 Hello and welcome to HCPLive® Peer Exchange titled Paradigm Shifts in Lipid Lowering. I'm Dr Keith C. Ferdinand from Tulane University School of Medicine in New Orleans, Louisiana, and I have some very experienced clinicians and researchers.

We are joined by Dr Linda Hemphill from Massachusetts General Hospital in Boston. How are you doing, Linda? Dr Dean Karalis from Thomas Jefferson University Hospital in Philadelphia, PA. Dr Norman Lepor, Cedars Sinai Medical Center, Los Angeles, California. And Dr Manesh Patel from Duke University School of Medicine in Durham, North Carolina.

In today's discussion we will provide a brief overview of the standards of care for lipid management, and focus on a rapidly emerging, newer treatment as an option for managing dyslipidemia. Let us get started.

Manesh, I know you do a lot of interventions and you see patients who are at high risk, but what is the pathophysiology of the relationship between hypercholesterolemia and cardiovascular disease? How is it actually related?

 Yeah, thanks, Keith, and thanks for having me on this program. This is potentially, and I think we've all now learned the single most common pathophysiological process that's leading to morbidity and mortality worldwide, even unfortunately in the setting of global pandemics and other things, heart disease is still the #1 killer through atherosclerosis. 

I often tell my patients the process is actually, we know from childbirth to, unfortunately, throughout our age of life that atherosclerosis happens as we start to have lipid plaques, and we'll go into sort of the particles of lipids with HDL, LDL, total cholesterol, but the cholesterol gets put down into the vessel. Over time, that cholesterol that has put down into the vessel actually incorporates sometimes into the wall under the endothelium and leads to narrowings. They don't have to actually narrow the entire artery. That leads to some inflammation as your body responds to that atherosclerosis, and that inflammation sometimes leads to occasionally plaque ruptures where some of that material is made evident in the blood vessel and leads to thrombosis. And some people have used the terms atherothrombosis when people have these events.

The risk factors, in addition to just sort of saying our diet and things that lead to how we manage that cholesterol also include high blood pressure, sort of our classical atherosclerotic cardiovascular disease respecters, diabetes, hypertension, the cholesterol level itself, your age, your sex, if you smoke tobacco. Those things go into something we have our patients do to calculate the ASCVD [atherosclerotic cardiovascular disease] risk score.

The two points that you made that I want to highlight, if you may, one is you said lifelong, because we think this is an adult disease since we are an adult patient population that we deal with. But it really starts in teenage years or before that.

 Yeah, I think we're learning more and more about primordial prevention to primary prevention to secondary prevention, and unfortunately, we know, as we've seen more recently, a lot of adverse childhood events and other things affect how our bodies are shaped during development, and then in addition to that, both habits, genetics, environmental influences affect what's happening, and I'm sure we're going to talk some about that.

Those lead to this atherosclerosis that is a lifelong process that often presents itself, as an interventional cardiologist, for me, sometimes when somebody is 50 or sometimes when they're 80, unfortunately sometimes when they're even younger these days. And those atherosclerotic events that people have are led to where those plaques have built up.

I tell our patients there's sort of the big three: the brain. We all care about the brain, and so atherosclerosis in the vessels that go to the brain leading to stroke or cerebrovascular events. Obviously, the heart, we think a lot about cardiovascular events that lead to the heart. And then what I call our peripheral extremities, the lower extremities and peripheral artery disease, and atherosclerotic events that lead to, eventually in life, limb limitation or limb loss.

So those are sort of the ways in which I describe the biology of that and to the clinical events. And there's chronic biology and then there's acute biology, when an acute event happens on top of that chronic, lifelong process.

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Pathophysiology of Hypercholesterolemia and Cardiovascular Disease 

 It's important to recognize that it's not just adult disease, that it is in fact childhood adolescence where these happen, and that tight stenosis that you intervene on has probably been there for decades before you have the thrombosis superimposed on the plaque, is that correct?

That's right. I think the couple things we most worry about that is happening in the United States. I know you are in New Orleans; I'm here in Durham, North Carolina, and so unfortunately the Southeast United States is the hypertension belt, the obesity belt, the diabetes belt. In addition to it being lifelong, unfortunately the childhood obesity and diabetes rates are going up higher and higher, and we know that that eventually leads to this plaque that has been in people's arteries for many years. 

