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

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

 Jen, for you in terms of…obviously there’s the prescribing of it, but I think you’ve served an equally important role in educating other HCPs [health care professionals], especially pharmacists. And so how do you, A, address this with patients? But also more importantly, there is a ton of confusion. Because even within the prescription, like Dr Bhatt alluded, there’s ones that have had data and there’s the ones that don’t have data. And then you have maybe that pharmacist that doesn’t know where it’s not covered, and they say it’s an IL-6 [interleukin 6] on the left-hand side. Which you also don’t want. If you can maybe walk us through kind of the over the counters and even within the prescription ones, how do you sort it, how do you not only educate your patients but also pharmacists and other HCPs?

Jennifer Goldman, RPh, PharmD, CDCES, BC-ADM, FCCP:

 I’m glad you asked that because I was listening to the 3 other panelists and what they’re saying and what they’re talking about is evidence that when I think back to 30 years ago, and I’ve been practicing over 30 years and my colleagues have been practicing quite a long time as well, and we gave drugs based on biomarkers, we were giving the fabric acid derivatives to lower a biomarker, but based on clinical trial, specifically the REDUCE-IT trial, and Dr Bhatt, we now have evidence. We have actual evidence that if we use icosapent ethyl [Vascepa] we not just lower a biomarker, we actually decrease cardiovascular events and so forth. So we have evidence. You can't just use the evidence when you feel like it. If you know the evidence, you have to use that evidence. The other fish oils, the various prescription plus supplements that are over-the-counter have been studied. They have been studied. And yes, they may reduce a biomarker. The triglyceride number might go down, but that does not translate to an outcome that we care about. So it doesn’t end up translating to a decreased cardiovascular event. So I think that’s 1 first educational piece that needs to go out to health care providers, but also to patients and particularly to pharmacists who are in the community, who might be the kind of end stop or the last provider that somebody actually speaks to. I’ll have patients that will come in and they’re on over-the-counter fish oil, and I’ll say, “Why are you taking that?” And they’ll say, “I don’t know. My doctor told me to take it.” So having that conversation. The other conversation is to make sure that everyone is educated about that biomarker. The point you just asked me about, Dhiren, is pharmacists in general. Supplements, fish oil supplements have been studied. They are not regulated. You don’t know what is in them. There could, there are all kinds of impurities in these supplements. The supplements that have been studied have not been shown to improve anything. When I have patients on that and when I advise other pharmacists, no, they’re wasting their money. Don’t get it. They’re not helping themselves. And the same thing with the prescription availability. The ones…you have to follow the evidence. So Dr Bhatt has done that for us. And Dr Busch is participating. For pharmacists out there in the community and for primary care, it’s not OK to just say go to the wholesale store and buy a big 5000 pills of fish oil. It’s not the same. So you can’t use evidence when it’s convenient. It’s all the time.

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

 I just wanted to jump here and say that there’s 2 points that I wanted to add to what you’re saying, Jen, which is so true. The patients don’t realize what they’re getting when they’re getting something over the counter. So really going through that. But what is worrisome to me is that we understand that the oxidized element of the fish oil over the counter, we have oxidation of the LDL [low-density lipoprotein], which is part of the problem. But we also have an increase in the LDL cholesterol in many of those products. And that is critically important. Saying to a patient, I think we’re shooting ourself in the foot when we’re just taking something that we know may increase your LDL cholesterol when all this time we’ve been working to reduce it. So again, taking the terms, look in the name of the trial, REDUCE-IT tells us all those things that are useful for education, both for the health care provider and for the patient as well.

 Yeah, no, absolutely. And I think hopefully what you saw here is that triglycerides are pretty well-established body of evidence now associated with it, but there’s a little bit of navigation that Jen, you pointed out that we need to make sure they get on the right product. Because there’s been a fair number of trials that haven’t had the positive cardiovascular data. And I say at the end of the day, we want to do things [that] are moving the needle from a population health standpoint and not just treating numbers that numerically make us feel better and they look pretty in a chart. At the end of the day that’s what we’re all here to do. So that’s excellent.

What pharmacists and providers need to know to counsel patients on when discussing the use of prescription or over-the-counter fish oil supplement as treatment for dyslipidemia and hypertriglyceridemia.

Efficacy of Prescription Vs OTC Fish Oil Products  

 I’d like to go around here because I think everyone, you were involved in the research side of it, and then now in the practice side, but Dr Busch, maybe if you can comment on that, and kind of what that looked like for you from the research side, now, how you’ve implemented that to the practice side and what that looks like. And we will go around the horn.

