Targeted Strategies in Lipid-Lowering Therapy: Where Do We Stand Now?

This transcript has been edited for clarity.

Seth J. Baum, MD, FACC, FAHA, FNLA, FASPC: Hi. My name is Seth Baum. I'm a preventive cardiologist and the chief scientific officer for Flourish Research. I'm very happy to be here today to discuss clinical research in lipid-lowering therapies and lipoprotein-lowering therapies with my colleagues, Drs Budoff and Shubrook.

I'll allow them to introduce themselves. First to you, Dr Budoff.

Matthew J. Budoff, MD: Hi. I'm Matt Budoff. I'm a preventive cardiologist. I work with lipids and imaging to identify patients with early heart disease. I'm a professor of medicine at UCLA in California.

Jay H. Shubrook, DO, FAAFP, FACOFP: I'm Jay Shubrook, a primary care professor at Touro University of California, a family physician, and a primary care diabetologist. I'm thrilled to hear about what's coming and how we can apply this to our patients.

Baum: Let's start with low-density lipoprotein cholesterol (LDL-C). We're going to look at LDL-C, lipoprotein(a) [Lp(a)], and triglycerides. We're going to look at different therapeutics and different mechanisms of action. Starting with LDL-C, we just heard some exciting news at the American College of Cardiology (ACC) meeting on bempedoic acid in the CLEAR Outcomes study. That's a small molecule.

Matt, why don't you share your thoughts about that study and then move us into some other LDL-C research.

Budoff: Yes, the CLEAR Outcomes study. I think this is another oral therapy, now once a day, that will allow us to lower LDL-C additionally. The study was actually very interesting. It was the first large outcome study looking at patients who are statin intolerant. Either a statin had failed in these patients or they had been on a subtherapeutic dose of a statin, something like 2.5 mg rosuvastatin or < 10 mg atorvastatin per day, and they were followed for outcomes.

It showed a 13% reduction in four-point major adverse cardiovascular events (MACEs) and a 15% reduction in three-point MACEs, including a 22% reduction in myocardial infarction over about a 5-year follow-up. We now have additional therapies that we can add onto or use as an alternative if our patients can't tolerate a statin. I think these are very exciting data and this is a very practical, easy, once-a-day oral pill.

Baum: Yes. This was high-risk primary prevention and secondary prevention. It gives us room to help our patients in need, especially the statin-intolerant patients.

That's a small molecule. Another small molecule that's in development now is obicetrapib in two phase 3 studies. One is a cardiovascular outcomes trial called PREVAIL. This is a cholesteryl ester transfer protein (CETP) inhibitor, and I'd like to get your take on that as well.

Budoff: We've had our ups and downs with CETP inhibitors. Some of the early ones did not show event reduction. Some had some off-target effects. This therapy seems to be more focused on LDL-C reduction rather than on increasing high-density lipoprotein cholesterol (HDL-C). I'm obviously very excited to see how this plays out in the large outcome study that is underway now.

Baum: This CETP inhibition, which exchanges a triglyceride molecule for a cholesteryl ester molecule between HDL-C–containing and apolipoprotein B (ApoB)–containing particles, also this particular therapeutic has been shown in prior studies to decrease ApoB significantly and, actually, to even decrease Lp(a), which is interesting. There's going to be more to come on that when we discuss the Lp(a) therapeutics.

Jay, as far as you're concerned, do we need more LDL-C–reducing therapeutics?

Shubrook: That's a great question. This is why it's so important to stay up to date, because I remember the days where you just got to an LDL-C level. Then you said, well, wait a minute. We need an intensity of statin level to reduce inflammation. I think we're back to a combination of intensity to reduce inflammation and a new LDL-C level.

At the American Diabetes Association (ADA) meeting, they highlighted that high-risk patients need to get their LDL-C down to 54 mg/dL (1.4 mmol/L). Certainly, most of my patients are not there, so we're going to need some help.

Baum: In the European guidelines, we're below 40 mg/dL (1.03 mmol/L) in the very high-risk patients with multiple events. We're definitely heading for a "lower is better" approach. For LDL-C, we have inclisiran, which is approved, and is possibly not getting the uptake that we thought it would or should get.

