Sodium Zirconium Cyclosilicate in the Therapeutic Management of Hyperkalemia: A Systematic Review of Efficacy and Safety

Abstract

Objective: The objective of this study is to evaluate the efficacy and safety of sodium zirconium cyclosilicate in the treatment of hyperkalemia in adult patients based on the available scientific evidence. Methods: A systematic review of randomized controlled trials evaluating SZC in adult patients with hyperkalemia was conducted, including populations with chronic kidney disease and heart failure and patients undergoing hemodialysis. Outcomes assessed included serum potassium reduction, achievement and maintenance of normokalaemia, and adverse events. Results: Seven randomized controlled trials were included. SZC produced a rapid and significant reduction in serum potassium, with reductions of up to 1.28 mmol/L within 48 h and onset of action observed as early as 1–4 h. Across studies, 63–92% of patients achieved normokalaemia within 24–48 h, and maintenance therapy sustained normokalaemia for up to 28 days and longer in selected populations. The most frequently reported adverse events were mild-to-moderate edema and constipation, while hypokalemia was infrequent (<5% in most studies). Conclusions: Sodium zirconium cyclosilicate is an effective and generally well-tolerated option for the management of hyperkalemia, providing rapid potassium reduction and sustained normokalaemia. However, no randomized controlled trial included in this review demonstrated a significant benefit of SZC over comparators in major clinical outcomes—hospitalizations, cardiovascular events, or mortality; the evidence of clinical benefit is therefore absent from the current randomized trial literature.

1. Introduction

Hyperkalemia is a disturbance in blood potassium levels, characterized by a serum concentration above 5.0 mEq/L. Although this value is generally accepted for diagnosis, some guidelines and studies prefer a threshold of 5.5 mEq/L to define the condition [1,2]. It can be classified into three grades according to the electrolyte concentration in blood as follows: mild (5.5 to 6.4 mmol/L), moderate (6.5 to 8.0 mmol/L), and severe (greater than 8.0 mmol/L) [3].

The outcome of hyperkalemia may be associated with a variety of factors; one of the most common is decreased renal excretion because, as the glomerular filtration rate (GFR) declines, the kidney’s capacity to excrete potassium becomes limited. For this reason, chronic kidney disease (CKD) is a significant risk factor for hyperkalemia, particularly when GFR is <60 mL/min/1.73 m² [4,5,6].

Antihypertensive medications such as angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), and potassium-sparing diuretics can increase serum potassium levels by interfering with the renin–angiotensin–aldosterone system, thereby reducing renal potassium excretion [7]. In addition, conditions such as diabetes mellitus and adrenal disorders affect potassium homeostasis, increasing the risk of hyperkalemia [4].

To a lesser extent, increased potassium intake may also contribute, especially to individuals with impaired renal function. Moreover, transcellular factors, such as changes in potassium distribution between the intracellular and extracellular compartments, can promote hyperkalemia. This phenomenon is common in situations such as metabolic acidosis, which disrupts normal potassium balance [1].

Untreated hyperkalemia, particularly in patients with renal dysfunction, significantly increases the risk of death due to the cardiac arrhythmias it may precipitate, in addition to altering cardiac excitability. It is also associated with complications such as peripheral neuropathy and renal tubular acidosis, underscoring the clinical relevance of appropriate management of this condition, particularly in vulnerable populations such as those with renal or cardiovascular diseases [4].

To prevent these complications, therapeutic options for hyperkalemia include potassium-binding agents, among which are sodium zirconium cyclosilicate (SZC), sodium polystyrene sulfonate (SPS), calcium polystyrene sulfonate (CPS), and patiromer. These compounds act mainly by promoting potassium elimination through the gastrointestinal tract [6,7,8].

Although SPS is effective for short-term potassium reduction, it is associated with severe gastrointestinal adverse effects, such as intestinal necrosis, which limits its long-term use [8]. Conversely, CPS helps maintain potassium levels in patients taking renin–angiotensin–aldosterone system inhibitors. It is likewise associated with gastrointestinal adverse effects, but these effects are usually less pronounced [9].

Patiromer lowers potassium levels and may reduce mortality in patients with CKD and hyperkalemia. Although it has adverse gastrointestinal effects, it allows continuation of ACEI therapy without the need for dietary potassium restrictions [9,10]. In turn, SZC acts rapidly, beginning to reduce serum potassium levels in less than one hour and generally achieving normokalaemia within 24 to 48 h [6,8,11].

SZC is well tolerated by patients and is associated with milder gastrointestinal adverse effects than SPS, although it may cause edema. This treatment is considered a promising option for the long-term management of hyperkalemia, especially when used in conjunction with ACEIs [6,8,11].

However, the available evidence on the safety and efficacy of potassium binders such as SZC and patiromer is predominantly based on clinical trials designed to evaluate biochemical outcomes, mainly reductions in serum potassium concentration and maintenance of normokalaemia. In this context, most studies have not been designed to directly assess high-impact clinical outcomes such as reductions in hospitalizations, the need for acute interventions (including emergency dialysis or rescue therapies), or mortality, which limits interpretation of the long-term clinical impact of these treatments [9].

Accordingly, the present systematic review aims to provide a comprehensive evaluation of SZC efficacy in terms of the magnitude and speed of serum potassium reduction and the duration of its effect, together with a characterization of its safety profile, including the incidence of reported adverse events. In addition, clinically relevant outcomes such as hospitalizations, acute interventions, and mortality will be explored when available to relate changes in serum potassium concentration to their practical relevance in the treatment of hyperkalemia, particularly in patients with CKD and other comorbidities.

2. Methods

This systematic review was conducted in accordance with the PRISMA 2020 guidelines. Additional details, including the PRISMA 2020 Checklist [12] and the full search strategies for each database, are provided in the Supplementary Materials Table S1. The aim was to evaluate the safety and efficacy of sodium zirconium cyclosilicate (SZC) in the therapeutic management of hyperkalemia by compiling the most relevant and recent scientific evidence available in the selected databases. The protocol of this study is registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD420261286227).

Although patiromer and other potassium binders are described in the Introduction within a clinical context, the present review was pre-registered with SZC as the sole index intervention (PROSPERO CRD420261286227), as no head-to-head randomized controlled trial comparing SZC with patiromer was identified in the search period (2020–2025); such a comparison would constitute a separate review protocol.

