New potassium binders reduce the risk of hyperkalaemia in patients treated with renin–angiotensin–aldosterone system inhibitors

Hyperkalaemia, defined as serum K+ levels (s-K+) >5.0 mEq/L, is a common electrolyte disorder associated with increased all-cause and in-hospital mortality.1–5 Potential mechanisms of hyperkalaemia include increased K+ intake, impaired distribution between intra-/extracellular spaces, and, mainly, decreased renal K+ excretion.5–7 Patients at higher risk of hyperkalaemia are those with chronic kidney disease (CKD), diabetes, and cardiovascular diseases [hypertension, heart failure (HF), or myocardial infarction], which are treated with renin–angiotensin–aldosterone system inhibitors (RAASIs: angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone receptor antagonists).3,5–9 In these patients, RAASIs significantly improve cardiovascular and renal outcomes, but they increase s-K+, hyperkalaemia being a key limitation to titrate the dose of RAASIs fully in those patients who are most likely to benefit from treatment.3,5–11 Long-term treatment of hyperkalaemia included reducing K+ intake and drugs that compromise renal function and/or increase faecal (resins, mainly sodium polystyrene sulphonate) and renal K+ excretion (loop/thiazide diuretics, haemodialysis).3,4,7,9,11 However, because of the limited effectiveness and safety concerns of these therapeutic options, clinicians frequently do not prescribe RAASIs, discontinue the treatment, or use RAASIs at doses lower than those recommended in clinical guidelines. However, patients on submaximum doses or who discontinue RAASIs have worse cardiovascular or renal outcomes than patients on maximum tolerated doses.5,11,12 Therefore, we need new drugs for the long-term treatment of hyperkalaemia in patients treated with RAASIs. Very recently, two new oral non-absorbed K+ binders, Patiromer sorbitex calcium (Veltassa®) and zirconium cyclosilicate (ZS-9), were developed to increase faecal K+ excretion acting mainly in the colon.9,13 In randomized clinical trials (RCTs), they produce a dose-dependent and sustained reduction of elevated s-K+, preventing the recurrences of hyperkalaemia in patients treated with RAASIs with an acceptable safety profile. Thus, for the first time in almost 50 years, Patiromer and ZS-9 may allow the titration and maintenance of guideline-recommended doses of RAASIs in high-risk patients who otherwise would not tolerate them due to hyperkalaemia. However, several questions remain regarding their efficacy and safety including the following. Colonic excretion of K+ increases as the estimated glomerular filtration rate (eGFR) declines below 20 mL/min/1.73 m2, representing a pathway that partially compensates for the reduced renal K+ excretion.13 However, the direct effects of Patiromer and ZS-9 on the mechanisms regulating colonic K+ excretion are still poorly understood, and it is uncertain whether bowel obstruction, major gastrointestinal (GI), or severe GI disorders may affect their efficacy because patients with serious GI disorder/surgery were excluded in the clinical studies. It is uncertain whether Patiromer and ZS-9 are useful to reduce s-K+ to a sufficient degree and within an acceptable time in patients with life-threatening hyperkalaemia. In hyperkalaemic patients (s-K+ 5.5 to <6.5 mEq/L) taking at least one RAASI, Patiromer (8.4 g b.i.d.) reduced s-K+ to 0.21 mEq/L after 7 h, which would limit its usefulness. However, in 45 patients with s-K+ 6.1–7.2 mEq/L, a single dose of ZS-9 (10 g) reduced s-K+ to 0.6 mEq/L at 2 h and, after 4 h, 52% of patients had an s-K+ ≤5.5 mEq/L.14 However, this study was not specifically designed to assess the effects of ZS-9 in patients with severe acute hyperkalaemia. Thus, further studies are needed to confirm the safety and efficacy of high doses of ZS-9 in these patients. Trials should include time to achieve normokalaemia (or a specific s-K+ threshold), incidence of arrhythmias, reduction in rescue therapy, and length of stay. The efficacy and safety reported in RCTs must be confirmed in the ‘real world’, i.e. the elderly and patients with co-morbidities and treated with multiple drugs, and thus excluded or under-represented in RCTs. This is the case for non-Caucasians, patients with diabetes, and those with eGFR <30 mL/min/1.72 m2, severe hyperkalaemia (≥6.5 mEq/L), HF (NYHA class IV), GI disorders, major GI surgery, and ECG changes/arrhythmias associated with hyperkalaemia. The incidence and severity of GI and electrolytic adverse effects (hypokalaemia, hypomagnaesemia) were reported in a relatively small number of patients, and few patients were treated with high dosages. Patiromer produces worsening of CKD and exchanges K+ for Ca2+; therefore, it has the potential to cause positive Ca2+ balance and ectopic calcifications.3 ZS-9 exchanges K+ for Na+ and produces Na+ retention and oedema, which may be of concern in patients with CKD, HF, and hypertension. Patiromer and ZS-9 bind to many orally administered medications and can decrease their bioavailability and clinical efficacy. Drug interactions were studied in vitro and in healthy volunteers, but not in high-risk patients or those with cardiovascular diseases treated with complex background therapy. Thus, possible interactions with drugs and nutrients must be clarified. While in RCTs dietary intake of K+ was limited, it is uncertain whether non-adherence to dietary restrictions might influence the efficacy of Patiromer or ZS-9, or whether they might allow fewer dietary restrictions, an effect that will improve the quality of life of hyperkalaemic patients. Recommendations for routine optimal monitoring of drug efficacy and safety (serum electrolytes and renal function) are required. In clinical trials, s-K+ was closely monitored 48–72 h after initiating the treatment and then weekly or even more frequently. Post-marketing studies are warranted to confirm/define the optimal dosing strategy in different subpopulations of high-risk patients. In RCTs, Patiromer was administered b.i.d., while the FDA-approved dosage is q.d. Head-to-head trials between Patiromer and ZS-9 are needed to determine the more effective and safer therapeutic alternative. The effects of Patiromer and ZS-9 on clinical outcomes other than s-K+ have not been evaluated and it remains uncertain whether the correction of hyperkalaemia in high-risk patients with cardiovascular and renal diseases that can facilitate the titration of RAASIs to the guideline-recommended optimal doses will translate into improved long-term cardiovascular and renal morbidity and mortality. In conclusion, Patiromer and ZS-9 (if approved) represent a promising new therapeutic approach for long-term treatment of chronic hyperkalaemia. Further research, however, is needed to fill these gaps in knowledge. In particular, there is a critical need for prospective long-term RCTs to confirm their long-term safety and efficacy in daily clinical practice and whether they can improve cardiovascular and renal outcomes by allowing the titration of RAASIs to the optimal doses in high-risk patients. This work was supported by grants from the Spanish Health Institute Carlos III (PI16/00398 and CB16/11/00303) as well as the BBVA Foundation. Conflict of interest: none declared.