Setting the Stage: The Unique Role of APPs in Optimizing Lipid Management

Laura Ross (Park Nicollet Heart and Vascular Center): I'm so excited for this talk for lots of reasons. A, adding more fiber is always good along with the other things. As you know, John, I'm passionate about lifestyle medicine, but in particular about all the tools in our toolbox now we have with medications to really optimize risk factors.

[0:05:15]

ACC 2020 Clinical Competencies

And the American College of Cardiology recognized that APPs, PAs, and nurse practitioners are pivotal in providing this care. So they came out with a 2020 Clinical Cardiology Competencies. This is really based on medical knowledge and patient care delivery and looking at professionalism, communication, collaboration within the team. In fact, it was a cardiologist who helped write the paper, Doctor Rogers. But Viet and I had the absolute pleasure and honor of contributing to these 2020 Clinical Competencies that were published in JAC and really saying, what are the skills and knowledge that PAs and nurse practitioners should have? But also how about more specialized care like congenital heart disease or things like electrophysiology and procedures that maybe not everyone has to know, but those PAs and in those specialties should know. And they came up with a Certified Cardiovascular Knowledge exam based on these clinical competencies. And prevention is a huge part of this knowledge and that part of what PAs and nurse practitioners can really be a part of.

[0:06:24]

ACC 2020 Clinical Competencies (cont’d)

So it's really exciting and really focused on the team that surrounds the patient. So instead of the provider being at the center of this wheel, it's really the patient and all the people that can help optimize their risk factors for success. It really looks at establishing a framework, looking at what should the knowledge be, what are the skills that physician associates and nurse practitioners should have, and what are the behaviors that should be expected? And working as a team, we can really optimize cardiovascular outcomes. These competencies now have cardiology fellowships that are based on them, bridge to practice programs for people maybe switching from another specialty to cardiology and really has showed quality improvement across all care settings. It really empowers advanced practice providers, who are really programmed to be lifelong learners, to lead team based care and in particular, lipid care. Viet and I have the distinct honor of really having most of our practice these days in prevention clinic. And so, I know my colleagues are so thankful for the knowledge and care that I'm able to provide for patients as well.

And how do we translate evolving evidence and guidelines into outcomes? Some of you saw that article in JAC that just came out that said less than 20% of people have their LDL to goal. It's not for lack of guidelines. It's not for lack of medications that can get them there. It's how can we get this into clinical practice.

And so with that framework, we are in the perfect position to be a solution to this problem of cardiovascular disease, and I will pass it to Viet.

[0:07:53]

Fundamentals I: ASCVD pathophysiology and the Importance of Achieving Lipid Targets

Viet Le (Intermountain Advanced Lipid and Cardiovascular Prevention Clinic): All right. Thank you. And I love that last graphic. I often tell patients, look, didn't come into clinical practice to have patients that are getting sick just so I can practice. I learned all of this so that we can put the patient at center and do our best for them. So as we kind of think about the physiology, pathophysiology and the importance of achieving lipid targets, I think that's really what helps patients to understand and become adherent to the therapies that we discuss and will be discussing today.

[0:08:32]

Abnormal Lipids Increase Risk of Myocardial Infarction

So as we kind of look through, you know, why are we here? Why do we understand lipids to be a target of therapies and why we use them as a way to reduce risk? So here's a nice study from the Interheart. And as you kind of go through from left to right here on this the axis of population-attributable risk. So we kind of look from 0% on up to 100% what is attributable to cardiovascular disease. And then along the bottom, I mean, people think, “Oh, yeah, smoking, of course. You know, fruits and vegetable, Laura's favorite subject. We don't get enough of that. Exercise, of course, same thing.” But as you move towards the right of your screen, what you find is 50% of attributable risk for cardiovascular disease is lipids. And that's not by accident. It's the lipids that invade the endothelial wall and develop plaque. And so it's important for us to recognize that not only is it a biomarker, but it is certainly a target for cardiovascular risk.

