Sodium zirconium cyclosilicate 10g oral powder sachets

BACKGROUND: Hyperkalemia is a frequent life-threatening condition in hemodialysis (HD) patients. Data comparing the usage of various K + binders in HD patients is still scarce. This study aimed to compare the efficacy and safety of Sodium zirconium cyclosilicate (SZC) and sodium polystyrene sulfonate (SPS) for treatment of hyperkalemia in HD patients. METHODS: This prospective, double-blinded, randomized multicenter clinical trial enrolled 120 HD patients with predialysis serum potassium > 5 mmol/L. Patients were randomized to receive SZC (5 g, 3 times/wk on non-dialysis days, 15 gm/wk) or SPS (15 g, 3 times/wk on non-dialysis days, 45 gm/wk) for 8 weeks. The change in serum potassium through the 8 weeks of the study was our primary outcome. RESULTS: Serum potassium significantly decreased in both groups compared to baseline values from the first week till the end of the study with p value of < 0.001 and < 0.001 respectively. Serum K levels in the SZC group were significantly lower (achieved normokalemia after 2 weeks) than K levels in the SPS group (achieved normokalemia after 6 weeks) through the study period (p < 0.001). Rescue therapy for hyperkalemia was less frequent in the SZC group (3.3%) than the SPS group (6.6%) (p = 0.678). Gastrointestinal side effects were non significantly fewer with SZC (5%) compared to SPS (11.6%). However, SPS was less palatable (p < 0.001). CONCLUSIONS: When compared to SPS treatment, SZC was associated with a more rapid and efficacious resolution of hyperkalemia with potentially a better safety profile and palatability among HD patients. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT06029179. First registration date: 9/01/2023.

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BACKGROUND: To effectively manage the progression of diabetic kidney disease, it is essential to address the associated hyperkalaemia while concurrently using renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists. In this study, we aim to evaluate the effects of administering sodium zirconium cyclosilicate (SZC) to patients with type 2 diabetes mellitus (T2DM) complicated by hyperkalaemia. METHODS AND ANALYSIS: A total of 80 patients with type 2 diabetes and hyperkalaemia will be included in the study and randomly stratified into two groups.After consent, both groups will enter an initiation phase, receiving 10 g of SZC, three times per day for 2 days. SZC administration (5 g once daily) will subsequently commence in group A, while dietary therapy will be initiated in group B by implementing a potassium-restricted diet. The primary endpoint of the study is the proportion of normokalaemic (3.5 mEq/L≤serum potassium (sK)<5.0 mEq/L) participants at visit 7. The secondary endpoints are: (a) the proportion of normokalaemic participants (3.5 mEq/L≤sK<5.0 mEq/L) at visit 4 and (b) serum potassium levels at visit 7. ETHICS AND DISSEMINATION: Written informed consent will be obtained from all participants prior to commencing the study. This study has been approved by the Kyoto Prefectural University of Medicine Clinical Research Review Board. All data obtained from this study will be published in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: jRCTs051230067.

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Background: Sodium zirconium cyclosilicate (SZC) is a novel potassium-binding agent with strong evidence supporting its efficacy in normalizing hyperkalemia. However, the long-term prognostic impact of SZC-integrated medical therapy in patients with systolic heart failure and baseline hyperkalemia remains uncertain. Methods: This study included patients with heart failure and a left ventricular ejection fraction (LVEF) of &lt;50% who were prescribed SZC for hyperkalemia between July 2020 and February 2025. Patients who continued SZC therapy for two years or until February 2025 were classified into the SZC continuation group and followed from the initiation of SZC. Those who discontinued SZC during the study period were assigned to the SZC discontinuation group, with follow-up commencing from the point of cessation. The two-year cumulative incidence of all-cause mortality or hospital readmission was compared between the groups. Results: A total of 61 patients (median age: 79 years; 33 men; median LVEF: 42%) were included in the analysis. Serum potassium levels significantly decreased in the SZC continuation group (p &lt; 0.001) but remained unchanged in the SZC discontinuation group (p = 0.23). The SZC continuation group demonstrated a trend toward a lower cumulative incidence of the primary outcome compared to the SZC discontinuation group (29% vs. 47%, p = 0.079). Additionally, in the SZC continuation group, the daily doses of renin-angiotensin system inhibitors and mineralocorticoid receptor antagonists increased significantly (p &lt; 0.05 for both). Furthermore, LVEF improved significantly with SZC-integrated medical therapy (p = 0.011), whereas no such changes were observed in the SZC discontinuation group (p &gt; 0.05 for all). Conclusions: Long-term SZC-integrated medical therapy was associated with the sustained normalization of hyperkalemia, optimization of heart failure pharmacotherapy, and improved clinical outcomes in patients with systolic heart failure and baseline hyperkalemia. These findings underscore the need for prospective randomized controlled trials in carefully selected patient populations to validate the benefits of SZC and establish its optimal supportive role in the management of systolic heart failure.

