Heather Johnson (00:06):
Welcome to Cholesterol Conversations, a podcast brought to you by Vasculearn Network with generous grant support from Esperion Therapeutics and Merck. I'm Dr. Heather Johnson, Director of Preventive Cardiology for Women's Services at the Christine E. Lynn Women's Health and Wellness Institute of Baptist Health South Florida in Boca Raton and Clinical Affiliate Associate Professor of Florida Atlantic University. I'm thrilled to be your host today for a robust discussion on “Mastering LDL Management in 2025.” I am honored because joining me today is Dr. Viet Le, an Associate Professor of Research and preventive cardiology physician, and Co-Director of the Preventive Cardiology Clinic at Intermountain Medical Center in Utah. Welcome, Viet. Thank you for joining us today.
Viet T Le (00:58):
Thank you so much, Heather. I appreciate it.
Heather Johnson (01:00):
So it is definitely my pleasure for us to be able to dive into this and just as a really brief outline as far as what to expect over the next few minutes here, we have a lot that you and I are going to be discussing.
Viet T Le (01:13):
We're going to do a masterclass in 30 minutes, I think.
Heather Johnson (01:18):
Sounds good. Well, we're going to highlight very briefly as far as LDL, its importance and some key screening topics. We'll talk about risk assessment and yes, our options have truly broadened over the years as far as statin and nonstatin options. And many times I believe you and I were both confronted to barriers to actually getting people to where they need to be and overall best prevention therapies in the world of LDL cholesterol. So let's just talk a little bit: why is LDL important? Why is it such a major focus regarding our prevention and treatment focus in clinical everyday care?
Viet T Le (01:56):
Yeah, I mean I think that's really the question because otherwise we're just treating a number and that really does ourselves and our patients a disservice. If we think of LDL cholesterol, it's just this number we have to treat. We have to remember that it's the substrate of atherosclerotic plaque at the physiologic level. It's the smallest Apo B 100 lipoprotein that can actually get in underneath that endothelial lining and then become inflamed, react with foam cells, et cetera. And then we have this plaque and I usually tell people it's kind of like traffic on the road. These are vehicles and when it's traffic I'm trying to get home, it's harder to get through areas and it's worse when there's a car accident. And so if we can limit the vehicles on the road, or in this case LDL cholesterol, then you're going to reduce the potential or probability. It doesn't mean that those car accidents don't happen when you reduce vehicles, but in this case, when we lower LDL cholesterol, then we're lowering the probability of events.
Heather Johnson (02:57):
That is well said. I love the analogy. I think it's truly outstanding and you hit on an important point many times we may know as clinicians why LDL is important, but oftentimes I talk about the importance of why should we tackle it and it's important for the person across from us, the patient to understand that. And one of the things we're highlighting too is that even when we're spreading the word and we're speaking at various CME events, the question sometimes is does it really matter? Should I focus a lot of time on this? And I say, if there is one major issue you want to address to decrease risk of population cardiovascular events in addition to helping to protect the person in front of you, let's lower LDL cholesterol. And I think that's truly outstanding.
Viet T Le (03:47):
Yeah, I mean that's it. I really do think of all the things that we in preventive cardiology that we address. It is, like I said, it's the substrate of atherosclerosis and so we really need to make sure that is one of the first foci that we address in preventive cardiology.
Heather Johnson (04:08):
I love it. I love it. So you were talking about as far as atherosclerosis and atherosclerotic plaque and if we highlight our primary prevention population and the screening tools that we have available. And there's been discussion as far as what we were previously focusing on the prude cohort equation. Now the prevent equation from the American Heart Association, and I know it definitely varies from person to person, but we can each share how are you using as far as these risk calculators for primary prevention?
