Is Bempedoic Acid the CLEAR Answer to Statin Intolerance?

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr. Michelle O'Donoghue, reporting for Medscape. Joining me today is Ann Marie Navar, who is an associate professor of medicine at UT Southwestern and is ostensibly one of the world's experts on lipid-lowering therapies and thinking about which therapies to use. Ann Marie, thanks for joining me today.

Ann Marie Navar, MD, PhD: Oh, total pleasure, Michelle.

O'Donoghue: Some of the buzz at ACC 2023 is the CLEAR Outcomes trial and bempedoic acid. This is the first clinical outcomes trial we have on bempedoic acid. Do you want to talk about what makes bempedoic acid different than other lipid-lowering therapies and what you think about the study results?

What's Unique About Bempedoic Acid

Navar: The first thing that's important to point out is what makes it the same. Bempedoic acid does something that we know works to lower cardiovascular disease, which is to upregulate low-density lipoprotein cholesterol (LDL-C) receptors. It works in the same pathway as statins, but it works upstream from statins. So it's a little bit different mechanistically.

What makes bempedoic acid perhaps a little bit special compared with statins is that it's actually a prodrug and the enzyme that makes it active is not present in skeletal muscle, and there's a hypothesis that that may make it better tolerated in people than statins.

Now, CLEAR Outcomes wasn't a head-to-head study of bempedoic acid vs statins; it looked at bempedoic acid in patients with statin intolerance. These are people who hadn't been able to tolerate a statin or were only able to tolerate a low-dose statin — so they were people who are potentially set up to have side effects from other lipid-lowering therapy. It was exciting to see the data that show really similar rates of tolerability compared with placebo but, more important, confirmation that upregulating the LDL-C receptor does in fact prevent cardiovascular events via LDL-C lowering. So the trial met its primary endpoint of lowering cardiovascular events compared with placebo.

O'Donoghue: I think it is exciting because until recently, our arsenal of nonstatin therapies for lipid lowering was relatively small. We had some therapies that we don't use very commonplace anymore, but ezetimibe was an option and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are an option as well. But I think that that there's certainly a lot of demand for different types of nonstatin lipid-lowering therapy. Here, you've got one that works like a statin and yet without, it appears, any of the muscle-related effects, and also it doesn't appear from CLEAR Outcomes that there was any increase in diabetes risk.

Navar: Correct, there was no increase in diabetes risk. The only two things that came out from CLEAR Outcomes in terms of risk would be about a 1% increase in gout and a 1% increase in cholelithiasis — but otherwise, it was generally exceptionally well tolerated. In terms of options, statins and ezetimibe are great, but many patients do not get to LDL-C targets with those two therapies alone. So 'until now, the only evidence-based therapy that we had were the PCSK9 inhibitor monoclonals. The challenge with that is that not everybody wants to do a shot, and those hadn't been specifically studied in statin-intolerant patients in an outcomes trial. So we're fortunate to have CLEAR Outcomes focusing on this hard-to-treat population.

O'Donoghue: To that point, so we now have data for bempedoic acid in patients who are statin intolerant. That in and of itself is a separate discussion, but we know that a lot of people cannot tolerate statins or are unwilling to take a statin, and this does help to potentially fill that unmet need. But where do you see bempedoic acid fitting in for patients who are otherwise able to tolerate statin therapy, given that we don't yet have clinical outcome data? Do you think we need that before using it for those patients?

Navar: I think the biology here is very clear: Lowering LDL-C, particularly through the pathway of upregulating the LDL receptor, works. I don't see this needing any more data to be used as an add-on to statin therapy. At this point, I think it really comes down to a conversation with patients about where their preferences are: Do you want to take a pill, or do you want to use a shot? Unfortunately, oftentimes, those decisions are made by the payors: What's the copay? What's their out-of-pocket costs? Are we going to be able to get the prior authorization through?

In secondary prevention, it should be easy. We've seen barriers come down for add-on nonstatin therapy in patients with atherosclerotic cardiovascular disease. It's going to be interesting to see what happens in the primary prevention population. I'm really excited to see the data from CLEAR Outcomes.