Now, all nine of them together then make up 90% of attributable risk, and I think of this as a probabilistic model. You can have all of these risks and still not have events. And you think, oh that's unfair. But, you know, I think it's just real that there are folks that accrue all of these risks and don't have events, but you're more likely to have an event as you accrue these risks.

[0:10:09]

LDL Is a Causal Agent in ASCVD

So how do we know that LDL is causal? Because, you know, I just had a text from a patient the other day and they wanted to go off their statins, because “I've listened to this cardiologist that says LDL cholesterol is not causal.” I don't know where this person gets their information. I know where my patient is getting it, but I don't know where this cardiologist is.

Look, it's causal. We have observational epidemiologic data. That Interheart study was 2004. This is 2022, right here this graphic, and it pulls together the observational epidemiologic data that has been since that time, 20 further years, and then Mendelian randomization and genetic analyses, randomized clinical trials. We're not guessing here, folks. These are trials that both Laura and I have been clinical trialists. I was on the FOURIER study for evolocumab, etc., and that's ten years ago. So, animal experiments, all of these demonstrate the pathophysiology of LDL cholesterol as 1 of the components, ApoB 100 proteins, and all of these and how they get into the endothelial wall and become plaque. So it's a target because it is causal.

[0:11:27]

LDL-C and Atherosclerosis

So as we kind of think of this next graphic, and it can look like a lot of information, but at the bottom, if you look at that center line zero, when you go down, these are like no atherosclerosis. So people in this area down to 100% in terms of no atherosclerosis. That first bar is an LDL cholesterol of 50-60 mg/dL. Okay. And then as you march to the right of there and you get more and more atherosclerosis all the way to the far right, that's 150-180 mg per deciliter, just shy of familial hypercholesterolemia levels of LDL cholesterol.

So then as we come back to that zero, there are less and less people, again, probabilistic model, less and less people that have zero atherosclerosis, but more and more people who develop more than 1 bed of vascular disease. Right. So as you accrue LDL cholesterol and have more and more sitting around in the bloodstream, then yes, you have more vascular beds that LDL cholesterol can then seed inside the endothelial wall from carotids to coronary to down below in the peripheral, the femoral arteries, etc.

So I think this is helpful for us to understand. The more you have of this lipoprotein that can then get into the walls of your arteries, then the more vascular beds that can be affected. So it is causal.

[0:13:08]

Why LDL Lowering Is Important: Cumulative LDL-C, Yr vs Age

So what do we do about it? Well, we'll talk about that. But here is 1 of the models that I think has given a lot of passion for me in terms of my preventive cardiology clinic, because we started as a lipid clinic with this model in mind. What you're seeing here is cumulative cholesterol years. Okay. So from time zero all the way from birth. And that's at that intersection there where x and y axes are. And as you accumulate cholesterol, so that first group of people, the severe hypercholesterolemia, light purple, think of it as homozygous FH. And these are people with 5-600 mg of LDL cholesterol from birth. And that first age bar would be like 20 years of age. They're having heart attacks, strokes, peripheral arterial disease at 20 years of age because the burden of LDL cholesterol is so high from birth to that time.

The next 1 is orange, and you might think of that as heterozygous FH. LDL cholesterol from 190 to 200, maybe 300. And so then that first column is maybe in the 30s. They're having their events in their 30 years of age, 40 years of age, early because the exposure is so massive from birth on to the third decade of life.

And then as you get to the green, modest hypercholesterolemia. These are individuals like us, you know, like anyone with a, quote unquote, normal LDL cholesterol. But it starts to go up. Our lifestyle kind of impacts this. We might smoke, we might be sedentary, and then we're having events.

But the PCSK9 story actually comes into that darker purple blue, where these are individuals with LDL cholesterols that are low to nonexistent, right. In that that bar of no atherosclerosis, where your LDL is 50 to 60 from birth to whatever, no events or very low event rate.

So this is very helpful for us to kind of understand cumulative burden when we think of LDL cholesterol.