2.1. Inclusion Criteria

For this systematic review, studies evaluating adult populations (≥18 years) with a diagnosis of acute or chronic hyperkalemia—operationally defined according to the threshold established in each study, generally >5.0–5.5 mEq/L—were included. Patients were considered regardless of the underlying etiology of hyperkalemia, including those with chronic kidney disease, heart failure, and diabetes mellitus.

Regarding the intervention, studies evaluating sodium zirconium cyclosilicate (SZC), administered at any dose and duration, either as monotherapy or in combination with other therapeutic strategies, were included. These studies compared SZC with placebo or with active treatments recognized for the management of hyperkalemia, such as ion-exchange resins, dialysis, diuretics, or dietary measures.

With respect to outcomes, clinical studies evaluating SZC efficacy in terms of serum potassium reduction, the time required to achieve this reduction, and, when available, the duration of the potassium-lowering effect were selected. For safety assessment, studies reporting the incidence of adverse events associated with SZC use or comparing safety outcomes against standard treatments were included. Additional clinical outcomes, such as reductions in hyperkalemia-related hospitalizations, the need for acute interventions (e.g., emergency dialysis or use of ion-exchange resins), and associated mortality, were analyzed only exploratorily in studies in which they were reported.

Finally, only randomized controlled trials evaluating the efficacy and safety of SZC were included. Only studies published in English or Spanish and corresponding to the period between 2020 and 2025 were selected.

2.2. Exclusion Criteria

Studies conducted in animals or preclinical models were excluded, as were those including pregnant women or patients with hyperkalemia secondary to transient conditions without clinical relevance. Likewise, studies lacking a valid comparison group, presenting incomplete or inaccessible data, or not permitting an adequate assessment of the outcomes of interest were excluded.

In addition, publications corresponding to letters to the editor, expert opinions, or conference abstracts without complete data were excluded. Studies with insufficient sample sizes that did not provide adequate statistical power or an appropriate statistical analysis were not considered. Publications prior to 2020 were excluded, except in the case of high-impact systematic reviews or key clinical trials related to the initial development and evaluation of sodium zirconium cyclosilicate.

2.3. Study Records

Two investigators (LHJ and JCG) independently reviewed the titles and abstracts of all references identified through the literature searches in order to select and assess the full texts of potentially eligible studies that met the inclusion criteria. Any discrepancies between the two reviewers were resolved through the involvement of a third reviewer (JMJ) until consensus was reached. In addition, a manual search of the reference lists of relevant original articles and reviews was performed.

2.4. Risk of Bias

Data extraction was performed using a pre-established table designed prior to the assessment of the selected articles. Two independent reviewers assessed the methodological quality of eligible studies. For randomized clinical trials, the Cochrane Risk of Bias Tool (RoB-2) was used, which examines seven domains related to the design, conduct, and reporting of studies. Any discrepancies between reviewers were resolved by consensus or with the involvement of a third assessor.

2.5. Eligibility Criteria

The criteria used were those described in the PRISMA Statement. The present systematic review aimed to answer the following “PICO” question: In adults with acute or chronic hyperkalemia, is the use of sodium zirconium cyclosilicate, compared with placebo or other standard treatments, effective in reducing serum potassium concentration and safe in terms of adverse events, and what evidence exists regarding its impact on major clinical outcomes such as hospitalization, need for emergency dialysis, or mortality? The PICO words were; Population (P): adult patients with acute or chronic hyperkalemia, including individuals with chronic kidney disease, heart failure, or diabetes mellitus; Intervention (I): administration of sodium zirconium cyclosilicate (SZC) at any dose and duration; Comparator (C): placebo or standard treatments for hyperkalemia, including ion-exchange resins (e.g., patiromer or sodium polystyrene sulfonate), dialysis, diuretics (potassium-sparing or non–potassium-sparing), or dietary potassium restriction; Outcomes (O): changes in serum potassium concentration, time to potassium reduction, and duration of the potassium-lowering effect; incidence of adverse events associated with SZC use; and clinically relevant outcomes such as hyperkalemia-related hospitalizations, need for emergency dialysis, and mortality, when reported.

2.6. Search Strategy

A systematic search was performed in PubMed/MEDLINE, Embase, Scopus, and ScienceDirect using MeSH terms, keywords, and Boolean operators adapted to each platform. The details can be checked on Appendix A,

Table A1. Selected databases, keywords, search strategies, and filters used in the initial article collection process.

Database	Keywords	Strategy	Filters Applied to the Database	Number of Possible Items to Select
PubMed	Sodium Zirconium Cyclosilicate, ZS-9, Lokelma, Hyperkalemia, Elevated Potassium, Potassium Disorder, Efficacy, Effectiveness, Therapeutic Use, Safety, Adverse Effects, Side Effects, Hospitalization, Acute Dialysis, Mortality	(“Sodium Zirconium Cyclosilicate”[Title/Abstract] OR “ZS-9”[Title/Abstract] OR “Lokelma”[Title/Abstract] OR “zirconium cyclosilicate”[Title/Abstract]) AND (“Hyperkalemia”[Mesh] OR “Hyperkalemia”[Title/Abstract] OR “elevated potassium”[Title/Abstract] OR “potassium disorder”[Title/Abstract] OR “hyperkalaemia”[Title/Abstract]) AND (“efficacy”[Title/Abstract] OR “effectiveness”[Title/Abstract] OR “therapeutic use”[Title/Abstract] OR “safety”[Title/Abstract] OR “adverse effects”[Title/Abstract] OR “side effects”[Title/Abstract] OR “hospitalization”[Title/Abstract] OR “dialysis”[Title/Abstract] OR “mortality”[Title/Abstract] OR “treatment outcome”[Mesh])	Meta-Analysis, Randomized Controlled Trial, Systematic Review; Publication Year 2020–2025; Language: English/Spanish	13
Embase	Sodium Zirconium Cyclosilicate, ZS-9, Lokelma, Hyperkalemia, Elevated Potassium, Efficacy, Effectiveness, Therapeutic Use, Safety, Adverse Effect, Side Effects, Hospitalization, Acute Dialysis, Mortality	(‘sodium zirconium cyclosilicate’:ti OR ‘ZS-9’:ti OR ‘Lokelma’:ti) AND (‘hyperkalemia’:ti OR ‘elevated potassium’:ti) AND (‘efficacy’:ti OR ‘effectiveness’:ti OR ‘therapeutic use’:ti OR ‘safety’:ti OR ‘adverse effect’:ti OR ‘side effects’:ti OR ‘hospitalization’:ti OR ‘acute dialysis’:ti OR ‘mortality’:ti)	Systematic Review, Meta-Analysis, Randomized Controlled Trial; Language: English/Spanish; Year 2020–2025	6
Science Direct	Sodium Zirconium Cyclosilicate, ZS-9, Lokelma, Hyperkalemia, Elevated Potassium, Potassium Disorder, Efficacy, Therapeutic Use, Safety, Adverse Effects, Side Effects, Hospitalization, Acute Dialysis, Mortality	(“Sodium Zirconium Cyclosilicate” OR “ZS-9” OR “Lokelma”)AND (“Hyperkalemia” OR “Elevated Potassium”) AND (“Efficacy” OR “Safety” OR “Mortality”)	Systematic Review, RCT; Language: English/Spanish; Year 2020–2025	2
Scopus	Sodium Zirconium Cyclosilicate, ZS-9, Lokelma, Hyperkalemia, Elevated Potassium, Potassium Disorder, Efficacy, Safety, Hospitalization, Acute Dialysis, Mortality	(“Sodium Zirconium Cyclosilicate” OR “ZS-9” OR “Lokelma”) AND (“Hyperkalemia” OR “Elevated Potassium” OR “Potassium Disorder”) AND (“Efficacy” OR “Safety” OR “Hospitalization” OR “Acute Dialysis” OR “Mortality”)	RCT; Language: English/Spanish; Year 2020–2025	41

