® titled “Case-Based Evidence for Cardiovascular Risk Reduction.” I’m Dr Deepak Bhatt from Brigham and Women’s Hospital and Harvard Medical School in Boston, Massachusetts. Today, to review various trial data investigating the lowering of atherosclerotic cardiovascular disease [ASCVD] event risk and to discuss real-world patient scenarios, I’m joined by Dr Matt Budoff from the David Geffen School of Medicine at UCLA in Los Angeles, California and Dr Bob Busch from Albany Medical College in Albany, New York. I’m also joined by Dr Brett Nowlan from Cottage Grove Cardiology in Bloomfield, Connecticut, and Dr Jamie Underberg from NYU Langone Health in New York, New York. Welcome, and let’s get started with today’s program.

 First, let’s talk a little about cardiovascular risk. You can never say enough about cardiovascular risk. Let’s start with you, Bob, discussing the burden of cardiovascular disease out there and the challenges of multiple morbidities along with the need for interdisciplinary research in the first place.

 I’m pleased to be surrounded by cardiologists and lipidologists, but even as an endocrinologist, my entire day is spent trying to lower cardiovascular risk. We know that cardiovascular disease is the No. 1 killer in the United States, the No. 1 cost in the United States. This is despite great drugs being available over the last 2 or 3 decades with statins and RAS [renin angiotensin system] blockers, and there is an uptick of cardiovascular deaths perhaps because of an increase in diabetes and obesity.

Smoking seems to have leveled off, but maybe people are not taking statins from some of the hype about statins. We’re very fortunate that we have a lot of great drugs to treat patients, but there is a high residual risk despite those drugs. We can always do 1 better.

 That’s really terrific. Matt, for our audience, what exactly is the pathophysiology of hypercholesterolemia, and what risk factors are associated with it?

 When we think about our high cholesterol as our risk, we have to remember that there are multiple factors that go into that. Their LDL cholesterol, the low-density lipoprotein, is clearly associated both as a marker of risk and as a direct pathogen. It causes the macrophages to become foam cells, and that starts the process of atherosclerosis.

We know that triglycerides are also related to atherosclerosis as a separate risk factor, and genetics tie that in quite tightly with that same story. When we talk about risk factors, obviously the people who have high cholesterol are those who have diabetes, renal disease, metabolic syndrome, among others—those that have the highest comorbid conditions with hypercholesterolemia.

 Terrific. Brett, perhaps I can ask you something that comes up all the time. When should patients be screened for cardiovascular risks? Who is it that’s actually classified as high risk?

 Yes, absolutely. As you mentioned, this is an absolute fundamental that we do in our office every day. If we referred to the 2019 ACC [American College of Cardiology]/AHA [American Heart Association] Guideline, that’s for the primary prevention of cardiovascular disease. If I had to boil that down, it’s very reasonable to start from quite a young age, such as from the age of 20 years old, and ask someone about their family history of premature ASCVD and certainly about any tobacco product use.

You would want to measure blood pressure. It’s very reasonable at that time to send someone for either a fasting or nonfasting lipid panel. If someone has other risk factors such as diabetes, you certainly may be inclined to measure their blood glucose. If all that looks completely normal, then you probably should do that roughly every 5 years until you get to the age of 40 years old, according to the guidelines.

You should do those things routinely. At that stage, you really want to calculate a formal 10-year ASCVD risk using some of the risk-scoring systems out there, such as the pooled cohort analysis. If someone is at a borderline or an intermediate risk, you would move beyond those conventional risk factors to consider other things. For example, this may be metabolic syndrome, chronic inflammatory conditions, looking at other lipid risks, such as the lack of protein levels or inflammatory markers, like high-sensitivity CRP [C-reactive protein]. In my practice, I’m very swayed by a plaque-driven approach to risk assessment.

If there is any uncertainty looking at those basic factors—about whether someone is at increased risk or if there is uncertainty about low risk—then something like a coronary calcium scan can be very helpful as an adjudicator.

 Those have been a little more popular in recent years, you’re right.

 Absolutely. As a tiebreaker, particularly in that borderline and intermediate-risk group of patients, it is exceedingly helpful. We know that it also drives patient engagement—engagement and lifestyle modification, engagement and keeping up with therapies and their visits. If you look at all those risk factors, you consider someone to be high risk if they had an LDL cholesterol of 190 mg/dL or above, and certainly if someone had had a clinical ASCVD event, that would be high risk.

