This transcript has been edited for readability.
Pam R. Taub, MD: Hello. I am Pam Taub. I am a heart specialist and professor of drugs at UC San Diego, and I’m right here at present with the one and solely Steve Nissen, who wants no introduction. We’ll discuss the way forward for lipid administration.
Steven E. Nissen, MD: Thanks very a lot. I am Steve Nissen. My present function is chief educational officer of the Coronary heart Vascular and Thoracic Institute on the Cleveland Clinic.
Taub: Steve, you have actually had a front-row seat to the evolution of lipid-lowering drugs. You have been in command of such wonderful landmark scientific trials. I need to get your insights on a number of the new drugs which have been permitted by the FDA, similar to inclisiran and bempedoic acid.
Eye-Opening Outcomes: Scientific Trial Outcomes and Follow Suggestions
Earlier than we discuss these drugs, I wished to get your perspective on the idea of plaque stabilization vs plaque regression. You confirmed very elegantly within the REVERSAL examine with atorvastatin 80 mg that there was stabilization of plaque with statins. Then you definately confirmed in GLAGOV with the PCSK9 inhibitor evolocumab that there was plaque regression.
What do you assume contributes to plaque regression? Is it the low-density lipoprotein ldl cholesterol (LDL-C) or is it the agent that you simply use?
Nissen: I feel it is all concerning the LDL-C. My very own view is that for any given diploma of LDL-C discount, all different issues being equal, you are going to get the identical consequence.
Once we began this work within the late Nineties, there was a raging debate. The argument had been made by numerous folks, notably in Boston, that reducing LDL-C beneath 125 mg/dL had no incremental profit. That was based mostly upon a publish hoc evaluation of the CARE trial.
We felt in a different way, 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 development with the high-dose atorvastatin, however there was clear minimize, unequivocal development with the LDL-C at 110 mg/dL (2.84 mmol/L) with pravastatin. We knew that a minimum of over that vary, decrease LDL-C was higher.
What then occurred is a sequence of trials that marched us to a decrease and decrease stage. The ASTEROID trial, which got here round 2005, achieved an LDL-C of 60 mg/dL (1.55 mmol/L). That was the primary of our research to indicate unequivocal regression. Then, amazingly, with a robust agent like evolocumab, we received all the way down to an LDL-C of 36 mg/dL (0.93 mmol/L) and there was much more regression. Our place has been that decrease is best.
We did do a meta-analysis of the entire trials. Steve Nicholls was the primary writer, and it was revealed in JAMA. It confirmed that the LDL-C stage displaying regression crosses zero at about 60 mg/dL (1.55 mmol/L). You go a lot beneath that, and also you see much less plaque on the finish of 18-24 months. For those who’re > 60 mg/dL (1.55 mmol/L), then you may even see stabilization or it’s possible you’ll even see development, however you are not more likely to see regression.
The Numbers Sport
Taub: You are saying an LDL-C < 60 mg/dL (1.55 mmol/L), is what we have to goal for plaque regression?
Nissen: I do assume that is true. I have been pissed off with the tips. I have been very vocal about that. They’re very conservative. They do not essentially have in mind all the info which can be obtainable. I do not like the truth that targets are gone. You are supposed to offer a high-intensity statin with out paying a lot consideration to the LDL-C stage.
I name it a fire-and-forget technique as a result of I do assume that it could be for some high-risk folks whose LDL-Cs are 65 mg/dL (1.68 mmol/L) and even 60 mg/dL (1.55 mmol/L), they might do higher with one other agent added on or a distinct drug as a result of they are going to get into hassle in the end. Though we do not have unequivocal proof evaluating 65 mg/dL (1.68 mmol/L) to 35 mg/dL (0.91 mmol/L), I feel that the regression/development information inform us that there are actual advantages to going decrease.
Taub: Sure. In my sufferers, I all the time goal for LDL-Cs < 60 mg/dL (1.55 mmol/L).
Finest Practices in Optimizing the Care Plan for Sufferers After ACS
That brings us to 2 current trials. One is HUYGENS, by which the LDL-C was within the mid-twenties, and that was one other examine with the PCSK9 inhibitor evolocumab. The examine confirmed that, along with a lower within the quantity of the plaque, there was a rise within the fibrous cap thickness, actually contributing to plaque stability in a publish–acute coronary syndrome (post-ACS) inhabitants.
There was one other examine, the PACMAN-AMI trial, once more the place the LDL-C was within the twenties, additionally displaying thickening of the fibrous cap. The query is, for our post-ACS sufferers, ought to we be concentrating on an LDL-C within the twenties based mostly on these research?
