® 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.

CVD: REDUCE-IT Trial

 Matt, we can just move to you while thinking about icosapent ethyl and the EVAPORATE trial, which was another trial using the same drug and same dose of icosapent ethyl. You presented it as a late-breaking clinical trial at the American Heart Association [AHA], the interim analysis, a prespecified interim analysis of that, just this past AHA. That was a study looking at progression of atherosclerosis on coronary CT [computed tomography] angiography. Do you want to review for the audience what that interim analysis found?

 Sure, it was a mechanistic study to parallel the REDUCE-IT trial. As you mentioned, it was looking at serial CT angiography. We did a study of CT angiography at baseline. We did a 9-month CT angiogram and then an 18-month CT angiogram. As you mentioned, we reported the interim analysis at American Heart Association as a late breaker, and that paper is now in press at cardiovascular research. It showed that with the administration of 4 g of icosapent ethyl, there was a 19% reduction in total noncalcified plaque and a 42% reduction in total plaque compared with placebo. It slowed the plaque progression. It did not achieve its primary stopping end point, which was a reduction in low-attenuation plaque that was significant enough to stop the trial. We’ve just completed the 18-month data, the final analysis, and I’ll be presenting that at the European Society of Cardiology Congress meeting in August 2020.

 That’s really exciting. Really terrific findings. I’ll interject with another study of the same drug, icosapent ethyl, which was a pilot study that just got started up in Toronto, Canada. It’s something that Subodh Verma and colleagues there are orchestrating. Basically, it’s a 100-patient pilot of individuals who tested COVID-19 [coronavirus disease 2019] positive and were randomized to either icosapent ethyl or no icosapent ethyl, and to assess the effect on inflammatory biomarkers, things like hsCRP [high-sensitivity C-reactive protein], at 2 weeks. It’s an assessment of icosapent ethyl on biomarkers earlier than it has ever been done, just at 2 weeks.

Furthermore, it is using a loading dose of icosapent ethyl. The usual dosage, which is a total of 4 g a day, or 2 g twice a day with meals, was how we studied it in REDUCE-IT. But what is being studied here is an 8 g total per day loading dose for 3 days and then the 4 g total per day thereafter for the remainder of those 2 weeks. I will hopefully provide some interesting information about COVID-19. But irrespective of the COVID-19 aspect of things, we want to see whether there are any early effects on inflammatory biomarkers. Also, even beyond that aspect, we want to see if a loading dose is tolerated. Potentially if a loading dose is tolerated in this situation, it might then be studied in other situations, such as acute MI [myocardial infarction], or acute stroke or at the time that we have perfusion or revascularization.

Hopefully this will open the door for lots of other studies. It’s just a pilot study, but nevertheless might open the door for future studies, not just in COVID-19 but for non–COVID-19 populations as well. I just mentioned that for the sake of interest.

CVD: EVAPORATE Trial and COVID-19 Pilot Study

 Let’s move on now to talk a little about other classes of drugs in terms of cardiovascular risk reduction. Jamie, tell us a little about your experience using ezetimibe as add-on to standard therapy.

 Sure, I’ve been using ezetimibe for a long time now. It’s a drug people love to hate, and then they love to love. It’s getting lost in the myriad of other options that we have out there. What’s great about ezetimibe is currently it’s inexpensive and it’s very well tolerated. One of the reasons that often gets overlooked is because it’s not that robust when it comes to LDL [low-density lipoprotein] lowering. When the pedal hits the road, so to speak, and you look at its impact on cardiovascular risk reduction, you have to treat a lot of patients for a long period of time to make a difference because the change in LDL in general is relatively small. As a lipidologist, I see a lot of patients with inherited LDL disorders, familial hypercholesterolemia. Some of those patients are hyperabsorbers. Ezetimibe works by blocking absorption of cholesterol in the proximal jejunum. Some people do respond to a greater extent than you would think when you give them ezetimibe.

In fact, our current guidelines suggest adding ezetimibe to statins before moving on to other LDL-lowering agents, such as PCSK9 inhibitors, for exactly that reason because it’s inexpensive, it’s well tolerated, and people may get more of a response than you think. If that happens, it’s great. But the experience is that in most cases it doesn’t get people to where they need to go.

If you look at patients who are taking both statins and ezetimibe, there’s still a significant number of high-risk ASCVD [atherosclerotic cardiovascular disease] patients who do not get to where their LDL cholesterol goal needs to be. While it’s a tool we can use, it leaves us wanting in some regard. It’s great that we’ve got a lot of other options for LDL lowering. But in concert with that, we also have options like EPA [eicosapentaenoic acid] for ASCVD risk reduction. This is really what we’re trying to do when we manage lipids in patients.

 That’s really a nice summary. I’m not sure who those haters are of ezetimibe. I don’t know why someone would hate such a drug.

 When it was first made available, it was branded. Those who did not prefer it were the payers because it was expensive. No one wanted us to use it in the beginning because it was a branded agent. Once it became unbranded, suddenly it was the step through that you had to use before you got to any other drug. This was a 180-degree change in a medication that never changed with regard to how it worked.

 I do remember all that controversy about ezetimibe. Is it causing cancer? I never really was concerned about any of that. The data ultimately disproved all that. But there was a lot of noise around ezetimibe for a while; you’re right. I know there were haters. I just never understood why.

 Brett, perhaps you can speak about PCSK9 inhibitors. There are definitely some haters there. Do you actually use these agents in your practice? How do you use them? Do you use them as single agents, with statins, with ezetimibe thrown in the mix, or all the above? What do you actually do?

 I am a very enthusiastic user of all those agents. Statins of course—I, like James, am a big user of ezetimibe. I use PCSK9 inhibitors in hundreds of my patients, literally. Certainly, I do all combinations of those and the largest factor driving that is patient tolerance and acceptance. I’m a pragmatist. I am where the rubber hits the road in terms of treating patients every day.