[0:15:15]

Statins Remain Mainstay Therapy for Key Risk Groups

So let's see what the data tells us in terms of trials. So what you see here in the orange are all of the secondary prevention trials. All of them in a line. If we go all the way to 5, to the far right, that's mmol/L but let me translate that to mg/dL for those in the states. That's about 190 mg/dL. So that number 26 in the far upper right corner is really the 4S trial. You remember this. This is the statin trial in the Scandinavian population. And they were really just enrolling FH patients, honestly. And if you can see from that top right, if you just follow that line, there's a 26 a little bit further down the line. They went from 190 to 130 and dropped nearly 20 to 30% events in that group. And so each trial subsequently went lower and lower and lower, where you see at 50-70 mg/dL or around that 2 mmol. And that's the secondary prevention trial. So it's not true to say that statins haven't led to a reduction in events. We've seen it over and over and over in the secondary.

Now, it's a flatter line when we look at the dark purple. Right. These are the primary prevention. And that's why it's so hard to see events change when they've not had an event. We're just looking at risk factors and then we're applying lipid lowering therapy. But it's also true to say that there is a reduction in events when we look at those trials that looked at primary prevention. And so that very far number 54 in the purple there, would be an FH population that did not have any events, they maybe have family history, but, boy, you keep them alive longer and events reduce when you can employ or deploy lipid lowering therapy.

[0:17:21]

Statin Intensity and LDL-C Reduction

So how do we do that? Well, statins are foundational. And I actually tell patients the LDL cholesterol lowering is kind of secondary in terms of statins because there's a pleiotropic effect of statins. They stabilize plaque, they reduce inflammation around where you already have plaque formation, making it less likely to rupture. And then we're reducing the LDL cholesterol because that is an effect of statins.

But you can see here, the very top, there's only 2 that are high intensity statins: atorvastatin, rosuvastatin. But you can see their doses: atorvastatin 40 to 80, and then rosuvastatin 20 to 40. Everything else kind of falls in this either moderate intensity or low.

And you would say well what does that mean when we say high, moderate or low? It's by percentage of reduction. So, high intensity, we assume or we've seen in the PKPD data from clinical trials that at minimum, 50% reduction or more occurs in this dosing range. And then everything else, you know, 30 to maybe 49% in the low intensity, then just under 30%. Okay.

[0:18:30]

Despite Statin Therapy, Residual Risk Remains

So then as we think of, “Oh, wow. This is showing me the all the secondary prevention, primary prevention trials. There's reduction.” But I'm a clinical trialist. What we see is from placebo to therapy, there's a reduction in risk, but even people on statins have events, just less so than if you didn't have any statin. So there's this residual risk that occurs in all of these trials. That first 1 is 4S on that first, gray and orange bar there, and it goes from 28% event rate down to 19%. That's 19% events still occurring in people on statins. And it's the same, we see that through the LIPID trial, the CARE trial, HPS, WOSCOPS. So, we have to do more. Statins is just not enough. And that number to treat, we need to really lower that and use combination therapy, lower that LDL cholesterol further and further down. So that's what this graphic tells us is that we still have room to go.

[0:19:38]

2018 Blood Cholesterol Guideline Recommendations

When we look at the 2018 cholesterol guidelines, they identified 4 key groups warranting LDL cholesterol lowering. So this is key. Let's do a thought experiment here. When someone has cancer we think about radiation therapy. We think of surgical therapy. We think of adjuvant with chemo after surgical therapy. Would you just say, well you know, people have cancer, so we're just going to give everyone chemo? That's just what we're going to do. It makes no sense. You have to contextualize risk. And that's where standard therapy makes sense, is when you identify people at risk.

So the 4 key groups here starting from left are the clinical ASCVD. They've already had events or they have known identified coronary disease. And then moving toward the light purple is primary severe hypercholesterolemia. These might be FH, or it might just be polygenic risk with high LDL cholesterol. Then you have individuals with diabetes. Of course, you know, 30 to 40% of them have an event cardiovascular. And then primary prevention. Kind of true, 40 to 75-year-olds that have some risk but do not have diabetes, don't have coronary disease. Okay. So now we're picking folks that contextually already have risk or we're trying to identify risk and then deploy therapies.