Viet T Le (04:41):
I'm grateful that the AHA has brought forward the PREVENT calculator – and for those that have been using the ASCVD or the Pooled Cohort Equation, just recognize that it's not like we had to retool everything. They were able to add BMI and also eGFR. So recognizing kidneys part in this, but obesity as well. And that's something else that we have to address at some point. Probably not in this podcast, but you still are assessing diabetes, smoking, antihypertensives, etc. But here those are extra features that provide a little bit more clarity as to risk. But I would say something in terms of primary prevention and when do we do this risk assessment, just think of colonoscopy. We know that it makes sense to do a colonoscopy in a 40- or 45-year-old person. You wouldn't do it in a 10-year-old and why? Because you wouldn't expect to see colon cancer or anything like that unless they have some type of genetic risk, which brings up a different thing in LDL cholesterol. But in general, when we think of using these risk calculators is there's a reason why it starts from 40 to 75 instead of earlier. But I would say it does miss primordial disease prevention and we should think about that. The current contemporary approach though is start 40 to 75 unless there are these other features of diabetes in familial hypercholesterolemia.
Heather Johnson (06:04):
No, that's a really, really good point. And I like what you said as far as clarity. I also talk about really individualizing and so for our audience when we say the American Heart Association PREVENT calculator standing for predicting risk of cardiovascular disease events, that's what PREVENT stands for. The calculator is readily available online through the American Heart Association. You just put AHA prevent, you will be able to see the calculator and you are right that it really does move us forward in the risk prediction realm. So traditionally we've started at 40, but gratefully with prevent, they're highlighting exactly what you talked about. We can actually start younger at age 30 from 30 to 79. And we're used to also looking at as far as atherosclerotic events, but also heart failure risk, which is important. And when we talk about again on a population level that focus on cardiac, kidney and metabolic relationship as far as overall cardiovascular health in general and arterial health is definitely playing a role.
(07:09):
Now, I know you and I have talked about as far as the addition of certain additional indices, but also urine albumin creatinine ratio. And another big conversation difference is that race was taken out, but the social deprivation index for social determinants of health added. So we say all this to say there are multiple factors that play a role in someone's risk for events. And I like to use these risk calculators really as a starter in conversation because we also know that there are other risk factors and other indices we can look at in biomarkers that may also sometimes shift that conversation a bit beyond just the initial risk score. So thank you for highlighting also primordial prevention and earlier, and I say “it's never too early, it's never too late,” when we talk about risk assessment.
Viet T Le (07:55):
Yeah, you definitely want to give your patients a longer runway to be able to fly free and have a healthy life. In this case, unlike colon cancer where we're predicting not seeing a 10-year-old, these are factors that occur earlier in life and are present earlier in life. One of the things that I do want to highlight is we don't do a really good job, I think in cardiology and some may, but I think on the whole we forget the female specific factors. So just remember that as we're adding all these other biomarkers, the woman in front of you may have had preeclampsia, may have gestational diabetes as part of the risk, and it's a very big risk elevator for those women. So I think that needs to be remembered as you're doing this risk assessment.
Heather Johnson (08:39):
You are correct. And when we talk about LDL cholesterol, that conversation is who are we starting prescription therapy on top of lifestyle? And so we touched on the risk score. Yes, thank you for binging up female specific risk factors. It's definitely one of my key things I love to address. And also like other rheumatologic conditions, rheumatoid arthritis, things like that, kudos to our rheumatology colleagues who are also highlighting cardiovascular risk and so many other things. So that guides the discussion of having a risk score. What are other enhancers to that risk of cardiovascular events and how does that move the needle in our discussion for LDL treatment when we talk about risk assessment Now I said the addition of treatment because lifestyle of course is our, it never goes away as much as we don't talk about it as much as we should at all.
Viet T Le (09:28):
Yeah, yeah, absolutely. First and foremost, that just makes sense that we should make sure that lifestyle is included in all of our conversations.
Heather Johnson (09:36):
No, I definitely appreciate that. And when we talk about, again, the whole metabolic or cardiometabolic area, of course we haven't forgotten about diabetes and then also really the push and highlight and focus that we've had now in relationship to metabolic liver disease too. And so these are all things sometimes on the report it may say quote fatty liver quote, Hepatic Steatosis, and we're recognizing this is a metabolic condition. Let's not think likely of those incidental findings or those because yes, we need to really target and address things like LDL cholesterol.