If a patient doesn’t accept and take a therapy, they’re not going to get any benefit from it. I really do use all those agents in various mixes. I am enthusiastic about ezetimibe, as James was alluding to, because if you use it as monotherapy you get about a 15% to 18% reduction. If you add that onto a statin, it will be like a 22% to 25% reduction. If you’re above the threshold that you’re treating someone but you’re close, then ezetimibe is a good option and generally very well tolerated as well as generic and inexpensive.

Something else I’d like to add is, James was alluding to the IMPROVE-IT trial, where over 6 years the absolute risk reduction of adding ezetimibe onto statins was 2%. But if you were diabetic in the IMPROVE-IT trial, that absolute risk reduction was more like 5.5% over 6 years. That’s nothing to ignore there. We also have IVUS [intravascular ultrasound] data from the precise IVUS trial showing that you can improve plaque regression if you add ezetimibe onto atorvastatin compared with atorvastatin alone. For those reasons, I do use ezetimibe a lot.

The circumstance in which I may reach for a PCSK9 inhibitor instead of ezetimibe would be in my patients with lipoprotein(a) [Lp(a)] elevation. We know that on average, 20% of the population probably carries elevated lipoprotein(a). I measured it in all my patients. We know that PCSK9 inhibitors are the only therapeutic out there that we can lower Lp(a) levels, on average about 20% to 30%. If you look at the ODYSSEY OUTCOMES trial, they did an analysis of those patients who carried Lp(a), and they realized that those patients were getting relatively more benefit from the PCSK9 inhibitor than they were from the statin in terms of MACE [major adverse cardiovascular event] reduction because of the lowering of Lp(a).

Of course, we have intriguing recent data from both the FOURIER trial and ODYSSEY OUTCOMES that show that there is a reduction in venous thromboembolism and a reduction in aortic stenosis events. Certainly 1 of the postulations there is from the reduction in Lp(a). To summarize, I’m an enthusiastic user of ezetimibe in my practice. The circumstances in which I would reach over ezetimibe for PCSK9 inhibitor would be for patients with significantly elevated lipoprotein(a), if someone is significantly above their threshold or their goal or target that we’re aiming for, and of course for that small number of patients who don’t tolerate ezetimibe. But the final statement is that choice is very often made for us by the insurance payers. That it is what it is.

 Those are really great points, Brett. What you mentioned about Lp(a), in particular, is really interesting. As you know, the European Atherosclerosis Society guidelines had said measure Lp(a) on everybody at least once in their lifetime.

Worldwide that’s going to be something we see more of. Companies are developing drugs to target Lp(a), so I’m glad you mentioned that.

Add-On Therapy With Statins and PCSK9 Inhibitors in CVD

 Brett, you have used PCSK9 inhibitors in a lot of patients, and the data from the clinical trials really don’t show much in the way of adverse effects other than minor site reactions. How about in your practice? Have you seen any real-world use, any adverse effects, beyond what was described in the trials?

 No, honestly. As an overall comment, that is 1 of the strongest things to be said about the drugs in that there’s really excellent tolerance. They have a very clean adverse-effect and safety profile in general. I like to explain this to patients. If you look at the commonly listed adverse effects—things like nasopharyngitis, injection site reactions, UTI [urinary tract infection], and diarrhea—what’s important is not that laundry list but how that laundry list compares with the laundry list on placebo. Of course that’s true for all clinical trials.

When you look at that comparison, the only thing that seems to be statistically significantly different is local injection site reactions. Certainly in my experience in my practice, these are usually quite minor. They’re not a hindrance to use. If someone is having problems with those injection site reactions, I’ll often tell them to make sure the drug is out of the refrigerator and at room temperature before using. If they’re having a problem with 1 site, perhaps you can change sites to the anterior thigh or back of the arm. If it’s a recurrent problem, which is really quite uncommon, perhaps they can take a nonsteroidal anti-inflammatory by mouth 30 minutes before the injection.

One interesting thing, if there is a recurrent problem with injection site reactions, there are some data to indicate that it’s actually the incipient—the polysorbate that comes with these drugs to prevent precipitation—that may be the problem. In evolocumab it is polysorbate 80. Thankfully those don’t actually cross-react. Certainly, if you have ongoing problems with injection site reactions, it’s very reasonable to switch agents because you won’t to tend to get crossover problem. But these reactions are typically infrequent. They’re minor, and they’re typically not recurrent. I really haven’t found them a hindrance to use.

 That’s a real pearl. Jamie, did you know that about different polysorbate concentrations?

 I did not. But I will tell you that given the fact that there are 2 of these medicines commercially available, something I commonly do is simply changed to the other 1. They’re slightly different or slightly different preparations, and there is no reason you shouldn’t give it a try. I will tell you that over the course of the several hundred patients who I have on these medications, I have had patients complain of things that I cannot myself ascribe to the medication. But if people believe, like other medications, that it is causing a problem, you’re going to have to stop it and try something else.

In our space, when we hear about those complaints, we also dutifully have to report them because that’s the appropriate thing to do. It finds its way into the database, and it becomes available as a known adverse effect. I think that’s good as well as bad because if you think about how these drugs work, they’re not metabolized through the kidney or the liver. They’re cleared through reticular endothelial system. You really shouldn’t have any of these issues with it. My experience has been excellent tolerability, especially in patients who come to me having failed multiple other medicines. By the time they come to a referral lipidologist, they’ve tried most of the reasonable stuff.

Having a PCSK9 inhibitor available has been extremely helpful, especially for my patients with severe inherited lipid disorders and the folks with ASCVD [atherosclerotic cardiovascular disease] who are really at high risk, we know that.

 Any thoughts, Jamie, about their cost effectiveness?