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INTRODUCTION: Hyperkalemia is a serious medical condition that often manifests in patients with chronic kidney disease and heart failure. Renin-angiotensin-aldosterone system inhibitors are known to improve outcomes in these disease states but can also cause drug-induced hyperkalemia. New therapeutic options exist for managing hyperkalemia in these patients which warrant evidence-based evaluation. AIM: The objective of this article was to review the efficacy and safety evidence for patiromer, sodium zirconium cyclosilicate (ZS9), and sodium polystyrene sulfonate (SPS) for the treatment of hyperkalemia. EVIDENCE REVIEW: Current treatment options to enhance potassium excretion are SPS and loop diuretics, which are complicated by ambiguous efficacy and known toxicities. Patiromer and ZS9 are new agents designed to address this treatment gap. Both unabsorbable compounds bind potassium in the gastrointestinal (GI) tract to facilitate fecal excretion. The capacity to bind other medications in the GI tract infers high drug-drug interaction potential, which has been demonstrated with patiromer but not yet investigated with ZS9 or SPS. Phase II and III clinical trials of patiromer and ZS9 demonstrated clear evidence of a dose-dependent potassium-lowering effect and the ability to initiate, maintain, or titrate renin-angiotensin-aldosterone system inhibitors. There is limited evidence base for SPS: two small clinical trials indicated potassium reduction in chronic hyperkalemia. All agents may cause adverse GI effects, although they are less frequent with ZS9. Concerns remain for SPS to cause rare GI damage. Electrolyte abnormalities occurred with patiromer and SPS, whereas urinary tract infections, edema, and corrected QT-interval prolongations were reported with ZS9. CONCLUSION: Patiromer and ZS9 have improved upon the age-old standard SPS for the treatment of hyperkalemia. Additional research should focus on drug-drug interactions in patients on multiple medications, incidence of rare adverse events, and use in high-risk populations.

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Sodium zirconium cyclosilicate (Lokelma™) [hereafter referred to as SZC] is a non-absorbed, non-polymer zirconium silicate compound that preferentially exchanges hydrogen and sodium for potassium and ammonium ions in the gastrointestinal tract (GIT), thereby increasing faecal potassium excretion and lowering serum potassium levels. It is available as a powder for oral suspension (in water) and is approved in the EU and the USA for the treatment of hyperkalaemia in adults. In two multinational, phase III studies in adults with hyperkalaemia, SZC 10 g three times daily lowered serum potassium levels to within the normal range (3.5-5.0 mmol/L) during the first 48 h of treatment, and SZC 5 and 10 g once daily maintained normokalaemia over ≤ 28 days' therapy. These beneficial effects were consistent across all patient subgroups (e.g. chronic kidney disease, diabetes, heart failure, concomitant use of RAAS inhibitor therapy), and appeared to be maintained over the longer term (≤ 12 months). SZC was generally well tolerated in adults with hyperkalaemia. Its tolerability profile was generally similar to that seen with placebo over ≤ 28 day, and its safety profile appeared to remain consistent over the longer term (≤ 12 months). Moreover, the incidence of hypokalemia was low. Current evidence indicates that SZC is a promising therapy for the management of hyperkalaemia in adults.