And then whether it is tight or whether or not it's sort of tight and then ruptures leads to whether or not they come in with symptoms that are chronic, or whether they come in with an acute heart attack. And unfortunately, our ability to predict what is going to happen with our patients is very poor and that's why we need systemic therapies. I say as an interventional cardiologist I am often in the vessel trying to treat the pothole on the highway, but I need something to fix the whole highway; I can't just fix that one little pothole. And so I often talk to my patients about I've done something to help this problem, but you have miles of road that need to be treated all the time.

I like that concept. In fact, if you look at various populations, for instance, African Americans have a high risk of premature disease and death, high incidence of heart failure, high incidence of stroke, peripheral vascular disease, limb loss, amputations. But if you then look in the MESA or NHANES, the LDL levels are about the same as everyone else. In fact, the HDL may be a little higher and the triglycerides, despite obesity especially in black females, may be a little lower. But then hypertension comes into play, diabetes comes into play, and of course issues of access and the social determinants of health, not having a primary care provider or usual source of care. Not getting appropriate adherence because you cannot afford the medications.

There's a hodge-podge of factors that come in to play then, then just the build-up of plaque. Would you agree with that?

 Absolutely. We often say in our area that unfortunately there's a mixture between your genetic code and your zip code that's determining what your health is, and it's the space between, as we just said for our children that are born with a certain genetic code and the environmental influences that lead to that, unfortunately the United States zip code where you're growing up and having different access and potentially social determinants of care, which lead to both obesity, food/nutritional insufficiency, a variety of things that you've highlighted. I think our global mission in trying to get to health equity and improved cardiovascular health is going to be focused on taking these concepts that start with the plaque and the biology and say what can we do across a population to lead to better health.

 Now I am going to say something but I am not trying to insult Duke, because I think it's the same for Tulane and I'm pretty sure it's the same for UCLA and Cedars Sinai. Some of the worst outcomes are in zip codes that are within walking or a long bike ride of major academic centers. People can live in areas in major cities with the best academic centers in the world and still have poor outcomes.

Oh, no, you are not upsetting me. It is one of the reasons I am doing what I'm doing. I think our focus must be -- Peter Smith, one of my colleagues in CT surgery says you cannot be the best in the world if you are not the best in your back yard. If we do not have people healthier in Durham, we are not going to be telling people how you could be healthier at worldwide. So, I fully agree with what you are saying.

I think unfortunately it starts not just with access, but what is the blood pressure of our population, what are we doing for activity, how are we getting this information out. And we are going to talk a little bit later in the program about disruptive therapies. But one could take the analogy of how well we are doing with COVID vaccines for our population. We have things that work, why cannot we get it to the people that need it the most.

Risk Factors for Developing Hyperlipidemia 

 Norm, the patient who comes in front of you now has risk. I already mentioned the lipid profile; it could be average, especially between the African Americans, the LDL might be 113, 120, HDL 50, triglycerides 80. It does not look that bad. Blood pressure is a little high, smokes, has some obesity. How do you then determine what patient really is at high risk, not just in terms of the simple metrics that we use in the conventional visit. What type of tools do you use to tease out those very high-risk patients?

What you are describing is the patient who has a little bit of this and a little bit of that, and I think that first off, in my evaluation of the patient, I am interested in really getting a detailed family history. Because genetics are such a strong component. And they always say you must know history because history repeats itself, and it is incredibly important to get really a feel for the genetic predisposition, which I think accounts for the predisposition to some of the other comorbidities you mentioned beyond lipids, hypertension.

Even a patient I saw today, I had to convince her to take her blood pressure medication, and then she tells about her sister who is also hypertensive and also I think when a patient presents, particularly a new patient, it's kind of like putting the pieces of a puzzle together, and what you're doing is you're getting the genetic information, then you're defining other risk factors, their history of perhaps tobacco use, and their tobacco use could be smoking or it could be -- probably more likely where you live, more like chewing tobacco. And then we get into some of the comorbidities.