 It’s interesting. As the price has come down, they have achieved greater cost effectiveness. The issue with PCSK9 inhibitors, from my perspective, and the cost-effectiveness space is oftentimes not related to the cost of the medication but what it takes to get the drug into the hands of the patient. Often that’s a co-pay issue. As the cost has come down, co-pay issues, especially with Medicare patients, have improved. But there are still problems sometimes with it.

We know that the patients who are prescribed PCSK9 inhibitors, who either don’t get them approved or have the prescriptions abandoned at the pharmacies—much like statin-intolerant patients—have significantly higher rates of recurrent ASCVD, MI [myocardial infarction], stroke, and combined cardiovascular end points. Getting drugs into the hands of a patient, as something that they can tolerate and be adherent to, is really important when it comes to ASCVD risk reduction—super important.

 One of the most fun things of a phone call you can make to a patient after they’re on this is, about a month in, to ask them if they have any grandchildren. This is because, guess what, their LDL [low-density lipoprotein] is lower than their grandchild’s LDL. I enjoy making that phone call, particularly if it’s 1 digit. I’m not striving for 1 digit, but when it’s there it’s unbelievable.

 The results can be quite impressive. You’re quite right. That was a great discussion about reducing cardiovascular risk, in particular focusing on LDL, cholesterol, and triglycerides.

Adverse Effects of PCSK9 Inhibitors in CVD

 Let’s move on to discuss some real-world case scenarios. Bob, you’re up first. Let’s say we’ve got a man in his late 50s. He’s got a history of hypertension, dyslipidemia, and type 2 diabetes. His blood pressure is 128/82 mmHg; his hemoglobin A1C [glycated hemoglobin] is 7.1%; his medications are telmisartan 80 mg a day, amlodipine 10 mg a day, Atorvastatin 40 mg once a day, and metformin 500 bid [twice a day]. His lipid profile shows a total cholesterol of 153 mg/dL, a non-HDL [high-density lipoprotein] cholesterol of 117 mg/dL, and triglycerides of 361 mg/dL. What’s your initial impression of this patient?

 He has diabetes, hypertension, and hyperlipidemia, so he’s significant high risk. My chief of medicine, who trained us years ago before seeing all the great diabetes drugs we have, would have said, “If you want to lower heart disease and diabetes, where is yourACR [albumin-creatinine ratio] or where’s your statin, based on the HOPE trial, and the statin studies? But forget the diabetes—that only lowers microvascular disease. Now we have a different ball game. We have diabetes drugs that even our cardiologists are warmly embracing.

He’s at high risk, and I want to do anything possible to lower his risk. As we discussed before, with the REDUCE-IT trial, his triglycerides are glaring us in the face. That’s our obligation to do something about it. He would have certainly been a candidate for the REDUCE-IT trial. He’s on a statin already, and his non–HDL [high-density lipoprotein] is 117 mg/dL. For our lipidologists, that goal is 30 points above our LDL [low-density lipoprotein] goal, non-HDL should be below 100 mg/dL. I’d like to do a little better with his non-HDL as well. Perhaps with ezetimibe, as was said before, the diabetics did particularly well in the IMPROVE-IT trial.

I’d probably add ezetimibe. But getting to his A1C, he’s close—his A1C is 7.1%. American College of Endocrinology would try to get up to 6.5% with drugs that don’t cause hypoglycemia. The 2 big classes that we all love now are SGLT2s and GLP1s. Both of them induce weight reduction as a nice side benefit. They don’t give the man’s weight, but he’s probably overweight, like most patients with diabetes. He has high triglycerides and low HDL, so he’s metabolic syndrome. Giving him a weight-reducing diabetes drug would be good. But that’s not the only reason. These drugs have cardiovascular benefits. If we want to strictly go on the label, he hasn’t had his first cardiac event.

In the GLP studies, the SUSTAIN 6 trial showed semaglutide lowered MI [myocardial infarction] stroke death by 26% and stroke by 39%. But these were patients on the label who have had a cardiac event. Recently from the ADA [American Diabetes Association] last year, dulaglutide—brand name Trulicity— in the REWIND trial lowered MI stroke death, even as primary prevention, which is on its label by 12%, driven by stroke reduction of 24%. He’d certainly be a candidate for weekly Trulicity [dulaglutide]. Or you could say, what about an SGLT2 inhibitor? It’s a pill, not a shot. An SGLT2 is, as a class, lower heart failure in EMPA-REG and in CANVAS—EMPA-REG with empagliflozin and CANVAS with canagliflozin.

For those, the label there is that you have to have had a cardiac event. In the DECLARE-TIMI58 trial with dapagliflozin, the coprimary end point was to lower heart failure, hospitalization, or cardiac death, which was a positive coprimary endpoint. This man would certainly qualify with his risk factors, being at risk for heart failure. You might give him dapagliflozin. Your choice would be dapagliflozin, dulaglutide, or both.

Both would lower his A1C, and they would lower his weight, so why not give both? But 1 or the other certainly would be appropriate regarding his A1C. Regarding his non-HDL, I would add ezetimibe, based on the IMPROVE-IT data, or you could give him a stronger statin since you still have a little room. In terms of the glaring thing, the high triglycerides, he’s the REDUCE-IT poster child and should do well. Maybe I should comment on the REDUCE-IT cardiovascular data in the diabetic population, which was most impressive. He hasn’t had his events yet, but certainly in the diabetics they did very well being on icosapent ethyl.

 Yeah, perhaps it would be better to get your perspective as an endocrinologist on the REDUCE-IT diabetes. Of course, you’re a coauthor on that. Perhaps you should first recap, what would it show for the audience? But then what are the implications for doctors managing diabetes? Endocrinologists, for sure, but primary care physicians and, as you said, increasingly in some aspects, cardiologists collaborating with primary care and endocrinology.

