Lokelma (Zirconium Cyclosilicate)
I’m sure everyone has seen our new friend, Lokelma, on the Rush hyperkalemia order set. Thought it would be fun to do a blog post to discuss our new medication. Also have quick blurbs about our friend, Kayexalate, as well as a small summary on Veltassa (Patiromer) that you may see used at other institutions.
So what is Lokelma?
First off, Lokelma is the brand name, and way more preferred over its generic name, Zirconium cyclosilicate, since it says right in the name what it does—it lowers your potassium. If you really want to show your age, you may see it sometimes referred to as ZS-9 when it was first being studied in the early 2010s.
Per Kidney International Journal (who knew this existed): “Zirconium is a biologically inert trace element found widely in nature.” And according to other sources, you likely eat ~4 mg of zirconium daily in your normal diet.
Furthermore, Lokelma differs from our friend, Kayexalate, and our other seen potassium lowering agent, Patiromer (Veltassa), in that Lokelma was specifically engineered as a lattice structure that preferentially traps monovalent cations specifically K+ and NH4+ over divalent cations (e.g. Ca2+ or Mg2+). In contrast, Kayexalate is a nonspecific binding agent which is why it can result in hypocalcemia and hypomagnesemia. In fact, zirconium has been known to have this unique “absorbing” property by nephrology groups for some time, and was actually used as the primary component of the sorbent column in early dialysis machines for its ability to bind urea.
Lastly, Lokelma is also a relatively safe agent as it is completely insoluble in aqueous solutions, and therefore, there is no systemic absorption in the GI tract. In fact, in mice models, there has been 99% recovery of Lokelma in stool of rats treated with Lokelma.
Does it work? What’s the evidence behind it?
There are 4 published studies on the use of Lokelma for treating hyperkalemia in patients with mild hyperkalemia in CKD. On average, onset of action was around 1 hour and median time to achieving normal potassium was 2.2 hours. In addition, ~92% of patients showed normal potassium levels within 48 hours. The most common side effect was mild-to-moderate edema (~6% of patients) which was thought to be from the sodium component of Lokelma. The other most common side effect was GI upset including mild diarrhea, nausea, and abdominal cramping. Most patients tolerated the medication without issue.
One important caveat of these trials is that Lokelma was studied in patients with CKD with mild hyperkalemia. These studies did not include patients with ESRD or emergency department patients with acute elevations in potassium levels. In fact, these trials primarily focused on the exciting new idea that Lokelma could be used concomitantly with ARB/ACE-I for treating CKD patients. For instance, it has been known that ARB/ACE-I are renal protective and would be the ideal HTN medication in patients with CKD. However, their use in this CKD population is limited by their hyperkalemia side effect. With Lokelma, nephrologist could safely give ARB/ACE-I to these CKD patients along with daily Lokelma in long term use.
Below are descriptions of the 4 studies including links to the primary source.
HARMONIZE Trial 2014 (Link)
258 patients with CKD and hyperkalemia received Lokelma 10 grams tid in 48-hour period. Of these patients, 237 patients achieved normokalemia, and were then randomized to the maintenance phase, where they either received Lokelma 5 g (45 pts), 10 g (51 pts), or 15 g (56 pts), or placebo (85 pts) for 28 days. The average potassium level at start of study was 5.6 mEq/L with decline to 4.5 mEq/L during the first 48-hour phase. In fact, median time to normokalemia was 2.2 hours with 84% achieving normokalemia by 24 hours and 98% by 48 hours. The potassium lowering effects of Lokelma were further evidenced by the maintenance phase that showed a stepwise decline in K levels depending on Lokelma dose. The percentage of patients who maintained normokalemia between days 8-29 was highest in the Lokelma 15-gram qd group including (36/45 (80%), 45/50 (90%), and 51/54 (94%) for the 5-g, 10-g, and 15-g Lokelma groups compared to placebo 38/82 (46%).
NEJM 2015 (Link)
Randomized 753 patients with CKD and hyperkalemia to Lokelma 2.5 g, 5 g, 10 g tid, or placebo for 48 hours. After achieving normokalemia, these patients were then randomized to receive Lokelma 5g, 10g, or placebo for 14 days. Again, this study excluded patients with K>6.5, EKG changes, patients requiring hospitalization, and patients receiving HD. These patients on average had K 5.3 mEq/L. The Lokelma 10-g group showed a mean reduction of 0.7 mEq/L vs. a 0.5 mEq/L reduction in both the 5-g and 2.5-g groups. The placebo group had a mean reduction 0.3 mEq/L. Again, this study showed improved rate of normokalemia in the Lokelma group vs. placebo in days 3-14.
