Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC

: Welcome back, again my name is Dr Harold E. Bays, and joining me is Dr Steven E. Nissen, and we’re discussing bempedoic acid today. We just had a discussion about this review article that was written about bempedoic acid, and some of the takeaway messages we had, from an efficacy standpoint, bempedoic acid by itself lowers LDL [low-density lipoprotein] cholesterol around 18%, and if it’s added to ezetimibe, in other words both at the same time, we get around a 38% reduction in LDL cholesterol. From a safety perspective, you do have to be on the lookout for the possibility of gout. The people most likely to get gout, have bouts of gout, would be those patients who have already had a history of gout and who have elevated uric acid levels. But as Dr Nissen pointed out, that’s the reason we need to monitor our patients and try to get that uric acid under control and certainly inform our patients about the potential for gout. Then there’s this safety issue with regard to tendon rupture. We’re going to know more about that when we have the outcome study, but if a patient has a history of tendon rupture on other medications like fluoroquinolones and such, at minimum, the patient should be educated to look out for potential tendon rupture. Steve, we just went over the data in the prior discussion; what do you think overall a clinician should know about the clinical use of bempedoic acid in combination with a statin and/or ezetimibe? What’s your sense about that?

: The most compelling information is that 38% and sometimes even 40% reduction in LDL cholesterol. That is a reduction that’s equivalent to 20 mg of atorvastatin, which generally produces about 40% reduction, or 40 mg of simvastatin. And 20 to 40 mg of simvastatin was what was used in the 4S trial, the classical post-MI [myocardial infarction] trial, that first showed that statins were efficacious. Many patients are benefited by that moderate reduction, even though very high doses of statins can get a bit more, that 40% reduction in clinical use is quite sufficient to control LDL cholesterol to guideline recommended levels, both in the United States and in European countries, and that is a particularly useful combination. Something we don’t want to miss out on is the reduction in hs-CRP [high-sensitivity C-reactive protein]. This has a very strong anti-inflammatory effect that’s seen, more so even than we see with statins, and that we know from the JUPITER trial is a predictor of the event rate. The higher the C-reactive protein, the higher the event rate, and that taking patients with a high hs-CRP and treating them with statins resulted in a reduction in morbidity and mortality. It’ll be interesting to see if we see the same thing with bempedoic acid.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: 

That’s an excellent summary of the efficacy side with regard to LDL cholesterol lowering and that CRP reduction, which could prove to be something really important. We’ve got to keep an eye on that. What would you say would be the key safety messages? Let’s start off with the gout. I talked about it a little bit, but what do you think? From a very practical taking care of a patient standpoint, what do you tell your patients with regard to the potential for gout?

: In most studies, bempedoic acid slightly reduced hemoglobin A1C [glycated hemoglobin], and that’s different from statins. Interesting enough, statins slightly increase hemoglobin A1C. If you compare the difference between the 2 classes of drugs, it’s a significant difference. People need to know about that because some of the reluctance of patients to take statins relates to the increase in Hb [hemoglobin] A1C that is seen with statins. All the studies show it, and bempedoic acid does not show it, which is a unique feature here for this pathway in this LDL reduction.

It used to be a lot bigger deal in the past than maybe it is now, but I’ll tell you that it is extraordinary the degree by which glucose is affected by lipid-altering drugs. Back when we did niacin, do you remember that?

Glucose levels would go through the roof with the niacin, or as you mentioned, certain statins in particular increase the glucose level. We looked at some data with regard to some of the fibrates, there could be a modest decrease, but your point’s very well taken. Way too many times we have patients who say, “I don’t want to take a statin because I’m afraid it’s going to give me diabetes.” To the extent there are people out there who may have the same sort of sense about bempedoic acid, maybe that’s a pretty good thing for them to know, that as you mentioned, it’s fairly consistent isn’t it? It’s certainly not a rise, but maybe even a little decrease.

It does, and this has come into play for me. Patients I see who have prediabetes, who are in that 5.7% to 6.5% Hb A1C, they’re worried, and I’m worried about them transitioning over to the point where they’re going to need to have treatment for their diabetes. It does give an edge to using bempedoic acid in those patients because you’re not as likely to have them cross over into that territory that’s considered diabetes. I keep that in mind when I use this drug.

