Hyperkalemia (HK), defined as elevated serum potassium (sK⁺) levels beyond the normal range (>5.0 mmol/L), is a potentially life-threatening condition characterized by poor clinical outcomes along with high mortality and morbidity (Amin et al., 2019; Esposito et al., 2020). HK is typically classified by severity levels such as mild (K⁺ 5.0–5.9 mmol/L), moderate (K⁺ 6.0–6.4 mmol/L), and severe (K⁺ ≥ 6.5 mmol/L) (Clase et al., 2020). Severe HK can cause cardiac arrhythmia and arrest, thereby increasing all-cause and cardiovascular mortality if not treated in time (An et al., 2012; McMahon et al., 2012). HK may occur due to the imbalance in K⁺ homeostasis, which is influenced by several parameters such as excessive dietary K⁺ intake, insufficient K⁺ excretion, as well as abnormal distribution of intracellular and extracellular K⁺ (Kovesdy, 2014; Någård et al., 2021). The incidence of HK is even high in patients with comorbidities such as chronic kidney disease (CKD), heart failure (HF), type 2 diabetes, and hypertension, and those treated with renin–angiotensin–aldosterone system inhibitors (RAASis) (Linder et al., 2016). A Chinese epidemiological study found that the incidence rate of HK was 3.86% in the general outpatient population, and patients with CKD, HF, diabetes, and hypertension reported even higher rates of HK (Bian et al., 2021).

HK can be managed through K⁺-restricted diet, administration of dextrose and insulin, intravenous sodium bicarbonate, potassium-binding agents, nonspecific polymeric exchange resins, diuretics, β-agonists, dialysis, and discontinuation or reduced doses of RAASis (Tamargo et al., 2018). Combination treatment using insulin and dextrose is among the most commonly used treatments for the management of HK (Peacock et al., 2018). Insulin reduces sK⁺ levels by activating sodium–potassium adenosine triphosphatase (Allon and Copkney, 1990; Li and Vijayan, 2014). Even though these treatments are rapid, they have a short duration of effect (approximately 4–6 h) and can cause rebound HK. Hence, the combination treatment is rarely considered to be a definitive therapy (Li and Vijayan, 2014). Dialysis is extremely effective in patients with severe HK; however, logistic issues often limit its rapid implementation (An et al., 2012; Peacock et al., 2020). Bicarbonates are only effective in patients with acidosis, and the efficacy of β-agonists can only last for a short period (Rafique et al., 2019). Nonspecific potassium binders, such as sodium or calcium polystyrene sulfonate (SPS/CPS) and patiromer have nonspecific modes of action, higher response time, and may cause severe gastrointestinal (GI) adverse events (AEs) including ischemic colitis, colonic necrosis, and intestinal perforation (Sterns et al., 2010; Chaitman et al., 2016). Therefore, there is a need for additional agents that can safely treat HK in both patients with acute and chronic HK.

Sodium zirconium cyclosilicate (SZC) is an oral, nonabsorbed, potassium binder, which selectively binds to potassium ions and exchanges them for hydrogen and sodium ions throughout the entire GI tract, thereby minimizing the concentration of free potassium in the GI lumen, ultimately lowering the sK⁺ levels and increasing fecal potassium excretion to resolve HK (Stavros et al., 2014). SZC was approved in December 2019 in China for the treatment of HK. Several clinical trials have reported lowering of sK⁺ levels in patients with HK as early as 1 h after the administration of SZC (Kosiborod et al., 2014; Ash et al., 2015; Kosiborod et al., 2015; Packham et al., 2015). The rapid action of SZC is due to its binding capacity to the potassium ions in the upper GI tract, and thus it may serve as a promising alternative treatment to insulin and glucose in the treatment of HK (Amin et al., 2019; Peacock et al., 2020). SZC has shown a promising efficacy and safety profile irrespective of underlying cause of HK, age, sex, race, comorbid diseases, or concomitant use of RAASis (Roger et al., 2019; Ash et al., 2022). Although these clinical trials imply that SZC could be an attractive therapeutic agent, there are very few studies that have evaluated its efficacy and safety in Chinese population in the real-world clinical practice. According to the guidelines from the National Medical Products Administration Drug Intensive Monitoring of Manufacturers, the real-world studies for evaluating the safety and efficacy of SZC are necessary for its extensive use, especially in Chinese population.

Therefore, we conducted this study to evaluate the safety, efficacy, and treatment patterns of SZC in patients with HK. Here, we present the interim results from this study.