 The REDUCE-IT study design, 30% of the patients had diabetes as a risk factor and of the other 70% of the patients, 27% of the total had diabetes and heart disease. If you pull out all the diabetics from REDUCE-IT, which you had just discussed at 1 of the heart meetings, these patients did extremely well. First, we looked at the patients with diabetes who had a previous cardiac event. Their event rate over the 5 years without icosapent ethyl was 40%, dropping down to 30%.

This is a 10% absolute risk reduction, which is unbelievable.… The absolute risk reduction in the multi-risk-factor diabetic was 6% and in the cardiac patient without diabetes was 8%. In each group, they did very well. Looking at patients with diabetes, if the triglycerides are elevated you have to prove why they shouldn’t be on icosapent—not that they should be on it—because the drug has such dramatic benefit, not only in the diabetics who had a cardiac event, but even the diabetics themselves who were just at risk with multiple risk factors. But it’s something our colleagues aren’t yet doing. It makes it too much fun to go to work, because we could always do 1 better than we did before.

 You’ve summed up in discussing this case the excitement in the field of diabetes, where there are so many new therapies. Even 10 years ago it was really much more restricted what we could do in terms of macrovascular events. The endocrinologists in particular had a lot of tricks up their sleeve, but for macrovascular events, that had been a real problem. In the heart failure risk, it was just plain underappreciated. Some of the trials of diabetes drugs, even the DPP4 inhibitor trials, help bring to light that the heart failure risk in these patients oftentimes exceeded the MI risk, so the SGLT2 inhibitors then of course came across as an effective therapy. Any other thoughts from the panel about this case? Anything you would do different from what Bob said? He mentioned lots of evidence-based therapies. Anything that you would do different? Looks like the panel unanimously agrees with your management. It’s a very agreeable panel, I should say.

 Bob has covered every aspect there. It’s hard to find a path of therapeutics you didn’t cover.

 I would say—and we will discuss this when we get to the next case, which is similar in some respects—1 thing I do try to create for the patient is a simple path to therapeutic options. I try not to overwhelm them too much with multiple choices. We focus on where we are and where we’d like to be. The simplest way to get there is to ultimately achieve the best adherence, which you’ve already discussed also is a path to improved outcomes.

CVD Real-World Case Scenario 1

: Speaking of the next case, maybe we should move on to that. Jamie, that case is going to be one that you tee up for us. This was a woman in her early 60s with a history of hypertension, type 2 diabetes, and dyslipidemia. They often travel together, those risk factors. She is taking hydrochlorothiazide 12.5 mg every day, ramipril 10 mg a day, metoprolol 50 mg once a day, metformin 1 g bid [twice a day], and saxagliptin 5 mg a day. As it turns out, she didn't tolerate any statin regimen due to muscle complaints. Her total cholesterol is 230 mg/dL, the non-HDL [high-density lipoprotein] is 180 mg/dL, the triglycerides are 348 mg/dL. What are you going to do with her next?

: This is an interesting case, and I think this speaks to the art of medicine, that often we don't have evidence-based data to guide us. If we truly believe this woman is unable to take a statin, and as an expert in this area, I often see patients like this and ask them what does that mean? When you query people about their statement that they cannot take statins, it's often that they've tried 1 or 2 at very high doses, and they’ve decided they’re allergic to them or can’t take them.

I always want to make sure that we’ve tried every path toward some statin regimen, even if it's a longer acting statin such as rosuvastatin, once a week at a low dose. We try to get them on something. That's the first thing I would try to do with this woman. Because she is a high-risk diabetic patient, and when you look at someone her age, with hypertension, and lipid disorders, optimally, you'd want her to be on a moderate to high intensity statin. But unfortunately, we don't have a lot of evidence-based data for lipid lowering agents in the primary prevention space as monotherapy, other than statins. You could make the case to add ezetimibe. However, again, even though we have good data showing that ezetimibe, when added to a statin, seemed to have the best effect in the diabetic patients, it was on top of statin therapy.

You could make the same case for PCSK9 inhibitors, as another lipid lowering agent that at least in 1 of the 2 outcomes studies seemed to have a little better effect in diabetic patients, but always on top of statin therapy. In this case I think if you're going to use further lipid lowering therapy, you're doing it without a lot of good evidence-based outcome data to support that. Again, the idea of using 1 or the other as monotherapy or the 2 together is something that could be done, but you don't have a lot of data to support it. The question is whether this idea of statin intolerance poses a hurdle?

I think it is one that clearly is true. That's why I think trying multiple statins, as again, multiple different types of dosing regimens is reasonable. There was a great study in a journal called 

, published several years ago. It was data from a lipid clinic in the United Kingdom. They looked at patients who were referred to them for muscle-related statin intolerance. Ultimately, they tried every statin available in the UK at the time. There were 6 different ones. They were able to get about 30% of those patients to be on a statin. We know, and again, from the PINNACLE data that somewhere between 29% and 37% of patients in high-risk cohorts don't get on statins or even non-statin therapies, so that's an issue.

But here is someone for whom we do have some evidence-based data when it comes to adding on icosapent ethyl, again on top of statin therapy, specifically in the primary prevention diabetic cohort, though, it's about as good as we're going to get. I do think that potentially ezetimibe and/or a PCSK9 inhibitor should be considered, but PCSK9 inhibitors are not approved for patients without heart disease or familial hypercholesterolemia. It's going to be very difficult to get her on that medication. I think ultimately this is a woman who may end up on ezetimibe as monotherapy and icosapent ethyl.

: Do you think that there is any particular value in pitavastatin in patients who are apparently intolerant to other statins?

: Well, I think there is value in another statin. Pitavastatin was the last statin available to us. Oftentimes when someone can take it and they do better, we have a moment of clarity and decide that it's better. It seems to probably have a better effect on dysglycemia and certainly the way it's metabolized gives you some reason to think that it might, in some patients, be better tolerated. I always try to use a different metabolic pathway than the one that's caused the problem. But ultimately, I think it's just because it's another statin that's available, it's always worth trying it if you can get a patient on it, and I'll try anything. So it’s a great thought.