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC:

 Going back to what we talked about before, how do you manage this potential for gout in your patients?

It doesn’t come up that much. Mainly you worry about patients who have had a pre-existing episode, particularly if it’s a severe episode of gout. Most of those patients who have had a severe episode of gout are on allopurinol, and so their uric acid levels have been reduced into the safe range. Our comfort level goes up. You want to always have it in the back of your mind. If there are alternatives for patients who have a strong history of gout, you want to consider the alternatives first. If you’re left with a patient who has a level of risk and a level of LDL cholesterol that you feel like you have to treat, then you make sure their uric acid is well-controlled, and I’d go ahead and put them on bempedoic acid. The point is that a myocardial infarction, stroke, or sudden death, reducing those end points is a whole lot more important than preventing, maybe, an episode or attack of gout.

 That brings us to, we’ve already talked about the tendon rupture. It’s rare. We don’t know its clinical meaning at this point. We’re going to know better. So, when we talk about a potential for cardiovascular disease reduction and we talk about getting a clearer viewpoint as to exactly what might or might not be going on with tendon rupture, is there an ongoing clinical trial for which we all could benefit from looking at those data to nail down these things from a cardiovascular standpoint, or from a tendon rupture standpoint? Do we have a study we could look toward to give us greater insight?

 We do, and I’m the study chairman for the CLEAR Outcomes trial. We’ve been doing this now for a number of years. These outcome trials take a long time to complete, and we were very excited to have the opportunity to lead the trial. The history of LDL-lowering drugs, whether they’d be in virtually everything, even the old cholesterol resin binding agents, when we lower LDL substantially, we have gotten a benefit on hard outcomes, cardiovascular death, stroke, and myocardial infarction, and even drugs that are less efficacious than bempedoic acid. In CLEAR Outcomes, it’s the first trial that I know of this size, that’s deliberately enrolled people who had trouble tolerating statins. We have 14,000 patients in the trial, so it’s a large outcome trial. We have a drug that lowers LDL cholesterol effectively, and a group of patients that are very hard to treat. They have very high baseline LDL cholesterol levels, and that means that they’re probably going to get a pretty big reduction with bempedoic acid. It’s easy to predict that if bempedoic acid, if lowering LDL with this agent produces a similar benefit to what is seen with statins, then the CLEAR Outcomes trial’s going to show a statistically significant benefit. 

I’m intrigued by the possibility that the benefits will be a little bit larger than you might project. Why do I think that? Bempedoic acid does rather substantially lower high-sensitivity C-reactive protein. The link between CRP and adverse cardiovascular outcomes has been well-established over a long period of time. The drug also slightly lowers hemoglobin A1C. Everything goes in the right direction, not in the wrong direction. If you add these additional benefits, our hope would be that we would see a pretty robust reduction in morbidity and mortality. The study is powered for about a 15% reduction, we’ve got plenty of statistical power for that, and we could see a whole lot more. We’re going to run the trial until we get 16,020 events, that’s death, stroke, and myocardial infarction, and that gives us a very substantial amount of statistical power. The trial will wind up perhaps in late 2022. We’ll have to take some time to get the database cleaned up, get all the final events adjudicated, and get everything done. You can expect us to present results in 2023, perhaps earlier in the year rather than later. That time’s going to come up pretty quickly. We’re already in the second half of 2021, and we’ll have an answer about whether this LDL-lowering drug does what other LDL-lowering drugs do and reduces morbidity and mortality.

 I’m going to throw you a couple curve balls here. First, we’re a participating site as you know, and we did fine with the recruitment. But I said, “You’re going to recruit a study just with patients with statin intolerance? We’re going to be recruiting for the next 15 years.” I didn’t think that we could recruit this study as well as we did. Is that just because there are way more patients out there with statin intolerance than we thought, or is it just because you have an amazing team?

