New Therapies for Hyperkalemia

Silvia J. Leon; Oksana Harasemiw; Navdeep Tangri


Curr Opin Nephrol Hypertens. 2019;28(3):238-244. 

In This Article

Abstract and Introduction


Purpose of review: Although renin–angiotensin aldosterone system (RAAS) inhibitors have become the mainstay treatment for patients with chronic diseases, hyperkalemia is a major contributory deterrent to their use in patients with chronic kidney disease (CKD) and heart failure. For the first time in 50 years, two new therapies (patiromer and ZS-9) have recently emerged for the concomitant treatment of hyperkalemia in these patients. The objective of this review is to discuss the efficacy and safety of these new agents.

Recent findings: Patiromer effectively reduces serum potassium in patients with CKD and heart failure, even with the concomitant use of RAAS inhibitors. The most common adverse events in clinical trials were gastrointestinal events. ZS-9 (Lokelma) rapidly reduces serum potassium levels and to a greater magnitude, and has a role in the acute management of hyperkalemia. Despite having more adverse events than patiromer, ZS-9 is overall well tolerated.

Summary: These new therapies show promising results for the chronic management of hyperkalemia, whilst also potentially allowing for the concomitant use of RAAS inhibitors at optimal doses. More research is needed to examine the benefits of continuation of RAAS inhibitors after an episode of hyperkalemia in patients with CKD and heart failure.


Hyperkalemia is a serious electrolyte disorder, and an independent risk factor for arrhythmias, mortality and hospitalizations.[1,2] The prevalence of hyperkalemia in the general population is only 2–3.5%;[3,4] however, it is significantly higher in hospitalized patients, with the prevalence ranging from 1 to 10%.[4–6] In a retrospective Canadian cohort study with 64 579 patients, hyperkalemia was diagnosed in 2.6% of all emergency department visits and in 3.5% of hospitalized patients.[7] Variation in prevalence rates is attributed to the study population studied and the cut-off level for serum potassium used (≥5.0 versus ≥5.5 mmol/l).[4] The development of hyperkalemia is multifactorial, with several known risk factors, including chronic kidney disease (CKD) stages 3–5,[8] advanced age, heart failure and diabetes mellitus.[3,9] In addition, although renin–angiotensin aldosterone system (RAAS) inhibitors are the first-line therapy in patients with diabetic nephropathy and CKD as they offer cardiovascular and renal protection beyond those resulting after blood pressure control, their use is also associated with an increased risk of hyperkalemia.

The increasing prevalence of chronic diseases, such as heart failure, diabetes mellitus and CKD, along with the presence of clinical guidelines recommending RAAS inhibitors as the first-line therapy for these diseases[10,11] is thought to be contributing to an increasing prevalence of hyperkalemia. Although much is known about hyperkalemia, there is currently no standard of care for its treatment.[12,13] The chronic treatment and prevention of recurrent hyperkalemia generally involves the discontinuation of medications associated with hyperkalemia, or the continuation at suboptimal doses. This is an important therapeutic barrier, considering the known benefits of RAAS inhibitor therapy.

Currently, long-term treatment relies on sodium polystyrene sulfonate (SPS), which is a cation exchange resin functioning on the lower gastrointestinal tract and distal colon. The potassium lowering effect of SPS takes several hours, which makes it less suited for acute management, and since SPS exchanges sodium for potassium which could increase the total body sodium, it should be used with caution in patients with heart failure. Furthermore, to avoid constipation, SPS is administered concomitantly with sorbitol. However, in 2009, the Food and Drug Administration (FDA) issued a drug warning regarding the use of SPS with sorbitol after studies reported intestinal necrosis associated with its use. In this regard, a systematic review concluded that SPS use with or without sorbitol may be associated with serious gastrointestinal mucosal injury and life-threatening events, finding a mortality rate of 33% among patients with gastrointestinal injury secondary to SPS use.[14] Furthermore, questions about its efficacy have also been raised, and several reviews of the management of hyperkalemia have highlighted the need for newer treatment options.[15,16] In recent years, two new agents for the treatment of hyperkalemia have become available – patiromer and sodium zirconium cyclosilicate.