REALIZE-K study of Sodium Zirconium Cyclosilicate for Hyperkalemia in Heart Failure

REALIZE-K study was a prospective, double-blind, randomized withdrawal trial in heart failure with reduced ejection fraction and prevalent or incident mineralocorticoid receptor antagonist induced hyperkalemia [1]. During the initial open-label run-in period, spironolactone titration was done and if hyperkalemia occurred, they were started on sodium zirconium cyclosilicate. Those maintaining normokalemia while on sodium zirconium cyclosilicate and spironolactone of 25 mg/day or more were randomized to either continue sodium zirconium cyclosilicate or placebo for 6 months. Primary endpoint was optimal response without need for rescue therapy for hyperkalemia. Sodium zirconium cyclosilicate is an orally administered inorganic crystal with high affinity for potassium ions. It exchanges potassium ions for hydrogen and sodium. Gastrointestinal absorption of potassium is reduced by this potassium binding agent. It has been demonstrated to be effective in rapidly lowering serum potassium and maintaining normokalemia on the long term in those prone for hyperkalemia [2].

In the REALIZE-K study, use of sodium zirconium cyclosilicate led to large improvements in the percentage of participants with normokalemia while on optimal dosage of spironolactone. Risk of hyperkalemia and down-titration/discontinuation of spironolactone were lesser. Ten heart failure events were noted in the active treatment group of 102 patients while there were only two in the placebo group of 101 patients. Possible reason has been explained in the accompanying editorial [3]. The drug itself adds to the dietary sodium load causing edema and worsening of heart failure. Low levels of dietary potassium per se can promote sodium retention by reducing renal excretion of sodium, independent of dietary sodium and aldosterone signaling [4].

References

1. Kosiborod MN, Cherney DZI, Desai AS, Testani JM, Verma S, Chinnakondepalli K, Dolling D, Patel S, Dahl M, Eudicone JM, Friberg L, Ouwens M, Antunes MO, Connelly KA, Madrini V Jr, Kuthi L, Lala A, Lorenzo M, Guimarães PO, Marcos MC, Merkely B, Nuñez J, Squire I, Václavík J, Wranicz J, Petrie MC. Sodium Zirconium Cyclosilicate for Management of Hyperkalemia During Spironolactone Optimization in Patients With Heart Failure. J Am Coll Cardiol. 2025 Mar 18;85(10):971-984. doi: 10.1016/j.jacc.2024.11.014. Epub 2024 Nov 18. PMID: 39566872.
2. Spinowitz BS, Fishbane S, Pergola PE, Roger SD, Lerma EV, Butler J, von Haehling S, Adler SH, Zhao J, Singh B, Lavin PT, McCullough PA, Kosiborod M, Packham DK; ZS-005 Study Investigators. Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study. Clin J Am Soc Nephrol. 2019 Jun 7;14(6):798-809. doi: 10.2215/CJN.12651018. Epub 2019 May 20. PMID: 31110051; PMCID: PMC6556727.
3. Packer M. Do Potassium Binders Block Both the Benefits and the Risks of Mineralocorticoid Receptor Antagonists in Heart Failure?: The Four Anti-Aldosterone Myths. J Am Coll Cardiol. 2025 Mar 18;85(10):985-987. doi: 10.1016/j.jacc.2025.01.011. PMID: 40074472.
4. Krishna GG, Chusid P, Hoeldtke RD. Mild potassium depletion provokes renal sodium retention. J Lab Clin Med. 1987 Jun;109(6):724-30. PMID: 3585146.