I work in a very large prevention clinic, here at the Cleveland Clinic, and the No. 1 reason for referral of patients to see us as a tertiary care center is statin intolerance. They come in and they have not well-controlled lipids, they have not tolerated statins, and their referring physician wants our help with those patients. My colleague Leslie Cho, [MD,] has published extensively on low dose, you start once a week and then you go to twice a week, and you try to get them on a low dose of statins. We have all these people like that. Harold, you probably see the same thing, and every practice around the country sees these patients. This we know is a very common disorder. Some report of statin intolerance is seen in 5%, 10%, even 15% of patients. There are 36 million people out there who are statin eligible. You add up the numbers, and there are a lot of people with statin intolerance, and we had no trouble finding them. The study enrolled very robustly. I’m not sure how many patients you put in, but it’s done very well, and we’re very pleased it enrolled so well.

 We’re at the end here. Could you give a closing comment as to the historic importance of this, with respect to when was the last time we had an LDL cholesterol drug approved as an oral agent that reduced cardiovascular events? When’s the last the time that happened?

 Ezetimibe was approved more than 20 years ago. We didn’t get a cardiovascular outcome trial going right away, so for a lot of years it was available, but we didn’t know if it really reduced events. We’ve gone 20 years without—we’ve gotten some injectable drugs, but we haven’t gotten an oral drug like this in a generation. We’ve got a historic opportunity now to study this agent, understand its benefits and its risks. And I might say that the CLEAR Outcomes trial will not only report the benefits, but we’re also going to report the risks. We’ll tell you whether there are tendon ruptures, maybe that problem goes away. We’ll tell you how many people have gout, that problem, we’ll clarify all of that. We are very hopeful that the medical community will understand the balance of benefit and risk from this very large trial, long term, in a difficult to treat patient population. I will also add that I don’t think there’s ever been a dedicated study anywhere near this size in patients with statin intolerance. It’s the first outcomes trial in this group of patients. It will have historical importance in terms of understanding what this agent can do in a very difficult to treat group of people.

That says it all. I want to thank you, Dr Nissen, for helping with this discussion with regard to bempedoic acid, and I hope you the viewer also got the answers to the questions you have about this novel agent.

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Experts discuss key takeaways from the review article “Role of Bempedoic Acid in Clinical Practice”, clinical implications, and the greatly anticipated CLEAR Outcomes trial.

Role of Bempedoic Acid in Clinical Practice

 experience. Today’s featured article is, the “Role of Bempedoic Acid in Clinical Practice.” My name is Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC, medical director and president of the Louisville Metabolic and Atherosclerosis Research Center, located in Louisville, Kentucky. Joining me today is my colleague Steven E. Nissen, MD, MACC, chief academic officer of the Heart, Vascular & Thoracic Institute at the Cleveland Clinic, in Ohio. Welcome, Steve. How are you doing?

: Thank you, Harold, I’m delighted to be with you and have thisinteresting discussion.

: Steve, I’m sure you’re the same way, for the past 20 to 30 years, we’ve been involved in all kinds of lipid-altering drug development, and ever since development of the statins we’ve always been looking for ways to alter that cholesterol production pathway. We did develop the statins, the HMG-CoA reductase inhibitors, and such, but we also worked on MTP inhibitors, ACAT inhibitors, and squalene synthase inhibitors. Now we have this drug that’s very active in development and is already approved for some indications, bempedoic acid. It’s this agent that is essentially a prodrug when it’s administered and gets activated in the liver, but not activated in the muscle. A lot of times people come up to me and ask, “What’s the clinical significance of that?” Steve, what do you think?

: I take care of a lot of these patients, and the clinical significance is pretty important. If you have a drug that is activated in the liver, the liver is where you want to inhibit this cholesterol synthesis pathway. That’s good. What you don’t want to do is have off-target effects involving other organs, and as everybody knows, many patients complain of muscle pain when you give them statins. Having in our therapeutic armamentarium a drug that doesn’t get in the skeletal muscle, doesn’t do anything in the skeletal muscle, it only works in the liver, has really important implications for patients who have difficulty with statins due to skeletal muscle symptomatology, and it’s pretty common in the literature.