. The search ended on 6 January 2026, and the retrieved records were managed using Zotero for duplicate removal. Subsequently, two independent reviewers screened titles and abstracts to identify potentially eligible studies, followed by full-text assessment of selected articles. From each included publication, relevant data were extracted for analysis, focusing on SZC efficacy, safety, and clinical outcomes in the management of hyperkalemia.

3. Results

3.1. Selection of Studies

As shown in Figure 1, a total of 62 records were identified through database searches in PubMed, ScienceDirect, Scopus, and Embase. After removing duplicates (n = 18), 44 titles and abstracts were screened. Of these, 35 were excluded for not meeting the eligibility criteria. 9 full-text articles were assessed; 2 were excluded. Finally, 7 studies were included in the systematic review.

3.2. Characteristics of the Included Studies

Seven randomized controlled trials met the inclusion criteria and were incorporated into this systematic review (

Table 1. Clinical characteristics, patient population, SZC doses, and main findings of the included studies.

Study	Study Type	Patient Population/Clinical Setting	SZC Dose(s) Evaluated	Study Focus/Outcomes	Summary of Findings
Kashihara et al. [13] (n = 101)	Phase II/III RCT, double-blind, placebo-controlled	Adults with hyperkalemia (K+ 5.1–6.5 mmol/L); mixed outpatient/hospitalized; CKD, HF, DM eligible	5 g TID 10 g TID (48 h correction)	Exponential rate of K+ change over 48 h; proportion achieving normokalaemia at 48 h; safety	Significant, dose-dependent serum K+ reduction vs. placebo. 91.7% normokalaemia at 48 h (10 g). Well, tolerated; no serious AEs.
Ni et al. [16] (n = 127)	Phase IIIb RCT, double-blind, placebo-controlled	Chinese adults on chronic hemodialysis with predialysis hyperkalemia (K+ > 5.4 mmol/L after LIDI)	5 g QD (inter-dialytic days)	Proportion of responders (K+ 4.0–5.0 mmol/L in ≥3/4 LIDI visits); predialysis K+ maintenance ≤ 5.5 mmol/L; K+ gradient < 3.0 mmol/L during LIDI	Significantly higher responder rate with SZC (37.3% vs. 10.4%; OR 5.10). Better predialysis of K+ control and gradient during LIDI.
Zannad et al. [14] (n = 248)	Phase III RCT, double-blind, placebo-controlled; two phases (correction + maintenance)	Adults with hyperkalemia (K+ ≥ 5.1 mmol/L, two consecutive readings); mixed outpatient/hospitalized; CKD, HF eligible	Correction: 10 g TID × 48 h Maintenance: 5 g QD or 10 g QD × 28 d	Change in K+ from baseline at 24 h and 48 h; proportion achieving normokalaemia; maintenance of normokalaemia up to 28 days; safety	Rapid correction (↓ 1.28 mmol/L at 48 h). 89.1% normokalaemia at 48 h. Normokalemia maintained over 28 days; risk of recurrent HK reduced by 56–84%. Edema and constipation are most frequent AEs.
Peacock et al. [19] (n = 250)	Phase II RCT, double-blind, placebo-controlled, multicenter (33 countries)	Adults ≥ 18 yr presenting to the emergency department with severe hyperkalemia (K+ ≥ 5.8 mmol/L); all SZC given with insulin + glucose	10 g single dose + standard care (insulin + glucose)	Proportion of patients achieving normokalaemia within 24 h of ED admission	Greater K+ reduction with SZC from 2 h. Trend toward higher ED discharge rate. No statistically significant difference in primary endpoint.
Liang et al. [15] (n = 250)	Phase III RCT, double-blind, placebo-controlled (China)	Chinese adults with hyperkalemia (K+ ≥ 5.1 mmol/L); outpatient/hospitalized; CKD, HF, DM eligible	Correction: 5 g TID or 10 g TID × OL Maintenance: 5 g QD or 10 g QD × 28 d	Effect of different SZC doses on K+ reduction (efficacy) and safety profile	Dose-dependent reduction (7% with 5 g vs. 15% with 10 g vs. placebo). 58.8–76.5% maintained normokalaemia over 28 days. Peripheral edema is the most frequent AE.
Elsayed et al. [17] (n = 120)	RCT, double-blind, multicenter (Alexandria, Egypt)	Adults on chronic dialysis with hyperkalemia; comparator was SPS (not placebo)	SZC (dose NR) vs. SPS; 8-week follow-up	Time to normokalaemia and K+ reduction vs. SPS; safety comparison	Both agents achieved normokalaemia; SZC reached target in 2 weeks vs. 6 weeks with SPS. Fewer GI adverse events with SZC.
Fishbane et al. [18] (n = 2690)	Phase III RCT, double-blind, placebo-controlled, international, event-driven, 3-year follow-up	Adults ≥ 18 yr with kidney failure on chronic hemodialysis; largest and longest study in this review	5 g QD on inter-dialytic days (maintenance)	Composite of CV events (primary); K+ control and safety (secondary); 3-year follow-up	No significant reduction in CV events vs. placebo (HR 0.98). 74% vs. 47% maintained normokalaemia (OR 3.36). Edema 4.7%; hypokalemia 3.0%; 30.4% discontinuation by year 3.