[0:21:01]

LDL <55 for Very High Risk ASCVD

So here when we think of that first group, that's probably the easiest to think about. It's coronary disease or stroke or peripheral arterial disease. Or maybe they have a coronary calcium or carotid intimal medial thickness that is positive or an ABI study that's positive. But very high risk is a different group. You have 70 in your head, and we've had 70 mg/dL in our head for a long time now through clinical trials, and we need to move it down to less than 55 in those individuals that have very high risk. And who are they?

So in the orange, this is an acute coronary syndrome within the past 12 months. So catch them quickly. They're going to have an event most likely, their risk of an event is really high after that first 1, especially when it's acute. There's just this inflammatory process that's going around those plaque. And then history of MI, history of ischemic stroke.

Now you're adding that plus 2 or more risk factors. So if you've had an event and then those high risk conditions in that second box. Well, I think many of us treat patients that are 65 and older. So they already have that risk. Then CKD. This is why it's so important to look at that EGFR and maybe get a uACR too, please. That’s coming up. And that's of course, John, our moderator has a lot of experience in the hypertension realm. We should all be doing a uACR. Smoking, diabetes, hypertension. I would argue that very few of our patients are on the other side where they're not very high risk. Most of our patients fall in this very high risk category and should be treated to an LDL cholesterol of less than 55.

[0:22:46]

2022 ACC Expert Decision Pathway: Clinical ASCVD (A)

So moving on. As we think of now, this Expert Decision Pathway that came out in 2022, really we had more data. Things are happening. And we didn't quite have the time to do a guideline. So an expert consensus really brings it back all together.

And this first group of A, is the very high risk. Again, arguably the majority of patients that you treat that have cardiovascular disease are very high risk. I promise you, you'll find that this Monday as you start treating patients again and going, “Whoa, yeah, Viet was right. They have 2 or more conditions along with their coronary or their stroke.”

What do we do? Well, at minimum, greater than 50% reduction in their LDL from baseline. And after you achieve that, you still should try to get people to less than 55. And so this is algorithmic, right. If you follow the left hand side, if no they haven't reached either one, if they haven't had a 50% reduction or reached less than 55, then really consider adding ezetimibe and up front maybe go ahead and do a combo ezetimibe and a PCSK9 inhibitor up front to get there.

And then you might consider adding bempedoic acid. And this is going to change. We've had more data since this 2022. It's, you know, 3 more years of time, but at least from the consensus guidelines from 2022, please, we need to be adding ezetimibe early and then really thinking PCSK9 and of course going down to bempedoic.

Now, if they've already reached that point, you would go ahead and monitor it and adhere or see if they've already adhered to that, if it's just on statin therapy and they've met goals, then fine. Just kind of continue to monitor and have those discussions.

[0:24:36]

2022 ACC Expert Decision Pathway: Clinical ASCVD (B)

So as we go to this group B, this is again, you know, folks with coronary disease, ischemic strokes, peripheral arterial, but no other risk factors, then it's okay to relax back. I'm a preventive cardiology PA, I really don't like saying relax, but less than 70 is currently the goal for those individuals. So statins and then adding ezetimibe and then checking again and if they haven't met goal adding then PCSK9 and bempedoic acid. Otherwise, if they've reached those thresholds, then please, please, please do not fire and forget. We really should be doing annual lipids, because it helps us to remind patients this is real, this is something we got to talk about. And some just forget to take their therapies. Okay.

[0:25:24]

2022 ACC Expert Decision Pathway: Clinical ASCVD (C)

As we get to the next group, these have clinical ASCVD. This is group C. And their LDL cholesterol started greater than or equal to 190, which means it's very difficult to get to goal. They might not have FH and their goal is still greater than 50% reduction from baseline and getting to less than 70. So after statin therapy, let's say it's 190, you add a statin like rosuvastatin and they'll drop from 190 to probably 95-ish, and that's well above 70. So you would need to add ezetimibe and probably then consider bempedoic acid or inclisiran, PCSK9‑interfering therapies.