But I've always felt that imaging plays a critical role. And I certainly early on took a lot of bullets, because early on you would hear people talking about how cost ineffective it would be to do calcium scoring and these other assessments. But as a cardiologist, I prefer living in a world of absolute risk rather than relative risk, and I think I would like really, at the end of the day, find out how all these risk factors that we know about, plus the others that we do not frankly know about, and see what it does in terms of defining phenotype. And how do you define phenotype? Well, you could define phenotype if the patient has had a history of an event. Have they had an MI [myocardial infarction], have they had a stroke, do they have PAD [peripheral artery disease], have they had a coronary stent?

But oftentimes I am seeing these patients before they manifest these secondary complications of disease, and I will be very aggressive about calcium scoring, and even in the diabetic patient I am very aggressive because even though diabetes is considered a cardiovascular disease equivalent, I know, and I see a very amount of heterogeneity even within the type II diabetic patient.

What I really try to do is define absolute risk, and then once I have defined that patient as being absolute -- at a high relative risk and high absolute risk, I'm very aggressive with a little bit of hypertension. I normalize their blood pressure. I try to make an effect with education on lifestyle modification, such as the salt in the diet, activity, alcohol use. I am very aggressive about getting my patients to lose weight by virtue of trying to minimize the development of diabetes and perpetuation of the metabolic syndrome, and yes, I will even use pharmacology as a cardiologist. We do have some good pharmacology; unfortunately, it is not that available to the Medicare population because of insurance issues. For some reason Medicare does not consider -- it does not take seriously obesity as a disease state, so I do not have as many tools. 

What I do is, I use imaging in a large extent, carotid ultrasound, I will use calcium scoring, and I'll use that to really, I think do a better job of defining the risk of disease in this population, and then the more malignant the risk. And we can talk about that later because it is not cookie cutter for me. The more malignant the presentation, just like cancer, and I have been quoted as saying atherosclerosis is like cancer of the arteries. And the more malignant the presentation, the more aggressive I am going to be in terms of goals for treatment.

I agree with you. Coronary calcium scoring now is readily available. In fact, the cost is down. In most places you can get it for $100 or less. The amount of radiation is not more than a mammogram with the new techniques, so it is a way of looking and discerning those high-risk patients who have the various risk factors, you put them together, it does not really impress you, but then with a strong family history you pick up something.

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Identifying Patients at High Risk for CV Morbidity and Mortality 

So even when we're looking at patients who have a normal coronary calcium score who have very elevated lipids, they may have familiar hypercholesterolemia, how common is FH [familial hypercholesterolemia] and how does that impact your assessment of some of these high-risk patients?

We now know from studies, in the Netherlands, that really the prevalence of FH is 1 in 250, not the 1 in 500 that we all learned in medical school. It is twice as common as we used to think, and very common in our clinical coronary patients. And a group of patients that we need to be very aggressive in primary prevention, and in fact FH is the only condition which the FDA approved the PCSK9 inhibitors and bempedoic acid.

We're going to talk about both of those drugs. Do you do genetic testing, or do you just do the surrogate of an LDH greater than 190? Or do you have to do genetic testing to make the diagnosis of FH?

The diagnosis of FH can be a sticky wicket. If you are trying to get the PCSK9 inhibitors or bempedoic acid approved in primary prevention, some insurance companies will insist on meeting the Dutch Lipid Clinic criteria. Well, this is very high bar. In essence, to be definite FH by the Dutch Lipid Clinic, you must have xanthomas, and we do not see xanthomas as much anymore because people are statin treated. Maybe they're not to a good level with statin, but low enough that they have not developed the xanthomas.

We could be missing them if we're just looking for those classic signs of FH. Family history, we heard earlier, was a part of the evaluation of these high-risk patients. Do you think that is one of the clues that will pick out those patients along with the markedly elevated LDL?

Very important, very helpful, but there is also something I call the disappearing family history syndrome, and this is where the parents have been taking statin since a fairly young age. And you have to go back to the grandparental level for your family history.

High Cholesterol Versus Familial Hypercholesterolemia 

Dean, we have different levels of intensification of LDL [low-density lipoprotein] lowering. We know that LDL less than 100 mg/dL in persons with diabetes, less than 70 mg/dL in patients who have atherosclerosis. The Europeans, for very high-risk patients, say less than 55 mg/dL. What’s your take? How low should we go? How aggressive or intensive? I like intensive because aggression is not good. How intensive should we be in our LDL lowering?