: That forms the basis of a lot of the bempedoic acid development program. Yes, we do have CLEAR Harmony, a standard lipid efficacy trial, and the same thing with CLEAR Wisdom, where we’re looking at lipid efficacy and such in patients who are on statin therapy. One of the things that was done very early on is to evaluate bempedoic acid in patients with statin intolerance, and that would include the CLEAR Serenity and the CLEAR Tranquility studies. I find it very interesting that a big part of the development program for bempedoic acid was in patients with statin intolerance. Do you know of another development program where so much emphasis was placed on patients with statin intolerance?

: From the very beginning, the development of this drug was targeting them. The developers understood that the lack of penetration of the drug in the skeletal muscle was a potential advantage. They knew that this was a clinical problem that had not been well addressed. What they have done now, a variety of these studies in phase 3, have shown that bempedoic acid alone in people on statins or not on statins lowers low-density lipoprotein [LDL] cholesterol, moderately. And if you add ezetimibe, you get kind an effect that is approximately equivalent to that of a moderate intensity statin, without using a statin at all, or using a statin in very low doses. Having that data really provided the basis for guidance for clinicians on how to use bempedoic acid in their practice.

: That’s spot on. How many times have we heard the overused term “unmet need?” Here’s at least one case where that really does apply. As you said, these folks recognized early on that there truly was an unmet need for treatment of patients with a statin intolerance. We’re going to get to that in time.

: I want to talk about this issue of statin intolerance because it’s become very controversial, and I have some things I want to say about that.

: This disorder of statin intolerance is being assaulted from a number of different directions. People have done what they call N-of-1 [single subject] trials, and there’s a very active group that said, “There’s no such thing as statin intolerance, it doesn’t exist.” But I take care of these patients, and here’s the problem, and every clinician who sees patients like this knows this is what happens. Somebody comes into my office, and I say, “You need to be on statins.” They say, “I have tried the drugs. I have tried 3 or 4 statins, and every time I get a statin, within a few days, I get muscle pain. It’s intolerable, and I stopped the drug.” I tell them I want to try again. They look me in the eye, and they say, “I will not take another statin.” What am I going to do? It is really helpful to have a drug like bempedoic acid in our toolkit, knowing we can get LDL lowering, we can have ezetimibe and get quite a bit of LDL lowering. We don’t have yet cardiovascular outcome data, but LDL-lowering drugs have a long track record of showing cardiovascular outcome benefits. We make the assumption when we give the drugs to these people that we’re going to get a similar benefit or more to what we see with statins. It’s tremendously important that statin intolerance is in the eye of the beholder, and that’s the patient, and you’ve got to listen to the patient.

: We don’t really have time to discuss it here but looking at all the GAUSS studies that were done, GAUSS-1, GAUSS-2, GAUSS-3, and those types of things, my interpretation of those studies at the end of the day was, yes, there are some patients where it’s difficult to objectively determine if they have statin intolerance. But I also believe those studies, particularly GAUSS-3, did suggest there are some patients who truly have statin intolerance. At the end of the day, as you said, the statin intolerance definition is whatever the patient tells you it is.

: Here we have these clinical trials, and the efficacy trials get around 18% LDL cholesterol lowering, but look at these studies over here, the CLEAR Serenity and CLEAR Tranquility. These are patients maybe with a little higher baseline LDL cholesterol, but these are patients who were, at best, on a very low-dose statin, yet look at their LDL cholesterol lowering with bempedoic acid—in the 20s [mg/dL]. What do you make of that? What do you make of what appears to be a difference in efficacy, when you compare patients who are not on statins versus patients who are on statins?

: There appears to be some interaction here. We sometimes use bempedoic acid for patients who are on full doses of statins, where we really need more LDL reduction, and that’s a perfectly appropriate thing to do. We might even add bempedoic acid and ezetimibe to try to get more efficacy. But the sweet spot here is in the patients who can’t tolerate much statin. Maybe they’re taking some rosuvastatin twice a week, and that’s not good enough and we need more. Their LDL cholesterol, as you can see here in CLEAR Tranquility, is 130 [mg/dL] or so, and that is, for a secondary prevention patient, that’s just not acceptable. You get 28%, 30% [cholesterol lowering] even, sometimes in some patients. You can see the 95% confidence intervals range from 22 and a half to 34, very strong efficacy. I would like to point out here another aspect of this drug that is interesting and may play out in the CLEAR Outcomes trial, and that is the drug has a strong anti-inflammatory effect. Hs-CRP [high-sensitivity C-reactive protein] goes down a lot, perhaps more than we see with comparable degrees of LDL reduction from statins. A number of us believe that CRP reduction is important. Paul M. Ridker, MD, MPH, and I both published manuscripts in the 

 as far back as 2005 that showed evidence that some of the statin benefit came from the anti-inflammatory effects of the drug. I’m intrigued by the fact that bempedoic acid does have a very strong anti-inflammatory effect.