Viet T Le (10:13):
Yeah, fantastic. And just as we close out screening and risk assessment, if you have a moment, go to the American Heart Association Presidential Advisory Scientific Statement on cardiovascular kidney metabolic health, CKMH, and you'll recognize that these are all on a continuum and ultimately all inflame endothelium all throughout the body. So they definitely kind of interact in a big way.
Heather Johnson (10:39):
Yes. And thank you for highlighting Apo B. And you've already talked about, and we talked about some other biomarkers, a quick word about lipoprotein a [Lp(a)] and how that may also be looked into? Yes, we're laughing, but we're laughing because it's a significant issue.
Viet T Le (10:55):
Yeah, mean, so of course we're talking about LDL cholesterol and Lp(a). We don't have any FDA-approved indicated therapies just yet, but that doesn't mean it's not a risk, especially when you recognize this is one in five globally. So 20% of our population globally has an elevated Lp(a) and for those that are keeping track, FH on the LDL cholesterol side tends to increase risk by three to five times over the general population. And elevated Lp(a) is very similar, three to five times the risk of the general population. You're only one in 250 for heterozygous FH, but you're one in five for elevated Lp(a). So this is something, please measure it and keep track of it. There will be therapies down the road.
Heather Johnson (11:41):
There you go. And until those therapies are available, our goal is also LDL cholesterol lowering further. When you see a high lipoprotein a, so let's talk treatment, what do we do have available? I start off in clinic and I say, listen, we have options, statins, nonstatins. I give the big picture. How do you talk about it?
Viet T Le (12:05):
Yeah, no, no, exactly that. I mean I think first and foremost, the foundational therapies that everything has been built upon has been statin therapy. And everyone can Google and find all sorts of odd things out there with regards to statins and how they’re deleterious or not. But the data is with statin therapy. And I tend to tell people, again using that car analogy, we're reducing cars on the road. And so there are multiple ways at it. I don't like to give up on statin therapy, but it doesn't mean that everyone needs high-intensity statin therapy. You can go to moderate and you can also go to a low dose and maybe some alternative regimens where you just want it on board for its other pleotropic effects, it reduces inflammation, it thickens the covering the cap, the fibrous cap on top of plaque. So there are other features of statins that you want.
(12:58):
I'm not sure necessarily you get all of the pleotropic effects at those lower doses, but we have adjunctive therapies. Fast forward to PCSK9 inhibitors and ezetimibe by the way, don't leave that behind. It's been out 20-25 years. And then bempedoic acid and along with the PCSK9 inhibitors, we have this small interfering RNA. So I like to keep the statin therapy question and answer as part of the whole, but I want to make sure that they don't lose sight of why we're doing this. We're lowering LDL cholesterol so that there are fewer cars on the road, but we're also shoring up the road and we're trying to put in traffic lights, that's the inflammation, all that good stuff. But we have adjunctive therapies as well with these nonstatins.
Heather Johnson (13:43):
You are exactly right. I greatly appreciate that. And many times there is hesitancy as far as statins, and we can talk about some of the barriers and inertia just a little bit. But I always tell everyone our goal is to find an individualized plan to lower the LDL to what your threshold should be. For example, we talked about heterozygous or familial hypercholesterolemia. And so looking at the magnitude as far as LDL reduction, we also talked about high lipoprotein a, we talked about diabetes. And so these thresholds are getting lower and lower. So we're shifting from less than a hundred, less than 70. We talk about our higher risk patients, more secondary prevention, less than 55. And as I tell people, our goal is not to frustrate our patients and our colleagues, but to really highlight that this is our pathway to lower heart disease, still our number one cause of death.