 First, Keith, thank you for inviting me here today. One of the things we do know is there’s a direct relationship between the level of LDL cholesterol lowering and cardiovascular risk. I think Norm Lepor said it earlier as well. The higher the risk an individual is, the lower we want to drive that LDL cholesterol.

There are 2 issues going on. One is that we need to be more aggressive early in identifying those high-risk primary prevention patients, getting them on at least a moderate-intensity statin, and bringing LDL cholesterol to less than 100 mg/dL. But once patients have established cardiovascular disease, or as Linda Hemphill was talking about with FH [familial hypercholesterolemia], we need to drive LDL cholesterol as low as we can, if we can do it safely and affordably. The evidence is clear from randomized clinical trials, observation, and even the genetic studies that the lower we can get LDL cholesterol, the better. One of the things I am really pleased about—and most of us are—is that the new cholesterol guidelines have now reintroduced lipid goals that we should be aiming for. The 2018 AHA/ACC [American Heart Association/American College of Cardiology] and multisociety guidelines did not specifically identify an LDL cholesterol goal for primary prevention; they did for higher-risk patients. For FH, less than 100 mg/dL; for patients with ASCVD [atherosclerotic cardiovascular disease], less than 70 mg/dL.

But lower is better, and as you mentioned, the European Society of Cardiology and the American Association of Clinical Endocrinologists—for patients with ASCVD and diabetes, who are very high-risk patients—have set a goal of less than 55 mg/dL, which is even more aggressive than the goal set by the 2018 AHA/ACC guidelines. The lower we can get cholesterol, the better.

The other point I want to make, and we see it from some of the genetic studies, is that if we use drugs that have a common mechanism of action—that is, they upregulate the LDL receptor to lower LDL, whether it’s ezetimibe, PCSK9 inhibitor or statins—it appears that they all work as effectively, to not only lower LDL but also have the same effect when we look at the reduction in LDL. We need to drive LDL, down and we’re going to see levels getting lower and lower, these goals getting lower and lower, and we have to start thinking about treating this lipidemia with combinations, just as we are used to with diabetes and hypertension.

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Aggressive LDL Lowering in High-Risk Patients 

 Manesh, there’s an emerging therapy that’s not approved, it’s still investigation: inclisiran. Tell us a little about this particular molecule, how it works, how you administer, and what type of results we have seen thus far.

Thanks, Keith. It’s a very exciting time for us. All of us in the last few years have seen that there are new pathways or potentially new ways to treat our patients with high cholesterol. We’ve heard a little about PCSK9, the protein—just to remind everyone, that’s a protein that’s a protease in your liver. It actually helps break down the LDL [low-density-lipoprotein] receptor. So, if you inhibit PCSK9, you prevent that LDL receptor on the cells from taking in LDL, and you allow them to be on the cell receptor, so they can take in more LDL and reduce your circulating LDL level by up to 50%, 60%.

Inclisiran is a newer molecule that’s interestingly different. We’ll talk about PCSK9 inhibitors in a second, the first range of the more antibodies to that protein. Inclisiran is a small interfering RNA molecule. Before the pandemic, people probably didn’t think as much about RNA and ways that that all works, but a small interfering RNA molecule is a strand of that molecule that actually goes to your liver after an injection and inhibits the translation of that PCSK9 protein, so potentially a longer-acting way of inhibiting the production of that PCSK9 protein or inhibiting that function.

How have we dosed it, and why are we so excited about it? I’ll talk about the dosing, and then we’re going to talk about some of the ORION trials that are coming out about it. The original studies looked to dose it day 1, at 90 days, and see people at 1 year to just see the effect. And it was really surprising that if you could give an injection at once and then out to 90 days or 6 months, you could get a reduction up to about 50%. The dosing schedule of this therapy, once you get started on it, is every 6 months. You would potentially inject this as this therapy, and it would inhibit the production of that protein at your liver. That certainly is a very innovative and potentially disruptive way to improve how we take care of our patients with high cholesterol.

