Sodium Zirconium Cyclosilicate (SZC) is a potassium-exchange resin similar in concept to sodium polystyrene sulfonate (Kayexalate). It’s not particularly new, as the original studies were performed around 2015. Accumulating evidence over the last five years supports the drug’s safety. The real question is how effective it may be.
Efficacy data for short-term improvement in potassium
The following studies on SZC were performed with some ties to pharma and presented in a favorable light.
Ash SR et al. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, XZ-9, is safe and efficient
This is a phase-II, multi-center, placebo-controlled, double-blind RCT evaluating various doses of SZC among outpatients with mild, stable hyperkalemia (potassium level of 5 – 6 mM).1 Patients were randomized to receive placebo or varying doses of SZC three times daily.
This study is small, but the results are reported in a more transparent fashion than the other studies:
Look carefully at what happens to potassium in the placebo group. Over the first eight hours, potassium decreases by 0.2 mM. This may reflect shifts due to hydration or circadian cycles in potassium regulation.2–4 This illustrates the importance of a placebo group! Without this placebo group, we would incorrectly conclude that SZC reduces potassium by 0.25 mM over four hours. In fact, the addition of SZC may cause only an additional reduction of ~0.1 mM when compared to the placebo group. Drug-induced reduction in potassium is more substantial at later timepoints.
Packham DK et al. NEJM. Sodium zirconium cyclosilicate in hyperkalemia
This is a phase-III multi-center, placebo-controlled, double-blind RCT evaluating various doses of SZC among outpatients with mild, stable hyperkalemia (K 5 – 6.5 mM). This is a rather complex, multi-step trial. For the sake of brevity I will discuss only the first 48 hours of the study, as this is what applies to the acute resuscitative phase.5
After an overnight fast, patients were initiated on 1.25, 2.5, 5, or 10 grams of SZC every eight hours. Potassium levels were measured over four hours, and later on at 24 and 48 hours. The study presents the data in a genuinely weird way, without error bars. This unfortunately seems to be the most accurate description of the data (the actual numbers, standard deviations, and p-values are absent).
As in Ash et al. above, potassium levels fall in the placebo group! Over the first four hours, SZC reduces potassium by an average of ~0.2 mM, compared to placebo. With repeated dosing over the first 24 hours, SZC reduces the potassium by an average of 0.4 mM.
Kosiborod M et al. JAMA. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: HAROMINZE Randomized clinical trial.
This is a phase-III multi-center, double-blind, placebo-controlled RCT evaluating the effect of SZC 10 grams q8hr in outpatients with mild hyperkalemia (K >5.1 mM).6 Unfortunately, it was a multi-phase study which was predominantly focused on the use of SZC as chronic maintenance therapy. During the initial phase of the study, all patients received open-label SZC (and subsequently patients were randomized to placebo vs. SZC).
258 patients were included in the initial phase of the study, all receiving open-label SZC 10 grams q8hr. Baseline characteristics are as shown here:
The effect on serum potassium is shown below:
Patients in this study experienced essentially the same absolute drop in serum potassium over four hours as seen in Packham et al (~0.4-0.5 mM). However, lack of a placebo group complicates the interpretation of this drop. In Packam et al. above, about half of this reduction was also seen in the placebo group. Thus, much of the initial drop in serum potassium seen in this current study is probably not due to SZC therapy. However, the reduction in potassium over 24 hours is more convincing.
Kosiborod M et al. NEJM Sodium zirconium cyclosilicate for urgent therapy of severe hyperkalemia
This is a retrospective re-analysis from the two phase-III trials above, focusing on 41 patients whose initial potassium level was >6 mM and who received 10 grams of SZC.7 Potassium levels dropped fairly impressively among these patients:
Unfortunately, once again there is a conspicuous lack of a placebo group here. As discussed above, it’s very likely that SZC was not fully responsible for the 0.7 mM drop in potassium seen at 4 hours after therapy.
Amin AN et al. Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level >5.5 mM: pooled analysis from two phase 3 trials
This study is another re-analysis of data from these same two phase-III studies, essentially a remix of the Kosiborod paper above.8 Some evidence is provided suggesting that SZC may be more effective in patients with greater baseline hyperkalemia (figure below). However, yet again, this analysis suffers from a lack of any control group.
Peacock et al. Emergency potassium normalization treatment including sodium zirconium cyclosilicate: A Phase II, randomized, double-blind, placebo-controlled study (ENERGIZE)
This is a multi-center, double-blind, placebo-controlled RCT testing the ability of SZC to treat emergency department patients with potassium >5.8 mM.9
Key inclusion criteria were:
- Patients admitted to the emergency department with potassium >5.8 mM
- No cardiac arrhythmia
- No plan for dialysis within 4 hours of randomization
- No medical problem other than hyperkalemia which would require hospital admission
- Hyperkalemia not caused by a condition for which a therapy directed against the underlying cause of hyperkalemia would be optimal
70 patients were included, with good matching between the groups. The initial plan was to randomize 132 patients, with no clear explanation of why enrollment was stopped prematurely.
