What is being investigated in the DIAMOND trial?

• A. The effect of patiromer on potassium in HF patients
• B. The effect of patiromer on enablement of RAASi therapy in CKD patients
• C. The effect of patiromer on potassium levels in CKD patients
• D. The effect of ZS-9 on CV outcomes in HF patients

The correct answer is A.

Potassium binding: what clinical data support the practical use? My name is Peter van der Meer, I work as a cardiologist at the University Medical Center Groningen in the Netherlands. Here you can see my disclosures.

What are the therapeutic options to treat hyperkalemia? In the acute setting, calcium gluconate can be given to stabilize the membrane. We can give insulin to move the potassium back into the cell, beta agonists are helpful. But also, the use of potassium binders, loop diuretics, and in very severe cases dialysis.

Other options for the treatment are dietary potassium restrictions. However, potassium is a very common ingredient in many foods. Many patients with heart failure are using RAAS inhibitors. So we could reduce them, because RAASi is associated with hyperkalemia. However, if we reduce these life-saving drugs, they may have an effect on the prognoses. We can give diuretics, to improve potassium loss by diuresis. Or we could give resonium or kayexelate. However, these drugs are associated with gastrointestinal adverse events. Given the non-selective binding and side effects of these drugs, there is a clear clinical need to treat hyperkalemia with this effective, safe and well tolerated drug.

And there are two relatively new potassium binders on the market. Patiromer and ZS-9. I will discuss both these binders and the clinical data.

One of the first trials was the AMETHYST trial. It was a trial, which studied patiromer, one of the potassium binders, in patients with hyperkalemia. So the patients had type 2 diabetes, a reduced kidney function, the patients were using RAAS inhibitors and they needed to have potassium above 5. So hyperkalemia, so really the treatment of hyperkalemia. The end point of this study was the change in potassium, between baseline and four weeks. And the adverse events, which happened during one year of follow-up.

Here you can see the results of the trial. Both in mild and moderate hyperkalemia, the drug was effective in lowering potassium. Already within one day, the majority of the patients was normalkalemic. On the right side, you can see the adverse events. However, please note that there was no placebo group included in this trial. And at the end of the graph you can see that when patients stopped their drug use, potassium levels increased quickly back to their higher values.

Also, ZS-9 was studied in patients with hyperkalemia. In this somewhat larger trial, with more than 750 patients, patients could be included if they had a potassium between 5 and 6.5. And also in this trial, the endpoint was change in serum potassium. On the left side, you can see the first 48 hours. And patients were randomized to different groups: Placebo, ZS-9 five grams or ZS-9 ten grams. And you can see that already within several hours, there is a clear reduction in potassium, which lasted over time. After these two days, patients on active drug were again randomized. You can see the patients who were previously treated in the active group, showed that, when they were randomized to placebo, their potassium levels increased quickly.

So the previous two trials were really about the treatment of hyperkalemia. What are the effects of these novel potassium binders on potassium? However, it is also important to understand whether a potassium binder leads to enablement of RAASi therapy. The PEARL-HF, published already ten years ago in European Heart Journal, investigated this. A little bit more than 100 patients with chronic heart failure, with either a history of hyperkalemia, or renal disfunction with an eGFR below 60. And the patients were randomized between patiromer, so the potassium binders, and placebo. And none of the patients at baseline were using spironolactone, and the goal of this study was to see whether a potassium binder leads to enablement of spironolactone use.

On the graph on the left side you can see both groups having a potassium level around 4.7 And in all patients, spironolactone was started. And patients were randomized between patiromer and placebo. And as you can see, with the patients who received

placebo after starting with spironolactone, there was an increase in potassium levels. Whereas the patients, who were randomized to the active treatment with patiromer and also started with spironolactone, showed a small decrease in their potassium levels. The efficacy endpoint of this trial was change in potassium and a safety endpoint. And to see how many patients could use 50 mg of spironolactone.

Here you see the efficacy and safety data of this trial. And as you can see on the left, significantly more often in the placebo group patients experience hyperkalemia. And significantly more often patients using patiromer were able to tolerate 50 mg of spironolactone. On the right side you can see the safety profile. Adverse events were more common in patients randomized to patiromer. Especially gastrointestinal side effects were significantly more often seen in patients treated with patiromer.

Here you can see a scheme of how the drug works. So there is dietary potassium and most of the potassium is being taken up in the colon. And by giving a potassium binder, the potassium is bound in the gastrointestinal tract and leads to potassium excretion. And therefore balancing the increase in potassium, seeing with spironolactone.

Now we know that both drugs ZS-9 and patiromer are both effective in reducing potassium. And we've seen with patiromer, that more patients were able to tolerate the highest dose of spironolactone compared to placebo. An important question now remains: whether the use of a potassium binder indeed leads to a better outcome. The DIAMOND-HF trial will answer this question. And more than 800 patient with HFrEF were included in the DIAMOND study. Patients need to have a history of hyperkaelemia and suboptimal RAASi dosages or patients need to have a current status of hyperkalemia. All patients were actively treated with patiromer in order to optimize their heart failure therapy with RAAS inhibitors, ACEi, ARB or ARNI together withan MRA of at least 50 mg. And then there was a randomized withdrawal of the active treatment. So one group continued the patiromer, whereas the other group was randomized to placebo. The results of this trial are expected at the ACC in 2022, and the primary endpoint in this study is a hierarchical endpoint. The primary endpoint will be the change in potassium,

but there are secondary endpoints which includes cardiovascular mortality, cardiovascular hospitalization and the use of RAASi therapy.

And late December 2021, topline results indicated that the primary endpoint was met in the DIAMOND study. To conclude, novel potassium binding drugs have a favourable safety profile and can be used chronically.Both drugs are highly efficient in lowering potassium. And patiromer use resulted in more patients being able to tolerate the highest dose of spironolactone. And the DIAMOND study will learn us about the clinical efficacy of patiromer in patients with heart failure. I thank you very much for your attention.

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