Experts discuss key takeaways from the review article “Role of Bempedoic Acid in Clinical Practice”, clinical implications, and the greatly anticipated CLEAR Outcomes trial.
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?
Steven E. Nissen, MD, MACC: 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?
Steven E. Nissen, MD, MACC: 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.
Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: 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?
Steven E. Nissen, MD, MACC: Yes.
Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: 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.
Steven E. Nissen, MD, MACC: 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?
Steven E. Nissen, MD, MACC: 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.
Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: 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?
Steven E. Nissen, MD, MACC: 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.
Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: 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?
Steven E. Nissen, MD, MACC: 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.
Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: 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?
Steven E. Nissen, MD, MACC: 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.
Harold E. Bays, MD, FOMA, FTOS, FACC, FNLA, FASPC: 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.
Steven E. Nissen, MD, MACC: Thank you very much.
Transcript edited for clarity.