[0:26:10]

2022 ACC Expert Decision Pathway: Clinical ASCVD (D)

And then this last group that I'm going to touch upon, because we won't really do primary prevention at this point, but this is the group that really is ASCVD, have coronary events, stroke, peripheral arterial disease, and their LDL cholesterol is greater than 190 and you've confirmed that they have FH. So you can see we just get really on top of these individuals. They're very similar to very high risk ASCVD. And I would argue FH itself, is kind of high risk anyways, less than 55 mg/dL. We know this. Statin. We have ezetimibe. There is PCSK9 inhibitors and bempedoic acid. All of these Laura will talk about mechanisms but are very important in reducing LDL cholesterol.

[0:26:59]

Estimating Cardiovascular Risk for Those Without DM

So here, those people without diabetes, this is the primary prevention folks. This is just an example. It's a little hard to read on the screen, but since we're virtual, you can kind of lean in and take a look. This is an individual that has had their risk score. They’re 62, male, white. You can see the blood pressure looks kind of under control, less than 120 or 120 and then 80. But their total cholesterol is 200 plus, HDL 66, LDL is 175. And this person happens to not smoke, not have diabetes, and not be on any hypertension treatment. Really age drove this 9.4%.

I will stop here really quickly and just say we need to move to the PREVENT calculator. This is pooled cohort equation. Please, from this point on look at the PREVENT. It's a little bit different and the calculations are also slightly different in terms of risk, borderline, intermediate and high risk. So just pay attention to that, PREVENT is the next risk calculator.

[0:28:11]

Setting the Stage for Shared Decision-making: 2018 Blood Cholesterol Guideline Checklist

So let's set the stage for shared decision making. We should not be paternalistic in terms of treating patients, but really thinking about: First assess that risk. Explain to patients why LDL cholesterol is causal in terms of atherogenesis. And then really the lifestyle. And, you know, Laura will talk a little bit more about this, but we need to make sure that we're assessing that lifestyle is first and foremost, that it improves quality of life and reduces risk. And those cost considerations, many of these medications are still brand. We have to think about copay cards, vouchers and really getting patients set up with caregiver support, where they're talking to individuals that can help with patient assistance. So again, discuss therapy, discuss those benefits, acknowledge that there's cost issues that may be part of this. Do not make patients feel guilty for making the decision that this is too costly, I cannot afford this. We will continue to work together to lower that LDL cholesterol.

[0:29:18]

Engaging Patients in Shared Decision-making: 2018 Blood Cholesterol Guideline Checklist

So, engaging patients. Really teach, teach, teach, ask and then invite. Invite them to ask questions. This is why I love having infographics in the room. They can think about these well ahead of time before I get into there. And then we need to ask them, what are your values? And some do not want to be on medical therapy, and we have to acknowledge that and discuss these things. And you know, now we can include our pharmacy partners, we can include patient assistance groups and collaborate with them to develop the plan.

So at the very end, as we kind of talk through this, just remember, as you teach patients and you discuss therapies, it's really about them in the center and what their values are. I have run a little over and I apologize. I'm going to move it back to John.

[0:30:11]

Skill Building and Feedback I

John Giacona: Thank you so much, Viet. And so we're already seeing some themes, patient-centered care for both PAH and hyperlipidemia. So coming back to skill building and feedback session for our audience, we'll bring it back with a case.

[0:30:28]

Patient Case 1: Maria, 56-Yr-Old Woman

So this is Maria a 56 year old woman. Her chief complaint, she has rising LDL levels and residual ASCVD risk despite adherence to high intensity statin. So she's really concerned about her cholesterol control and her risk, as her LDL-C remains at about 115. She has a strong family history for premature ASCVD, and she expresses frustration that her cholesterol is not going down enough. She is currently on atorvastatin 40. Her past medical history, she has hypertension, type 2 diabetes, hyperlipidemia, and obesity with a BMI of 31.