Norm, we have some data from the ORION studies. Manesh talked about that 50% to 60% reduction. We have some evidence from clinical trials—peer reviewed, publicly available. What did it show?

 I was an investigator on a number of the ORION trials, including ORION-2, ORION-10, and ORION-8, and I’m an investigator on the ORION-4 cardiovascular outcome trial. But what the pooled analysis showed, No. 1, was that you’re able to achieve a very consistent level of LDL lowering in the 55% range with this twice-a-year or every-6-month subcutaneous injection of inclisiran, a 30-mg dose of inclisiran.

The area under the curve is very consistent. The levels of LDL reduction are consistent at a variety of end points, so what we were able to see in terms of efficacy—the definition of efficacy we’re talking about, pending the results of the cardiovascular outcome trial ORION-4, which hopefully we’ll have in a couple of years—was significant LDL reduction, similar to what we see with the currently available higher doses of PCSK9 inhibition, but certainly those we know are given on an every-2-week schedule vs the inclisiran, which is given only twice a year, every 6 months.

We know from an efficacy point of view; we’re getting LDL reductions of about 55%. This is on top of patients who are receiving statin therapy. A minority of patients were also receiving treatment at baseline and continuing through the trial with ezetimibe. We found that to be consistent.

In the safety analysis, we found that the drug, certainly in terms of treatments, emerged in adverse events. They were consistent with by far most of these events being placebo-like. I am talking about, for instance, the development of diabetes was placebo-like. Hypertension, arthralgias—most of these adverse events were placebo-like, including the development of liver function abnormalities, muscle adverse events, and abnormalities of liver function.

What we have been able to find in these particular trials is certainly efficacy as well as safety.

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Mechanism of Action of Inclisiran in Lipid Lowering  

 Linda, Dean, what do you think about inclisiran? We’ve heard wonderful things. Anything bad? Anything they’re missing?

It’s interesting, this whole question of RNA at this point in history, because of course we have the messenger RNA vaccines for COVID-19. I have had the question asked of me by patients and even by some physicians, are you changing the cell machinery? How long is this going to be a problem?

Are you changing the cell machinery? How long is this going to be a problem?

 In ORION-1, the first inclisiran study, published in the New England Journal of Medicine in 2017, after a single shot, the LDL [low-density-lipoprotein] was trending back up at 180 days. The cell machinery is not permanently changed. That’s very reassuring, and we would not expect it to be.

This is acting through what’s called a risk complex, which is of course different from the messenger RNA for the vaccines is working through the ribosomes. But basically, RNA is disposable. You are not changing the DNA. This isn’t crisper.

All right, Dean, make it practical for our physicians out there.

Yeah, I am pretty optimistic about this. At least from the early data we’ve seen from the ORION trials, inclisiran appears to be not only very effective but very safe. We will have more evidence from the outcome trial.

But we must weigh the risk vs the benefit. The real problem is not will this medicine hang around too long and give us too low LDL. The problem we face in clinical practice is that most of our patients have too high LDL cholesterol for their risk, and cardiovascular [CV] disease still remains the leading cause of death among all the patients we see in our offices, compared with other causes of death.

We can’t forget therapeutic lifestyle interventions. Big words for healthy eating, physical activity, maintenance, weight loss, etc.

Absolutely. And if you look at the 2019 AHA [American Heart Association] and ACC [American College of Cardiology] general prevention guidelines, there’s a great figure in there of a large circle of all the things we need to do. Even though we may be talking about pharmacological therapy and lipid lowering, lifestyle plays a key role, especially early on when you see a patient who has a family history of early heart disease. Even if they don’t have genetic factors, you want to get their kids on a heart-healthy lifestyle, exercise, and focus on not only exercise and diet but also diabetic control, hypertension control, smoking cessation, and lipids.

 When we were talking earlier, Manesh, you said you were going to bring in the PCSK9 inhibitors. We don’t want to forget that group. What is the outcome study show with that group of agents?

Yeah, it is important to think about the fact that we just discussed inclisiran. We are definitely very enthusiastic about it and have, as Norm has highlighted, really great studies to tell us that the LDL has been reduced, and there are ongoing cardiovascular outcomes studies. Those would be what key studies that would help us feel really comfortable, to know that we lowered LDL. We all believe lowering LDL leads to better outcomes, and we’ll prove that. The safety profile has been good.

