Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC

Dhiren Patel, PharmD, CDCES, BC-ADM, BCACP:

 I did want to mention about a recent approval of bempedoic acid. I know it exists as monotherapy and in combination. And so, maybe Dr Busch, what’s the role of that in your toolbox? When do you kind of use it? If you could talk to us a little bit about bempedoic acid.

 So bempedoic acid blocks the pathway to generate cholesterol in the liver higher up than where a statin does. Statins are HMG-CoA blockers, and this is an ATP-citrate lyase blocker. So basically [it] stops cholesterol synthesis within the liver. The liver is hungry for cholesterol and upregulates the LDL [low-density lipoprotein] receptors. Which is what Brown [Michael S. Brown] and Goldstein [Joseph L. Goldstein] won the Nobel prize for in the 80s. It works higher in the pathway, but interestingly, it is not activated in the muscle, even though it’s activated in the liver so that it doesn’t affect the muscle cholesterol. There’s very little myopathy with the drug. The potential side effects are few. It can raise uric acid a little bit, so you have to be cautious if you give it to someone who’s had gout in the past. And there’s very rare cases of muscle rupture, although that’s not clear that that will happen. There’s no outcome study yet, the outcome study is in progress, fully recruited. It’s called the CLEAR-outcomes [Cholesterol Lowering via Bempedoic acid, an ACL-Inhibiting Regimen] study. And interestingly about that outcome study, the patients are either on no statin or very low dose statin. Very different than all of the other trials. Where the IMPROVE-IT trial, they were all on a statin. In the PCSK9 studies, they were on statins. And obviously the statin outcome studies were on statin. This will be 1 of the first studies in someone on no or low dose statin where a drug that is not a statin should show benefit. The LDL drop is about 18% monotherapy. And when it’s with ezetimibe [Zetia] as a combination drug, it’s about 38%, 40%. And those are patients already on a statin. If they’re not on a statin, can’t tolerate a statin, the drops might even be more. So personally, if someone’s on ezetimibe and their LDLs is not at goal and they can’t afford or close to LDL goal, I’ll upgrade it to the next—bempedoic acid with ezetimibe together. And the cost of it, to quote what Jen said, it’s a $10 copay for commercial insurance. It’s almost the same price as Dr Bhatt said for generic ezetimibe, and you get an extra 20% LDL. Again, there’s no outcome yet, but there [is] no reason you wouldn’t expect a positive outcome because it upregulates LDL receptors like all the other drugs that have outcomes.

 That's really helpful. And Dr Bhatt, I know Dr Busch just mentioned the outcomes are pending, but where does this fit into your toolbox? And maybe if you could kind of give it to us from a cardiology perspective, I think that would be helpful for the audience.

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC:

 Sure. I think it’s a good question. Data to date of bempedoic acid looked good in terms of safety and in terms of efficacy, especially for that statin intolerant patient and when combined with ezetimibe, it seems to be respectable reductions in LDL cholesterol. Of course, in the cardiovascular community, we’re often looking for outcome trials and there is an ongoing outcome trial. And I think many cardiologists are really waiting for that before jumping on board. I guess I would see in terms of algorithms there’s outcome trial data for the PCSK9 inhibitors, the 2 monoclonal antibodies that are approved. So at least in my own, my algorithms typically statin, ezetimibe, PCSK9 inhibitor. And if the patient’s intolerant to statins, then ezetimibe, then PCSK9 inhibitor. And frankly, ezetimibe may not be doing that much with the PCSK9 inhibitor on board, but I usually still leave it in there. So that’s my typical algorithm. I think that once there’s outcome data for bempedoic acid, I probably feel more comfortable in its broader use. Right now, I think its use is probably, at least what I’ve seen in cardiology practices, more limited to patients who are statin intolerant. Ezetimibe doesn’t do the trick alone in terms of getting their LDL to go and they’re resistant to actually taking an injectable agent i.e. PCSK9 inhibitor. I must say, however, I’ve been surprised how few patients have objected to the injectable nature of the PCSK9 inhibitors. There were concerns that that was going to be a major barrier, but I haven’t actually seen that play out in clinical practice. Whether it’s a sort of a plus in terms of improving adherence, I haven’t necessarily seen that either, at least with the currently available PCSK9 inhibitors. Though there is a longer acting version inclisiran [Leqvio] that’s a bit of a different technology to monoclonal antibody technology where it could be given every 6 months for example, or even in some patients potentially if a lower degree of LDL lowering is required every year. Now, every year in terms of dosing, to me that could actually improve adherence, every 6 months potentially as well. But when the dosing interval is shorter, I haven’t necessarily seen an improvement in adherence from that versus oral therapies. But again, I haven’t seen such a resistance to injectable therapies as Dr Busch provided the anecdote. When you tell a patient that their LDL is dropped by 50%, usually that provides a lot of positive reinforcement to continue the PCSK9 inhibitor. So anyway, I see a much more limited role right now for bempedoic acid until the cardiovascular outcome data are available.

