Two new agents under development may help curb and prevent elevated potassium levels, the common and serious side effect of drugs that inhibit the renin-angiotensin-aldosterone system (RAAS). These drugs, which include the popular ACE inhibitors and ARBs, are the cornerstones of the treatment of chronic kidney disease and heart failure. Current treatments for high potassium levels, also called hyperkalemia, are often poorly tolerated and ineffective, meaning that a substantial number of seriously ill patients with heart failure and chronic kidney disease can't receive the full benefits of the RAAS drugs.
In a phase 3 study, published online in the New England Journal of Medicine, researchers first randomized 753 patients with hyperkalemia to treatment for 48 hours with either placebo or 1 of 4 different doses of sodium zirconium cyclosilicate (ZS-9), a novel agent from ZS Pharma that captures potassium in the GI tract and rapidly lowers serum potassium. Treatment with ZS-9 was associated with clinically important and statistically significant reductions in potassium during this period. At the highest 2 doses the investigators reported normalization of serum potassium, with the highest dose leading to a mean reduction in serum potassium of 1.1 mmol/liter in patients who had levels greater than 5.5 mmol/liter at baseline.
Patients who achieve normal potassium levels during the initial phase were then randomized in a maintenance phase of the study to continued treatment with ZS-9 or placebo on days 3-14. In the placebo group potassium levels remained elevated above 5.0 mmol/liter, while in the groups taking the two highest doses of ZS-9 potassium levels were 4.7 and 4.5 mmol/liter. ZS-9 treatment did not lead to an excess of adverse events. The most common complication was diarrhea.
In a second report, also published in the New England Journal of Medicine, investigators first treated 237 chronic kidney disease patients who had elevated potassium levels with patiromer, a nonabsorbed polymer that binds potassium and which is under development by Relypsa. After 4 weeks of treatment potassium was reduced by 1 mmol/liter and 76% of the patients had reached target levels.
In a second, withdrawal phase of the study, 107 patients were randomized to placebo or patiromer for 8 weeks. Hyperkalemia occurred in 60% of patients in the placebo group compared with only 15% of patients in the treatment group. Constipation was the most common adverse event linked to patiromer.
In an accompanying editorial, Julia Ingelfinger states that both agents "appear to offer some promise for the treatment of hyperkalemia in patients with chronic kidney and cardiac disease." She is concerned, however, about the long-term "durability and side-effect profile of these agents" given the relatively short span of these two studies. "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."
