Sodium Zirconium Cyclosilicate for Renin-Angiotensin-Aldosterone System Inhibitor Therapy Optimization: A Systematic Review and Meta-Analysis with Meta-Regression

fx1 • SZC increases RAAS inhibitor maintenance by 26% • SZC enables 47% higher RAASi up-titration • SZC reduces RAASi dose reduction or discontinuation risk by 44% • Greater potassium reduction boosts higher RAASi maintenance Introduction and objectives: Renin–angiotensin–aldosterone system inhibitors (RAASi) are essential in chronic kidney disease (CKD) and heart failure (HF) management but may increase the risk of hyperkalemia (HK). Sodium zirconium cyclosilicate (SZC), a novel potassium binder, may enable sustained RAASi use and dose optimization. This meta-analysis evaluated the association between SZC therapy and RAASi maintenance and optimization. Methods: We systematically searched PubMed, Embase, Cochrane, and Web of Science from inception until August 2025 for RCTs, observational studies and post-hoc analyses comparing SZC with placebo or standard care in RAASi-treated patients with HK (PROSPERO registration: CRD42024603403). Six studies (3 RCTs, 3 observational; n=79,956 patients) with 3–12 months follow-up were included. Primary outcomes were: RAASi maintenance, up-titration, and discontinuation/down-titration. Subgroup analyses and comparator-stratified analyses were performed. An exploratory meta-regression was conducted to evaluate potassium reduction magnitude and RAASi maintenance association. Results: SZC was associated with a higher likelihood of RAASi maintenance (RR 1.26; 95% CI 1.14–1.40; I² = 77%) and up-titration (RR 1.47; 95% CI 1.20–1.80), and with a lower risk of discontinuation or down-titration (RR 0.56; 95% CI 0.46–0.68). Subgroup analyses showed consistent benefits in patients with baseline potassium >5.0 mEq/L and in RCT-only analyses. The exploratory meta-regression revealed a statistically significant ecological association between the magnitude of potassium reduction and RAASi maintenance (p=0.002). SZC was associated with improved maintenance and optimization of RAASi therapy in hyperkalemic patients with CKD and HF. These findings reflect treatment optimization as a process outcome rather than demonstrated clinical benefit. Randomized trials powered for cardiovascular and renal endpoints are needed to determine whether facilitating RAASi continuation translates into improved clinical outcomes. Conclusion: SZC was associated with improved maintenance and optimization of RAASi therapy, while reducing the risk of down-titration or discontinuation. Randomized trials powered for cardiovascular and renal endpoints are needed to determine whether SZC use translates into improved patient outcomes.