Safety and Efficacy of Bempedoic Acid for ASCVD and Hypercholesterolemia

Yehuda Handelsman, MD: Christie, can you explain why we don't see with bempedoic acid that muscle impact? You said it's kind of the same line, just higher up on how we…

Christie Ballantyne, MD: It's a pro drug, it gets converted to the active drug in the liver. That enzyme for conversion, that's an issue in terms of muscle. Bempedoic acid is a new agent that many people have not used. There is the issue of uric acid, it gets excreted by the kidney, so there's a transporter that can be competing with uric acid. If someone has hyperuricemia, that would be a relative contraindication, although you could see what happens. If they had gout and were treated with allopurinol, it's not an issue. If you looked at the study, if uric acid levels were normal, then people did not end up with gout, but if they were high -

Handelsman: You said the study, but let’s describe the studies because not everybody is familiar.

Ballantyne: There was a large phase 3 program, the CLEAR program. They were monotherapy combination therapies. We've looked at this in terms of the safety aspects. With hyperuricemia, there's a slight increase that 1 to 2 % of people could get elevations of uric acid that might lead to gout. That can be avoided simply by measuring it at baseline, and if it's low, you don't have to worry, but if it's borderline or high, then you should repeat it. There was also an increased numerical imbalance of tendon rupture. If someone has a history of tendon rupture, tendinopathy, or something else, then this is probably not the right agent for that patient. Those were very rare, they were infrequent, but those are the 2 that I think for consideration.

Handelsman: The mono trials were CLEAR Harmony and CLEAR Wisdom. The combo trial was 53, something like that. Do you want to touch on the efficacy?

Matthew J. Budoff, MD: Yeah and just to go back quickly, because I think it's important to recognize and Christie talked about it being a pro drug. Statins are not a pro drug, they go into the liver and inhibit the liver, they go into the brain, that's the cognitive stuff, and they go into the muscle, which might cause real or perceived statin intolerance. Bempedoic acid can only be, that we know of, converted, and the only place this conversion enzyme exists is in the liver, so it can't go into the muscle. Muscle adverse reactions were comparable to placebo across all the trials that we've seen so far.

Ballantyne: Will not inhibit cholesterol synthesis in the muscle, with statins. The statin that had the greatest viability was cerivastatin, and we know what happened with cerivastatin, it had the greatest amount of myopathy. We have some data that the greater the viability of the statin, the more it goes in the muscle and the greater the chance of having muscle problems.

Budoff: We have the CLEAR combo study, that 053, renamed as CLEAR Combo, which added ezetimibe plus bempedoic acid into a combination, and now we’re seeing LDL [low-density lipoproteins] reductions closer to 40%, which is statin-esque. If you can't take a statin, that benefit might be greater because you're not dual inhibiting that pathway that Christie described.

Michos: You mentioned, as monotherapy, so on top of a statin, it's about 18% reduction. Because both statins and bempedoic acid work on the same pathway, so not in combination with a statin, it's about 24% LDL reduction. In combination with ezetimibe, you're getting to 38% or 40% reduction.

Paul S. Jellinger, MD, MACE: A comment about the well-known doubling of the statin dose and what resultant LDL, the 6% rule. I've seen many exceptions to that, it's absurd, that's a population-based study. Individual patients are extremely variable, so don't hesitate to double the statin dose. You may get a 20% reduction or you may get a 2%, depending on their LP(a) level. One of the nice clinical pearls that I've appreciated over the years is that patients whose LDL do not decrease on a statin probably have an elevated LP(a), and look for that there because that will not respond to statins. That will serve you well by doing that. Don't be timid about doubling the dose of statin and see what your individual patients will do. Secondly, in terms of the gout, the increased uric acid with bempedoic acid was 0.8%, it's very small.

Ballantyne: Overall, it's very small, it's only a concern if someone has a history of gout or a high uric acid. You make a really important point–we treat one patient at a time. That's the issue if you have someone who is not at their target. When you give a trial of an agent, be it ezetimibe, bempedoic acid, you get your effect within 4 weeks. You can even give samples. You can see, do they respond, here's the number, and you will see that some people have very big responses. Overall, people who are not on statins, over half got a 30% or more reduction. Someone who's been struggling with their lipids, when they see that, they are very pleased. That's the experience in my practice. We've had some people get 50% reductions, and you'll have some that get less. We treat one patient at a time, if someone responds well and they do that, then you've helped that patient.

Jellinger: Don't be married to the 6% rule.

Ballantyne: Correct.

Handelsman: Part of the impact that we believe that statins have, is a pleiotropic effect. It's beyond the LDL reduction, the impact on inflammation, which we call pleiotropic effect. When we look at bempedoic acid, it has impact on inflammation. If a patient cannot be on a statin, and you put them on this combination drug, they still get some impact on inflammation, which I think is 4 on the pleiotropic effect. There's also slight reduction in glucose, it's not huge, but unlike what was said with statin, that can push sugars up and not be clear why it's happening; we don't see it with bempedoic acid in that kind of a combination. I don't know if you do it, but I have 2 patients on the combination of colesevelam with bempedoic acid, ezetimibe, and I have huge reductions in cholesterol, inflammation, and glucose. It's not difficult, it's easy to do and a statin is better if we can get them to take it.

Budoff: It's nice that we're seeing the opposite effect on diabetes. It will not be listed as a diabetes agent, but it was statistically significant. Less for new onset diabetes if you're on the bempedoic acid than if you're on placebo in these trials so far. CLEAR outcomes will be 14,000 patients and that will give us a much clearer look, but the signals are not there.

Handelsman: Can you tell us more about the study?

Budoff: Christie described it earlier, but CLEAR outcomes look at 14,000 patients who must be statin intolerant, and are randomized to bempedoic acid or placebo. I'm pretty sure it's going to finish this year, it's an event-driven trial. We're coming up on the very end of the study and hopefully we'll have some announcement later this year. I'm not sure if it'll be presented at AHA [American Heart Association] early next year.

Ballantyne: ACC [American Cardiology College] maybe? The thing that was impressive is, it didn't take that long to recruit.

Handelsman: I was very surprised.

Ballantyne: That will be the issue, is this happening in practice? All you get to see is when they recruit 14,000 people rapidly, it tells you something.

Michos: There's a lot of statin intolerance.

Ballantyne: There's a lot of people looking for something.

Handelsman: It's very interesting because I was supposed to be part of the phase 3 trial, I ended up not being part of it because I could not recruit in my population, but today it probably would have been easier to recruit.

Transcript Edited for Clarity