So, for the research side, as Dr Bhatt mentioned, it was very easy to find these patients. They were in front of us every day. And what was so unique in that study, you saw even though these patients were all on a statin with an LDL [low-density lipoprotein] in the mid-70s, it was a 28% rate of events over the 5 years on the statin already. It shows huge residual risk, and anything you could do to lower that residual risk. And that’s what we do all day long. We’re giving heart-smart diabetes drugs. We’re giving aggressive blood pressure drugs. So, as a clinician, you always want to do 1 better than you did before, as long as the drug is safe and affordable for the patient. So, of course, bringing in 4 capsules a day that are not small capsules on top of what the patient was on to treat something that’s a marker, because even if their triglycerides didn’t drop that much, it still had benefit. The trick is not only to initiate it, but to get the patient to stay on it because what do you do? You’re lowering heart attack, stroke, and death, and each individual parameter was lowered, which is very unusual in these cardiovascular trials. EMPEROR-Red lowered cardiac death but didn’t lower stroke. Some of the other trials, nothing was low in 1 thing, but all is a conglomerate here. Each individual factor was lowered, and that’s what’s so important with this. As I icosapent ethalized my patients over the 3 months after the study came out, you watch through your practice. Not of all of our partners do it. Dr Bhatt is running another study by another company with an EPA [eicosapentaenoic acid] S-drug. And it’s still easy to find these patients in my partner’s practices. And. as Jen mentioned earlier, where there’s a will, there’s a way. There’s a $9 copay card to get branded icosapent [Vascepa] and for $9 it’s worth having the discussion with the patient. And with our pharm D backup, we can get the drug into the patient that’s affordable. That lowers their event rate, which is pretty dramatic.

 That makes sense. And I have a pressing question for Jen, but Joyce, what has this done for you guys in your practice, where you’ve been very hyper focused on all of the newer agents that come and monitoring this from a clinical practice standpoint, what does this look like for you from a prescribing standpoint now?

 I think the most important thing is that it really solidified the fact that it’s not just about LDL cholesterol as Dr Bhatt very elegantly discussed. And I think that what has [been] very frustrating for patients over time is to get that LDL cholesterol down that we’ve been harboring on and pushing and raising amazing medications to get there, and yet they still have other vascular events. For many years, Dan Rader [Daniel J. Rader, MD, FAHA, University of Pennsylvania] and I thought that there’s something about these triglycerides. While I couldn’t put my finger on it and while we didn’t have the research that we have now, I was sure there was something with triglyceride that had something to do with the inflammation and the oxidation of the LDL cholesterol. When you start to talk to a patient about you’re really doing—you’re doing well, and what if we could add something that was going to change [the] outcome for you toward the next event by 25%? Well, as you go back to what Bob said earlier, that’s double, double, double, double, all the statins. And here you go with 1 addition. Yes, it’s 4 pills, but that’s a major outcome. And what you’re doing is treating all the [I have no clue] particles. For me that’s what’s important. And helping a patient who’s so frustrated that they continue to have events going to other vascular beds that there’s something to do and we know it’s not just about the LDL.

Takeaways of the REDUCE-IT trial of icosapent ethyl as treatment for dyslipidemia and hypertriglyceridemia.

Implications for Prescribing Icosapent Ethyl to Prevent CVD

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

 Jen, cost was just mentioned with the PCSK9 inhibitors, and you recently did a webinar that addresses it. At the end of the day, we could prescribe the world’s best medication, but if the patient can’t afford it, that’s a challenge. How have you worked with some of your patients to address some of the costs associated with some of the more higher-ticket items?

 If there’s a will, there’s a way. I can absolutely promise that. In some of the commercial insurances, drug companies have made available savings co-pay cards to cover the co-payment. Even for someone who has a high-deductible plan, these co-pay cards have a maximum per month that they’ll cover, and that will go toward that person’s deductible. That’s very helpful. Most of the time, these co-pay cards lower their co-pay anywhere from $0 to $25. Costs are often $0. That’s for commercial.

One issue that we’ve been facing for years is Medicare? With Medicare, there’s a maximum…. We’ve heard about the doughnut hole. What that means is when you have Medicare at the beginning, they may have a deductible. They may not, depending on their plan. Health insurance pays a certain amount, the patient pays a co-payment, and once they’ve spent a certain amount of money—it’s $4000—they go into this doughnut hole. What happens is the patient will have to pay 25%. The doughnut hole has changed. Before this, the patient had to pay the full amount. The drug plan will pay 5%, the patient pays 25%, and drug companies pay 70%. Once they get to that amount, at the end, it’s catastrophic, and everything is covered again. But drug companies are stepping up and paying that difference. That will help patients with Medicare also avoid catastrophic costs in that doughnut hole.

 That makes sense. As I said, you have to work a little harder, with a little more paperwork, but there’s some level of assistance that you can usually offer patients.

Opportunities to reduce costs and improve accessibility to therapies used for hypercholesterolemia and prophylaxis against cardiovascular events.

Coverage and Access to Therapies Used to Reduce Cholesterol Levels

 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.