Videos

An expert panel discusses where bempedoic acid currently fits into the treatment of hypercholesterolemia. 

Bempedoic Acid for Hypercholesterolemia

Dhiren Patel, PharmD, CDCES, BC-ADM, BCACP: 

So, up until now, we’ve talked a lot about LDL [low-density lipoprotein] and some of the fluids that we have there. Dr Bhatt, I would love it if you can maybe kick off and talk a little bit about triglycerides. It’s not something that we’ve focused a lot of our attention on until recently. You led the REDUCE-IT [Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia] trial, and Dr Busch, I think you were 1 of the sites there. So very rarely do I get to hear it from the primary source, but maybe if you could just talk a little bit about the REDUCE-IT trial. And then what the quick adoption by medical guidelines and societies all over the world and what that now means from a clinical practice standpoint.

 Absolutely. I think that it’s a great question. It’s an important aspect of cardiovascular risk reduction. We’ve been focusing on LDL and, indeed, the world of cardiovascular risk reduction has been very LDL-centric. Rightly so, lots of progress there. But there are other cardiovascular risk factors even in the lipid domain, and triglycerides are really 1 of them. And in different years, triglycerides have been in, they’ve been out, but they’re back in again as a risk factor. And that’s based on a number of different lines of evidence, lots of science now supporting the triglycerides, much like LDL are directly causal or directly atherogenic. Though, to be scientifically precise, it’s really triglyceride-rich lipoproteins more than just what we measure in terms of triglycerides, per se. But regardless, they do appear to have an independent effect on cardiovascular risk above and beyond LDL cholesterol. How to modulate that risk has also been a source of contention and debate. In the REDUCE-IT trial, we studied patients with elevated triglycerides. I should point out that that was just sort of something we did because a number of members of the steering committee were very lipid focused. I must say, personally, I didn’t really think there needed to be a triglyceride entry criterion in the trial, but ultimately, there was. Patients had to have elevated triglycerides above about 135 or so milligrams per deciliter, and less than 500 milligrams per deciliter. So, in that range, we enrolled patients, about 70% of them were stable secondary prevention. By that, I mean atherosclerosis and their coronary or peripheral or cerebral vasculature. But another 30%, I’ll say are high-risk primary prevention, but specifically were those patients with diabetes and at least 1 additional cardiovascular risk factor. So that was the overall population, 8000 patients followed for an average of about 5 years. And we randomized them to icosapent ethyl [Vascepa] or to placebo.

And icosapent ethyl is a medicine that had already been approved for triglyceride reduction, based on a trial called MARINE [Marine Omega-3 Supplementation and Cardiovascular Disease: An Updated Meta-Analysis of 13 Randomized Controlled Trials Involving 127 477 Participants] for people with really high triglycerides, over 500, to hopefully prevent pancreatitis. But we were studying it in patients with a lower level of triglycerides in that, not to see if it will prevent pancreatitis, but rather to see if it reduced cardiovascular events. Just to say a quick word about what icosapent ethyl is, it’s an omega-3 fatty acid, but specifically a highly purified ethyl ester of EPA, or eicosapentaenoic acid, which is 1 of many different omega-3 fatty acids. It’s a prescription medicine, not a supplement. And it is pure EPA, unlike most of the different prescription or supplements out there of omega-3s that are mixtures of EPA and docosahexaenoic acid, DHA, and other fatty acids. So pure ethyl ester of EPA. And what we found then with this drug was a significant reduction in cardiovascular events, about a 25% reduction in ischemic events, specifically a 26% reduction in death from cardiovascular causes, heart attacks, stroke, so really important cardiovascular end points with large risk reductions. So that’s the overall trial. And, it was, again, over 8000 patients, I think very representative of clinical practice, in fact. Dr Busch was 1 of the leading enrollers of patients in the trial, and I think it reflects real world practice, that these weren’t some super carefully selected patients. These were just patients at high cardiovascular risk that happened to have elevated triglycerides. Certainly, the trial does support measurement of triglycerides to identify patients who then, for the U.S. label, would be candidates for icosapent ethyl to reduce cardiovascular risk.

An overview of the REDUCE-IT trial of icosapent ethyl for the management of triglycerides and prevention of cardiovascular events.

The REDUCE-IT Trial and CVD Prevention

 Dr Bhatt, obviously not all patients are going to get to their goals with just statins. What’s the role of ezetimibe? You’ve been very involved in some of these pivotal trials. Talk to us about your experience and where that fits into your toolbox as we think about these additional tools in our toolbox.