↓ disminution of serum K⁺ concentration.

). All studies evaluated adult patients with hyperkalemia but differed in their clinical setting, comparator, and population characteristics: three studies enrolled outpatients or hospitalized patients without a specific organ comorbidity requirement [13,14,15]; two studies focused on patients receiving chronic hemodialysis [16,17,18]; and one study included patients presenting to the emergency department with severe hyperkalemia [19]. SZC doses evaluated across studies ranged from 5 g to 10 g, administered once daily (QD) during maintenance phases or three times daily (TID) during acute correction phases. Given the heterogeneity in populations, dosing regimens, and outcome definitions, a quantitative meta-analysis was not performed; results are presented descriptively.

3.3. Primary Results

3.3.1. Serum K⁺ Reduction

Across all seven included trials, SZC produced a consistent and statistically significant reduction in serum potassium compared with placebo or the active comparator (

Table 2. Effects of sodium zirconium cyclosilicate on hyperkalemia-related parameters, by patient population.

Study (n)	Patient Population	Serum K+ Reduction	Time to Achieve Reduction	Duration of K+-Lowering Effect
Kashihara et al. [13] (n = 101)	Mixed outpatient/hospitalized; CKD, HF, DM eligible	0.27–0.51% per hour during first 48 h vs. placebo (p < 0.0001 for both doses). Normokalemia at 48 h: 91.7% (10 g) vs. placebo.	Median time to normokalemia: 1.8 h (10 g) vs. 3.9 h (placebo). No significant difference for 5 g.	Maintained during the 48-h study period. No follow-up beyond this interval due to study design.
Ni et al. [16] (n = 127)	Chronic haemodialysis (CKD); predialysis HK > 5.4 mmol/L	Responder rate: 37.3% (SZC) vs. 10.4% (placebo); OR 5.10 (95% CI: 1.90–15.12; p < 0.001). Predialysis K+ ≤ 5.5 mmol/L at LIDI: 58% vs. 17% (OR 6.41).	Not reported as time-to-event; responder status evaluated over 4-week maintenance period.	Maintained during the 4-week stable-dose evaluation phase (LIDI and SIDI visits).
Zannad et al. [14] (n = 248)	Mixed outpatient/hospitalized; CKD, HF eligible; two-phase design	Correction: ↓ 0.81 mmol/L at 24 h; ↓ 1.28 mmol/L at 48 h (p < 0.001). Maintenance: relative reduction 9.6% (5 g) and 17.7% (10 g) vs. placebo (p < 0.001 both).	Onset from 1 h. Normokalemia at 24 h: 63.3%; at 48 h: 89.1% (10 g TID).	Maintained 28 days. Odds of remaining normokalemic: ~6 × (5 g) and ~18 × (10 g) vs. placebo. Normokalemic days increased by 7 (5 g) and 12 (10 g). HK recurrence risk reduced 56–84%.
Peacock et al. [19] (n = 250)	Emergency department; severe HK ≥ 5.8 mmol/L; all patients received insulin + glucose	At 4 h: −0.36 (±0.57) mmol/L (SZC) vs. −0.25 (±0.63) mmol/L (placebo). Adjusted diff. −0.13 mmol/L (95% CI: −0.44 to 0.17); not significant.	Similar reduction at 1 h; greater K+ reduction with SZC from 2 h (−0.72 vs. −0.36 mmol/L; diff. −0.35; 95% CI: −0.68 to −0.02).	Measurements to 24 h; Day 8 assessment for safety only. Duration of effect not evaluable by study design.
Liang et al. [15] (n = 250)	Mixed outpatient/hospitalized (China); CKD, HF, DM eligible	Days 8 and 29: K+ 4.9 mmol/L (5 g), 4.4 mmol/L (10 g), 5.2 mmol/L (placebo). Reductions: 7% (5 g) and 15% (10 g) vs. placebo. Dose-dependent.	10 g TID achieved normokalemia in 69.0% at 24 h; 87.4% by end of open-label phase.	28-day maintenance. Normokalemia maintained: 58.8% (5 g), 76.5% (10 g), 36.8% (placebo); p < 0.001 for both SZC groups.
Elsayed et al. [17] (n = 120)	Chronic dialysis; active comparator (SPS), not placebo	SZC K+ levels significantly lower than SPS throughout 8-week study (p < 0.001). Both groups reduced K+ from baseline from week 1 onward.	SZC group achieved normokalemia (<5 mmol/L) by 2 weeks; SPS group reached target only by 6 weeks.	Effect maintained throughout 8-week study period; specific maintenance proportions not reported.
Fishbane et al. [18] (n = 2690)	Chronic haemodialysis (CKD); longest follow-up (3 years); largest sample	Normokalemia during 3-year follow-up: 74.0% (SZC) vs. 47.0% (placebo); OR 3.36 (95% CI: 2.64–4.26; p < 0.0001). Rescue therapy need: 8.7% vs. 20.4% (HR 0.39; p < 0.001).	Time to K+ normalization not specifically reported.	K+-lowering benefit sustained throughout 3-year study. Primary CV endpoint not met (HR 0.98; p = 0.867).

Clinical trials assessed efficacy regarding serum K⁺ reduction using different approaches; these approaches are described below. ↓ disminution of serum K⁺ concentration.

). A dose-dependent relationship was evident in studies that evaluated more than one dose level: Kashihara et al. [13] and Liang et al. [15] both reported greater potassium reductions with the 10 g dose than with the 5 g dose, a pattern that was also reflected in the higher proportions of patients achieving normokalemia at both doses relative to placebo. In the largest study, Fishbane et al. [18] reported that 74.0% of patients in the SZC group remained normokalemic during the three-year follow-up compared with 47.0% with placebo (OR 3.36; 95% CI: 2.64–4.26).

In patients receiving chronic haemodialysis, the magnitude of response was assessed differently owing to the episodic nature of potassium changes across dialytic intervals. Ni et al. [16] defined response as maintaining predialysis K⁺ within 4.0–5.0 mmol/L in at least three of four visits after the long interdialytic interval (LIDI); this was achieved in 37.3% of SZC-treated patients versus only 10.4% with placebo (OR 5.10; 95% CI: 1.90–15.12). Elsayed et al. [17] compared SZC directly with sodium polystyrene sulfonate (SPS) in a dialysis population and found lower serum K⁺ levels with SZC throughout the entire study period (p < 0.001). In the acute emergency context, Peacock et al. [19] reported a numerically greater K⁺ reduction with SZC plus standard care compared with placebo plus standard care at four hours (−0.36 vs. −0.25 mmol/L), though the adjusted mean difference did not reach statistical significance (−0.13 mmol/L; 95% CI: −0.44 to 0.17).

