Treatment with patiromer, an investigational hyperkalemia drug, results in significant decreases in serum potassium levels after 4 weeks and consistently maintains normal serum potassium levels over 52 weeks in patients with diabetic kidney disease taking renin-angiotensin-aldosterone system (RAAS) inhibitors, according to a new study.
The phase 2 AMETHYST-DN study, which included 306 hyperkalemic patients with type 2 diabetes and chronic kidney disease (CKD) randomized to 1 of 3 starting doses of patiromer, also demonstrated that, over a 52-week period, the drug was associated with high patient adherence, a low risk of hypokalemia, and minimal discontinuations because of adverse events.
During post-treatment follow-up of 238 patients, researchers observed significant increases in mean serum potassium levels by day 3 post-treatment.
Based on the findings of this study, researchers performed a phase 3 study (OPAL-HK) in which patiromer demonstrated consistent efficacy as shown in the AMETHYST-DN study.
“The 52-week data support the finding of OPAL-HK, demonstrating that long-term management of serum potassium level is needed in patients with CKD taking RAAS inhibitors to reduce recurrence of hyperkalemia,” the investigators, led by George L. Bakris, MD, of the University of Chicago, wrote in the Journal of the American Medical Association (2015;314:151-161). Results of the OPAL-HK were published earlier this year in the New England Journal of Medicine (2015;372:211-221). That trial, led by Matthew R. Weir, MD, of the University of Maryland Medical Center in Baltimore, included 237 patients treated with patiromer. After 4 weeks of treatment, 76% of patients had achieved target potassium levels. In a subsequent randomized withdrawal phase, the investigators assigned 107 patients to receive either patiromer (55 patients) or placebo (52 patients). The median increase in the potassium level from baseline of that phase was significantly greater in the placebo than patiromer arm. In addition, 60% of the placebo arm experienced a recurrence of hyperkalemia through week 8 compared with 15% in the patiromer arm, a significant difference between the groups.
Patiromer is a potassium-binding polymer is an orally administered drug that binds potassium throughout the gastrointestinal tract. It consists of smooth, spherical beads approximately 100 µm in diameter that do not swell appreciably in liquids, Dr. Bakris’ group noted.
In the AMETHYST-DN study, patients with mild hyperkalemia received starting doses of patiromer of 4.2, 8.4, or 12.6 grams twice daily. Patients with moderate hyperkalemia received starting doses of 8.4, 12.6, or 16.8 grams twice daily.
The mean reduction from baseline in serum potassium level at week 4 or time of first dose titration in patients with mild hyperkalemia was 0.35, 0.51, and 0.55 mEq/L for the 4.2, 8.4, and 12.6 gram starting-dose groups, respectively. In the moderate hyperkalemia group, the reduction was 0.87, 0.97, and 0.92 mEq/L for the 8.4, 12.6, and 16.8 gram twice daily starting-dose groups, respectively.
From week 4 through week 52, statistically significant mean decreases in serum potassium levels were observed at each monthly point in patients with mild and moderate hyperkalemia, according to the researchers. Over the 52 weeks, hypomagnesemia was the most common treatment-related adverse event (AE), occurring in 7.2% of patients, the investigators reported. The most common gastrointestinal AE was mild to moderate constipation. Hypokalemia (serum potassium level less than 3.5 mEq/L) developed in 5.6% of patients.
Diabetics with stage 3 or greater CKD taking RAAS inhibitors are the patients at highest risk for hyperkalemia, Dr. Bakris and his colleagues noted. “Owing to the limited utility of current options to manage hyperkalemia, particularly over the long term, clinicians frequently must either avoid using RAAS inhibitors or use them at lower than recommended doses.”
In an accompanying editorial (pp. 129-130), Wolfgang C. Winkelmayer, MD, ScD, of Baylor College of Medicine in Houston, wrote that the findings of Dr. Bakris’ team “have the potential to fundamentally change the current treatment approach for hyperkalemia.”
Dr. Winkelmayer observed that hyperkalemia “is a major factor limiting the longer-term use of RAAS inhibitors in a sizeable proportion of patients using such treatment and has emerged as a major (and treatment-limiting) adverse effect in trials of combination RAAS blockade.”