: What do you think about the β-blocker here for presumably hypertension?

: If I were going to tweak her other medications, if we're starting to get outside of the lipid space now, I think there are 2 ideas. One, Bob spoke very eloquently about, some of the diabetes medicines of the newer classes, such as SGLT2 inhibitors and GLP-1 [glucagon-like peptide-1] agonists, especially in high-risk diabetic patients that I think might be more appropriate in a patient like this. Metoprolol is probably not the most lipid friendly agent that one could use for blood pressure control.

Even when you think about our newer blood pressure guidelines, it's lower down on the list now for management, so certainly that could have an impact on her triglycerides. We know that β-blockers can raise triglycerides, they can lower HDL cholesterol. She does have a rather significant dyslipidemia with a high non-HDL cholesterol. If you were going to use some of the newer formulas, like a Martin-Hopkins equation, to calculate her LDL [low-density lipoprotein], it would still be higher than it should be.

Ideally, she needs lipid lowering, but she really needs cardiovascular risk reduction more than anything.

: Right. The other thing that you alluded to, potentially her diabetic regimen could be tweaked. Saxagliptin is certainly a reasonable way to lower the glucose, but if she is just going to be on 1 other thing after metformin, I might have gone with an SGLT2 inhibitor or a GLP-1 agonist.

: We don't know her weight, but if she is obese or overweight that would be another reason that I would probably push in the direction of a GLP-1 agonist in that setting. She's already on metformin, and I'd leave her on that.

: Yes, I think I would do the same. Any other thoughts on her from the panel?

: Deepak, if you added the SGLT2 inhibitor, you probably could get rid of the thiazide, and as you know, patients like getting rid of something when you add something, so the glucoretic effect of the SGLT2 might equal the diuretic effect of 12.5 mg of thiazide. There's where you negotiate, “I'll get rid of this, but I'm going to add this. This is a twofer that will lower your weight and your blood pressure.” And you can probably get rid of her saxagliptin then, if her A1C [glycated hemoglobin] was at goal. If not, I'd add it to that. This is because, as you said, saxagliptin has no cardiac benefit. It's safe but not beneficial.

: Yes, that's a great point. Not only could we add a number of medicines, as we said we would, but perhaps…

: Yes, patients always like that. Any other thoughts on this case before we move on? All right, that was a good one there. We really completely redid her regimen.

CVD Real-World Case Scenario 2

: Let's move onto the final of our 3 cases. Let's go ahead to you, Brett. The case is a 66-year-old man with hypertension, arthralgias and arthritis. He presents with a lipid panel that was taken before and after being on atorvastatin 10 mg a day and fenofibrate of 145 mg. His trigs [triglyceride] levels were reduced from 592 to 217 mg/dL, the non-HDL [high-density lipoprotein] from 228 to 175 mg/dL, and total cholesterol from 232 to 158 mg/dL. What would you go ahead and do with this person?

: Got it. I know my colleagues here tonight do what I’m about to describe first, but it always bears repeating and emphasizing. I want to make sure that he is not on any offending medications such as steroids that might be causing these numbers. I really would want to check his thyroid function, his liver and renal function, urinalysis, and make sure there is not another primary condition going on that’s driving these numbers.

Certainly in all of my patients, I take a diet history. I’m very diet obsessed with my patients, and inevitably with his triglycerides the way that they are, I'm going to yell at him about excessive refined carbohydrates, and I would also want to check his alcohol intake. That's going to be very important for all of our patients, but I know my colleagues here tonight do that. Having said that, this gentleman has mixed dyslipidemia, possibly familial combined hyperlipidemia. His non-HDL cholesterol is very high.

If you look at the comparison between his total cholesterol and is non-HDL cholesterol, that would actually suggest that his HDL is extremely low. If you assume the rest of his risk factors are perfect, which I'm sure they are not, and you did a risk evaluation or a 10-year risk, you would certainly be above 20% risk. That would potentially warrant high intensity statin therapy. You also may have some risk enhancers there. We've got persistent triglycerides, and he's got aches and pains. Does he have a chronic inflammatory condition like rheumatoid arthritis? There is a strong suspicion for hyperinsulinemia in this man, based on his numbers, so metabolic syndrome, prediabetes, or type 2 diabetes. So on the blush of it, he is high risk.

As I said, the way that I like to approach patients is a plaque-driven phenomenon because I certainly would want to optimize his medications. But depending on how far I would go, I would like to be guided by presence or absence or degree of plaque with a calcium scan. I tend to evaluate most of my patients in that context and interpret their lipid numbers within that context. As I said, if you did not have that available to you, it's certainly reasonable to increase this gentleman’s statin dose because he is high risk.

When it comes to that fenofibrate, I'm definitely less enthusiastic about that. I understand why it may have been done. When he first presented, his triglycerides were above 500 mg/dL, and certainly some guidelines recommend that then being your first issue to address in a mixed dyslipidemia. However, we have better stuff available. If you look at the ACCORD-Lipid, it was a cardiovascular outcome trial that did look specifically at fenofibrate. Adding to a statin, there was really no cardiovascular benefit. If you drilled down into the subgroups and you looked at those people with high triglycerides and low HDL, they came close, but they didn't quite make it.

However, if you look at what we have available today, icosapent ethyl, we know that that is very effective at lowering triglycerides. That was studied in the MARINE trial. Certainly in that trial, if you had triglycerides over 500 mg/dL, and you used icosapent ethyl at 4 g per day, you would lower your triglycerides by about 33%. Of course we now have data in a different pool of patients, but I can't see why they wouldn't also get that benefit. We know that there is ASCVD [atherosclerotic cardiovascular disease] event reduction with that medication.