3.3.2. Time to Achieve Reduction

SZC demonstrated an early onset of action across studies, with detectable potassium reductions observed within the first one to four hours of administration in all trials that reported time-course data. Zannad et al. [14] found that serum K⁺ reduction was measurable from the first hour after SZC 10 g TID administration and that 63.3% of patients had achieved normokalemia by 24 h and 89.1% by 48 h. Kashihara et al. [13] reported a median time to normokalemia of 1.8 h with SZC 10 g versus 3.9 h with placebo, with no significant difference between SZC 5 g and placebo, suggesting a dose threshold for speed of response.

In studies with twice-daily measurement schedules, Liang et al. [15] showed that 69.0% of patients treated with SZC 10 g TID achieved normokalemia within 24 h. In the emergency department setting, Peacock et al. [19] found that both SZC and placebo groups reduced serum K⁺ within the first hour (consistent with the effect of co-administered insulin and glucose), but the SZC group showed a meaningfully greater reduction from two hours onward. Among dialysis patients, Elsayed et al. [17] found that the SZC group reached normokalemia in two weeks, compared with six weeks in the SPS group, indicating a clinically relevant speed advantage even in this more complex population.

3.3.3. Duration of Potassium-Lowering Effect

The sustained effect of SZC was evaluated across study durations ranging from 48 h to three years, and all trials reporting maintenance-phase data demonstrated persistence of the potassium-lowering effect beyond the acute correction period. Zannad et al. [14] provided the most granular maintenance data: during the 28-day maintenance phase, SZC 10 g once daily was associated with 18-fold higher odds of remaining normokalaemic compared with placebo, an increase of 12 normokalaemic days, and an 84% reduction in the instantaneous risk of recurrent hyperkalemia. Liang et al. [15] independently confirmed these findings, reporting normokalaemia maintenance rates of 58.8% (5 g) and 76.5% (10 g) versus 36.8% with placebo across 28 days (p < 0.001 for both SZC groups).

In the hemodialysis setting, Ni et al. [16] demonstrated more consistent potassium control over a four-week evaluation period, with significantly higher proportions of SZC-treated patients maintaining predialysis K⁺ within target ranges across both LIDI and SIDI visits. At the longest follow-up, Fishbane et al. [18] showed that the potassium-lowering benefit was sustained over three years and was accompanied by a significantly reduced need for rescue therapy (8.7% vs. 20.4%; HR 0.39; 95% CI: 0.31–0.48). Short-duration studies [13,19] could not provide data on maintenance beyond their follow-up windows, which represents a design-related limitation for those specific trials.

3.4. Secondary Outcomes

The available evidence on major clinical outcomes is limited and reflects the design constraints of most included trials, which were primarily powered to detect biochemical endpoints rather than clinical events (

Table 3. Evidence on major clínical outcomes associated with SZC use.

Study (n)	Patient Population	SZC Dose	Hospitalizations	Emergency Dialysis	Cardiovascular Events
Kashihara et al. [13] (n = 101)	Mixed; CKD, HF, DM	5 g/10 g TID × 48 h	Not reported	Not reported	Not reported
Ni et al. [16] (n = 127)	Chronic hemodialysis	5 g QD	Not reported	No rescue therapy required (SZC group)	Not reported
Zannad et al. [14] (n = 248)	Mixed; CKD, HF	5 g/10 g QD × 28 d	Not reported	Not reported	Not reported
Peacock et al. [19] (n = 250)	Emergency dept; severe HK	10 g single dose	Discharge rates: 39.4% (SZC) vs. 32.4% (Placebo). Mean time to discharge: 27.9 vs. 24.3 h (NS)	Dialysis initiated: 33.3% (SZC) vs. 48.6% (placebo). 0–4 h: 9.4% vs. 13.9% (NS)	Not primary outcome: 1 HF event (SZC group, not related per investigators)
Liang et al. [15] (n = 250)	Mixed; CKD, HF, DM (China)	5 g/10 g QD × 28 d	Not reported	Not reported	Not reported
Elsayed et al. [17] (n = 120)	Chronic dialysis vs. SPS	vs. SPS (dose NR)	Not reported	Not reported	Not reported
Fishbane et al. [18] (n = 2690)	Chronic hemodialysis; 3-year follow-up	5 g QD	Overall: 0.07 vs. 0.07 per person-year (RR 0.96; NS). HF hosp. arrhythmia: 5.5% vs. 4.8% (HR 1.12; NS)	Not reported	Primary endpoint (composite CV): 8.8% vs. 8.9% (HR 0.98; 95% CI: 0.76–1.26; p = 0.867). Sudden cardiac death: HR 0.95 (NS). Stroke: HR 0.95 (NS)

). Among the seven studies, only two were specifically designed or reported to capture clinical outcomes as primary or pre-specified secondary endpoints: Peacock et al. [19], which evaluated emergency department utilization in a high-acuity population, and Fishbane et al. [18], a large event-driven trial powered to detect a reduction in cardiovascular events over three years.

In neither study did SZC demonstrate a statistically significant benefit over placebo in hard clinical endpoints. Peacock et al. [19] found no meaningful difference between groups in the need for acute interventions, time to hospital discharge, or rate of dialysis initiation, although the study was not powered for these secondary outcomes. Fishbane et al. [18] found no reduction in the composite of major cardiovascular events (HR 0.98; 95% CI: 0.76–1.26; p = 0.867), sudden cardiac death (HR 0.95), or stroke (HR 0.95), and observed numerically more hospitalizations for arrhythmia in the SZC group than in the placebo group (5.5% vs. 4.8%; HR 1.12; p = 0.510), though the difference was not significant. The remaining five studies did not report hospitalizations, emergency dialysis requirements, or mortality as outcomes.

3.5. Safety

The overall safety profile of SZC was favorable and broadly consistent across the included studies (

Table 4. Clinical studies with safety outcomes effectively reported.

