Therapeutic Potential of Newer Drugs for Treating Hyperkalemia

Hyperkalemia is a potentially serious medical condition that can result in cardiac arrhythmia and sudden death. It is more commonly seen in patients who are older, have CKD, have diabetes, or are receiving renin-angiotensin aldosterone-system inhibitors (RAASis). The problem is frequent in clinical practice and often leads to increased use of health care resources. An episode of hyperkalemia in hospitalized patients with or without CKD increases the odds of mortality within 1 day of the event (1). RAASis are some of the most important therapies to use in patients with CKD and/or cardiovascular disease. RAASis are either underdosed or stopped in patients who develop hyperkalemia. Although there are a number of effective therapeutic options for the acute management of chronic hyperkalemia, opportunities to provide safe, effective, and well tolerated management of chronic hyperkalemia are limited. Traditionally, health care providers focus on diet, although there are limited data to suggest that dietary modification chronically controls hyperkalemia over the long-term in patients with CKD (2). Intensified use of diuretics (especially loop diuretics), reduction or cessation of RAASi, or intermittent use of sodium polystyrene sulfonate are other strategies. The latter drug has been in use for many decades. Yet, because of its foul taste and consistency and the potential risk for colonic injury (3), it has not been demonstrated to be an effective approach in long-term clinical studies to manage chronic hyperkalemia.

Over the last few years, two new potassium binding therapies have been in development. In 2015, the Food and Drug Administration (FDA) approved patiromer, a polymer that exchanges calcium for potassium, as a chronic treatment for hyperkalemia (4). In the past year, the FDA has approved sodium zirconium cyclosilicate (SZC) for management of hyperkalemia. The report by Spinowitz et al. (5) is important, because it provides 1-year data on the use of this drug to control hyperkalemia in a group of participants who are hyperkalemic, many of whom had an eGFR below 60 ml/1.73 m². Many patients (65%) were also taking RAASis. The main strength of the paper is the large number of participants (n=745) and the 1-year duration of treatment. The only weakness is the lack of a placebo group to provide contrast with the treatment group with regard to adverse events. Overall, the SZC therapy was well tolerated, and it was simply administered as a once a day medication dissolved in a small amount of water, preferably taken separately from other medications by at least 2 hours. Side effects likely related to the medication included constipation (6%), hypertension (11%), and peripheral edema (10%). However, the latter two side effects are often seen in patients with CKD and may not necessarily be related to the therapy. It should be noted, however, that sodium is exchanged for potassium with this medication, which could potentially explain some of the observations, especially if higher doses are used. During the study, the serum potassium was maintained at ≤5.1 mEq/L in 88% of participants and ≤5.5 mEq/L in 99% of participants. Perhaps the most important observations in the study were that, of the 483 hyperkalemic RAASi users at baseline, 87% continued on therapy or had their dose increased, and only 11% of patients had RAASis discontinued. Among 263 RAASi-naïve participants, 14% were initiated on RAASi therapy.

Given that both patiromer and SZC are simply administered, well tolerated, safe, and effective, health care providers now have two viable choices to consider for long-term management of hyperkalemia. This leads to an important question: is it possible now to safely enable optimal RAASi (evidenced-based dosing) in patients who have been previously untreated, dose reduced, or stopped in the past. As such, these new potassium binders may be more than a treatment for hyperkalemia but a means for facilitating RAASi in patients with kidney and/or cardiovascular disease. Health care providers are well aware of evidence-based treatment recommendations for RAASis in patients with proteinuric diabetic kidney disease (6,7). Only full therapeutic doses of RAASi have been demonstrated to being effective in providing a 20% relative risk reduction benefit on the progression of established CKD to an end point of doubling of creatinine, ESKD, or death (6,7). Yet, the vast majority of patients with diabetic kidney disease, especially if it is more advanced, either are not on RAASis or are on much lower doses, which have been demonstrated to be beneficial in protecting and stabilizing kidney function. Likewise, patients with systolic heart failure, especially if they have reduced kidney function or cardiorenal syndrome, often are underdosed with RAASis. In addition, patients with congestive heart failure often do not receive mineralocorticoid receptor antagonists, despite the benefit of these drugs for reducing morbidity and mortality in patients with congestive heart failure (8). Interestingly, patients with congestive heart failure treated with mineralocorticoid receptor antagonists derive mortality benefit even in the presence of higher serum potassium levels (9).

From a pragmatic standpoint, enabling RAASi sounds so simple. Yet, it does require more effort on part of the health care provider to carefully monitor the patient, encourage adherence and insist that the patient return for follow-up laboratory appointments. Despite the increased work load, the long-term benefits for the patient could be substantial.

Given the cost of these new therapies, studies need to be designed to demonstrate the utility of RAASi enabling in patients with CKD, congestive heart failure, or both. This would provide an opportunity to examine the value of controlling hyperkalemia and maintaining evidence-based doses of RAASi, mineralocorticoids receptor antagonists, or both. A study conducted in patients with congestive heart failure demonstrated the short-term benefits of using a potassium-binding therapy with patiromer in enabling and maintaining spironolactone therapy over a period of 4 weeks (10). However, this pilot study was not of sufficient duration to allow an assessment on mortality. Consequently, longer-term studies are needed to demonstrate that RAASi enabling does provide a demonstrable clinical benefit.

From a safety standpoint, it may be more practical to use a potassium binder rather than increase the dose of loop diuretics to control hyperkalemia. This could lead to volume depletion and worsening azotemia in patients with CKD or hypotension and AKI in patients with congestive heart failure. Additionally, in one study with placebo-controlled withdrawal of the potassium binder patiromer, there was no evidence of a rapid return of hyperkalemia after cessation of the potassium binder. The slow return of serum potassium to baseline is important and indicates no evidence of a quick rebound.

Thus, if there is an unanticipated cessation of therapy or nonadherence sufficient homeostatic mechanisms are in place to avoid abrupt changes in serum potassium, which could be life threatening.

There are some minor obstacles, however, with these newer therapies. The potassium binders need to be separated from other medications (for 2 hours for SZC and for 3 hours for patiromer) due to the potential of binding other drugs. However, this is a minor inconvenience relative to the opportunity to maintain RAASi. Incidentally, all of the development studies with these drugs were done without any separation from other medications, and there was no clinical evidence of an interaction.

The introduction of safe, effective, and well tolerated potassium binders is not simply a measure to treat hyperkalemia, but it may facilitate more opportunity to optimize RAASi use in patients with CKD and/or cardiovascular disease.

Disclosures

Dr. Weir reports personal fees from Relypsa, personal fees from ZS Pharma during the conduct of the study, personal fees from Akebia, personal fees from Janssen, personal fees from AstraZeneca, personal fees from Amgen, personal fees from MSD, personal fees from AbbVie, personal fees from Novartis, personal fees from Boston Scientific, and personal fees from Sandoz outside the submitted work.