(14:40):
And so I do highlight that statins are our foundation and when we talk about what the opportunities and options are out there, I say “you may not tolerate even the highest dose, but let's not forget combination therapy.” It still breaks my heart that the use of combination therapy is very low when we look throughout the United States as far as medications that have been out for a while, you mentioned ezetimibe and bempedoic acid that are also available when we talk about our primary prevention dyslipidemia. And also when we look at, for example, PCSK9 inhibitors in relationship to familial hypercholesterolemia, also established coronary disease. And then we have inclisiran, which we have not discussed yet, but at the same time we're still waiting on some outcome data in relationship to inclisiran, but also ann understanding that that is also still an option when we look as far as opportunities to lower LDL cholesterol. So I think these are key factors, but understanding and yes, also if there's concern about what a patient may qualify for, what options are really highlighting a team-based approach to care.
Viet T Le (15:49):
I love that. And I would just remind everyone that this is mainly primary prevention we're talking about, but in secondary prevention, these individuals often have heart failure. They often have other comorbid conditions and multiple, multiple therapies. So when you have an option such as a combination ezetimibe-bempedoic acid, it comes that way. There is separately bempedoic acid, but when you can kind of give them one pill that has two medications, please think about that. I love the PCSK9 inhibitors, both the monoclonals and small interfering, because then it's not a daily dose. You're able to go out every two weeks or in some cases every six months. You're adding value without adding burden in terms of a daily oral medication. So I think it bears thinking about with each individual patient and their case and recognizing that again, as you say, LDL cholesterol lowering is the goal.
(16:44):
One of the things that I learned from Dr. Karol Watson was, and I didn't realize this, when we think of physiologic, normal LDL cholesterol is really between 20 and 40 milligrams per deciliter. So ,when people are like, you went below 55 and I go “yeah, into the normal physiologic range folks!” Those trials for the PCSK9 inhibitors, they got to 29 milligrams per deciliter in the ODYSSEY and the FOURIER trials, and at least for the FOURIER, they have the extension trial that went 7- 10 years now in these individuals and 29 is okay. Furthermore, you have fewer events. So it's okay to get into the physiologic range folks.
Heather Johnson (17:24):
I love it. Not only did they have fewer events with even lower LDL, but also no significantly adverse events. Exactly. And that's an important point. I actually have that discussion with patients because they bring the question of, “well, I need some cholesterol, what is too low?” And then I also add to my note, “please do not stop my cholesterol medication.” It's not too low, or I'll put it is not too low. And I say why and what the threshold is. I say, “let's have a conversation, but it is not too low.” And so that's how we get to move the needle on this. As far as understanding, we do have options, and I even break it up as far as with patients. We talk about oral options, we talk about injectable options and what their thoughts are, how can we combine them? So I think that's key.
(18:11):
I also want to highlight the term “statin intolerant” and one of the key points of the definition they talk about is really a patient-based guidance. Now of course, if we see something clinical that stands out, that's something. But at the same time, many times that discussion has really led to—and even the diagnosis or label in relationship to patient concerns and patient symptoms—that it is really felt it's gotten better with either dose reduction or discontinuation of medication. But it doesn't mean that if they can only tolerate a little bit of statin, we have to stop it. So we talk about partial intolerance that yes, they may not be able to tolerate higher doses, but what they do tolerate, let's leave it on board and then be able to add to it. I think it's great. So compared to what we call “complete intolerance.” And then you and I were having a great conversation and I hopefully we can also highlight that team-based collegial discussion, the conversations back and forth. I had someone reach out to me the other day, what should I do? A different health system. And I love it. I think it's a great way and as much as we talk about preventive cardiology, understanding that it's not widely available yet every place. And so we're always happy exactly to be able to help with that.