Study (n)	Patient Population	SZC Dose	Edema n (%)	Constipation n (%)	Hypokalemia n (%)	Discontinuation. n (%)	Serious/Notable AEs
Kashihara et al. [13] (n = 101)	Mixed; CKD, HF, DM	5/10 g TID	NR	1 (2.9%) (5 g group)	0	0	Tremor and ventricular extrasystoles (2 pts, 10 g group); all non-serious per investigators
Ni et al. [16] (n = 127)	Hemodialysis	5 g QD	1	6 (9.1%)	7 (10.6%)	4 (2 SZC, 2 PBO)	2 SZC discontinuations due to hypokalemia
Zannad et al. [14] (n = 248)	Mixed; CKD, HF	5/10 g QD	4 (SZC 10 g: 15.2%; 5 g: 5.1%; PBO: 0%)	4 (SZC 10 g: 9.1%; 5 g: 1.0%; PBO: 0%)	1 (SZC 10 g: 1.0%)	17 (14 SZC/3 PBO) 7.1% each SZC arm	Dose-related pattern for edema and constipation
Peacock et al. [19] (n = 250)	Emergency dept	10 g single dose	NR	NR	NR	1	SZC: tibial fracture, GI hemorrhage, HF (1 each, not related). PBO: hypotension, respiratory failure, seizures, pneumonia, 2× hyperkalemia
Liang et al. [15] (n = 250)	Mixed; CKD, HF, DM (China)	5/10 g QD	21 (5 g: 9.0%; 10 g: 12.0%; PBO: 0%)	12 (5 g: 7.0%; 10 g: 5.0%; PBO: 0%)	NR	NR	Most AEs mild-to-moderate
Elsayed et al. [17] (n = 120)	Chronic dialysis vs. SPS	vs. SPS (NR)	0	2	0	NR	2 serious AEs: MI and catheter bloodstream infection (both SZC group). Diarrhea × 1; headache × 1; unpleasant taste × 2
Fishbane et al. [18] (n = 2690)	Hemodialysis; 3-year follow-up	5 g QD	64 (4.7%)	NR	40 (3.0%)	30.4% by 2023	SARS-CoV-2 infection was most frequent AE overall (temporal context, not drug-related). Higher cumulative discontinuation with SZC over 3 years

). The two most frequently reported adverse events were peripheral edema and constipation, both of which displayed a dose-dependent pattern in studies that evaluated more than one dose level. Zannad et al. [14] reported the clearest dose–response relationship for edema, with rates of 0% (placebo), 5.1% (5 g), and 15.2% (10 g) during the maintenance phase, a finding corroborated by Liang et al. [15], who similarly observed higher edema rates with the 10 g dose. The mechanism is likely related to SZC’s sodium content and associated sodium retention, which is clinically relevant in patients with concomitant heart failure or volume-sensitive conditions.

Hypokalemia, while a recognized risk given the drug’s mechanism of action, was infrequent and predominantly observed at higher doses and in haemodialysis populations. Ni et al. [16] reported the highest hypokalemia rate across studies (10.6% in the SZC group), consistent with the narrower therapeutic window in dialysis patients, where baseline potassium fluctuations are already pronounced. In contrast, Elsayed et al. [17] reported no cases of hypokalemia in their dialysis population, a discrepancy possibly attributable to differences in dose, monitoring intensity, or patient selection.

Treatment discontinuation rates were low and comparable between SZC and placebo in all short- and medium-duration trials. The exception was the three-year DIALIZE-Outcomes trial [18], in which 30.4% of SZC-treated patients had discontinued by 2023; this finding should be interpreted in the context of an extended follow-up period in a high-risk dialysis population rather than as evidence of systematic intolerability. Serious adverse events were reported across several studies but were generally deemed unrelated to SZC by the respective investigators. No deaths were attributable to SZC treatment in any included trial.

3.6. Methodological Quality

Assessment Using the Rob-2 Tool

The quality assessment was done by two reviewers (L.H.-J and J.C.-G) independently. The results from the seven studies can be seen in Figure 2. All the studies in general managed all the deviation: randomization process (D1), intended intervention (D2), missing data outcome (D3), reliability of the outcome measurements (D4) and selection of the reported outcomes (D5). Because of these, all the studies received a global judgment of minimal risk of bias, so the confidence in the overall results is high.

4. Discussion

The evidence synthesized in this systematic review consistently demonstrates that SZC is effective in reducing serum potassium concentration across a range of clinical settings, from acute hospital care to long-term outpatient management and hemodialysis maintenance. Across all seven included randomized controlled trials, SZC produced significant potassium reductions compared with placebo or the active comparator sodium polystyrene sulfonate (SPS). However, the translation of this biochemical benefit into measurable improvements in clinical outcomes—hospitalizations, cardiovascular events, and mortality—has not been demonstrated in the available controlled trial evidence, a distinction that is central to interpreting SZC’s role in clinical practice.

4.1. Efficacy in K⁺ Reduction

The potassium-lowering efficacy of SZC was one of the most consistent findings across this review. A dose-dependent relationship was replicated independently across three trials conducted in different geographic contexts and populations [13,14,15]. All of which demonstrated greater reductions in serum potassium and higher rates of normokalaemia with the 10 g dose compared with the 5 g dose. This consistency across independent research groups strengthens confidence in the pharmacological dose–response relationship and aligns with the mechanism of action of SZC as a non-absorbed cation exchanger that captures potassium stoichiometrically in the gastrointestinal tract [20].

These findings are concordant with prior systematic reviews of novel potassium binders. Riaz et al. [20] documented significant reductions in serum potassium across 14 randomized controlled trials evaluating both SZC and patiromer versus placebo, concluding that both agents are effective for chronic hyperkalemia management. Importantly, that review identified dose as a significant predictor of potassium reduction, a pattern corroborated by the present analysis.

The magnitude of response differed across clinical settings in a way that reflects both pharmacological and methodological factors. In controlled correction-phase trials such as Zannad et al. [14], SZC produced mean reductions of up to 1.28 mmol/L within 48 h—a clinically meaningful change given that reductions of 0.5–1.0 mmol/L are considered relevant in clinical management guidelines. In contrast, the emergency department trial by Peacock et al. [19] did not reach statistical significance in its primary endpoint due to the confounding effect of co-administered insulin and glucose, which independently reduced serum potassium in both groups, thereby narrowing the detectable difference attributable to SZC. This design feature should not be interpreted as evidence of reduced efficacy in that setting but as a methodological challenge inherent to studying potassium-lowering agents in the context of acute rescue therapy.

In hemodialysis populations, where potassium fluctuates episodically across dialytic intervals, Ni et al. [16] and Elsayed et al. [17] both reported clinically meaningful improvements in potassium control with SZC relative to comparators. The notably higher responder rate in Ni et al. [16] (37.3% vs. 10.4%) highlights the specific challenge of interdialytic hyperkalemia management and suggests that inter-dialytic SZC administration may reduce the potassium burden between dialysis sessions.