Clinical Journal of American Society of Nephrology 2019 (Link)
751 patients with CKD received Lokelma 10 g tid for 24-72 hours. Once they achieved normokalemia, they were randomized to receive Lokelma 5-g qd for 12 months without any dietary or medication restrictions. Of the 751 patients, 746 (99%) achieved normokalemia during the first 72 hours. The mean starting potassium level was 5.5 mEq/L with 82% reaching normokalemia within 24 hours with mean reduction 0.72 mEq/L at 24 hours. However, the main objective of this trial was to observe the real-life compliance of Lokelma as well as to investigate if rates of ARB/ACE-I use increased while on Lokelma. Of these studied patients, 63% of patients completed the 12-month time period. 65% also used ARB/ACE-I with 87% of these patients able to continue or even have their dose increased while on the maintenance dose of Lokelma.
Kidney International 2015 (Link)
This was the first study of Lokelma in Humans. It was a Phase 2 trial that included 90 patients that were randomized to receive Lokelma 0.3 gram (12 pts), 3 gram (24 pts), and 10 grams (24 pts), or placebo (30 pts) tid. The 10-g group saw K levels decrease on average 0.92 mEq/L after 38 hours of treatment. This study also showed that Lokelma was relatively well tolerated.
On the Horizon… Study evaluating Lokelma in patients with acutely elevated K>5.8
There is currently a phase 2, multicenter, randomized, double-blind, placebo study underway called “A Study to Evaluate a Potassium Normalization Treatment Regiment Including Sodium Zirconium Cyclosilicate (ZS) among Patients with S-K >5.8 (ENERGIZE)” (Link). This study is right in the ED realm! It is designed to investigate the use of Lokelma in patients with acute hyperkalemia with K>5.8. The experimental arm will receive Lokelma 10 mg tid in addition to insulin/dextrose, while the control arm will receive placebo in addition to insulin/dextrose. Preliminary results have been released but no formal study results have been compiled. But be on the lookout for this!
Kayexalate hasn’t gotten a lot of love as of late. There’s a lot of blog posts and podcasts (can take a look on EMCrit 2011 and RebelEM 2015) on their view of low evidence and potential GI side effects of using Kayexalate. However, just recently, we do have some evidence on the efficacy of Kayexalate… and it’s actually in conjunction with some of our own Rush ED pharmacy (shout out to Josh DeMott and Gary Peska).
Their paper titled, “Single-dose sodium polystyrene sulfonate for hyperkalemia in chronic kidney disease or end-stage renal disease” from 2019 (Link) used retrospective data of 114 CKD/ESRD patients with hyperkalemia. It showed that a single-dose Kayexalate of 30-gram had a median decrease of 0.8 mEq/L while a single dose of 15-gram kayexalate had median decrease 0.5 mEq/L within 24-hours of treatment. The median starting potassium level was 5.7 mEq/L. The benefit of this study was that it included patients with CKD and ESRD on dialysis, and excluded patients who received other medical therapies to treat their hyperkalemia. This is a good design since we can say that the decrease in K is likely largely from the use of single-dose Kayexalate. However, a limitation is that there is no placebo arm, so it is difficult to say this decrease is solely from the use of Kayexalate. This paper is definitely worth a read! It also addresses some other retrospective studies on Kayexalate as well as the only RCT of Kayexalate I can find (linked here “Randomized Clinical Trial of Sodium Polystyrene Sulfonate for the Treatment of Mild Hyperkalemia in CKD 2015), which showed a mean reduction of 1.25 mEq/L at 7 days compared to placebo with reduction 0.21 mEq/L at 7 days (sample size of total 33 patients).
Veltassa works similarly to Kayexalate and Lokelma in that it absorbs potassium in the GI tract. Veltassa was FDA approved in 2015 before Lokelma (2018) and may see at certain institutions. One issue with this medication is that it also binds magnesium and can result in hypomagnesemia (5.3% of patients), which is not seen with Lokelma. It can also bind certain medications, and therefore, it is recommended that you do not take Veltassa 3 hours before or after taking other oral medications, which seems impossible in the patient population I would want to give this to. In vitro studies showed medications including amlodipine, ciprofloxacin, levothyroxine, and others were bound >50% to Veltassa. Other medications like clopidogrel, furosemide, metformin, metoprolol, and warfarin were bound 30-50% to Veltassa. Essentially, all the best drugs were bound by Veltassa. It also has a slower onset of action ~7 hours while onset for Lokelma is ~ 1 hour.
Lokelma seems like it has a lot of promise. It’s shown it can lower potassium and seems fairly well tolerated by patients even in longterm use. I’m very curious to see what this next study on Lokelma in acutely elelvated K>5.8 will show. Mostly, though, I’m just excited that there’s some new players entering the resin game of lowering potassium. It seems prior to 2015 when the other resin medications weren’t yet available, there was little interest in further studying Kayexalate as there were no other options. Since 2015, however, there have been multiple studies on Kayexelate as well as these new trials on Lokelma and Veltassa. Maybe one day we’ll even see a randomized, controlled, head-to-head trial of all these medications…