Viet T Le (19:20):
Please reach out to us. Yeah, please reach out to us. I love that you will send a note. Please do not stop the therapy. Often in my consultations, if someone has sent someone to me, my assessment and plan, I still like the original SOAP note, but it ends up being a mini-CME tutorial for folks. I do actually put references in including, FOURIER, FOURIER-OLE, and the ODYSSEY trials, and links to guidelines, and let folks know this is physiologically normal, this is where they went, please don't stop the therapy. And that way they know I actually do that upfront and it’s saved me a lot versus the first two years I was doing consults referrals, I learned, I'm so grateful that you brought up partial, incomplete, and complete. It's so binary to say “statin intolerance” yes, no, and it isn't that way. It's a continuum. And I would submit that really the complete intolerance is rare. It's very rare to have complete intolerance, but partial, it happens. Incomplete. Yes, it happens. So it's one of those things that really just kind of talk it through with your patients. They will understand and as long as they understand why they're lowering their LDL cholesterol and the other pleiotropic effects that benefits that they get from a statin, I think they'll recognize that okay, they might have a partial or incomplete and not just yes-no.
Heather Johnson (20:39):
That's a really, really good point. And that's also steps as far as addressing many of the barriers that we have to LDL cholesterol reduction as far as patients understanding why going back to that, why, what are some options? And I do listen when they have concerns of other family members that may have had some adverse effects or potential adverse effects related to a particular cholesterol medication. We also talk, they talk about intolerance too as far as significant vitamin D deficiency, thyroid issues, things like that. And so we even have a discussion and I also take inventory of what's already hurting or bothering you, what are some chronic things that are going on? And so we sort of have a baseline as to what may be more chronic issues rather than precipitated by a particular cholesterol treatment. So just tell me a little bit as far as alternative dosing, is it something or when we talk about lower dose, different days, how are we addressing that with statin intolerance?
Viet T Le (21:37):
I love that question. To be honest for everyone, I am partial to rosuvastatin actually upfront for many, as you say, when they have a family member that's already reported statin myalgias, I'll say, let's just do a 10 and 10, let's do a rosuvastatin 10, ezetimibe 10 out of the gate. And generally speaking, the two together provide between 50 to 60% reduction in LDL cholesterol and that way we avoid any high-intensity statin side effects at the 20 and 40 level. But you get very similar LDL cholesterol reductions upfront and mentally folks accept the 10, especially when you give the dosing range 5, 10, 20, 40 and they're like, “whoa, I'm on the bottom end of this.” It is a little bit of a mind game we play with ourselves! I lean into that and I don't keep them from having the benefit of statin, but at the same time allow them this idea that they can tolerate this and that they actually get an effective dose with 10 mg. So that's usually out the gate what I've shown. And there's a couple of papers recently that have shown that that's very effective over a high-intensity statin. And also I'm okay in having this discussion of maybe lickable doses. I always make that joke like, hey look, if we get to a five and you're like once a week licking it, okay, I recognize we're in a non-data space, but I really emphasize the importance of those pleiotropic effects of statin and we have other ways to lower the LDL.
Heather Johnson (23:08):
But that's a super important point. We're getting the LDL down lower, we're doing it in a timely manner. So getting it lower, getting it down faster. And also understanding we have both statin and non-statin options. And you're also, as far as with oral therapies too, I think that's truly outstanding. And so that's key. And we've talked a lot too as far as when we say studies that have been done as far as in different populations and what some definite options are. So thank you so much for highlighting that. As far as also nonstatins, getting them on sooner, which we definitely have some work to do, but the data has not been kind. And unfortunately 50% of patients are still well above the threshold and with little use of other non-statin options. So let's highlight those and I think that's outstanding. So we have talked about a lot of important points as far as screening treatment options, statin, nonstatin barriers. I just want to touch on and really acknowledge things like access costs and prior authorization…
(24:09):
When we talk about some of the “newer,” newer in quotes at times, but prior authorizations that are needed, especially when we talk about different types of PCSK9 inhibitors and bempedoic acid. And so I do walk a lot of clinicians through as far as important diagnoses to be able to hopefully help get it covered. But even if it's on formulary and approved, working with patients on cost too, and I recognize that is an important barrier as far as using available savings options, sometimes using through certain companies that may have some coupon reductions. But also understanding too that may not be applicable. But I also tell patients that even if cost is an issue now, it doesn't mean that we can't retry it down the road. And so I definitely do that over time and over different calendar years. But I look at other options to avoid delay in LDL cholesterol.
