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Amid positive data from three trials on two novel agents for hyperkalemia, questions about long-term safety and efficacy remain, researchers said.

In the last few weeks, there have been three studies on two drugs: the Journal of the American Medical Association published the results of the looking at zirconium cyclosilicate (ZS-9), and the New England Journal of Medicine published as well as .

According to an , the long-term side effect profile of the drugs is unclear, but "both agents appear to offer some promise for the treatment of hyperkalemia in patients with chronic kidney and cardiac disease."

Current Landscape

Elevated potassium levels are common in chronic kidney disease and heart failure and are often exacerbated by the mainstay of therapy, renin-angiotensin-aldosterone system (RAAS) inhibition.

Hyperkalemia is typically treated with sodium polystyrene sulfonate (Kayexalate), but some questions have arisen about its potential intestinal toxicity.

Nephrologists have acknowledged a need for additional therapies for hyperkalemia.

ZS-9 Studies

ZS-9 is an inorganic cation exchanger with a high selectivity for potassium, and drugmaker ZS Pharma says its product can bind nine times as much potassium as Kayexalate, an organic polymer resin. The drug comes as a fine powder that dissolves in water and is tasteless.

In the HARMONIZE trial, 258 patients were assigned to 10 g of the drug three times daily in the initial 48-hour open-label phase. Patients who achieved normokalemia were then randomized to one of three doses of the drug (5, 10, or 15 g) or to placebo for 28 days.

, of Saint Luke's Heart Institute in Kansas City, Mo., and colleagues that the drug reduced serum potassium to normal levels within 48 hours, and that all three doses of the drug resulted in lower potassium levels for up to 28 days.

Adverse events were comparable between the drug and placebo groups, but edema was more common among patients taking 15 g of ZS-9, the researchers said.

A second trial randomized 753 patients with hyperkalemia to either placebo or ZS-9 three times a day (at a dose of 1.25, 2.5, 5, or 10 g) for 48 hours. Again, patients who hit normal potassium levels were then randomized to the drug or placebo once daily for 14 days.

, of the Melbourne Renal Research Group in Australia, and colleagues found that potassium levels fell in all drug groups, with better decreases for higher doses of the drug.

Those taking 5 and 10 g maintained those decreases in the long run compared with placebo, the researchers said.

Adverse event rates were similar between drug and placebo groups, and diarrhea was the most common complication.

Patiromer Study

looked at a second investigational agent for hyperkalemia: patiromer, a nonabsorbed polymer that binds potassium in exchange for calcium, predominantly in the distal colon where the concentration of free potassium is the highest.

, of the University of Maryland, and colleagues evaluated 237 patients given the drug to treat high potassium levels.

Within 4 weeks, 76% of patients hit the target potassium level of 3.8 to 5.0 mmol/L, they reported, and 107 of those patients were then randomly assigned to either the drug or placebo for the randomized withdrawal phase.

Weir and colleagues found that more patients on placebo had a recurrence in hyperkalemia compared with those on the drug by an additional 8 weeks (60% versus 15%, P<0.001).

Mild-to-moderate constipation was the most common adverse event, and hypokalemia occurred in 3% of patients, they added.

"Although this study showed the benefit of patiromer in treating hyperkalemia and in reducing the risk of recurrence and also showed that more patients in the patiromer group than in the placebo group were able to continue taking RAAS inhibitors, additional data evaluating patiromer therapy in the long term are needed," they wrote.

New Era for Hyperkalemia Treatment?

In an , , of Massachusetts General Hospital, wrote that neither of the current drug therapies for hyperkalemia -- Kayexalate nor calcium polystyrene sulfonate -- is an "appealing option."

"Kayexalate, which was developed in the mid-20th century, requires administration with water, most often with sorbitol added. The preparation, which is taken by mouth, has a noxious taste and may cause diarrhea," she wrote. "When administered as an enema, it is also unpleasant. On rare occasions, necrosis of the colon may occur with its administration, a complication that has resulted in a black-box warning. Loop diuretics, such as furosemide, may not work well in patients with chronic kidney disease. Therefore, new medications would be welcome."

With regard to patiromer, Ingelfinger wrote that the drug needs to be studied for longer than 12 weeks: "Caution is required since many patients are likely to take this agent for a much longer time. In addition, the decrease in potassium with patiromer therapy appears to be gradual, so how well this agent would perform in the acute situation is unclear."

She added that the ZS-9 studies were also relatively short and would need longer-term follow-up, and an also acknowledged that its long-term effects are unknown.

"Certainly, whether either or both of these agents will permit long-term administration of renoprotective and cardioprotective agents that block the RAAS will require more investigation," Ingelfinger wrote.

, of North Shore-LIJ, who was not involved in the study, the decision not to use Kayexalate as a comparator in any of the trials.

"Since all three trials were pharmaceutical company sponsored, placebo was used to compare the agents for efficacy. Why not Kayexalate? It works and it's cheaper. The authors in one study did state that the agent was not compared to sodium or calcium polystyrene since prospective studies are lacking in the latter and also agents cause bowel necrosis," he wrote.

"But there are significant years of experience and pathophysiology that it works. Side effects are part and parcel of every agent. The above agents had constipation as a side effect, and some might have calcium and magnesium concerns if used long-term given how they work. Also, all three trials were very short term, and long-term trials are needed still. FDA approval is also warranted before any use."

"Nevertheless, for the patients we have that have CKD and/or heart failure and we really want them to be on ACEI, ARB or Aldactone but cannot due to K-related concerns and/or require diuretics with them -- now we may have an alternative option for the situation."

, of Duke University, who also was not involved in the study, told 番茄社区app that while the possibility of having new agents for hyperkalemia is exciting, significant questions remain.

"Having an alternative to [Kayexalate] for the treatment of hyperkalemia is exciting. [Kayexalate] was approved by the FDA in 1958 before rigid requirements to show effectiveness and safety. Thus the data in randomized clinical trials are quite slim. Side effects such as intestinal necrosis, particularly when used in combination with sorbitol, and concerns of efficacy have recently intensified ()."

"Both ZS-9 and patiromer appear to be quite effective at lowering serum potassium compared with placebo," Sparks added. "Furthermore, the side effect profile, at least in the short term, appears mild with constipation leading the list for patiromer. No significant safety signals were seen in the two ZS-9 trials."

"Whether or not these therapies will alter important clinical outcomes, particularly in patients prone to develop hyperkalemia, such as those on RAAS blockade, will be the true test," he said. "Will the side effect profile enable chronic therapy and allow patients to continue on RAAS blockade? Will this translate into improved clinical outcomes? These are important questions to ask."

From the American Heart Association:

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