It gives us an opportunity to create preventive cardiology clinics where patients come in twice a year; they get their injection, we have them as a captive audience, and we get to talk to them about all elements of cardiovascular risk reduction. I personally thought that would be really nice in the primary care setting.

Jay, what do you think about that?

Shubrook: It's a tough time for us. As these medicines become available, we really have had a hard time getting coverage. I think that certainly statins are all generic now. We get them covered pretty well, and we could do better with our intensity. If you're trying to do anything beyond a statin or ezetimibe, there's often pushback, particularly for government employees or insurances, to send them to cardiology. We're going to need some help on when to refer but also how to get better coverage.

Baum: Interesting.

Budoff: I would hope that the CLEAR Outcomes study helps that a little bit because the biggest benefit in that trial with bempedoic acid was actually in the primary prevention arm of the trial, which is interesting. They did very well in reducing events in high-risk primary prevention.

It would be disadvantageous, I think, to say that every primary prevention patient who can't tolerate a statin has to see a cardiologist, lipidologist, or endocrinologist to get simple oral therapies approved. I would hope that some of this changes, especially when we talk about treating primary prevention patients rather than secondary prevention patients.

Baum: It's probably even worse than just a coverage issue. It's a prescribing pattern problem as well, even among cardiologists. We had some data coming out of ACC. The Family Heart Foundation did a study demonstrating that fewer than 1% of eligible patients were prescribed a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.

We definitely have a large amount of work to do to prescribe these drugs. This brings me to another future therapeutic, hopefully, which is an oral PCSK9 inhibitor that's in clinical trials right now.

Matt, do you think that would be not only effective but also highly utilized by cardiologists, and more utilized, perhaps, than some of the injectable therapeutics?

Budoff: I think that, at least in cardiology, we're much more comfortable with orals. There is a number of injectables that we have available. Even the glucagon-like peptide 1 (GLP-1) receptor agonists, being injectable with cardiovascular benefits, are starting to get some traction in cardiology. I think having an oral pill is an easier discussion with the patient.

Hopefully, it's a slightly lower price point because it's cheaper to make pills than it is to make these injectors with needles and all these complex autoinjectors that are so nice for patient compliance. I think an oral PCSK9 inhibitor will garner traction right away, especially as we continue to emphasize that lower is better with LDL-C. We have to move way beyond an LDL-C of 100 mg/dL (2.59 mmol/L) and even beyond an LDL-C of 70 mg/dL (1.81 mmol/L) for high-risk patients.

Baum: A question I always have — but I think I know the answer to this — is if there were no side effects to medications and if there were no costs associated with medications, wouldn't we be getting all of us to an LDL-C under 40 mg/dL (1.03 mmol/L)? Wouldn't we do that? What are your thoughts about that?

Budoff: I think some patients get nervous about too low. I think LDL-C in the 50-mg/dL range affords regression of atherosclerosis as well, which is something that patients really like to hear, that their plaque may actually be getting better from year to year over time. I agree with you. We definitely know that we're born with LDL-C levels in the 30s.

There's no reason to run an LDL-C of 70, 80, or 100 mg/dL (1.81, 2.07, or 2.59 mmol/L) from a biological sense. I think we will continue to move lower. Right now, I would say 55 is the new 70. We really need to start targeting 55 mg/dL (1.42 mmol/L) in a much broader sense.

Baum: I would just say for the record even though patients are concerned about a very, very low LDL-C, there is no evidence to suggest that having an extremely low LDL-C level, even under 25 mg/dL (0.65 mmol/L), is harmful. As long as we have the capacity to make very low-density lipoprotein cholesterol (VLDL-C), then we're really safe.

Shubrook: I think the other thing is that communication tool with your patients. We've watched the guidelines change, and patients don't always understand why they change. I think, Matt, what you said was so important — that we went from a time from halting disease to now stopping the progression or even reversing progression of disease. I think that's an important message of why the guidelines have changed.

When you talk about injectables, we're very comfortable in the primary care space with patient-driven injectables. In the day of most physicians — at least primary care physicians — being employees, we wouldn't maybe have that same luxury. If someone had to get an infusion, they'd have to go to an infusion center. That is an additional step that is confusing for some patients.