: That’s all very interesting. That’s the efficacy side. Here on the safety side, it looks pretty good with regard to the liver, creatinine. If you had to focus on the things most clinicians, when they read the prescribing information, they zero in on gout and tendon rupture. We did an analysis of the gout issue, and it should come as no surprise that the people most likely to get gout are those who already had a history of gout, and who had high uric acid levels. If they didn’t have gout and their uric acid levels were normal, then they approximated in the placebo group with regard to the incidence of gout. But then there’s this very curious thing about tendon rupture, what do you make of that?

: I disagreed with the FDA on putting this into the label. I thought the data on tendon rupture were very weak. I’m not sure it’s going to be confirmed in the very large CLEAR Outcomes cardiovascular trial, but it’s in the label. If it’s in the label, it’s prudent for physicians to pay attention to it. Now, keep in mind, that fluroquinolones can produce tendon rupture on their own. I would be careful about adding bempedoic acid for these patients on corticosteroids or fluoroquinolones, but I’m not sure it’s going to turn out to be a real effect. It certainly is not a very common effect. The gout issue is more significant, and we have seen some patients with gout. I have given bempedoic acid to some patients with gout when I thought the benefits exceeded the risks, particularly if they were having their uric acid treated with allopurinol. If they’re really well controlled, as long as you’re careful, you can use bempedoic acid in these patients, but you have to be aware there’s a potential risk. If I had to trade an attack of gout for a myocardial infarction or a stroke, the reduction of myocardial infarction and stroke is what we expect to see from this drug, then I might accept the fact that I would occasionally have an episode of gout in patients.

: As I said before, the risk of gout, as you might expect, does go down with the lower uric acid levels. That speaks to exactly what you said, you’ve got to know about it, you’ve got to treat it, and you’ve got to try to prevent it. Then there are also some restrictions on the particular doses of simvastatin and pravastatin, but other than that, one of the positives of bempedoic acid is that it does seem, at least thus far, to have a pretty reasonable safety profile. Would you agree with that?

: Absolutely. I’m not concerned about safety. I’m aware of these issues that have popped up, and they’re in the label, and you want to consider the FDA-approved label whenever you give a drug. The issue of pregnancy has not been well studied or the problem of breast feeding. These are all very reasonable things to put in a label, and it’s not really been studied in those patients.One has to be careful with a history of gout, and I would be very careful about giving bempedoic acid to somebody on a fluoroquinolone. Most people getting fluoroquinolones are getting them for a short course of treatment, for say, a urinary tract infection. These are not drugs that are given chronically. We’ll see if the tendon rupture problem is actually observed in the very large CLEAR Outcomes trial, but for now, this is really an easy-to-give drug with a good safety record.

: In summary, we have this newer agent that has been approved for some time. One of the nice things is it works through impairment of some of the enzymes in the cholesterol synthesis pathway, and that’s a mechanism we’ve all come to know, and we’re comfortable with that. It lowers LDL cholesterol pretty reasonably as monotherapy, and as you mentioned, you can get, say, 38% LDL cholesterol lowering if you administer it with ezetimibe. That approximates the LDL cholesterol lowering by a moderate intensity statin. We have an outcomes study we’re going to be talking about, where we’re going to be able to see the impact on cardiovascular disease, and with regard to safety, it’s mainly focused on gout and possibly, tendon rupture. We’re going to get more information about that with longer-term studies. Do you have any additional things to close this section?

: I don’t. I’ve used the drug in quite a number of patients, and I find it to be something that’s very well tolerated.

Experts examine the safety and efficacy data presented within the review article, “Role of Bempedoic Acid in Clinical Practice.” 

Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC

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