The study intervention was SZC dosed at 10 grams, given up to three times during a 10-hour period (at approximately 1, 4, and 10 hours after inclusion). All patients were treated with dextrose and insulin.
The rate of requiring dialysis was higher among patients treated with placebo than those treated with SZC (16/37 vs. 10/33)(flow diagram below). Patients who underwent dialysis were excluded from further analysis.
The primary endpoint was the mean change in potassium from baseline to 4 hours. This “least mean squares” potassium seems to be a potassium value which is corrected for baseline potassium, time from the start of insulin dosing, and dose of insulin. The need to correct for these factors is debatable, given that randomization should evenly distribute confounding variables among both groups. Regardless, no matter how you slice this data, there was no difference in the four-hour potassium levels. Patients treated with SZC experienced a 0.13 mM greater drop in potassium, but this was not statistically significant.
Looking at the huge confidence intervals in the change in potassium over time (figure below) may begin to explain why this study detected no benefit. The confidence intervals are large for two reasons. First, with seventy patients, this study is more of a pilot study than a definitive trial. Second, patients were receiving a variety of different therapies which could affect potassium (e.g., insulin, glucose, albuterol, furosemide, various quantities of different fluids). In the context of this very dynamic situation, detecting small differences in potassium is impossible. So ultimately, this study was underpowered to determine whether SZC causes small changes in potassium.
There were some signals of possible clinical efficacy. There was a trend towards more patients treated with SZC achieving a potassium below 6 mM (figure below). Likewise, there was a non-significant trend towards patients treated with SZC being less likely to require additional therapies for hyperkalemia (16% vs. 31%). Finally, as mentioned earlier, there was a trend towards a lower rate of dialysis in patients treated with SZC.
SZC appears to be safe. At this point, it has been tested in a number of trials, including long-term administration to relatively fragile renal failure patients.10–12 These studies have not revealed any serious side-effects.
As a large and non-absorbable molecule, SZC stays in the gut (rather than entering the bloodstream). This should limit the potential toxicity that it might cause. Unlike sodium polystyrene sulfonate, SZC doesn’t appear to cause bowel necrosis.
Potential side effects of SZC include constipation, hypokalemia, and volume overload (each 10 gram dose contains ~800 mg of sodium).13 None of these appear to be particularly common. Side-effects seem to be more problematic when the drug is taken chronically (particularly, hypokalemia or volume overload).
So, is SZC clinically useful for emergency management of hyperkalemia?
To summarize the best evidence that we have:
- SZC appears to be safe.
- SZC dosed at 10 grams every eight hours causes an average of ~0.2 mM reduction of potassium after four hours, and ~0.4 mM reduction of potassium after 24 hours.
Are those reductions in serum potassium clinically relevant? It depends! For example:
- For a patient with severe hyperkalemia (e.g., K=8 mM) and chronic anuric renal failure, SZC won’t work. This patient needs dialysis. SZC could be harmful here by providing the illusion that we are giving the patient therapy, when in fact we are providing no effective treatment.
- For a patient with mild hyperkalemia (e.g., K=6.3 mM) who is beginning to recover from renal failure, perhaps SZC could lower the potassium enough to avoid the need for dialysis (when combined with standard therapies for hyperkalemia). Thus, one could imagine some patients with mild hyperkalemia who are on the verge of requiring dialysis, where treatment with SZC could help avoid or delay the need for dialysis.
In short, SZC will only change the potassium a little. For most patients, this won’t be clinically relevant. However, there may be some patients who are sitting on the borderline of requiring dialysis, for whom SZC might help drag down the potassium enough to avoid dialysis.
So for many patients with intermediate severity hyperkalemia, SZC seems like a reasonable adjunctive therapy. Both the risks and benefits of SZC are low (this isn’t a game-changer). Overall, the potential benefits seem likely to outweigh the risks for patients with intermediate-severity hyperkalemia. However, some clinicians might view the ENERGIZE trial as negative and thus see SZC as not worth bothering with – and this is a wholly valid perspective as well.
- Sodium Zirconium Cyclosilicate (SZC) is an oral potassium binder, essentially an upgrade of sodium polystyrene sulfonate (Kayexalate). Unlike sodium polystyrene sulfonate, SZC doesn’t appear to cause bowel necrosis.
- SZC is studied predominantly for subacute to chronic reduction in potassium. However, it does appear to cause some reduction in potassium levels acutely (perhaps ~0.2 mM within 4 hours, and ~0.4 mM within 24 hours).
