What's New on the Lipid Management Landscape? The Experts Compare Notes

Pam R. Taub, MD, FACC, FASPC; Steven E. Nissen, MD, MACC


August 01, 2022

Editorial Collaboration

Medscape &

This transcript has been edited for clarity.

Pam R. Taub, MD: Hi. I'm Pam Taub. I'm a cardiologist and professor of medicine at UC San Diego, and I am here today with the one and only Steve Nissen, who needs no introduction. We're going to talk about the future of lipid management.

Steven E. Nissen, MD: Thank you very much. I'm Steve Nissen. My current role is chief academic officer of the Heart Vascular and Thoracic Institute at the Cleveland Clinic.

Taub: Steve, you've really had a front-row seat to the evolution of lipid-lowering medications. You've been in charge of such amazing landmark clinical trials. I want to get your insights on some of the new medications that have been approved by the FDA, such as inclisiran and bempedoic acid.

Eye-Opening Outcomes: Clinical Trial Results and Practice Recommendations

Before we talk about these medications, I wanted to get your perspective on the concept of plaque stabilization vs plaque regression. You showed very elegantly in the REVERSAL study with atorvastatin 80 mg that there was stabilization of plaque with statins. Then you showed in GLAGOV with the PCSK9 inhibitor evolocumab that there was plaque regression.

What do you think contributes to plaque regression? Is it the low-density lipoprotein cholesterol (LDL-C) or is it the agent that you use?

Nissen: I think it's all about the LDL-C. My own view is that for any given degree of LDL-C reduction, all other things being equal, you're going to get the same result.

When we started this work in the late 1990s, there was a raging debate. The argument had been made by a number of people, particularly in Boston, that lowering LDL-C below 125 mg/dL had no incremental benefit. That was based upon a post hoc analysis of the CARE trial.

We felt differently, and so we designed the REVERSAL trial. We achieved an LDL-C of 110 mg/dL (2.84 mmol/L) with a dose of 40 mg of pravastatin and 79 mg/dL (2.04 mmol/L) with 80 mg of atorvastatin. There was neither regression nor progression with the high-dose atorvastatin, but there was clear cut, unequivocal progression with the LDL-C at 110 mg/dL (2.84 mmol/L) with pravastatin. We knew that at least over that range, lower LDL-C was better.

What then happened is a series of trials that marched us to a lower and lower level. The ASTEROID trial, which came around 2005, achieved an LDL-C of 60 mg/dL (1.55 mmol/L). That was the first of our studies to show unequivocal regression. Then, amazingly, with a powerful agent like evolocumab, we got down to an LDL-C of 36 mg/dL (0.93 mmol/L) and there was even more regression. Our position has been that lower is better.

We did do a meta-analysis of all of the trials. Steve Nicholls was the first author, and it was published in JAMA. It showed that the LDL-C level showing regression crosses zero at about 60 mg/dL (1.55 mmol/L). You go much below that, and you see less plaque at the end of 18-24 months. If you're > 60 mg/dL (1.55 mmol/L), then you may see stabilization or you may even see progression, but you're not likely to see regression.

The Numbers Game

Taub: You're saying an LDL-C < 60 mg/dL (1.55 mmol/L), is what we need to target for plaque regression?

Nissen: I do think that's true. I've been frustrated with the guidelines. I've been very vocal about that. They're very conservative. They don't necessarily take into account all the data that are available. I don't like the fact that targets are gone. You're supposed to give a high-intensity statin without paying much attention to the LDL-C level.

I call it a fire-and-forget strategy because I do think that it may be for some high-risk people whose LDL-Cs are 65 mg/dL (1.68 mmol/L) or even 60 mg/dL (1.55 mmol/L), they would do better with another agent added on or a different drug because they're going to get into trouble sooner or later. Although we don't have unequivocal evidence comparing 65 mg/dL (1.68 mmol/L) to 35 mg/dL (0.91 mmol/L), I think that the regression/progression data tell us that there are real benefits to going lower.

Taub: Yes. In my patients, I always aim for LDL-Cs < 60 mg/dL (1.55 mmol/L).