Nissen: To start with, I do imagine the research. I feel they had been each very nicely accomplished. I used to be truly on the manager committee for HUYGENS, and it was directed by my former postdoc and colleague, Dr Nicholls, who has now come into his personal very properly.
Once you get decrease and decrease, you see numerous issues occur. Not solely do the lipid-rich plaques regress, however there’s a change on this fibrous cap, which a minimum of some folks have linked to plaque vulnerability. I am very cautious concerning the time period plaque vulnerability as a result of I feel the jury continues to be out. It appears to be a very good factor to have a thicker fibrous cap, to be extra proof against plaque fracture or erosion with subsequent thrombosis resulting in an occasion.
For those who’ve had one occasion, the chance of getting one other occasion is way, a lot increased. What you are arguing for right here, and I agree with you fully, is as soon as you have had an acute occasion, attending to the bottom LDL-C you may to guard these sufferers in opposition to a recurrent occasion is sensible.
Taub: What do you goal in your post-ACS sufferers?
Nissen: I inform all people — sufferers, colleagues, and others — that I imagine that what tips ought to say is to get your sufferers to the bottom LDL-C you can obtain safely with out antagonistic results. We all know that we have now sufferers with LDL-Cs within the single digits they usually appear wonderful. We’ve got people who find themselves born with LDL-Cs that low and have them for his or her whole lifetime, they usually have regular reproductive physiology and every little thing appears okay. If you will get there with out inflicting hurt, that is good.
The one draw back that I see is the slight uptick in diabetes with high-intensity statin administration. Pointedly, these sufferers, even when they’ve a rise of their A1c, have the identical discount in morbidity and mortality. There’s actually not a draw back to attending to very, very low ranges. I counsel sufferers and we interact in what’s now known as shared decision-making. We discuss it, I present them the articles, and we determine collectively what to focus on.
Thrilling Developments in Remedy Choices
Taub: Talking of recent brokers and the entire concern round new-onset diabetes, bempedoic acid is an interesting molecule. It acts upstream to HMG-CoA reductase on ATP citrate lyase, and clinically, it does not have lots of the musculoskeletal unwanted effects of statins. I feel it is very attention-grabbing the way it lowers high-sensitivity C-reactive protein (CRP), and it does not have the influence of accelerating glucose ranges.
Are you able to discuss just a little bit extra concerning the mechanism and what you assume is exclusive about bempedoic acid?
Nissen: You outlined a number of of the distinctive options. I agree with you that the LDL-C reducing is modest. It is most likely considerably greater than ezetimibe however not as a lot because the statins can obtain. It is a prodrug so it needs to be activated within the liver, which signifies that nothing occurs in muscle. It is fairly troublesome for it to provide a musculoskeletal antagonistic impact when it actually does not even get activated in muscle.
It has a powerful anti-inflammatory impact, and this has been seen in a number of trials. Within the CLEAR-outcomes trial, which shall be introduced and revealed someday quickly, the impact on CRP was not factored into the powering of the trial. It is a bonus.
The query to be requested is are the outcomes going to fall off of the ldl cholesterol therapy trialists’ collaborative regression line? Is it going to be above the road or beneath the road? If it is beneath the road, it signifies that there’s extra impact than could be predicted for the LDL-C reducing. Now, we hope it is greater than, for instance, what was seen in IMPROVE-IT. The IMPROVE-IT trial went on for 7 years and achieved a 6% discount in morbidity and mortality. It wasn’t very spectacular. We’re hoping to see a lot better than that.
This concern of statin intolerance, as we have talked about, could be very controversial. There are folks, notably within the UK, who say it does not exist; folks like me who work in a prevention clinic see folks day by day which have tried a number of statins and have antagonistic results. The trials which have been accomplished in search of a nocebo impact have steered that it actually is not actual.
We did a trial known as GAUSS-3 that confirmed that most likely as many as half of the folks with well-documented statin intolerance do, in reality, have goal proof of statin intolerance. It is a sophisticated examine design. It is in JAMA. All people can learn it.
The underside line is, if a affected person appears us within the eye and says, “Dr Nissen, Dr Taub, I cannot take a statin. I’ve tried them and I can’t tolerate them,” what are we going to do? We’d like options. We’ve got PCSK9 inhibitors. They’re potent, costly, and injectable. They work very nicely. Bempedoic acid fills in that hole between PCSK9 inhibitors and never doing something. It has a very good LDL-C reducing impact, good anti-inflammatory impact, and no enhance in blood sugar. We’re very hopeful that when the CLEAR-outcomes trial is finished, we’ll see that it has a scientific profit on morbidity and mortality.
