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.