If I had to meet this gentleman, I think I would clean up his regimen, and this is what I spend a lot of time doing in my office, in that I would take him off the fenofibrate. I think I would put him on icosapent ethyl 4 g per day and combine that with statin therapy and then recheck. There is a little caveat in this particular case, this gentleman already has aches and pains, and so I would want to be a little bit gentle with him with the statin that I use. As I like to tell people, the only benefit you get from statins is the statin that you take.

If I came out of the gates and blasted at him with high intensity statin therapy and his aches got worse, I may lose him and the therapeutic relationship that we have. I think if I were to continue him on atorvastatin 10 mg per day, we know that that has about a 20% triglyceride reduction. It has about a 35% reduction in non-HDL cholesterol. If you combine that with the EPA [eicosapentaenoic acid] 4 g per day, it gives you a non-HDL reduction of about 18% and triglyceride reduction about 33%, so that combination is actually lowering your non-HDL by 55% as well as your triglycerides by 55%.

That's a very good start in terms of risk modification. To clarify whether I should actually move on to a third-line agent, which I think is certainly possible in this gentleman because he has a very high non-HDL, I would want to be plaque driven. So I would do a coronary calcium scan in him and evaluate plaque. Certainly if he has an Agatston score of 0, then I would not feel compelled to go further. This is because if the Agatston score is positive, and obviously the higher it is the more abnormal it is, then I might be compelled to move on to add-on therapies like ezetimibe or a PCSK9 inhibitor.

: In your practice, has that approach worked? I don't mean clinically, but let's say this person, I guess most people would bin him as primary prevention. But do you think the PCSK9 inhibitor approvals are a bit easier if you've proven that there is actually plaque there?

: Absolutely, no question about it. I'm actually very careful about tracking my own numbers of PCSK9 approvals, and right now it's at 98%. In other words, 98% of patients for whom I request PCSK9 inhibitors are approved. The only thing that I'm very slavish about doing when I want to use a PCSK9 inhibitor is to perform plaque testing. The heavy lifter there that I use is the calcium scan.

But certainly I use other things like carotid ultrasounds and measuring intima-media thickness and ABI [ankle-brachial index] tests. This is because I think if you use a plaque-driven approach, firstly it reassures you that you are using these agents appropriately and cost-effectively, it makes patients much more likely to engage in the therapy that you're offering them. And I have found from the insurance payers it gives me a much higher chance of success of that script, if I can label them as having plaque, which clearly you can do with these studies.

: Yes, 98%—it's hard to beat that. That's quite impressive. Matt, I'm curious what your thoughts are with this concept of using imaging to enhance risk stratification, here, to guide therapy ultimately. First, perhaps you can talk about just with coronary calcium specifically, but then whether you think there is a role of going beyond that in the primary prevention patient.

: I agree with Dr Nowlan, as far as plaque-driven, I think it really helps us in cases like this especially in primary prevention, where we just don't know what their underlying cardiovascular risk is. We know that it dramatically drops the number needed to treat. If we look at population-based studies like the MESA study, the Multi-Ethnic Study of Atherosclerosis. We can drop the number needed to treat from something like 500 patients to maybe 20 by having an elevated calcium score. While I can't claim 98% success with my PCSK9 approvals, a high calcium score does help drive approval rates in my practice.

I think I would agree with that, especially in a patient like this, who doesn't have any overt risks that would automatically put him at secondary prevention targets. I have to say I might try atorvastatin 80 mg in him and see if he tolerates it. I agree he has to take it to benefit from it, but my experience is once they're already on a lower dose of the statin that they tend to tolerate that same statin at higher doses more frequently than not. You can always back off again, but I think that would get additional LDL [low-density lipoprotein] lowering and certainly additional triglyceride lowering as well, along with the icosapent ethyl.

: Well, that's a terrific discussion of 3 challenging real-world cases, lots of real-world experience on this panel. I think it illustrates just how much we can do for patients. Even though people are coming in stable, not necessarily with a complaint, that doesn't mean there aren’t things we can or should do to further reduce their cardiovascular risk. I think that's the challenging thing about patients who aren't coming in with a specific symptom. It's easy just to say, “Don't rock the boat, they're not complaining. Get them out of the office.” But in fact, there is a lot we can and should do with multiple advances that have occurred in cardiovascular prevention and risk reduction.

CVD Real-World Case Scenario 3

 Let’s move on to discuss the future, specifically what may be coming down the pike in terms of emerging therapies? Jamie, perhaps we can start with you and the recent approval for bempedoic acid as monotherapy and combination therapy with ezetimibe? What is the future for statin-intolerant patients?

 I want to echo your comments from a couple of years ago. Rumor had it that lipidology and cardiovascular disease prevention were dead. There were no treatments available that were going to be new and helping us. You all probably remember what was going on. Look at where we are now. There are new treatments available all the time for us to utilize when we try to take care of patients at high risk for recurrent cardiovascular events or even initial events.

Bempedoic acid is newly available, but unlike icosapent ethyl, we do not yet have any outcome data accessible regarding its effect on heart attack, stroke rates, or cardiovascular end points. It is an ATP citrate lyse inhibitor that inhibits the cholesterol synthesis pathway. Bempedoic acid is 2 steps higher from the rate-limiting enzyme—HMG coenzyme, a reductase that we all know and remember as the target for statins. Because it’s not the rate-limiting step in cholesterol synthesis, inhibiting it doesn’t have the same robust effect on LDL [low-density lipoprotein] lowering that we see with statins.

When used as monotherapy, it lowers LDL cholesterol about 17%. When used in combination with ezetimibe, because there was a fixed-dose combination product available with bempedoic acid and ezetimibe, it does lower LDL cholesterol about 38%, which is a slightly more robust reduction in LDL cholesterol. However, some of that is from the ezetimibe, much like combining statins and ezetimibe. What is unique about bempedoic acid is that when it’s delivered, it’s delivered in an inactive form. Bempedoic acid is converted to its active form by an enzyme specific to the liver but not found in the muscle.