Most adults in the 40-to-75-years-old age range with diabetes will be at least intermediate risk. If they have any additional risk factors, certainly that would be likely high risk. If you were older than 75 with diabetes, you’re almost automatically high risk. Certainly if you have chronic kidney disease, stage III or IV, that would put you in a high-risk category. If you’ve gotten to the point of measuring a 10-year ASCVD risk and that risk is more than 20%, those are high-risk people. If you’ve taken a plaque-driven approach and you have a calcium scan, Agatston score of more than 400 Hu or worse than 75th percentile for age, gender, or race-matched cohorts. Those will be considered high-risk people.

 Yeah, that’s very useful for our audience.

Overview of Cardiovascular Risks

 Jamie, can you discuss with the audience exactly what the prevalence is of cardiovascular disease associated with hypercholesterolemia overall? Also, can you talk about this specifically in different ethnic and geographic groups, socioeconomic disparities, and so forth?

 That’s a great question, and I think part of what makes that a complicated answer is what we just heard from my copanelists. These are the comorbidities that play into the role that cholesterol has in driving cardiovascular risk. We know that the impact of cholesterol on heart disease risk is often driven by other risks associated with that patient. For the patients with preexisting heart disease or hypertension or diabetes, what is elevated cholesterol for them is different for what is considered elevated for patients who have fewer risk factors or lower risk in general.

We can take a closer look at the data, let’s say from 2018, and the American Heart Association for heart and stroke statistics. If we look at patients who simply have a total cholesterol over 200 mg/dL, it’s somewhere between about 35% and 48% of the population. If you break that down into different ethnic groups, the group that seems to lead the way with cholesterol issues, are Hispanic patients—men more than women—followed by non-Hispanic whites and then non-Hispanic blacks. Why is this such a concern? It’s a concern because cardiovascular disease prevalence was going down for a very long time, and death and mortality from heart disease had really dropped over the last 15 or 20 years.

But you know as well as I do that over the last about 5 years, there’s been a bit of a U-turn. Things have started to progress back upward. If you look at cholesterol control in general, it has gotten better. We’ll talk about some of the gaps in that and get further along in our program. But the accumulation of other cardiovascular risk factors—especially diabetes, obesity, inactivity, diet—drive part of the complication of this. If you look at socioeconomic features, it is exactly what you would expect, right?

This is in regard to those who have less access to health care, those who are less likely to be able to exercise, less likely to eat a heart-healthy diet, and less likely to have access to appropriate screening programs—those who do not do as well as those who do have access. If you look at the shift in heart disease globally, it’s moving from the more developed Western countries to those that are less developed. If you look even within the United States, if you look at a map of heart disease in this country, it’s exactly, again, what you would expect.

In areas of this country where people tend to be more obese, have less healthy diets—in the Southeast, in part of the central part of the South like Oklahoma, and even a little further north into Indiana, we have much higher rates than we see on the East and West Coast of the United States. There is much to be learned from looking at these ethnic and socioeconomic diversities and disparities that drive heart disease risk and informs us on who we need to be focusing on going forward.

 Those are all really great points. In parts of the coronavirus pandemic in New York brought light to racial disparities that are affecting African Americans.

 You mentioned geography too. There has been a lot written recently. In fact, there was a paper published in 

 just about a month or 2 ago highlighting rural health care disparities as it pertains to cardiovascular medicine, whereas in rural parts of this country cardiovascular disease is making a comeback like there is no tomorrow.

It is really something that we all need to be vigilant about and not feel like we’ve won the battle against heart disease. It’s certainly encouraging all the scientific advances that have occurred, but with a lot of work to do in terms of implementation, science, and making sure all patients benefit from these advances. That was really an interesting discussion about cardiovascular risk in general.

Prevalence of CVD Associated With Hypercholesterolemia

 We can pivot a little to cardiovascular disease risk reduction and prevention. Jamie, since you’re on a roll, what are the treatment goals in managing hypercholesterolemia? In particular, what are lipid levels in general as far as targets for people with high blood pressure, for people with diabetes? What do you recommend in your practice? What does the evidence say?

 In our practice, we try to follow the current guidelines. In primary prevention we’re talking about patients with type 1 or type 2 diabetes. We always start with the risk assessment, and we heard a little about risk assessment already. Calculating 10-year risk is an important part of that.

Anyone over the age of 40 years old with diabetes should be on a statin, period. That should be moderate intensity. That is, unless they have additional risk factors. That’s why risk assessment is so key as part of managing patients with type 2 diabetes. As far as a target, the target is LDL [low-density lipoprotein]. Goals? We have moved away from that because, again, everyone should be on a statin that’s either moderate or high intensity based on their risk.