- The role of SZC for acute management of hyperkalemia is currently unclear. SZC appears to be safe, but it’s debatable whether it is effective enough to cause meaningful patient-centered benefit. SZC may be considered as an adjunctive therapy for the management of moderate hyperkalemia, but it must be used with recognition of its minimal efficacy.
- SZC may help put the nails in the coffin of sodium polystyrene sulfonate (Kayexalate). Specifically, if there are any residual situations where sodium polystyrene sulfonate may be considered or recommended, these patients can be treated more safely and effectively with SZC.
- Treatment of severe hyperkalemia (Scott Weingart, EMCrit)
- Management of severe hyperkalemia (PulmCrit)
- BRASH syndrome: Hyperkalemia plus AV blocker (PulmCrit)
- Updates in management of hyperkalemia (Brit Long and Justin Warix, EMDocs).
- Hyperkalemia (Kane Guthrie) & Hyperkalemia Management (Chris Nickson), LITFL
- Hyperkalemia (Anand Swaminathan, CoreEM)
- Management of life-threatening hyperkalemia (First10EM)
- Hyperkalemia management: preventing hypoglycemia from insulin (Bryan Hayes ALiEM)
- Is kayexalate useless? (Scott Weingart, EMCrit)
- Is kayexalate useful in treatment of hyperkalemia in the ED? (Salim Rezaie, RebelEM)
- Myths in Emergency Medicine: Kayexalate (Anand Swaminathan, EM News)
Conflicts of interest: None (aside from having reached a point in my career where I'd really rather not put in hemodialysis catheters if I don't have to).
- 1.Ash S, Singh B, Lavin P, Stavros F, Rasmussen H. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient. Kidney Int. 2015;88(2):404-411. doi:10.1038/ki.2014.382
- 2.Fijorek K, Puskulluoglu M, Polak S. Circadian Models of Serum Potassium, Sodium, and Calcium Concentrations in Healthy Individuals and Their Application to Cardiac Electrophysiology Simulations at Individual Level. Computational and Mathematical Methods in Medicine. Published online 2013:1-8. doi:10.1155/2013/429037
- 3.Henslee EA, Crosby P, Kitcatt SJ, et al. Rhythmic potassium transport regulates the circadian clock in human red blood cells. Nat Commun. Published online December 2017. doi:10.1038/s41467-017-02161-4
- 4.Gumz M, Rabinowitz L. Role of circadian rhythms in potassium homeostasis. Semin Nephrol. 2013;33(3):229-236. doi:10.1016/j.semnephrol.2013.04.003
- 5.Packham D, Rasmussen H, Lavin P, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222-231. doi:10.1056/NEJMoa1411487
- 6.Kosiborod M, Rasmussen H, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223-2233. doi:10.1001/jama.2014.15688
- 7.Kosiborod M, Peacock W, Packham D. Sodium zirconium cyclosilicate for urgent therapy of severe hyperkalemia. N Engl J Med. 2015;372(16):1577-1578. doi:10.1056/NEJMc1500353
- 8.Amin A, Menoyo J, Singh B, Kim C. Efficacy and safety of sodium zirconium cyclosilicate in patients with baseline serum potassium level ≥ 5.5 mmol/L: pooled analysis from two phase 3 trials. BMC Nephrol. 2019;20(1):440. doi:10.1186/s12882-019-1611-8
- 9.Peacock W, Rafique Z, Vishnevskiy K, et al. Emergency Potassium Normalization Treatment Including Sodium Zirconium Cyclosilicate: A Phase II, Randomized, Double-blind, Placebo-controlled Study (ENERGIZE). Acad Emerg Med. Published online March 9, 2020. doi:10.1111/acem.13954
- 10.Roger S, Spinowitz B, Lerma E, et al. Efficacy and Safety of Sodium Zirconium Cyclosilicate for Treatment of Hyperkalemia: An 11-Month Open-Label Extension of HARMONIZE. Am J Nephrol. 2019;50(6):473-480. doi:10.1159/000504078
- 11.Roger S, Lavin P, Lerma E, et al. Long-term safety and efficacy of sodium zirconium cyclosilicate for hyperkalaemia in patients with mild/moderate versus severe/end-stage chronic kidney disease: comparative results from an open-label, Phase 3 study. Nephrol Dial Transplant. Published online February 6, 2020. doi:10.1093/ndt/gfz285
- 12.Spinowitz B, Fishbane S, Pergola P, et al. Sodium Zirconium Cyclosilicate among Individuals with Hyperkalemia: A 12-Month Phase 3 Study. Clin J Am Soc Nephrol. 2019;14(6):798-809. doi:10.2215/CJN.12651018
- 13.Levien T, Baker D. Sodium Zirconium Cyclosilicate. Hosp Pharm. 2019;54(1):12-19. doi:10.1177/0018578718817470
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