For the PCSK9 inhibitors, there are 2 of them that are actual antibodies—directed monoclonal antibodies to that protein—given twice a month or maybe once a month at the least frequent. The frequency is important because what we’ve heard is obviously that adherence is hard. Taking a statin every day, taking a shot twice a month or once a month, or taking a shot twice a year. Those are the choices of what we are getting at.

For the monoclonal antibodies, both of those drugs have—in the ODYSSEY Outcomes trial and FOURIER and other trials, we have seen cardiovascular outcomes improve in those patients. We’re encouraged that this pathophysiological mechanism, when we’ve done it in patients who have cardiovascular risk or bad cardiovascular events, we’ve reduced future cardiovascular events. We have reduced future cardiovascular events to include myocardial infarction, CV death, nonfatal stroke, but we have also seen it in some of these other vascular events. As I said, irrespective of whether you had peripheral artery disease, we reduced some of those limb outcomes.

We still have add-on ezetimibe. It is old-school right now, but it gives you maybe 18%, 20% added to statins, even up to 25%, depending on how active the uptake of statin is through your…receptors.

 Yeah, that is a great point. Obviously, we can talk about the therapies and the cost and different things, but ezetimibe is certainly a therapy that a lot of us are using when you don’t get to go with a statin, and you need to make sure the patient is able to take the statin.

For sure we should focus on usual care and escalation as one might think to get people to reduce their risk.

Outcomes and Practical Implications of Newer Agents 

Norman, give me a short take on where EPA [eicosapentaenoic acid] makes it into this commentary of lipid-lowering agents changing the lipid profile for patients who have high risk.

Great question. I was a PI [primary investigator] on the REDUCE-IT trial, which was a CV [cardiovascular] outcome trial assessing the impact of eicosapentaenoic acid, in terms of its ability to impact cardiovascular events in a patient population that was mild to more moderately hypertriglyceridemic. 

As an investigator, I remember the phone call we received from the sponsor about a day or 2—Manesh is smiling; he was probably on that call too. I remember being at the TCT [Transcatheter Cardiovascular Therapeutics] meeting, and they said we want you to be out of the public area. When they told us there was this 25% cut in CV outcomes with a P value of something like less than .00000001, it blew us away. It blew me away. 

And the data looked real. You looked at all the different CV events on their own, and there were significant reductions. The EPA is the real deal, and what we’re going to find from the label recommendation is to use it with patients who have triglycerides over 150 mg/dL, although its mode of action seems to be unrelated to actual triglyceride reduction. 

There are some theories that the EPA actually enters the vascular wall and impedes the development of plaque progression and impedes plaque rupture and thrombosis. It’s the real deal. It seems that with all the clinical trials we have seen, these mixtures of DHA [docosahexaenoic acid] and EPA have not worked out in terms of cutting events. 

I am very assertive in using EPA in the patient population with the elevated triglycerides. But I have a theory, and then I will let others opine. Just as we have seen the goals for LDL [low-density-lipoprotein] reduction going down and the recommendations in terms of when we start to initiate treatment and such, I think we’re going to see the same thing with triglycerides. What we are going to see going forward is that “normal” levels of triglyceride aren’t really normal, and they are pathologic.

I have a funny feeling that we are going to see the use of drugs like EPA at least being studies in a non-hypertriglyceridemic patient population, and we may see efficacy there. But I have definitely introduced it into my clinical practice in an assertive way, on top of very aggressive LDL aggression in terms of really taking a global approach to mitigating cardiovascular risk.

I asked everyone to give me their take-home message on how they think inclisiran is going to be built into our practices in the future, so let me hold on hat. How is EPA, eicosapentaenoic, going to be built into our practices? Norm told me about the studies and the wonderful results that came from those studies. It is here; it’s approved. Linda, Manesh, Dean, how does it affect your practice?

 I can start. I think Norm is correct. If you look at the cardiovascular risk associated with triglycerides, that risk starts to rise sharply when the triglycerides are over 100 mg/dL.

