Sodium zirconium cyclosilicate for renin-angiotensin-aldosterone system inhibitor therapy optimization: A systematic review and meta-analysis with meta-regression.

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 >5.0mEq/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). 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.