Best Practices in Optimizing the Care Plan for Patients After ACS

That brings us to two recent trials. One is HUYGENS, in which the LDL-C was in the mid-twenties, and that was another study with the PCSK9 inhibitor evolocumab. The study showed that, in addition to a decrease in the volume of the plaque, there was an increase in the fibrous cap thickness, really contributing to plaque stability in a post–acute coronary syndrome (post-ACS) population.

There was another study, the PACMAN-AMI trial, again where the LDL-C was in the twenties, also showing thickening of the fibrous cap. The question is, for our post-ACS patients, should we be targeting an LDL-C in the twenties based on these studies?

Nissen: First of all, I do believe the studies. I think they were both very well done. I was actually on the executive committee for HUYGENS, and it was directed by my former postdoc and colleague, Dr Nicholls, who has now come into his own very nicely.

When you get lower and lower, you see a number of things happen. Not only do the lipid-rich plaques regress, but there is a change in this fibrous cap, which at least some people have linked to plaque vulnerability. I'm very careful about the term plaque vulnerability because I think the jury is still out. It seems to be a good thing to have a thicker fibrous cap, to be more resistant to plaque fracture or erosion with subsequent thrombosis leading to an event.

If you've had one event, the likelihood of having another event is much, much higher. What you're arguing for here, and I agree with you completely, is once you've had an acute event, getting to the lowest LDL-C you can to protect those patients against a recurrent event makes sense.

Taub: What do you target for your post-ACS patients?

Nissen: I tell everybody — patients, colleagues, and others — that I believe that what guidelines should say is to get your patients to the lowest LDL-C that you can achieve safely without adverse effects. We know that we have patients with LDL-Cs in the single digits and they seem fine. We have people who are born with LDL-Cs that low and have them for their entire lifetime, and they have normal reproductive physiology and everything looks okay. If you can get there without causing harm, that's good.

The only downside that I see is the slight uptick in diabetes with high-intensity statin administration. Pointedly, those patients, even if they have an increase in their A1c, have the same reduction in morbidity and mortality. There's really not a downside to getting to very, very low levels. I counsel patients and we engage in what is now called shared decision-making. We talk about it, I show them the articles, and we decide together what to target.

Exciting Developments in Therapy Options

Taub: Speaking of new agents and the whole issue around new-onset diabetes, bempedoic acid is a fascinating molecule. It acts upstream to HMG-CoA reductase on ATP citrate lyase, and clinically, it doesn't have many of the musculoskeletal side effects of statins. I think it's very interesting how it lowers high-sensitivity C-reactive protein (CRP), and it doesn't have the impact of increasing glucose levels.

Can you talk a little bit more about the mechanism and what you think is unique about bempedoic acid?

Nissen: You outlined several of the unique features. I agree with you that the LDL-C lowering is modest. It's probably somewhat more than ezetimibe but not as much as the statins can achieve. It's a prodrug so it has to be activated in the liver, which means that nothing happens in muscle. It's pretty difficult for it to produce a musculoskeletal adverse effect when it really doesn't even get activated in muscle.

It has a strong anti-inflammatory effect, and this has been seen in multiple trials. In the CLEAR-outcomes trial, which will be presented and published sometime soon, the effect on CRP was not factored into the powering of the trial. It's a bonus.

The question to be asked is are the results going to fall off of the cholesterol treatment trialists' collaborative regression line? Is it going to be above the line or below the line? If it's below the line, it means that there's more effect than would be predicted for the LDL-C lowering. Now, we hope it's more than, for example, what was seen in IMPROVE-IT. The IMPROVE-IT trial went on for 7 years and achieved a 6% reduction in morbidity and mortality. It wasn't very impressive. We're hoping to see much better than that.

This issue of statin intolerance, as we've talked about, is very controversial. There are people, particularly in the UK, who say it doesn't exist; people like me who work in a prevention clinic see people every day that have tried multiple statins and have adverse effects. The trials that have been done looking for a nocebo effect have suggested that it really isn't real.

We did a trial called GAUSS-3 that showed that probably as many as half of the people with well-documented statin intolerance do, in fact, have objective evidence of statin intolerance. It's a complicated study design. It's in JAMA. Everybody can read it.

