (25% vs 37%; OR, 0.58; 95% CI, 0.38-0.89), as well as a 19% lower total health care spending rate (spending rate ratio [SRR], 0.81; 95% CI, 0.67-0.98). Among patients with prior inpatient or ED utilization, relative reductions in total health care spending were even greater (SRR, 0.66; 95% CI, 0.47-0.92), with cost savings primarily driven by reductions in outpatient medical service expenditures despite higher pharmacy costs.56
Additional real-world evidence comparing K+ binder strategies demonstrated that patients continuously exposed to patiromer experienced reductions in hospitalizations and ED visits over 6 months, whereas patients not receiving a K+ binder had increased utilization during the same period. Continuous patiromer exposure was also associated with a greater proportion of patients remaining on RAASi(78%; 95% CI, 61%-90%) compared with patients not receiving a K+ binder (≈ 56%), supporting the role of K+ binders in facilitating continuation of guideline-recommended cardiorenal therapies.57
Collectively, these real-world analyses suggest that K+ binder therapy, including both SZC and patiromer, may reduce hyperkalemia-related HCRU, lower total medical costs driven primarily by reductions in inpatient care, and support continuation of RAASi across patients with cardiorenal comorbidities while increasing pharmacy expenditures associated with chronic K+-lowering treatment.
Implications for Managed Care Decision Makers
From a managed care perspective, hyperkalemia is a meaningful driver of health care utilization and the total cost of care, particularly among patients with stage 3/4 CKD and HF. Real-world analyses demonstrate that recurrent hyperkalemia in this population is associated with substantially greater health care resource utilization and medical economic burden compared with normokalemia or nonrecurrent hyperkalemia.3 These findings suggest that proactive hyperkalemia control may present opportunities to reduce downstream costs, especially those related to inpatient admissions and acute care use.
Hyperkalemia also has important implications for the use of RAASi, which are foundational therapies for both HF and CKD. Dose reductions compromise the established cardiorenal benefits of these therapies,8 and the data presented herein clarified the similar risks of both RAASi discontinuation or down-titration.15,30
Reflecting this evidence, treatment and management guidelines for both CKD and HF recommend against RAASi dose reduction or discontinuation, except in extenuating circumstances,2,8 and the guidelines for patients with CKD further suggest that RAASi should be restarted following clinical stabilization.2 K+ binders provide a mechanism to excrete excess K+, offering a strategy to manage hyperkalemia while maintaining RAASi and potentially preventing costly HF and/or CKD exacerbations. In OPTIMIZE II, patients who continued RAASi with concurrent SZC experienced significantly lower 3-month hyperkalemia-related costs compared with patients who discontinued RAASi and were not treated with SZC (mean [SD] 2021 US$, $2259 [$13,740] vs $4475 [$13,828]; mean difference, $2217; P < .01). Results were similar for 3-month all-cause medical costs (mean [SD] 2021 US$, $8051 [$20,168] vs $14,154 [$29,826]; mean difference, $6102; P < .001).58 Additionally, longer duration of SZC therapy has been associated with higher rates of RAASi continuation among US patients with HF and/or CKD.59 Together, these data highlight the potential value of sustained hyperkalemia management strategies in supporting guideline-directed therapy, reducing rehospitalization risk, and optimizing the total cost of care in cardiorenal populations.
Conclusions
Hyperkalemia is a common and recurrent electrolyte complication, with prevalence and recurrence increasing as renal function declines.2,8 Recurrent hyperkalemia is clinically consequential, conferring higher risks of mortality, cardiovascular events, and cardiac arrhythmias while also driving substantial increases in health care utilization and total medical costs.3,20 Interruptions in RAASi therapy remain a critical concern, as both dose reduction and discontinuation undermine cardiorenal protection and worsen long-term outcomes.8,23 Current guidelines emphasize proactive hyperkalemia management, prioritizing only the most feasible lifestyle modifications, medication optimization, and early use of K+ binders, which may allow select patients to maintain RAASi therapy whenever possible.2,9 Real-world evidence supports the use of sustained, long-term K+ control strategies, which can reduce hyperkalemia-related events, support RAASi continuation, and lower the total cost of care for managed populations with CKD and HF,53,58 representing an opportunity to improve clinical outcomes across patient populations.
Authorship Affiliation: Department of Medicine, University of Illinois at Chicago (EL), Chicago, IL; University of Kentucky College of Pharmacy (CJB), Lexington, KY.
Source of Funding: This supplement was supported by AstraZeneca.
Author Disclosures: Dr Lerma reports consultancies or paid advisory boards at the invitation of Boehringer Ingleheim, OPKO, Otsuka, Travere, Vera Therapeutics, and Vertex Pharmaceuticals. He further reports receipt of honoraria from Boehringer Ingelheim, OPKO, Otsuka, Travere, Vera Therapeutics, and Vertex Pharmaceuticals; lecture fees for speaking at the invitation of OPKO, Otsuka, Travere, and Vertex Pharmaceuticals; meeting/conference attendance on behalf of Travere, Vera Therapeutics, and Vertex Pharmaceuticals; and receipt of royalties from Elsevier, McGraw Hill, Springer, and Wolters Kluwer.
Authorship Information: Concept and design (EL); drafting of the manuscript (EL, CJB); critical revision of the manuscript for important intellectual content (EL, CJB); supervision (EL, CJB).
Address Correspondence To: Edgar Lerma, MD. 335 Selborne Rd, Riverside, IL 60546. Email: nephron0@gmail.com
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