Baum: You bring up an infusion, which I think could be our last LDL-C drug that we can discuss, which is evinacumab. I bring up evinacumab because it just recently got approved for 5- to 11-year-olds with homozygous familial hypercholesterolemia (FH). It's an ANGPTL3 inhibitor. It's a human monoclonal antibody. It reduces LDL-C by 50% through an LDL receptor–independent fashion. Therefore, it is very highly effective and there's a great need for it. I'd love to hear your comments on that.

Budoff: Although it recently got approved for children aged 5-11 years, it's already approved for people aged 12 years and up.

Baum: Yes.

Budoff: Many people may not be familiar with it. For homozygous FH, a place where we have very few well-tolerated therapies and many patients end up on apheresis or other kind of extreme measures, it's really nice to have a very effective therapy. It does require infusion. It's given once a month, but I think it's well tolerated overall. For those patients with homozygous or complex heterozygous FH, I think this is really going to be an important therapy for them.

Baum: I agree. It is, in my experience, well tolerated as well.

Let's move on to Lp(a). Here, we have a few drugs in development for Lp(a), which is a particularly dangerous type of LDL particle with an apolipoprotein a (ApoA) attached to it that increases atherosclerosis, inflammation, and clotting.

It's sort of a triple threat, if you will. There are a couple of drugs in phase 3 studies right now. One is an antisense oligonucleotide, and another is a small interfering RNA (siRNA).

Matt and Jay, your comments on this.

Budoff: I think that we're going to continue to recognize how important this very small LDL particle is and how it's going to affect progression of atherosclerosis. It does require a separate test. It's not part of our standard lipid panel. The European Society of Cardiology already recommends that every human being get tested for Lp(a) because it's a one-time measurement that gives us an idea if they're at increased cardiovascular risk.

As these two new drugs potentially go through development — and one of them is fairly far along, pelacarsen — if that trial works and lowers events, I think we're going to have a new target for treating atherosclerosis that's independent of LDL-C, but complementary for sure to LDL-C lowering.

Shubrook: I think it's exciting. I've been hearing about Lp(a) for a while, and it sounds like we've got to a point now where there's some evidence to say yes, we can check it, and then we have some actual steps that are coming. That's really exciting.

Baum: These drugs are going to be studied in aortic stenosis as well. It is very exciting. I would differentiate the antisense oligonucleotide from the siRNA. They are somewhat different, of course. The siRNA can be delivered every 3 or 6 months, whereas the antisense oligonucleotides typically are given on a monthly basis. They are both very effective, with antisense oligonucleotides leading to perhaps a reduction of 80% or more in Lp(a) and 95% with the siRNA.

I'd love to mention something a little bit off topic here, which relates to the Inflation Reduction Act. I'm bringing it up now because I had a conversation at ACC with the US president of Novartis, and they have pelacarsen, which is, as Matt mentioned, far along in its phase 3 program.

He said that, had he known that the Inflation Reduction Act were going to occur, he would not have continued the drug in development. He would have killed that program. Let that sink in for a moment. He would have killed the Lp(a) program, which then would have, I think, trickled down to Amgen. Their program would not have occurred. Silence Therapeutics probably would not have occurred. A whole area of potential cardiovascular risk reduction would not be taking place. Now, why is that?

Well, the Inflation Reduction Act stipulates that, at a certain time point, drugs are going to be able to be negotiated by Medicare and Medicaid. This sounds good on its face. However, if you look at it carefully, what does this mean? For drugs that are small molecules, at 9 years after approval, negotiation can occur where the price can fall up to 95%; the timeframe is 13 years for biologics.

You might say, well, wait a second, the siRNAs and the antisense oligonucleotides are biologics; they're going to be safe. Well, that's not true. They're actually categorized as small molecules. It turns out that cardiovascular medicine is particularly vulnerable to this act — which by the way, will come up in the fall in Congress to be discussed further and perhaps modified.

The reason I'm bringing it up is that cardiovascular medicine is so vulnerable. In cardiology, most of our drugs are small molecules. Second, most of our patients are older, so this pricing change would affect them. Third, our studies are very long and very expensive. The fourth issue is that cardiologists are perhaps the slowest adopters of medications of all specialties.

That translates into where most drugs become profitable for pharmaceutical companies at about year 4 to 5, in cardiovascular medicine, it's at year 9 (Figure 1). As a consequence, if these drugs are renegotiated at year 9, the pharmaceutical companies are going to lose their motivation to actually develop these drugs.