Taub: One factor that I am very enthusiastic about with CLEAR-outcomes is that you’ve over 50% ladies in your trial. Congratulations on that as a result of it is actually necessary for us to have a greater illustration of ladies and minorities in our scientific trials.
Nissen: We’ve got labored extraordinarily exhausting to try this. By the best way, I do know you are on some government committees. All the manager committees now that I am forming, we’re attempting to have 50% ladies. There are numerous actually gifted ladies developing in cardiology. They simply should be given a chance. Within the final decade of my profession, I’ll be an enabler. I’ve met some incredible ladies in the middle of this coverage who actually should be the place they’re. We’ll give them a chance to steer in these trials.
Taub: Congratulations! I feel CLEAR-outcomes is basically going to set the precedent for the way all trials needs to be with enrollment of ladies.
What do you assume are the mechanisms of statin intolerance?
Nissen: Oh, my goodness. It is the $64,000 query. I’ve checked out it. Paul Thompson and I’ve talked about it. He is one of many specialists on this subject. I simply do not assume we perceive. Coenzyme Q10 (CoQ10) did not work in a randomized trial. Clearly, depletion of CoQ10 just isn’t a mechanism. I do not know. Do you will have a speculation, Pam?
Taub: I feel it is one thing with the mitochondria. I do know that sufferers who’ve statin intolerance have decrease ranges of CoQ10, a minimum of on the mobile stage. It hasn’t translated within the scientific trials, however that’s concerned. We additionally know that mitochondria are actually necessary for metabolism and blood glucose ranges. I do assume that statins one way or the other influence mitochondrial perform.
We additionally see that people who find themselves very athletic who take statins report a small lower in VO2 max. Paul Thompson truly revealed a paper in JACC a number of years on that and modifications in citrate synthase ranges within the mitochondria. I feel there’s a mitochondrial mechanism that we have now to know higher.
Nissen: Another level is that folks need to be very cautious that they rule out different causes for statin intolerance. I am unable to let you know how many individuals I’ve seen who say, “I am unable to take statins,” however then you definately test their TSH [thyroid-stimulating hormone] they usually have hypothyroid. You appropriate their hypothyroidism, they usually now tolerate the statins, so there are some issues to be accomplished. Folks should be considerate about this earlier than declaring the affected person statin illiberal.
By the best way, in our CLEAR-outcomes trial, sufferers and suppliers need to signal a press release that they perceive that statins are the gold normal for discount in morbidity and mortality, and the sufferers need to declare that they won’t take a statin below any circumstances. We’re doing this in what we expect is a really moral technique to guarantee that we’re getting individuals who actually, really won’t take a statin. If sufferers will not take a statin, we will have to supply them with an alternate.
A Extremely Anticipated Heavy Hitter Enters the Scene
Lastly, let’s discuss concerning the newest LDL-C–reducing agent, which is inclisiran. I’ve began to make use of it in my scientific apply. What do you assume the function of inclisiran is in the entire armamentarium we have now now of LDL-C-lowering therapies?
Nissen: It’s actually a outstanding drug. We have been investigating numerous short-interfering RNAs that produce other targets. Inclisiran is nearly the best PCSK9 inhibitor, for my part. You can provide it twice a yr. A affected person is available in to see us twice a yr, the nurse within the workplace offers them their shot. You understand that they are taking the drug, so there is no compliance concern.
I do know you recognize this, and I feel lots of our viewers know this, however the common length of a statin prescription in America is 9 months. We simply cannot preserve folks on every day oral drugs very successfully. If we will get them to see us and provides them their shot twice a yr — it is virtually like a vaccine in opposition to ldl cholesterol — and get a 50% discount in LDL-C, then I’ll sleep higher at evening understanding that affected person is basically getting the therapy that they most want. I am very enthusiastic about inclisiran and I want we hadn’t needed to wait so lengthy for it to be permitted by FDA.
Taub: Thanks a lot for spending a while with us and giving us your insights into the house the place you have actually pioneered so many areas, similar to utilizing IVUS [intravascular ultrasound] to know mechanistically what is going on on within the coronary plaque. All of the scientific trials that you have been concerned with have actually modified our scientific apply. It was a pleasure to be with you and get your insights at present.
Nissen: I loved it very a lot, Pam.