Unlike statins that are taken up and active in both the muscle and the liver, bempedoic acid is active only in the liver. Whether that ascribes to it a better muscle-related adverse-effect profile is unclear. In its clinical trial data, it seems to be well tolerated from a muscle-related adverse-effect perspective, but there are no head-to-head data with statins as monotherapy. In most of the trials it was given on top of statin therapy. It is indicated to be given in patients only with either ASCVD [atherosclerotic cardiovascular disease] or familial hypercholesterolemia or on optimal statin therapy, which could be 0 mg a day of a statin if they can’t take any.

Also, it is used to lower LDL cholesterol, which is the indication it has right now. It’s not outlined as an option in the guidelines because it wasn’t available to us when the guidelines were written; they’re very evidence-based in utilizing medications in the guidelines. If someone is going to use it now, you’re using it based on the FDA indication for the medication, and I believe its role is to be later on down the pathway after many of the medications we’ve spoken about for which we do have the data regarding cardiovascular risk reduction.

 That’s terrific. Any specific comments about outcomes studies and when they might come and how that might influence this discussion?

 There is an outcome study being done right now. It’s interesting because it’s being done in high-risk patients, mostly patients with ASCVD who are statin intolerant. Although the drug is not as robust as some of our other lipid-lowering agents, it’s being compared in many cases with placebo. As a result, there is a good chance that we may see a positive outcome in this trial. However, while the result is 3 or 4 years away, it is close to being fully enrolled. We will have that data, but it will not be available for several years.

Treatment of CVD: Bempedoic Acid Monotherapy + Ezetimibe

 There was a press release stating that the STRENGTH trial—a cardiovascular outcome trial with a particular type of omega-3 fatty acid mixture of EPA [eicosapentaenoic acid] and DHA [docosahexaenoic acid] at a high dose of 4 g per day—was stopped because it did not indicate a high likelihood of benefit. Matt, do you have any thoughts about why that is? Of course, that’s a different drug from what was studied in the REDUCE-IT trial, which was 4 g per day of a highly purified ethyl ester EPA, icosapent ethyl. It’s essentially a different drug, but a high dose of an EPA-DHA mixture. Why didn’t it provide a significant benefit?

 The difference was that the STRENGTH trial was larger and had a higher-risk population than the REDUCE-IT trial, which also used 4 g of a combination of DHA-EPA this time. I believe DHA has an adverse effect on our LDL [low-density lipoprotein] and likely is not the best cardiovascular protective therapy. We have seen that from a lot of the smaller trials, and STRENGTH is proof of that concept because there are no other great reasons based on study design or dose of therapy being given.

It’s a 13,000-person trial, so it was more than 50% larger than REDUCE-IT. It should have had the power to show a benefit if there was going to be a benefit from a combination of an EPA-DHA product. Additionally, as Preston Mason and Harvard Medical School have shown several times, the effect of DHA is significantly different from EPA or icosapent ethyl on the lipid membrane.

 That’s a great explanation. We’ll see what the trial shows when it’s presented ultimately. Matt, what are you excited about in this therapeutic area? We have talked about bempedoic acid, but what else are you interested in?

 I share Jamie’s enthusiasm with all the new studies that are coming out now. It’s really an exciting time in lipids. Moreover, we talked about bempedoic acid, specifically pemafibrate, which is being studied in the PROMINENT trial, a large outcome study looking at a new fibrate for patients with high triglycerides and low HDL [high-density lipoprotein], which may be an improved targeted population for fibrates.

Perhaps that will be the first of the fibrates to show real cardiovascular benefit in the age of statins. There is inclisiran, possibly the next generation of PCSK9 inhibition, working at a 3- to 6-month interval rather than twice a month or monthly injections. Of course, like bempedoic acid, the outcome study is several years away so we will have to wait to see how well inclisiran works when it is available. Additionally, the price point of inclisiran will also be of great interest as we see how that is introduced to the market. Finally, the last thing I am excited about in the lipid world—and I would love to hear more from others regarding this topic—is the antisense therapies coming out for LP(a) [lipoprotein(a)].

We previously spoke of the benefits of PCSK9 inhibition on lowering LP(a) by 30%, 35%. These antisense therapies look as though they’re going to lower LP(a) by up to 80%. For patients with isolated elevations of lipoprotein(a), this is potentially a great new therapy for them as a targeted population.

 Yes, that’s good thinking. Bob, what are you excited about as far as emerging therapies? Specifically, it doesn’t have to just be in the lipid space. It can be in the diabetes space too.

 All the drugs that Matt had mentioned excite me as well. In the diabetes space there are the GLP1-GIPs, which are a combination of the GIP and GLP1 receptor agonists. These drugs have better weight-loss effects and compare very favorably with semaglutide, which are best in class for A1C [glycated hemoglobin] and weight. The oral semaglutide has a big cardiovascular trial for MI [myocardial infarction] stroke deaths, so that will be exciting as an oral agent, besides the SGLT2 inhibitors that might lower heart disease with the combinations of SGLT2s and GLP1 agonists. Regarding having more of our cardiologists widely embrace these drugs, it’s 1 thing to put it in that note, but it’s another thing to write it. Writing that these drugs don’t cause hypoglycemia will teach you the dose of Diflucan [fluconazole] to treat yeast infections if you aren’t comfortable with it, but just do it. These drugs are phenomenal, and we get all the hugs. You could get the hugs too if your patients lose weight and drop some of their other drugs for diabetes as well.

 Yes, we could use some hugs in cardiology. How bad an issue is the infection you mentioned earlier regarding the fungal infections?

 Choose the appropriate patient. It may not be the 1 woman who’s had 5 yeast infections and comes into you on an antibiotic, or an uncircumcised size man who was at balanitis. You must choose the right patient. The same goes with frequent urination: If you have a man with BPH [benign prostatic hyperplasia] who is urinating every hour at night that is not a great patient to give an SGLT2 inhibitor. Perhaps, you could sneak it in every other day or every third day in the beginning and then get it on board? As a result, many of your colleagues are starting to put it in the note, which is great.