Download PDF version of Figure 1

The American Society for Preventive Cardiology has started a town hall series. The first one was at ACC, where we discussed this and learned more about it. Interestingly, a number of people from pharmaceutical companies came up to me after this town hall and said that they have already eliminated drugs in the pipeline for this reason. I'd love to hear your thoughts on that.

Budoff: If you think about it, we always talk about Big Pharma in all that. We wouldn't have statins, angiotensin-converting enzyme (ACE) inhibitors, or the cornerstones of our current therapies if it weren't for pharma development. These are not developed by the National Institutes of Health (NIH) and passed along. All these drug discoveries are done through pharma companies. It's the only way that we have of really developing a robust spectrum of disease.

If you think about something like Lp(a), which is a major cardiac risk factor, hopefully we'll have therapies for it. If not, we're left with off-target treatments, where Lp(a) goes down by 20% or 30% with a PCSK9 or maybe 20% with inclisiran, which is not effective to get the numbers down to where we need them to be for our patients. This can have huge cardiovascular implications.

I would remind everybody that, since 2010, cardiovascular disease is back on the rise as a cause of death. It's not like the game is over and we've won. We're literally seeing rising rates of cardiovascular death. We're going to need new therapies, and we're going to need to partner with pharma to get there.

Shubrook: I might play devil's advocate and say that we certainly need novel agents to improve unmet burdens for many diseases, including cardiovascular disease. We should have a holistic approach about this. I think that there has to be investment in current and future treatments.

We have to balance that out in the big picture because if there's going to be less of a market incentive, then maybe there has to be more of a governmental investment in answers if we want to take a public health approach. Certainly, preventive cardiology, in many ways, could have a public health approach as well.

Budoff: How about something so simple as allowing our Medicare patients to use the copay cards that they can use up until their 65th birthday to bring the price of these drugs and out-of-pocket costs down to almost zero? It's such a tragedy that the day they turn 65, their copay goes from 0 or $5 a month to $35, $50, or $65 a month because they're not allowed to, by government law, apply the copay cards to that population. I think that would be a simpler answer for me.

Baum: That is a simpler answer. Also, it's shining a light on the pharmacy benefit managers (PBMs) and what they're doing, and how much money they're taking out of the system for what many people consider to be of no value. The PBMs are being looked at by Congress right now. That's good news on that front.

Thank you for that interlude. We'll move on to triglycerides now. We know triglycerides, when they're severely elevated over 500, increase the risk for pancreatitis. This can be devastating and life-threatening.

I know we've all had patients who have had pancreatitis in the setting of severe hypertriglyceridemia. Some of our therapeutics for hypertriglyceridemia are geared to those patients. They typically have high chylomicrons, not only high VLDL particles.

Then there's the lower end of the spectrum, 150 and above, where there's definitely an increased risk for cardiovascular events, although we are yet to prove causality to the extent that we've not been able to reduce triglycerides and therefore reduce event rates. It's hard to say that it's a definite cardiovascular risk factor if we're going to be very strict with the criteria that we set for establishing that.

We have a couple of therapeutics in development. We have the antisense oligonucleotides and the siRNAs. They're often geared toward apolipoprotein C-III (ApoC-III).

Matt, why don't you tell us about ApoC-III and these therapeutics.

Budoff: We have this target where triglycerides go down by 70% or 80% with these new therapies. We know that they're effective at lowering triglycerides. As you nicely pointed out, Seth, we still need that outcome link with the triglyceride-lowering significantly going along with event reduction, just like we need with Lp(a).

I think it's a very parallel story with slightly different therapeutics. These ApoC-III drugs are being used in other capacities. Evkeeza, as we talked about earlier, is one of them. I think we will see some robust drug development here. It's going to be very necessary even for those patients with severe hypertriglyceridemia, who are still above 500 mg/dL (5.65 mmol/L) after traditional therapies, such as omega-3s, maybe niacin, and certainly fibrates.

Baum: Jay.

Shubrook: In my world, triglycerides are the second level of priority. For people with metabolic syndrome and diabetes, it's very hard to get them down to goal. Certainly, we would welcome anything that would not worsen hyperglycemia and improve triglycerides, as it is a great need.

Baum: Well, I think they're coming soon.