Viet T Le (25:00):
Yeah, those are all important points and great acknowledgements. The pushback I always get when I talk to my colleagues is “what about the cost?” I say, I get it, but that's across the board on all things. So it's not like this is new to us and it doesn't mean we shouldn't offer these therapies for patients, especially because one of the things I'll lean into at this point is, we have talked about, the different combinations, i.e., like rosuvastatin and ezetimibe as a 10-10, but in those patients that are statin intolerant, and especially in the primary prevention folks, because most of these were geared towards secondary people who've already had a heart attack, stroke, etc. But I do like the CLEAR Outcomes trial where we do have evidence in statin-intolerant patients with bempedoic acid, where a good portion of that population of that cohort was primary prevention and high risk.
(25:50):
And what we did see was a reduction in major adverse cardiovascular events. So you have to think about the evidence also as you're thinking of prescribing these things. So, in that complete intolerant, statin patient, bempedoic acid, add ezetimibe, those are excellent options. It wasn't studied in statin intolerant, but PCSK9 inhibitors also are a fantastic option in those patients. And we have the data, at least for the primary prevention and using bempedoic acid to lower LDL cholesterol, but also to get a reduction in downstream MACE events. So I think that's important. And of course, as we said at the very beginning, lifestyle, lifestyle is foundational. We're not going to forget that. We don't have a lot of time to delve into that. Those are specific different details, but these are foundational, you have to mention these things with patients. I'm curious your thoughts, Heather, on the emerging, will we have different guidance in a new, is it going to be an expert consensus or is it going to be a new guideline? And what are we going to be told for the primary prevention folks?
Heather Johnson (26:52):
Well, I think it's truly outstanding and as we look forward as far as to updates and guidance, especially here within the US workspace, we have quite a few options that are out there. Since the last guidelines. I want to also acknowledge with the CLEAR Outcomes trial, as far as the huge enrollment of women in that particular trial. Yes, exactly. I see you…
Viet T Le (27:18):
Clapping. I'm clapping,
Heather Johnson (27:19):
Yes. And I do share that with patients when we talk about “were you represented in the clinical trial?” And so we are very excited and it pushes other trials also as far as, yes, it is possible to ensure that there is definitely inclusion of women and also various populations when we look at how to best treat people individually and also addressing population reduction. So really briefly, yes, we are excited. You already touched on also of upcoming lipoprotein a therapies. Our goal is to let's continue to build our armamentarium to lower cardiovascular events. So I know that we're about out of time for our podcast, but I can tell you that the story is not over. I can tell you that there's going to be also further building based upon RNA therapies and other options that are out there. However, for today, and for now we have tools to lower LDL with both statin and non-statin therapy. Let's use combination therapy. Let's use all the options that are available. So Viet, I'll let you be able to close out as far as any final words at all.
Viet T Le (28:23):
Yeah, I think here are, for me, these are the clinical pearls we need to make sure we do the risk assessment. We need to lean into shared decision-making. So make sure the patient understands why we're lowering LDL cholesterol and then we have to remember the combo therapies, yes, that we have to acknowledge their statin, partial intolerance, complete intolerance. But there are so many wonderful nonstatin therapies, so we're not left in this vague area. Please lean into those and please get a lipid profile, start using the PREVENT calculator. You can use it as early as 30. And we have tools. We have tools to do this. So I appreciate it. Thank you, Heather.
Heather Johnson (29:03):
Thank you so much for this conversation today. So this is your host, Dr. Heather Johnson, and I want to thank my co-discussant, Professor Viet Le, and you, our listeners for joining our conversation today. Special thanks again to Esperion Therapeutics and Merck for their generous grant support. I invite you to continue the conversation and check out more education on LDL Cholesterol Management at the Vasculearn Network website at vln.thrombosis.org.