The second is if you think back to a number of years back, when the American Heart Association came out with guidelines on hypertriglyceridemia, they actually called a normal triglyceride or an optimal less than 100 mg/dL. Norm is correct on this. Triglyceride levels between that 100-and-200-mg/dL range, which are often the levels that are overlooked by clinicians when they see that in their patients, should be a red flag as a marker of increased residual risk. 

It appears that the mechanism by which EPA works is through multiple mechanisms and not just triglyceride lowering. Plaque stabilization, inflammatory, anti-inflammatory effects. If you look at the study, patients could get into the REDUCE-IT trial if their triglycerides were from 135 mg/dL or higher. In the group of patients with triglycerides of 15 to 150 mg/dL, it appeared to have the same benefit as those who had triglycerides that are higher.

We’re going to approach treating cardiovascular disease in a multifaceted approach—targeting LDL, using other agents that have cardiovascular benefit like EPA—just like we’re seeing now with the SGLT2 inhibitors and the GLP1 agonists. The future is going to be on combination therapy to drive down cardiovascular risk in these high-risk patients.

Linda, Manesh, how does EPA fit into your practice?

It is very hard to argue with a P value of .000001.

Yes, I am using it in my secondary prevention patients who I have achieved—or wherever they are regarding their LDL, if their triglycerides are over 150 mg/dL.

Yeah, that is the message for me. We are at a great place with lipid and risk reduction in that we have multiple options. We are almost at the place where, like with heart failure, we are going to have to think about sequencing things and which 1 goes when, but almost everybody says statins are first, and we recognize that’s what has to be first, and we’ll talk about tolerance and everything.

If I can get LDL to goal in secondary prevention patients, or even toward it, and triglycerides as Norm and others have just said really well, we have underrepresented and under-recognized that risk, likely because we haven’t had therapies that work. Once you have a therapy that works, you start paying attention to things a little more because you have something to do for that patient.

We are using it now, and there’s going to be increasing use. There probably are more studies coming too. The patient who gets high-dose EPA, as we just described, is the patient for me who is secondary prevention, with an LDL hopefully near goal, who still has an elevated triglyceride. The higher the triglycerides, the more likely the person is going to get the therapy. Obviously, there’s a risk of cost and all the other things we do for our patients to get them on it.

EPA in the Prevention of CV Risk 

I’ll give you a chance, Manesh, to get a little more detailed about inclisiran. Exactly how does it work, and how is it going to be used if it’s approved by the FDA in clinical practice?

Thanks, Keith. I appreciate the opportunity, and the first thing to think about with inclisiran is to recognize that the target of inclisiran is the protein PCSK9, which we know about because there are monoclonal antibodies to that protein that helps break down the LDL [low-density lipoprotein] receptor. So if you can inhibit that protein, you’ll have more LDL receptors, and you’ll lower LDL. We know that’s the target.

Then inclisiran itself; it’s important to recognize that it’s a small RNA molecule that’s interfering with RNA. Some have said what exactly does that mean? It follows a natural pathway of RNA interference. There’s a complex in your cells called the RNA inducing or silencing complex; some people have called that the risk complex. That complex is where 2 RNA molecules are often together. And if you have a small one that enables cleavage of that mRNA [messenger RNA] molecule specifically in coding for PCSK9, you potentially inhibit the production or the translation of the messenger RNA into PCSK9.

You’re not interfering with the DNA in the cell?

You’re not interfering with the DNA at all. What you’re doing is you’re putting a small piece of RNA that goes in and interferes with the translation of the mRNA that’s leading the PCSK9. I think that’s an important message because that happens in your liver, and so you can give that shot and inhibit the production or the translation of the PCSK9 molecule, and that prevents that protein.

That’s the first message for people, that it’s an inhibiting RNA molecule.

 Now this idea of it lasting for 6 months, why would a drug last for 6 months? That sounds unusual.

It’s a great point, because the first thing we always think about is, “The things I’m used to taking are proteins that I take in my body, I break down, and then it inhibits a receptor, or most of the medicines I take, do something to protein.” This is actually an inhibiting RNA molecule, a small molecule that’s going to your liver, inhibiting the translation of that protein. You’re a little upstream, so that if you can have enough of that molecule in your liver, you can prevent enough of that protein from forming so that that machinery slows down, and you may not break down LDL receptors for a period of time. In fact, they studied that, and we’re going to hear about some of the studies about how long that effect might last, which might also give us comfort in understanding this.

