REVIEW ARTICLE New Therapeutic Approaches for the Treatment of Hyperkalemia in Patients Treated with Renin-Angiotensin-Aldosterone System Inhibitors Juan Tamargo 1 & Ricardo Caballero 1 & Eva Delpón 1 # Springer Science+Business Media, LLC, part of Springer Nature 2018 Abstract Hyperkalemia (serum potassium > 5.5 mEq/L) is a common clinical problem in patients with chronic kidney disease, hyperten- sion, diabetes, and heart failure. It can result from increased K + intake, impaired distribution between intracellular and extracel- lular spaces, and most frequently, decreased renal excretion. Patients at the highest risk of hyperkalemia are treated with renin- angiotensin-aldosterone system inhibitors (RAASIs) as they improve cardiovascular and renal outcomes and are strongly rec- ommended in clinical guidelines. However, RAASIs cause or increase the risk of hyperkalemia, a key limitation to fully titrate RAASIs in patients who are most likely to benefit from treatment. Until recently, drugs for the treatment of hyperkalemia presented limited efficacy and/or safety concerns and there was an unmet need of new drugs to control hyperkalemia while maintaining RAASI therapy. We provide an overview of the mechanisms involved in K + homeostasis and the epidemiology and management of hyperkalemia as a complication in cardiovascular patients and, finally, analyze the efficacy and safety of two new polymer-based, non-systemic agents, patiromer calcium and sodium zirconium cyclosilicate (ZS-9), designed to increase fecal K + loss and to normalize elevated serum K + levels and chronically maintain K + homeostasis in hyperkalemic patients treated with RAASIs. Keywords Hyperkalemia . Chronic kidney disease . Heart failure . Patiromer sorbitex calcium . Potassium binders . Renin-angiotensin-aldosterone inhibitors . Sodium zirconium cyclosilicate Abbreviations ACEIs Angiotensin-converting enzyme inhibitors AEs Adverse events ARBs Angiotensin receptor blockers CKD Chronic kidney disease eGFR Estimated glomerular filtration rate HF Heart failure K + Potassium ions MRAs Mineralocorticoid receptor antagonists s-K + Serum K + RAASIs Renin-angiotensin-aldosterone system inhibitors ZS-9 Sodium zirconium cyclosilicate Introduction Potassium (K + ) is the most abundant cation in the human body (50–75 mEq/kg). Under physiological conditions, 98% of K + is found in the intracellular space (3500 mEq, ~ 140– 150 mEq/L) and only 2% in the extracellular space (70 mEq, 3.8–5.0 mEq/L) [1–3]. This large K + gradient is critical for maintaining the resting membrane potential, cellu- lar excitability, muscle cell contraction, cardiac action poten- tial duration, gastrointestinal motility, neurotransmitter and hormone secretion, and acid-based and hydroelectrolyte bal- ance [1–4]. Total body K + content and tissular distribution of K + depend on dietary K + and supplemental intake and coor- dination of physiological mechanisms that maintain K + ho- meostasis [1–4]. As a result, serum K + (s-K + ) levels are tightly regulated between 3.5 and 5.0 mEq/L. In individuals on a normal Western diet, the daily K + intake (80–100 mEq) is matched by rapid and equivalent increases in K + excretion (90–95% by the kidneys; 5–10% in feces) and the rapid * Juan Tamargo jtamargo@med.ucm.es 1 Department of Pharmacology, School of Medicine, Instituto de Investigación Sanitaria Gregorio Marañón, CIBERCV, Universidad Complutense, 28040 Madrid, Spain Cardiovascular Drugs and Therapy https://doi.org/10.1007/s10557-017-6767-5