4.2. Onset of Action: Clinical Significance of Rapid K⁺ Reduction

The speed with which SZC lowers serum potassium represents one of its most clinically distinctive characteristics relative to traditional potassium-binding agents. Sodium polystyrene sulfonate (SPS), the most historically used alternative, has been shown in comparative studies—including Elsayed et al. [17] in this review—to require up to six weeks to achieve normokalaemia in dialysis patients, compared with two weeks with SZC. This difference is not merely a matter of convenience; delayed correction of hyperkalemia prolongs the period of cardiac risk, including the risk of malignant arrhythmias, in patients who are often already compromised by comorbid cardiac or renal disease.

Across the included trials with time-course data, SZC consistently produced measurable potassium reductions within the first one to four hours of administration. Zannad et al. [14] documented a potassium reduction observable from the first hour, reaching clinically meaningful normokalaemia rates (63.3%) by 24 h. Kashihara et al. [13] found a median time to normokalaemia of 1.8 h with the 10 g dose versus 3.9 h with placebo. These findings are consistent with the systematic review by Shrestha et al. [21], who reported early potassium reduction with SZC within 48 h as a shared feature across multiple trial designs and populations.

The clinical implications of this rapid onset are most evident in two settings. First, in the emergency department, Peacock et al. [19] observed that SZC produced greater potassium reductions from two hours onward compared with standard care alone, suggesting a potential role as an adjunct to acute management alongside insulin and glucose—agents that shift potassium intracellularly but do not eliminate it from the body. Second, in the hemodialysis context, the ability to achieve predialysis normokalaemia within days rather than weeks could reduce the proportion of patients arriving at dialysis with dangerous pre-session potassium levels, potentially decreasing session-related arrhythmic risk. These potential clinical applications, however, remain to be formally evaluated in trials powered by clinical rather than biochemical endpoints.

4.3. Sustained K⁺ Control: Duration of Effect and Maintenance Implications

The value of any potassium binder extends beyond the initial correction of a hyperkalemic episode; the clinical objective in most patients with chronic kidney disease, heart failure, or diabetes is the sustained prevention of recurrent hyperkalemia over weeks and months, often in the context of ongoing treatment with renin–angiotensin–aldosterone system (RAAS) inhibitors that continuously promote potassium retention. From this perspective, the duration of SZC’s potassium-lowering effect is its most clinically relevant property.

Evidence from the maintenance phases of is particularly informative [14,15]. In Zannad et al., SZC 10 g once daily was associated with 18-fold greater odds of remaining normokalaemic compared with placebo over 28 days, an increase of 12 normokalaemic days, and an 84% reduction in the instantaneous risk of recurrent hyperkalemia. This last metric—the instantaneous hazard of recurrence—is analytically important because it captures not just whether normokalaemia was achieved, but how stable it was. A patient who oscillates in and out of normokalaemia multiple times per week carries a higher arrhythmic risk than one with sustained control, a distinction that point-in-time measurements of serum potassium do not capture.

In the hemodialysis setting, Ni et al. [16] demonstrated that SZC maintained better potassium control across both the long and short interdialytic intervals, with significantly higher proportions of patients within target ranges at each measured time point. This is a clinically meaningful finding because the potassium gradient across the long interdialytic interval is one of the primary determinants of dialysis-associated cardiac arrhythmias. The long-term perspective is further provided by Fishbane et al. [18], in which 74% of SZC-treated patients maintained normokalaemia over three years versus 47% with placebo—a difference that also translated into a significantly reduced need for rescue therapy (HR 0.39).

However, the evidence must be interpreted within its design constraints. Studies with the most granular maintenance data [14,15] had follow-up periods of 28 days, which, while informative for phase III dose-finding, may not adequately represent the durability of treatment response in chronic patients over six to twelve months. The short-duration studies [13,19] cannot contribute to this question at all by design. This long-term maintenance context is distinct from the acute emergency use described in Section 4.2, and it is precisely in this chronic setting—where patients receive daily SZC for weeks to months—that the cumulative sodium burden of SZC (quantified in Section 4.4) becomes clinically most relevant, particularly in patients with heart failure or advanced CKD. Future trials should explicitly include six- to twelve-month maintenance phases as primary outcome periods, rather than treating maintenance as secondary to an acute correction phase.

4.4. Safety Profile, Clinical Risk, and Practical Considerations for Use

The overall safety profile of SZC was consistent and favorable across the included studies, with adverse events that were mild to moderate in severity and manageable in clinical practice. Three adverse events merit specific analytical discussion: edema, hypokalemia, and the signal from real-world comparative data that was not captured in the included randomized trials.

Edema was the most frequently reported adverse event and displayed a clear dose-dependent pattern. Zannad et al. [14] reported edema rates of 0% (placebo), 5.1% (SZC 5 g), and 15.2% (SZC 10 g) during the maintenance phase, a dose–response relationship corroborated by Liang et al. [15] and consistent with the findings of Shrestha et al. [21] and Zhang et al. [22] in prior systematic reviews and meta-analyses. The likely mechanism is the sodium content inherent to SZC’s structure as a sodium zirconium silicate compound: each gram of SZC contains approximately 400 mg of sodium, meaning that a 10 g daily dose adds approximately 4 g of sodium—a clinically significant sodium load in patients with heart failure or advanced CKD who are already fluid-overloaded or on strict sodium restriction. Clinicians should factor this sodium burden explicitly into dosing decisions in these populations, particularly at the 10 g maintenance dose.

Hypokalemia was infrequent across included trials (<5% in most studies), but the dialysis-specific data from Ni et al. [16]—which reported the highest hypokalemia rate of 10.6%—underscores that this adverse event carries heightened clinical relevance in patients whose baseline potassium is already tightly regulated by dialysis scheduling. The discrepancy between Ni et al. (10.6%) and Elsayed et al. [17] (0%) in dialysis populations reflects differences in monitoring intensity, SZC dose, and patient selection rather than a true pharmacological inconsistency. This variability reinforces the importance of individualized potassium monitoring protocols, particularly during the first weeks of therapy.

Treatment discontinuation rates were low and comparable between SZC and placebo in short- and medium-duration trials. The 30.4% cumulative discontinuation rate observed by Fishbane et al. [18] over three years reflects the expected attrition of any chronic therapy in a high-burden dialysis population rather than a drug-specific intolerability signal. Most serious adverse events across all included studies were deemed unrelated to SZC by the respective investigators.