 That’s a great question. Ezetimibe is an underutilized drug. It’s inexpensive—it’s generic now—very safe, very well tolerated other than the occasional gastrointestinal adverse effects or discomfort. There’s very little in the way of systemic adverse effects. For patients who are truly statin intolerant, it’s a terrific option. For patients who have myalgia on ezetimibe, that’s a pretty good sign that the myalgias they had on the statin were not related to the drug. Sometimes patients who have statins with the 1, have it with the other, and then you can be quite sure that it wasn’t because of the drug. But it doesn’t matter in some respects if the patient thought it was because of the drug.

Dr Busch alluded to this, though he didn’t call it as such. The nocebo effect is a well-understood phenomenon. Much as there can be placebo effects, where a placebo makes a patient feel better, sometimes that can be used to therapeutic advantage. But the nocebo is the opposite, where there are assumed adverse effects from something. With statins, unfortunately, it’s all over the internet—all sorts of things they might do. It’s a shame because with the widespread generic availability of statins, they remain underutilized. For the patient who’s truly statin intolerant, ezetimibe is a great option. For the patient who’s on a statin already, and their LDL [low-density lipoprotein] hasn’t gotten to their goal—that goal may vary depending on the patient type, and the guidelines are clear in terms of what targets should be and thresholds should be—adding ezetimibe wouldn’t be expected to interact with the statin or increase adverse effects but can get some additional LDL lowering. It’s a great but underutilized tool in our armamentarium.

If that doesn’t work, then we can step it up a notch in patients at high risk. This is applicable to patients in the secondary prevention universe. Though in patients who have familial hypercholesterolemia, it would be in the primary prevention universe, like PCSK9 inhibitors, which are, at least as formulated, injectable agents that are very potent. They lower LDL cholesterol by 50% or 60% and can be useful for patients whose LDL is very elevated, but statins and ezetimibe don’t do the trick—patients who are statin intolerant, who can’t go on just ezetimibe. These are agents that are very well tolerated, with very few adverse effects other than injection site reactions—not much speak of. These are branded, so they’re expensive. That’s the major barrier in terms of their use and what limits their uptake.

Perhaps in the future, if more PCSK9 inhibitors enter clinical practice, several are being tested and are in development, that might lower the costs. There are other ways of targeting PCSK9 other than the available monoclonal antibodies that at least theoretically should be cheaper than a monoclonal antibody. Very recently, there have been some very preliminary data presented about oral PCSK9 inhibitors. So a lot of interesting things are going on. But in terms of what’s actionable, the algorithm beyond lifestyle modification would be statin, ezetimibe, and PCSK9 inhibitor.

 As a provider, there’s nothing more fun than calling the patient who’s on the PCSK9 to tell them that their LDL is lower than their grandchild’s LDL. I like making that phone call to tell someone their LDL is in 1 digit, which is incredible. They almost always work.

The role of ezetimibe and PCSK9 inhibitors as treatment for patients who are statin intolerant or require add-on therapy to help reduce cholesterol levels.

Statin Add-On Therapy for Hypercholesterolemia

Dr Bhatt, maybe before we dive into how we can play a role and what tools we have in our toolbox, walk us through the pathophysiology of hypercholesterolemia and cardiovascular disease to get us started.

 Yes, absolutely. This is really an important topic. I recall a time when there was some controversy around the role of cholesterol and atherosclerosis, but that time has well past. At this point, there’s no credible voice out there that’s debating the point that cholesterol is directly causal in terms of atherosclerosis. This is true of coronary atherosclerosis, peripheral cerebrovascular disease, and LDL [low-density lipoprotein] cholesterol in particular, an elevation in that, is a potent risk marker for the development of cardiovascular diseases, and it’s a modifiable risk factor. And there’s no question that LDL cholesterol, especially more atherogenic forms, such as when it gets oxidized, is really toxic to blood vessels. The good news is there’s something we can do about that. The first line of attack is lifestyle modification, and diets that are healthy. I would in particular endorse a plant-based diet to the extent one can adhere to that. And by that, I mean a diet that’s high in fresh fruit and vegetables and whole grain intake, to the extent that that forms the majority of a diet, that’s better for retarding atherosclerosis. Not just in terms of only trying to lower cholesterol, but also other beneficial cardiovascular effects.

Beyond diet, regular daily physical activity, even exercise I’ll say, can be usefulin terms of maintaining one’s cholesterol, but other associated risk factors like blood pressure, weight, glucose, etc. And when those measures aren’t enough, then pharmacotherapy is certainly indicated. We’re lucky that we’ve got generic statins and generic ezetimibe, relatively safe, well-tolerated, inexpensive ways to lower LDL cholesterol when lifestyle management is not enough. One concept that’s been introduced into the literature, in fact Mike Shapiro, [DO,] and I wrote an editorial on this in the 

Journal of the American College of Cardiology

 recently, is the idea of cholesterol years.