The bottom line is, if a patient looks us in the eye and says, "Dr Nissen, Dr Taub, I will not take a statin. I've tried them and I cannot tolerate them," what are we going to do? We need alternatives. We have PCSK9 inhibitors. They're potent, expensive, and injectable. They work very well. Bempedoic acid fills in that gap between PCSK9 inhibitors and not doing anything. It has a good LDL-C lowering effect, good anti-inflammatory effect, and no increase in blood sugar. We're very hopeful that when the CLEAR-outcomes trial is done, we'll see that it has a clinical benefit on morbidity and mortality.

Taub: One thing that I'm very excited about with CLEAR-outcomes is that you have over 50% women in your trial. Congratulations on that because it's really important for us to have a better representation of women and minorities in our clinical trials.

Nissen: We have worked extremely hard to do that. By the way, I know you're on some executive committees. All the executive committees now that I'm forming, we're trying to have 50% women. There are many really talented women coming up in cardiology. They just need to be given an opportunity. In the last decade of my career, I'm going to be an enabler. I have met some fantastic women in the course of this policy who really deserve to be where they are. We're going to give them an opportunity to lead in these trials.

Taub: Congratulations! I think CLEAR-outcomes is really going to set the precedent for how all trials should be with enrollment of women.

What do you think are the mechanisms of statin intolerance?

Nissen: Oh, my goodness. It's the $64,000 question. I've looked at it. Paul Thompson and I have talked about it. He's one of the experts on this topic. I just don't think we understand. Coenzyme Q10 (CoQ10) didn't work in a randomized trial. Clearly, depletion of CoQ10 is not a mechanism. I don't know. Do you have a hypothesis, Pam?

Taub: I think it's something with the mitochondria. I do know that patients who have statin intolerance have lower levels of CoQ10, at least at the cellular level. It hasn't translated in the clinical trials, but that is involved. We also know that mitochondria are really important for metabolism and blood glucose levels. I do think that statins somehow impact mitochondrial function.

We also see that people who are very athletic who take statins report a small decrease in VO2 max. Paul Thompson actually published a paper in JACC a few years on that and changes in citrate synthase levels in the mitochondria. I think there is a mitochondrial mechanism that we have to understand better.

Nissen: One more point is that people have to be very careful that they rule out other causes for statin intolerance. I can't tell you how many people I've seen who say, "I can't take statins," but then you check their TSH [thyroid-stimulating hormone] and they have hypothyroid. You correct their hypothyroidism, and they now tolerate the statins, so there are some things to be done. People need to be thoughtful about this before declaring the patient statin intolerant.

By the way, in our CLEAR-outcomes trial, patients and providers have to sign a statement that they understand that statins are the gold standard for reduction in morbidity and mortality, and the patients have to declare that they will not take a statin under any circumstances. We're doing this in what we think is a very ethical way to make sure that we're getting people who really, truly will not take a statin. If patients won't take a statin, we're going to have to provide them with an alternative.

Taub: Similar to thyroid, the other thing to check is vitamin D. I find if we optimize vitamin D, a large amount of statin intolerance goes away.

A Highly Anticipated Heavy Hitter Enters the Scene

Finally, let's talk about the latest LDL-C–lowering agent, which is inclisiran. I've started to use it in my clinical practice. What do you think the role of inclisiran is in the whole armamentarium we have now of LDL-C-lowering therapies?

Nissen: It is really a remarkable drug. We've been investigating a number of short-interfering RNAs that have other targets. Inclisiran is almost the ideal PCSK9 inhibitor, in my view. You can give it twice a year. A patient comes in to see us twice a year, the nurse in the office gives them their shot. You know that they're taking the drug, so there's no compliance issue.

I know you know this, and I think many of our viewers know this, but the average duration of a statin prescription in America is 9 months. We just can't keep people on daily oral medications very effectively. If we can get them to see us and give them their shot twice a year — it's almost like a vaccine against cholesterol — and get a 50% reduction in LDL-C, then I'm going to sleep better at night knowing that patient is really getting the treatment that they most need. I'm very excited about inclisiran and I wish we hadn't had to wait so long for it to be approved by FDA.

Taub: Thank you so much for spending some time with us and giving us your insights into the space where you've really pioneered so many areas, such as using IVUS [intravascular ultrasound] to understand mechanistically what's going on in the coronary plaque. All the clinical trials that you've been involved with have really changed our clinical practice. It was a pleasure to be with you and get your insights today.

Nissen: I enjoyed it very much, Pam.

Follow Medscape on Facebook, Twitter, Instagram, and YouTube


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.