Beyond the controlled trial setting, a large retrospective real-world pharmacoepidemiologic study by Desai et al. [23] provides a safety signal that warrants explicit discussion. Comparing SZC (n = 19,849) with patiromer (n = 9929) using real-world data from a United States healthcare database, Desai et al. found that SZC was associated with a significantly higher hazard of hospitalization for heart failure (+37%), major oedema (+33%), and all-cause mortality (+29%) compared with patiromer. These findings must be interpreted cautiously: observational studies cannot establish causation and confounding by indication—the possibility that patients prescribed SZC may have had more severe underlying disease cannot be excluded without propensity-score-matched or instrumental variable analyses. Nevertheless, the scale of the study (n > 29,000) and the consistency of the direction of effect across multiple clinical endpoints raise a hypothesis that requires prospective evaluation. The sodium-loading mechanism described above provides a biologically plausible explanation for the observed increase in heart failure hospitalizations and oedema risk with SZC relative to patiromer, which does not have a comparable sodium content.

Taken together, these findings indicate that the safety profiles of SZC and patiromer are not equivalent, and that comparative effectiveness and safety data from head-to-head randomized trials are needed before clinicians can make evidence-based choices between these two agents in sodium-sensitive populations such as those with heart failure or advanced CKD.

Regarding major clinical endpoints—hospitalizations, cardiovascular events, and mortality—the available randomized trial evidence does not demonstrate a benefit of SZC over placebo. This is not a matter of insufficient evidence leaving the question open: the DIALIZE-Outcomes trial [18] the largest and longest RCT in this review (n = 2690; 3-year follow-up), was specifically designed and powered to detect a reduction in major cardiovascular events and found no significant difference (HR 0.98; 95% CI: 0.76–1.26; p = 0.867). No reduction was observed for sudden cardiac death, stroke, hospitalization for arrhythmias, or all-cause hospitalization. In the emergency setting, Peacock et al. [19] found no difference in time to hospital discharge, rate of dialysis initiation, or need for acute interventions. The absence of demonstrated benefit on clinical outcomes across two purpose-designed studies—one long-term in a high-risk population, one in an acute high-severity setting—should be stated directly rather than characterized as merely uncertain.

The foregoing clinical and safety considerations—the absence of demonstrated benefit on hard outcomes, the dose-dependent sodium burden with implications for heart failure and volume-overloaded patients, and the comparative safety signal reported by Desai et al. [22] must be weighed alongside the substantially higher acquisition cost of SZC relative to conventional potassium binders. Although a formal pharmacoeconomic analysis was beyond the pre-registered scope of this review, the cost differential is a clinically relevant dimension of treatment decisions in chronic hyperkalemia management: when biochemical efficacy is comparable across agents and clinical outcome benefit has not been demonstrated for any agent, cost becomes a meaningful discriminator for formulary positioning and patient access, particularly in resource-constrained healthcare settings or in patients who require indefinite maintenance therapy. Existing health economic models have projected SZC to be cost-effective in specific national contexts [24,25], but these analyses rely on modelled clinical benefit assumptions—primarily reductions in hyperkalemia-related hospitalizations—that have not been confirmed in the randomized trial evidence synthesized here. Future health technology assessments directly comparing the cost-effectiveness of SZC, patiromer, and conventional agents in clearly defined patient populations are therefore a necessary complement to the clinical evidence synthesized here.

4.5. Limitations

This systematic review has several limitations that should be considered when interpreting the findings. First, the included studies were heterogeneous in their design, comparators, populations, outcome definitions, and follow-up durations—ranging from 48-h correction studies to three-year event-driven trials. This heterogeneity precluded quantitative meta-analysis and limits direct comparisons of effect sizes across studies. In particular, the differences in SZC dosing regimens (5 g versus 10 g; once-daily versus three-times-daily) and in the definition of normokalaemia (ranging from <5.0 to ≤5.5 mmol/L depending on study) mean that pooled estimates would be methodologically inappropriate and potentially misleading.

Second, and most importantly from a clinical perspective, most included trials were designed to evaluate biochemical outcomes—primarily serum potassium reduction and normokalaemia maintenance—and were neither powered nor intended to detect differences in hospitalizations, cardiovascular events, or mortality. The absence of clinical benefit should be viewed as a true finding rather than a power limitation: DIALIZE-Outcomes was explicitly event-driven and powered for the composite cardiovascular endpoint [18,19]. The conclusion that no randomized trial has demonstrated clinical benefit for SZC is therefore not a gap in evidence but a finding.

Third, no included study directly compared SZC with patiromer, the other novel potassium binder currently available in clinical practice. Given the observational signal reported by Desai et al. [23] suggesting potentially important safety differences between these two agents—particularly regarding heart failure hospitalizations and mortality—this absence of head-to-head comparative data represents a critical research gap. Future trials directly comparing SZC with patiromer on pre-specified hard clinical endpoints, particularly in patients with heart failure and reduced ejection fraction or in those with advanced CKD on RAAS inhibitor therapy, should be considered a research priority.

Fourth, the evidence base is limited to published randomized controlled trials from 2020 to 2025, and real-world effectiveness studies were not included in the systematic review. The growing body of pharmacoepidemiologic data—including the Desai et al. report—suggests that the safety and comparative effectiveness picture in routine clinical practice may differ from the controlled trial environment.

5. Conclusions

Available evidence indicates that SZC is effective in reducing serum potassium and facilitates the achievement and maintenance of normokalaemia in adult patients with hyperkalemia, including those with chronic kidney disease and patients receiving hemodialysis. The reviewed clinical trials consistently demonstrate an early onset of action and a sustained potassium-lowering effect during the evaluated follow-up periods.

Overall, SZC’s safety profile was favorable, with mild-to-moderate adverse events—edema, constipation, and hypokalemia—and low discontinuation rates in most short- and medium-duration studies. However, edema shows a dose-dependent pattern with potential clinical significance in sodium-sensitive patients, and real-world comparative data suggest that the safety profile of SZC may differ from that of patiromer in clinically important ways that require prospective evaluation.

In this context, although SZC represents an effective and well-tolerated therapeutic option for serum potassium control, evidence regarding its impact on major clinical outcomes—hospitalizations, cardiovascular events, and mortality—is not limited; it is absent from the available randomized trial evidence. Additional studies, particularly head-to-head comparative trials between SZC and patiromer with hard clinical endpoints, are required to define SZC’s long-term clinical impact and guide its selection within the therapeutic landscape of hyperkalemia management.