Patients with hypertension generally have other comorbidities. This is based on their risk-assessment model, whether they have subclinical atherosclerosis based on a CT [computed tomography] scan and other what we call risk-modifying concerns: Do they have an elevated lipase protein A? Do they come from populations of risk or family history?

Again, we would try to target them with moderate to high-intensity statin based on their reasonable risk status. I would tell you that if we were looking for a magical number in primary prevention it certainly would be 100 mg/dL. But we try to get away from goals in LDL lowering right now and focus on the appropriate risk management for those patients, which is first getting them on statin.

 Those are really terrific points and something probably everyone in the audience is facing—when do you exactly pull the trigger in terms of LDL management? Along those lines, Matt, what factors do you consider when choosing among statins of varying intensity? Once you’ve made that decision, what percentage of the patients actually fail to meet cholesterol-lowering targets despite statin use and despite using whatever you think is appropriate and that the patient can tolerate?

 Building on what Jamie had just said, looking at where their LDL is and what their target is for most of us, for high-risk LDL targets, it will be less than 70 mg/dL. Our goal will be to be more aggressive from a pure LDL perspective. Unfortunately, a vast majority of patients fail to meet those goals. There are great data out of multiple guidelines. The PINNACLE Registry, with 1.9 million people, mentioned that 21% of patients who had established heart disease were not on statin therapy and had no history of lipid-lowering therapy use at all. About 5 of 6 patients did not achieve that LDL target of less than 70 mg/dL.

When we think about targets that are potentially even more stringent, the AACE [American Association of Clinical Endocrinologists]/ACE [American College of Endocrinology] Clinical Practice Guidelines, for example, talk about LDL targets of 55 mg/dL. The Europeans have targets as low as 40 mg/dL, yet we’re just not achieving even a modest goal of 70 mg/dL in the vast majority of our patients.

 That’s such an important point that we can do more with respect to LDL reduction, even just with the statins, and of course there are other things such as ezetimibe and PCSK9 inhibitors. Before getting more into that, perhaps I can turn to you, Brett, when considering simple stuff to do. We talked about statins, though as I was saying, it’s not always so simple to implement. What about your thoughts on icosapent ethyl and its potential role in cardiovascular risk?

 Icosapent ethyl is of course the darling right now for very good reason. It is an incredibly exciting therapy, and I use it very enthusiastically in my office. Here, you have something that seems to be very safe, and it’s very well tolerated. It has excellent patient acceptance and seems to be cost effective, and we have tremendous data for major adverse cardiovascular event reduction from the REDUCE-IT trial.

It does it in a theoretical, completely unique mechanism from what we’ve been targeting up to now, which is focused on LDL lowering. It’s an orphan drug or an orphan therapy in the space. As we move historically from our patients who are more pure hypercholesterolemia in the past to more mixed dyslipidemia now and driven by the tidal wave of hyperinsulinemia and metabolic syndrome and type 2 diabetes, a therapy like this—with this theoretical mechanism of action—is very important. This antioxidant effect, anti-inflammatory effect, platelet inhibition, antithrombosis effect, and plaque stabilization is very exciting, and I’ve embraced it fully in my practice.

CVD Risk Reduction and Prevention

 We’re lucky here, in terms of folks involved with the REDUCE-IT trial. I could turn to either Bob or Matt. But Bob, I’ll just turn to you for this 1. Could you, just for the audience, describe the REDUCE-IT study? You of course enrolled lots of patients in there. Perhaps you can review, for the benefit of the audience, what the trial objectives were, the study design, and the outcomes.

 Like Brett, I also feel icosapent ethyl is the darling of cardiology, given all the other treatments we’ve had in the past. The REDUCE-IT trial is the study of over 8000 patients at high risk for heart disease. They either had a cardiovascular event in the past, an MI [myocardial infarction], a stroke or peripheral vascular disease, angioplasty and stents, or some type of ASCVD [atherosclerotic cardiovascular disease] event in the past, or are in the 30% of the patients who were high-risk diabetics. These were diabetics who had an additional risk factor. These patients were well managed.

In fact, they all were on a satin. They had to be on a statin, their LDL [low-density lipoprotein] had to be between 40 and 100 mg/dL. The average was about 75 mg/dL, but what got them into the study is they had the additional risk of having high triglycerides, 135 to 500 mg/dL. Given that additional risk that might be an indicator of persistent risk, half the patients were given icosapent ethyl—2 g twice a day—and the other half were given a placebo.