This interim analysis evaluated the efficacy and safety profiles of SZC after 1 month of treatment in patients with HK (Einhorn et al., 2009; Goyal et al., 2012; McMahon et al., 2012). It has been demonstrated that there was a rapid reduction of sK⁺ levels to normal levels, which were maintained for up to 1 month in patients with HK. This significant reduction of sK⁺ levels was consistent across all patient populations, that is, FAS-P1, FAS-P2 new, and ongoing user as well as FAS-H subgroups. SZC was effective in maintaining normokalemia in patients with HK by reducing sK⁺ levels with good tolerability profile.

This study showed a mean daily dose of 11.5 g in FAS-P1 during the correction phase. During the maintenance phase, a mean daily dose of 5.0 mg/day, 6.6 mg/day, and 6.7 mg/day was used in the FAS-P2 new user group, FAS-P2 ongoing user group, and FAS-H subgroup analysis. This was in line with the previous randomized controlled studies of SZC in patients with HK, which reported the use of SZC doses of 2.5–10 g three times a day (Kosiborod et al., 2014; Ash et al., 2015; Packham et al., 2015) resulting in a clinically significant reduction of sK⁺ levels in these patients with HK, and dosages of 5–15 g QD resulting in sustained normokalemia during the maintenance phase up to 12 months in different clinical studies (Kosiborod et al., 2014; Packham et al., 2015).

The reduced sK⁺ levels of 5.0 mmol/L were observed on day 3 in FAS-P1, 5.2 mmol/L and 5.0 mmol/L in the FAS-P2 new and ongoing user groups and 5.3 mmol/L in FAS-H population, in comparison with 5.9 mmol/L at baseline. The criteria for treatment discontinuation after SZC treatment in patients with HK were not sK⁺ levels 5.0 mmol/L according to the international guidelines, but the actual laboratory report cutoff value of HK (>5.3 or 5.5 mmol/L) at study sites in China, thus reflecting actual treatment patterns of SZC treatment in the real-world clinical practice. This is the first real-world study in China showing reduced sK⁺ levels after SZC treatment. These results are consistent with the previous studies reporting lowering of sK⁺ levels >5.5 mmol/L in 52% of patients within 4 h after the first SZC dose of 10 g dose (Kosiborod et al., 2015). Another phase I study conducted in healthy adults showed significantly decreased sK⁺ concentrations with 10 g of SZC, which were similar to a study conducted in healthy adults in China (Någård et al., 2021; Cheung et al., 2022). In a phase II ZS002 clinical study, a significant decrease in sK⁺ levels was observed in patients with CKD and HK after SZC treatment at a dosage of 3 and 10 g as compared with placebo. There was a reduction in sK⁺ levels after SZC treatment administered at a dose of 10 g for an additional 3.5 days as compared with the placebo group, thereby emphasizing the effectiveness of SZC in the treatment of HK. Also, no significant difference was observed with respect to serum calcium, magnesium, and sodium levels along with other kidney function parameters in both the groups. Similarly, a significant, dose-dependent decline was observed in the mean sK⁺ levels in patients receiving SZC compared with those receiving placebo within the first 48 h in the ZS003 and HARMONIZE clinical studies (Kosiborod et al., 2014; Packham et al., 2015).

SZC treatment was effective with the majority of patients (51.3%) being normokalemic in the FAS-P1 group with sK⁺ levels between 3.5 and 5.0 mmol/L at visit 2, while 77.8% of patients had sK⁺ levels in the range of 3.5–5.5 mmol/L. Similarly, the proportion of patients with sK⁺ levels between 3.5 and 5.0 mmol/L (normokalemic) and 3.5–5.5 mmol/L was 44% and 68%, respectively, in the FAS-P2 group at visit 6. These results were similar to the HARMONIZE study, which showed a rapid attainment of normokalemia in most patients after 10 g SZC TID treatment for 48 h, with a maintenance phase of 29 days with SZC at 5–15 g QD (Kosiborod et al., 2014). The HARMONIZE trial showed normokalemia in 84% and 98% of patients within 24 and 48 h of treatment initiation, respectively (Kosiborod et al., 2014). Another prospective, open-label, single-arm, phase III ZS-005 clinical trial evaluated the long-term efficacy and safety of SZC in 751 outpatients with HK (K⁺ > 5.1 mmol/L) after 12 months of treatment and demonstrated that SZC restored normokalemia in more than 99% of outpatients within 24–72 h in the correction phase. Normokalemia was maintained for up to 12 months in 87% and 99% of participants achieving serum K⁺ ≤ 5.1 mmol/L and ≤5.5 mmol/L, respectively (Spinowitz et al., 2019). The HARMONIZE extension study showed that normokalemia was maintained for up to 11 months during the ongoing SZC QD treatment in 79% of patients, and the treatment was generally well tolerated (Roger et al., 2019).