Primary vs Secondary Prevention

O'Donoghue: One of the interesting things in the trial is that there was this perplexing trend toward greater benefit in primary prevention vs secondary prevention. Some of it might just be the play of chance, of course, but there are also quirks in terms of there being more lipid-lowering therapy additions or uptitrations for patients in the placebo group. Some of that is just the mechanics of trial and some of the complexity that goes into it. But part of me was wondering whether there might have been more uptitration of lipid-lowering therapies that occurred in the secondary prevention patients, and that might have contributed to that attenuation of benefit in that group.

Navar: I had the exact same questions. I think this is something we're going to see explored in a lot more detail. It's most likely a statistical play of chance. I'm really struggling to imagine a biological explanation for why it works better in primary vs secondary prevention. That's usually not what we see in lipid-lowering trials, because historically, it's stronger in secondary prevention. We're going to have to look more into the trial data to see if there's an explanation beyond play of chance.

From my perspective, I think it's really reassuring that there wasn't a signal in the opposite direction, whereby it didn't work at all in primary prevention. It's more confirmation that lower is better in secondary prevention, but it's also lower is better in primary prevention. I hope that trials like this will continue to move that needle and have us thinking about preventing atherosclerosis in the first place, rather than thinking about these add-on therapies only in secondary prevention where the horse is already out of the barn.

No Reduction in Mortality

O'Donoghue: The curves did diverge quite early, which I thought was interesting. Very often we see the Kaplan-Meier curves superimposed for the first couple of years, suggesting a lagging effect, but it did appear early, which is nice.

My final question for you is that some are saying that the relative risk reduction is not that big, and we didn't see a reduction in cardiovascular mortality or all-cause mortality. What do you say to that?

Navar: The first thing I would put in context is that these are very well-treated patients who are on good background medical therapy. If we look at the relative risk reduction for evolocumab or alirocumab, you're looking at a 15% relative reduction, compared with 13% in CLEAR Outcomes, so it's actually pretty much what we would expect. It's in line with what we'd expect based on the amount of LDL-C reduction. But the most important thing is that this trial was looking at the bempedoic acid monotherapy. This is available in a combination tablet with ezetimibe as well, and you get a much bigger LDL-C reduction when you use it in combination with ezetimibe.

Then extrapolating what's known from the benefit of ezetimibe, adding it in, you get a pretty solid LDL-C reduction with the two combined of about 35%. So if you think about adding on to statin therapy, if we're adding on ezetimibe plus bempedoic acid, we're going to see a bigger relative risk reduction than with monotherapy alone. In terms of mortality, I think we're a victim of our own success. It's hard to die in short-term trials of coronary artery disease and stroke. Our systems of care are better; our acute treatments are better.

The gap of time between when you develop incident atherosclerotic cardiovascular disease or an incident event when you finally die is really pushed out, and we just don't have the follow-up. But lipid-lowering trials are consistent. Those Kaplan-Meier curves always get wider over time. We just saw the follow-up data from FOURIER and FOURIER-OLE, seeing long-term follow-up for patients treated with evolocumab, and that benefit increases over time. I think that's been consistent with all lipid-lowering therapy. So really reemphasize getting patients on treatment early and have them stick — emphasize adherence and keep them on therapy. I think that what we're seeing in this trial is only the very beginning of sustained benefit over time.

O'Donoghue: It is exciting just to have another nonstatin lipid-lowering therapy that appears to be effective in our arsenal. There will continue to be conversations about cost and where it fits into the algorithm. But these results are still quite interesting.

Navar: I totally agree. Treating people with statin intolerance is hard, and it's frustrating for the patients. It's nice to have a therapy that works, and it's nice to be able to tell our patients that this therapy was studied in patients just like them. Almost 50% of the people in the trial were women, which is reflected in what we see: Statin intolerance tends to affect women more than men.

From a communication standpoint, being able to tell patients this therapy was developed specifically for people like you, I'm really optimistic — hopeful, maybe — that that's going to improve uptake at the patient level and maybe improve adherence over time too. But that's where the rubber meets the road. We as clinicians are going to have to really think about who's eligible for therapy, identify people who need uptitration, and figure out how to get them to goal with any of the multiple tools we have.

O'Donoghue: Thank you again for joining me today. I really appreciate your time and I'll look forward to talking about this more in the future. It's been my pleasure. Signing off Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

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