They were followed for an average of 5 years. The primary end point was a 5-point MACE [major adverse cardiovascular events]: a nonfatal MI, a nonfatal stroke, a cardiovascular death, revascularization, or unstable angina hospitalization. Then there was a 3-point MACE, what we call hard MACE: nonfatal MI, nonfatal stroke, or cardiovascular death. That was the end point. There have been several substudies that Dr Bhatt actually has presented at many cardiovascular meetings that we can get into.

The bottom line, why it’s the darling of all of us and why it’s a game-changing therapy, is that 5-point MACE went down 25% as a primary end point, 3-point MACE, nonfatal MI, nonfatal stroke, cardiovascular death down 26%. Each individual part, the nonfatal MI went down 31%, stroke 28%, and cardiovascular death 20%. To me, as an endocrinologist, what’s unique is many of our trials with some of our heart-smart drugs might lower MI stroke and death, but they don’t lower each individual end point. Even in the trials with PCSK9 inhibitors, where you lowered MI and nonfatal stroke, you didn’t lower cardiovascular death. To lower each individual end point as well as the conglomerate is most impressive, with 

The other thing is that the number needed to treat in the primary end point was 21 patients, just looking at the overall population. Dr Bhatt, I’m sure you’ll be discussing some of the substudies done, whether revascularization for patients, total end points rather than first end point, having total events looking at the US population. The most recent 1, looking just at the diabetic population, not only in that primary prevention group but the very high-risk diabetics who already had cardiac events in the past. The results are quite astounding. Basically, it’s a game changer to create an obligation for all of us to look at the triglycerides in patients now.

In the past we looked at them only if they were 500 mg/dL or more to hopefully prevent pancreatitis with a drug therapy. But the patient whose triglycerides are as low as 135 to 500 mg/dL, to have such dramatic events, not because of just the triglyceride lowering but other unique factors about the EPA that lowered each of these individual events, as a whole, was a game changer for all of us. Walking in the exam room, it’s not just, “How is your blood pressure?” and as a diabetic, “How is your A1C [glycated hemoglobin]?” and “Am I using heart-smart drugs?” and “Is your LDL low enough?” This is because with the drugs we have now, we can always try to lower LDL. But to look at triglycerides, it’s an obligation to do something about it by instituting icosapent ethyl.

 That’s a really nice summary of those trials’ overall results. We’ll come back to the diabetes subgroup and get your particular endocrinology viewpoint on that in a bit. Can you also describe the safety profile and any contraindications for EPA?

 In terms of the safety profile, there was a slightly higher risk of atrial fibrillation and atrial fibrillation hospitalizations, mainly in patients who had preexisting disease. There was a slightly higher rate of bleeding, usually in patients who are on an anticoagulant beforehand. Those would be the major 2 things that we could look out for. I suppose if the patient were allergic to EPA, that would probably be the only contraindication that I would think of with this. So the risk benefit far outweighs this minimal risk.

You can assess the minimal risk if the patient had preexisting atrial fib. Still, these patients had excellent outcomes, less stroke, less V-fib [ventricular fibrillation], V-tach [ventricular tachycardia] arrest as well, despite having the atrial fibrillation. In terms of bleeding outcomes, I don’t believe there was any increase of hemorrhagic strokes, but more minor bleeding type things.

 Adjudicated hemorrhagic stroke was not significantly different between the 2 arms. There was no significant difference in fatal bleeding. It was really more minor bleeding that was increased. There was no significant excess in GI [gastrointestinal] bleeding. So you got it right. Finally, any comments about the cost effectiveness of icosapent ethyl? There have been a couple of analyses done.

 It was a good analysis. I believe a MedStar analysis talked about that cost effectiveness over a lifetime, that it saves money. If you look at the cost of cardiac disease and the cost of icosapent ethyl and the dramatic decrease of events, particularly the comorbidity of stroke and rehab after stroke or an MI or the other interventional things that have to be done with cardiac disease, it was very cost effective as well.

We have lots of different tools available to lower cardiac risk. This would be 1. It really is an obligation to look at the triglycerides and do something about it as well as to lower the persistent cardiovascular risk that these patients who are well managed on a statin. Perhaps the LDL could have been lower, as we talked about guidelines below 70 or 55 mg/dL. But an average LDL of 75 mg/dL to start with in these patients was not bad, and they were all on a statin to start with.

Case-Based Evidence for Cardiovascular Risk Reduction

Overview of Cardiovascular Risks

Prevalence of CVD Associated With Hypercholesterolemia

CVD Risk Reduction and Prevention

CVD: REDUCE-IT Trial