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.
The following studies on SZC were performed with some ties to pharma and presented in a favorable light.
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.
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.
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.
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.
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.
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:
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).
To summarize the best evidence that we have:
Are those reductions in serum potassium clinically relevant? It depends! For example:
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.
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).