I think most folks, at least in health care, are aware of the concept of pack years of tobacco exposure. The more pack years, the worse off someone is in terms of their cardiovascular, and in that case, also cancer risk. Cholesterol years is similar. It’s looking at the number of years that someone has cholesterol elevation, and the degree of elevation of cholesterol, and that product, or the area under the curve, essentially represents their cumulative risk for atherosclerosis, at least attributable to LDL cholesterol. And thinking about it that way then forces us to realize, well, for some people, you really do want to start therapy, at minimum lifestyle modification recommendations, but potentially pharmacotherapy much earlier in life if their LDL is extremely high, such as someone with a genetic disorder or familial hypercholesterolemia. Whereas for someone who has good LDL cholesterol due to diet, genetics, nature, whatever, that sort of person perhaps they don’t need pharmacotherapy until maybe much later in life when their cardiovascular risk is higher, and perhaps their LDL cholesterol has drifted higher.

So, the pathophysiology and the epidemiology, I think, are quite interlinked, but importantly, in a way that’s actionable. And for myself, in cardiology, of course, I’m always thinking about cardiovascular risk. But these are lessons that can apply at the many points where we may touch a patient. That is, they might show up for their screening before their knee surgery at a relatively young age, maybe. But if they’ve got identified cardiovascular risk factors, well, that provides an opportunity to act, even though they’re not there at that exact moment to get cholesterol management advice.

That makes sense, and those are all great points.

The standard of care for managing high cholesterol levels.

Strategies Used to Treat Hypercholesterolemia

 presentation, “Multidisciplinary Lipid Management for Prevention of Cardiovascular Risks.” I am your host, Dr Dhiren Patel, adjunct associate professor of pharmacy practice at the Massachusetts College of Pharmacy and Health Sciences in Boston, and an endocrine clinical pharmacy specialist. Joining me today are: Dr Deepak Bhatt, professor of medicine at Harvard Medical School in Boston, Massachusetts; Dr Robert Busch, director of clinical research at the Community Endocrine Group in Albany, New York; Dr Jennifer Goldman, professor of pharmacy practice at the Massachusetts College of Pharmacy in Boston; and Joyce Ross, certified registered nurse practitioner and clinical lipid specialist with concentrated training in preventive cardiology from Philadelphia, Pennsylvania. Thank you all for joining me today. We’re going to start at the 10,000-foot overview and talk a bit about hypercholesterolemia and cardiovascular risk reduction. Joyce, Jen, I know you guys have practiced in a variety of different clinics over the years and have participated in a lot of not, only interdisciplinary research, but interdisciplinary practice. So maybe you guys can start. Joyce, you can start off talking a little about the burden of cardiovascular disease. And then Jen, maybe you can talk a little about that interdisciplinary practice. Joyce, we’ll start with you.

Joyce Ross, MSN, RNC, CRNP, CS, FNLA, FPCNA: 

Thank you very much for the opportunity to be here and work with all of you on this program today. This is a very important question. If we’re talking about the burden of cardiovascular disease, what comes to mind first to me is I believe that there’s an inertia both in the patient population as well as, unfortunately, the medical population. It seems we’ve had so many changes of what our targets are, what our thresholds are over a period of time. For the primary practitioner, and others, it may be difficult to keep up with all the changes. I sometimes think that maybe a provider says the patient is on a statin, go and sin no more, and we don’t do as much as we could. I think the other part is, so many people have familial hypercholesterolemia. And of course, that’s been one of my areas of interest over the last 25 years. Most of them do not know they have a problem until they have an event. Then, of course, we have the opportunity to capture the rest of the family. But I think the inertia that I was talking about, if we could get people to go in for well visits, which of course has been sabotaged over the pandemic, we would be able to get people before they have their disease. I think cardiovascular disease is still the No. 1 killer, and we still have a long way to go.



 Excellent. Thank you. Jen, as you kind of think about some of these challenges that we have, I think, we’ve talked about this in the past, none of our patients just have high cholesterol, no one just has diabetes. We can see here with the panel that we have here, we have cardiology represented, primary care, endocrine, pharmacy. If you could talk a little bit about this multimorbid chronic management that we’re dealing with, and how it needs to be a team sport, as we tackle cardiovascular disease.

The value of interdisciplinary research and multidisciplinary care of patients at high risk for cardiovascular events.

Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI, FESC

Articles

Bempedoic Acid for Hypercholesterolemia

The REDUCE-IT Trial and CVD Prevention

Statin Add-On Therapy for Hypercholesterolemia

Strategies Used to Treat Hypercholesterolemia

Multidisciplinary Approaches to Reducing CVD Risk