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BACKGROUND: Mineralocorticoid receptor antagonists (MRA) improve outcomes in patients with heart failure and reduced ejection fraction (HFrEF) but are underused in clinical practice. Observational data suggest that hyperkalemia is the leading obstacle for the suboptimal use of MRA. OBJECTIVES: This study sought to evaluate the effects of sodium zirconium cyclosilicate (SZC) in optimizing use of spironolactone among participants with HFrEF and hyperkalemia. METHODS: REALIZE-K (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone) was a prospective, double-blind, randomized- withdrawal trial in participants with HFrEF (NYHA functional class II-IV; left ventricular ejection fraction ≤40%), optimal guideline-directed therapy (except MRA), and prevalent or incident MRA-induced hyperkalemia. During open-label run-in, participants underwent spironolactone titration (target: 50 mg/day); those with hyperkalemia started SZC. Participants with normokalemia (potassium: 3.5-5.0 mEq/L) on SZC and spironolactone ≥25 mg/day were randomized to continued SZC or placebo for 6 months. The primary endpoint was optimal treatment response (normokalemia on spironolactone ≥25 mg/day without rescue therapy for hyperkalemia [months 1-6]). The 5 secondary endpoints were tested hierarchically. Exploratory endpoints included a composite of adjudicated cardiovascular death or worsening heart failure (HF) events (hospitalizations and urgent visits). RESULTS: Overall, 203 participants were randomized (SZC: 102; placebo: 101). Higher percentage of SZC- vs placebo-treated participants had optimal response (71% vs 36%; OR: 4.45; 95% CI: 2.89-6.86; P < 0.001). SZC (vs placebo) improved the first 4 secondary endpoints: normokalemia on randomization dose of spironolactone and without rescue therapy (58% vs 23%; OR: 4.58; 95% CI: 2.78-7.55; P < 0.001); receiving spironolactone ≥25 mg/day (81% vs 50%; OR: 4.33; 95% CI: 2.50-7.52; P < 0.001); time to hyperkalemia (HR: 0.51; 95% CI: 0.37-0.71; P < 0.001); and time to decrease/discontinuation of spironolactone due to hyperkalemia (HR: 0.37; 95% CI: 0.17-0.73; P = 0.006). There was no between-group difference in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score at 6 months (-1.01 points; 95% CI: -6.64 to 4.63; P = 0.72). Adverse events (64% vs 63%) and serious adverse events (23% vs 22%) were balanced between SZC and placebo, respectively. Composite of cardiovascular (CV) death or worsening HF occurred in 11 (11%) participants in the SZC group (1 with CV death, 10 with HF events) and 3 (3%) participants in the placebo group (1 with CV death, 2 with HF events; log-rank nominal P = 0.034). CONCLUSIONS: In participants with HFrEF and hyperkalemia, SZC led to large improvements in the percentage of participants with normokalemia while on optimal spironolactone dose, and reduced risk of hyperkalemia and down-titration/discontinuation of spironolactone. Although underpowered for clinical outcomes, more participants had HF events with SZC than placebo, which should be factored into the clinical decision making. (Study to Assess Efficacy and Safety of SZC for the Management of High Potassium in Patients With Symptomatic HFrEF Receiving Spironolactone; NCT04676646).

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Sodium zirconium cyclosilicate (SZC) is a novel therapeutic agent for hyperkalemia. However, limited reports have described its real-world safety. In this study, we used the Food and Drug Administration Adverse Event Reporting System (FAERS) database to evaluate the safety profilet of SZC. This retrospective analysis involved FAERS data from the third quarter of 2018 to the fourth quarter of 2023. A disproportionality analysis, including reporting odds ratio (ROR), proportional reporting ratio (PRR), empirical bayesian geometric mean(EBGM), and bayesian confidence propagation neural network (BCPNN), was conducted to quantify the signals of SZC-related adverse events (AEs). Sex subgroup analyses were also conducted. A total of 1,154 SZC-related AE reports were obtained from the FAERS database. SZC-related AEs primarily targeted 21 system organ classes after simultaneously conforming to the four algorithms. The most common AEs included X-ray gastrointestinal tract abnormalities(ROR = 3888.02[1051.8, 14372.15]) and blood potassium abnormal(ROR = 212.53[134.73, 335.26]), consistent with prior findings and clinical trials. Unexpected significant AEs included ileus (ROR = 27.82[14.44, 53.59]), death (ROR = 17.49[15.7, 19.49]) and congestive cardiac failure (ROR = 16.66[10.94, 25.37]). Sex-based differences were observed for AEs. The median onset time of SZC-related AEs was 33 days. This study confirms common AEs of SZC and identifies new ones, highlighting the need for careful monitoring and facilitating its safe use in clinical settings. However, disproportionality analysis cannot formally prove causation and further studies are needed to confirm these associations.

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INTRODUCTION: Sodium zirconium cyclosilicate (SZC) binds with potassium in the gastrointestinal tract and increases fecal potassium excretion. Since SZC is a novel and non-swelling drug, the risk of intestinal perforation is not mentioned in the package insert. We hereby report the case of sigmoid colon perforation caused by hard stools and severe hypokalemia in a patient suffering from advanced rectal cancer, who was taking SZC. CASE PRESENTATION: A woman in her 80s with a history of primary biliary cirrhosis and decompensated cirrhosis accompanied by hyperkalemia was administered SZC. The patient was rushed to the hospital on the 23rd day following the commencement of SZC, complaining of abdominal pain and nausea. She suffered from sigmoid colon perforation. Hartmann's operation with drainage was performed. SZC was discontinued after admission, following which the serum potassium levels normalized. Despite the diagnosis of advanced rectal cancer during her hospital stay, the curative operation and stoma closure were judged to be inoperable because of her physical condition. CONCLUSIONS: SZC is said to be associated with a lower risk of intestinal perforation compared with other similar drugs; however, in patients with certain conditions, such as intestinal obstruction or transit disorder resulting from malignant disease, adhesion, and inflammatory diseases, the accumulation of SZC in the intestinal lumen might increase the risk of perforation.

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