Budoff: I know there's some controversy around the icosapent ethyl story, but we've seen seven plaque reduction trials in Japan and one in the US, EVAPORATE, which show that if you treat with a pure eicosapentaenoic acid (EPA), you do reduce plaque. We've also seen now three outcome studies, two in Japan and one in the US, that show cardiovascular benefit.

For now, at least, we have icosapent ethyl. It has a generic arm to it, so hopefully, that will help with availability. I think that we still need to think about that in the short run while we're waiting for these new therapies, these siRNA and antisense oligonucleotides, to work their way through drug development and outcomes.

Baum: Just to be clear, it's not the triglyceride reduction that's giving the benefit here with icosapent ethyl. It's something else, right?

Budoff: It's treating the high-triglyceride patient or that metabolic syndrome patient that Jay just mentioned. It's still treating that same patient. It only lowers triglycerides by 22%, but it lowers C-reactive protein and it has other effects, but you're right. Still, I think it falls into that population with metabolic syndrome and diabetes where we have a need and a risk. Right now, that's our only risk-reducing therapy in that arm.

Baum: Agreed. For our final few moments, Jay, you have a case to present. Let's see how these therapeutics can be worked into your case.

Shubrook: I was thinking of this patient, Stefan. He's 54 years old, and he's got what's very common in my practice, which is type 2 diabetes, obesity, hypertension, and dyslipidemia. He's on metformin, he's on losartan 100 mg/d, and he's on atorvastatin 40 mg/d.

He doesn't drink and doesn't smoke, but he's sedentary. His blood pressure is 128/78 mm Hg, and his body mass index (BMI) is 32.

Let's get to the lipids. Before the statin, his total cholesterol was 248. His LDL-C was 171 mg/dL (4.42 mmol/L), HDL-C was 36 mg/dL (0.93 mmol/L), and triglycerides were above 200 mg/dL (2.26 mmol/L).

Since the statin, his LDL-C is now 118 mg/dL (3.05 mmol/L). By the way, his A1c is 7.8%. As we think about this, clearly, he's not meeting goals. I know I'm only going to get a tiny benefit from doubling that statin. In the primary care space, what do we do next?

Baum: There are different ways to skin this cat. From doubling of the statin standpoint — and we've had this discussion before — I'm not a fan of our guidelines talking about doubling statins. You get very little bang for the buck. I typically will add additional therapy. What are our options now?

We've heard about bempedoic acid. That's an option. We know about ezetimibe. We know about the PCSK9 inhibitors. We also have inclisiran as another approach to PCSK9.

Again, I think there are many ways you can do this. If you're looking for, let's say, a 40% or 50% reduction, which I think you are here, probably ezetimibe is not going to be adequate. The PCSK9 inhibitors would be adequate, so I would go that route. I would choose either a monoclonal antibody or inclisiran.

Budoff: Yeah. I agree. If the patient's not willing to get the injection, there is a combination pill of bempedoic acid and ezetimibe, which lowers LDL-C about 38%, so nowhere near the efficacy of inclisiran and even further from that of PCSK9 inhibitors.

You would probably get pretty close to a goal of 70 mg/dL (1.81 mmol/L) if he refused an injectable to get him an oral pill. That's a combo pill, again, of bempedoic acid plus ezetimibe, which is well tolerated at least.

I totally agree with Seth. I would approach him with PCSK9 inhibitors as my first plan of action here.

Shubrook: In the best of worlds, I'll be able to get that covered.

Budoff: Well, he's high risk and lipids are clearly way above any threshold. There's no threshold out there that would say his LDL-C is adequate. There's no way doubling of statins with that rule of 6% additional reduction is going to get him to below 100 mg/dL (2.59 mmol/L).

Baum: At least if you do this, then you're in that 1%, so you've added to that tiny number. That'll be a wonderful thing.

Shubrook: I love it. Thank you.

Baum: I've really enjoyed this conversation and I've learned so much. We've discussed many different aspects of drugs in the pipeline, lipid-lowering therapies, and a real clinical case. I've enjoyed it.

I thank you both for being here today, and I thank the audience for being with us.

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© 2023 American College of Cardiology & Medscape

Cite this: Seth J. Baum, Matthew J. Budoff, Jay H. Shubrook. Targeted Strategies in Lipid-Lowering Therapy: Where Do We Stand Now? - Medscape - May 12, 2023.