But it is important because I think a lot of people are worried, and understandably, that when you do something that has the word RNA or DNA, or something that might get confused for that, that might worry you that you’re going to have some long-lasting effect. We now have at least some longer studies here that have shown us that when we dose this therapy, and the dosing of this is, I think Linda mentioned in one of the prior programs, in the very first ORION study the 300-mg dose was given once or twice, and just with 1 dose the LDL came down, but at about 6 months started going back up. With 2 doses it seemed to last out to a year, getting close to a year, and then that led to a dosing regimen that is about twice a year, to reduce LDL.

Yes, Linda, I think you were making that point earlier because of the pushback that somehow you were changing the very nature of the person’s body by giving this particular compound. You said with time the body returns to baseline unless you give another shot of inclisiran. Is that the point you were making?

 Yes. And thinking about this at a simple level, the inclisiran is working out in the cytoplasm. It does not enter the nucleus.

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Emerging Use of Inclisiran as Adjunct Therapy in Hyperlipidemia 

 Norm, you’ve been an investigator for ORION. You introduced it earlier in our first segment when we were talking about some novel agents, but I’ll give you a little more time. Talk about the efficacy in terms of the LDL [low-density lipoprotein] reductions and revisit the safety. I’m not convinced. Is it safe?

That was an important series of trials, and the data, you had ORION-9, which looked at the heterozygotes, and you had ORION-10 and 11, which looked at variety of patients either with ASCVD [atherosclerotic cardiovascular disease], or ASCVD with high-risk features including diabetics and heterozygotes. When they put all the data together from these phase 3 trials, which represented somewhere around 3700 patients, what they found was the type of LDL reduction that I had mentioned, LDL reduction in excess of 50%, closer to 55%. If you want to look at how this worked with a heterozygote versus the other populations, the heterozygotes seem to have an effect that was closer to about 50% LDL reduction. In the secondary, the other trials, it was closer to 53%, 55% reduction, versus with placebo subtraction. So definitely robust LDL reduction.

I think what was also interesting, and again, we don’t know exactly, it will be interesting to see what Manesh, Dean, and Linda feel, there was also some reduction of lipoprotein(a), in about the 20% range. The question is similar to what we see with the PCSK9 inhibitors, do we think that’s kind of a “pleiotropic effect” that perhaps contributed to what we saw with the PCSK9 inhibitors, and perhaps what we will see when the ORION-4 CV [cardiovascular] outcomes trial comes about? I think that’s what we’re looking at in terms of efficacy.

In terms of safety, we’re not seeing really any safety issues. I know that Linda, Dean, and Manesh commented about the fact that the RNA plays its role in the cytoplasm and doesn’t affect the nucleus. We’ll see what the longer term shows, the outcomes trial will give us perhaps more comfort with longer-term data, but the development of renal, of hepatic, hematologic adverse events was basically placebo-like. And again, just like the PCSK9 inhibitors, you generally will see some small increase in terms of injection site reactions.

Phase 3 ORION Trials for Inclisiran 

Paradigm Shifts in Lipid Lowering

Expert cardiologists provide a brief overview of the standard of care for lipid disorders and focus on a rapidly emerging, newer treatment option for managing dyslipidemia.

Paradigm Shifts in Lipid Lowering

EP 1: Pathophysiology of Hypercholesterolemia and Cardiovascular Disease

EP 2: Risk Factors for Developing Hyperlipidemia

EP 3: Identifying Patients at High Risk for CV Morbidity and Mortality

EP 4: High Cholesterol Versus Familial Hypercholesterolemia

EP 5: Aggressive LDL Lowering in High-Risk Patients

EP 6: Mechanism of Action of Inclisiran in Lipid Lowering

EP 7: Outcomes and Practical Implications of Newer Agents

EP 8: EPA in the Prevention of CV Risk

EP 9: Emerging Use of Inclisiran as Adjunct Therapy in Hyperlipidemia

EP 10: Phase 3 ORION Trials for Inclisiran