Some don’t because they do not want to step on the primary care physician’s toes. I use PCSK9 inhibitors as much as all of you do. In fact, if my patients aren’t an injectable, there is no injectable objection that the patient must giving an injectable because they’re already on injectables. As such, I have no problem writing the lipid drugs in the beyond-lipid therapy or beyond-LDL therapy for my patients, just as cardiologists should have no problem writing these drugs either.

 Those are great points. I believe there really is a need for more education in the cardiology community to really gain comfort with SGLT2 inhibitors. Although with the heart failure data that are coming out, that comfort is going to grow rapidly with SGLT2 inhibitors. Regarding the GLP1 agonists, having oral availability might change their perception and utilization for the better. Brett, is there anything you’re particularly excited about in terms of emerging therapies in this space?

 Most of what I’m interested in and what I have been keeping my eye on has been mentioned. Again, I’m someone that follows lipoprotein(a) levels in all my patients. I have some patients who have tremendously elevated numbers. In fact, I have some patients who even supersede the range that the lab I send to measures at somewhere up there in the stratosphere. There is very little we can offer these patients right now. We have patients currently on antiplatelet therapy.

I try to get them on PCSK9 inhibitors, but it’s not very much. What is also very intriguing about these antisense agents, and the lowering of LP(a), is that they might also give us the first medical therapy as a prevention against aortic stenosis. A whole fascinating idea came up from that analysis of the FOURIER data, that there was a separation of curves after a year of aortic stenosis events.

This was lowering that LP(a) by 20% to 30%. If we had an agent that was lowering 80% plus and doing it persistently, we might be in a whole different realm when it comes to aortic stenosis and being able to prevent aortic stenosis, which is very fascinating to me right now.

Emerging Therapies for the Treatment of CVD

 Thanks to all of you for this rich and informative discussion. I’ve certainly enjoyed it and learned a lot from all of you. Hopefully the audience has too. Before we conclude, I’d just like to get some final thoughts from each of you. We’ll go in alphabetic order and start with you, Matt.

 We had some great cases today and a great discussion. At least from my perspective, we have to reprioritize where triglycerides fit into our algorithm of care. We’ve been focused on LDL [low-density lipoprotein] for so long, and that’s appropriate, but we had some interesting cases where the triglycerides were in the 300s mg/dL, and the LDL might have been mildly elevated.

In my algorithm of care, I would add icosapent ethyl first and then later add some of these additional LDL therapies, because the absolute benefit is so much greater in reducing triglycerides, as was discussed with the REDUCE-IT trial and some of the subgroups, than what we’ve seen with some of the LDL therapies to date. It is a changing world, and it will be interesting to see how all these therapies play together in the sandbox, so to speak, as we start using them together in our patients.

 To highlight what Matt said, looking at the triglycerides is key. The comedian Rodney Dangerfield said he gets no respect. Triglycerides get respect, not just 500 mg/dL or more. If the triglycerides are high—over 135 or 150 mg/dL—that’s an indicator that action must be taken; the patient has persistent cardiac risk. Just because the patient is on a statin and all these other great drugs, you could lower MI [myocardial infarction] stroke death. Look at each individual thing, the composite, and act on that. Don’t ignore triglycerides. Your should focus on not only the blood pressure, the A1C [glycated hemoglobin], and the LDL but also triglycerides and do something about it.

 That’s good advice. Brett, what are your thoughts in closing?

 First, I’d like to say that it was my pleasure and privilege to join all of you today. I certainly learned a lot from this discussion. This is an exciting time to be a practitioner who is prevention focused, because we have a lot of options, we have expanding options, and we have tools to assist with risk evaluation. In my practice and my practice habit—which is taking a plaque-driven approach—1 of the challenges now, because we’re spoiled for choice, is who should get therapy and who shouldn’t. We have a fistful of agents that we could potentially give to everyone.

We need to get better at selecting who is truly going to get the most benefit out of those agents and who should be de-medicated and shouldn’t receive those therapies. Taking a plaque-driven approach with imaging tests like the coronary calcium scan can be helpful to figure out which patients we should be offering the fistful of agents to and which patients we shouldn’t.

 Great points. Jamie, you can close for us with your thoughts about the future.

 It’s hard to add much to the eloquent words of my copanelists, and they summarize the discussion well. One point I can end with is the importance of identifying high-risk patients. It’s not just the patients with ASCVD [atherosclerotic cardiovascular disease], but it’s patients with diabetes, multiple risk factors, subclinical atherosclerosis, and elevated lipase protein A. We know that patients with the highest risk are the ones who benefit the most from the interventions that have been documented to show risk reduction.

Therefore, there is an urgency to identify, act, and treat. Too often we get caught up in the issues around watching and waiting. We’ve all heard our patients’ responses when we ask them about their blood sugar, cholesterol, or blood pressure. They respond with, “We’re watching it. We’re following it.” We don’t wait by watching these things. We act, and we treat. Finally, the last part of the equation—and what everyone has so nicely shown around the cases—is don’t just add treatments; simplify treatments. Many times you can use dual therapies that are in 1 tablet or you can add 1 medicine and subtract 2 because you’ve taken away adverse effects. You don’t want to add more drugs and more co-pays. You want to make the regimen simpler and more effective, and you want to do it quickly.

 There’s a lot of wisdom in what you just said and what all of you said. It is a matter of applying the evidence but also using common sense. We want to make sure that as we are making lifestyle modification recommendations and we’re potentially adding, subtracting, or substituting medicines, we are enhancing the outcomes of the patient and take into account the patient’s preferences as well. I’d like to thank you all and thank our audience as well. Hopefully this was educational, useful, and informative. You’ve been listening to 

Case-Based Evidence for Cardiovascular Risk Reduction