Furthermore, our study reported that 47.4% of patients to be normokalemic with sK⁺ levels between 3.5 and 5.0 mmol/L, while 73.7% of patients had sK⁺ levels in the range of 3.5–5.5 mmol/L in the FAS-H population at visit 6. Similar results were observed in the DIALIZE study, where a significantly higher proportion of responders was observed in the SZC group compared with the placebo group: 41.2% (n = 40 of 97) versus 1.0% (n = 1 of 99; OR, 68.8; 95% CI, 10.9 to 2810.9; P < 0.001) during the evaluation period, which included patients with a maintained predialytic sK⁺ of 4.0–5.0 mmol/L during three or more of four hemodialysis treatments after the long interdialytic interval and who did not require urgent rescue therapy (Fishbane et al., 2019). The DIALIZE China study that evaluated SZC for the management of HK in Chinese patients undergoing hemodialysis showed a significantly higher proportion of responders in the SZC group (37.3%) compared with the placebo group (10.4%), with an estimated OR of 5.10 (95% CI, 1.9–15.1; P < 0.001) (Ni et al., 2023). Another ongoing clinical trial, PRECEDE-K, is the first prospective study evaluating the prevalence, recurrence, and treatment pattern in patients with HK undergoing hemodialysis in China and provided high-quality evidence and meaningful insights for guiding physicians in clinical practice (Ni et al., 2021).

SZC was generally well tolerated in this interim analysis, and no major safety concerns were reported. The incidence of treatment-related AEs was comparable, and no major SAEs were reported in all the groups. Although this study lacks data from a control group, thereby restricting the interpretation of safety data, GI disorders are among the most commonly occurring AEs reported in other short-term placebo-controlled studies (Packham et al., 2015; Spinowitz et al., 2019). In this study, reported AEs were generally mild to moderate in severity and manageable. GI AEs were commonly observed in the FAS-P1 and FAS-P2 ongoing user groups with an incidence rate of 0.3 (0.1, 1.1) and 0.2 (0.1, 0.2), respectively. The incidence rate of GI AEs reported in this study is similar to the previous studies showing GI-related disorders in 2.9% of the total patient population, with constipation being the most frequent GI AE (1.8%) (Amin et al., 2019). The HARMONIZE study showed edema to be the most common AE (Packham and Kosiborod, 2016), whereas diarrhea was commonly reported in the ZS-003 study in both the placebo and SZC treatment groups (Ash et al., 2015). A higher incidence of edema observed in HARMONIZE may be due to significantly higher baseline rates of HF and estimated glomerular filtration rate <60 mL/min/1.7 m² and higher baseline levels of brain natriuretic peptide in patients with HK receiving SZC (Kosiborod et al., 2014). However, the present study showed no incidence of edema in all groups. HK is higher in the FAS-P1 and FAS-P2 ongoing user groups with an incidence rate of 0.1 (0.0, 1.0). These results are very similar to previous studies with numerically higher rate of hypokalemia, especially with higher SZC doses due to its mechanism of action (Hoy, 2018). However, hypokalemic patients could be managed via protocol-directed dose adjustments. Nevertheless, monitoring of HK and appropriate dose optimization are essential when administering SZC at higher doses.

Our study demonstrated effective reduction of sK⁺ levels with manageable AEs. This and previous studies of SZC showed that SZC primarily targets potassium ions in the GI tract, is well tolerated with only minor AEs and no SAEs, and is not associated with a large release and systemic absorption of Na⁺ ions. SZC enables effective binding of potassium ions throughout the GIT, which probably explains the significant decrease in sK⁺ levels within 1 h after the administration of the first 10 g dose in patients with HK. These features may also contribute to the low incidence of GI and systemic AEs (Packham et al., 2015).

This interim analysis has several limitations. As this is a real-world study, the effectiveness and safety after SZC treatment is not comparable to that of non-SZC treatment or placebo group. Moreover, a limited number of patients in a specific treatment option may introduce some extent of bias as it is a single-arm study. Also, as this is an interim analysis, effectiveness and safety data of SZC treatment in the long term are awaited.

The results from the interim analysis of this real-world study demonstrated that SZC was generally well tolerated with low incidences of SAEs and AEs leading to discontinuation in the Chinese population. It was also effective in reducing sK⁺ levels in patients with HK, with a considerable proportion of patients achieving normokalemia after 48 h of treatment and was further maintained up to 6 months in the maintenance phase. Our study results corroborate findings of prior clinical trials and hence SZC could be considered as a good choice for the treatment of acute and chronic HK in China.