For lifestyle, she has improved her diet and she's regularly walking. She struggles with adherence due to reported some muscle symptoms.

Recent lab work shows LDL at 115, which is down from 145. Her Non-HDL is 135. ApoB came in at 115 LP. Lp(a) was elevated at 95, as well as hsCRP at 2.8.

[0:31:30]

Poll 3

So with this patient in mind, let's move to our poll. What is the primary driver of Maria's residual ASCVD risk?

1. Inadequate LDL-C reduction due to submaximal statin effect.
2. Elevated lipoprotein (a) contributing to ongoing atherogenesis.
3. Persistent systemic inflammation, as evidenced by her elevated hsCRP or
4. Multifactorial residual risk despite optimal statin adherence.

Excellent. Thank you for staying engaged and participating.

[0:32:20]

Let’s Discuss: From Pathophysiology to Practice

So let's take a little moment to talk about what might be happening. So in this patient, because she has persistent LDL, that is continuing to drive atherogenesis. And this is despite her being on atorvastatin, being on statin therapy. She does have some genetic and inflammatory contributors. Both her Lp(a) and high sensitivity CRP were elevated. And she was very forthcoming and said that she had some non-adherence to her statin because she's having some muscle symptoms. And that, of course, will limit increasing statin intensity, but it's also limiting the current statin that she's on.

And so what are some things we can do? Always reassess lipid levels and therapeutic goals. See where she fits in in the 2022 ACC Expert Consensus Pathway. We can consider add on nonstatin therapy such as Zetia, bempedoic acid, PCSK9, or inclisiran to try and help with her residual risk. We need to also address her muscle symptoms and adherence barriers. And like Viet said, in all patients, reinforce that it's a shared decision-making process, focusing on patient education and really putting them in the driver's seat of what needs to happen next.

[0:33:32]

Faculty Discussion

And so at this point, I'll bring Viet and Laura back in and kind of let's get their thoughts on how to frame the conversation around treatment and optimization for this particular type of patient.

Laura Ross: Yeah, I really like that word optimization. And often tell patients think of your LDL like a finish line, the ribbon at the end of the race. And although statins might not get you all the way, they are getting you closer. Or if you can't tolerate it, what can we add to finish the race? We all want to be winners, right? So rephrasing it a little bit that way.

And then also to address adherence, what has been successful for me is to really say “Are there any barriers to taking your medication?” instead of “I can tell you haven't been taking it. Your LDL is, you know, way higher than it used to be.” And then you get a conversation about the cost, or they're a caretaker for somebody else or, you know, it's just they're having side effects that they didn't want to tell you about. So those are some hints for myself. How about you Viet?

Viet Le: Yes, I think what I find in terms of any type of hesitancy or movement forward is just a lack of understanding from the patient with regards to what LDL cholesterol is. Is it this just this thing that we're trying to address? It's a number? Or does it drive risk. And so as I talk to patients, first I set the scene and then I'm asking them, you know, so what are your thoughts here? Often they drive the questions. Many of them, when I tell them look, normal physiology for LDL cholesterol is 20 to 40, then they don't worry about, “Oh, is it too low?” because that's the normal physiology.

And then the second part is really like you said, tell me about your thoughts on medicine. It sounds like you're hesitant. So where does that come from? What are your thoughts here? And if it's “Oh well, I want to try lifestyle,” I'm like great, I know Laura, but I also know that a lot of these therapies, especially like familial hypercholesterolemia, guess what? That does not respond to lifestyle. But it doesn't mean that lifestyle is not what you do. You still have to run the engine and make sure it's got great fuel.

But these are things that, you know, it just might be a misunderstanding of how that LDL cholesterol is derived and what their situation is. When they understand the risk, they understand what LDL cholesterol is and then their personal risk of events, then many of them, you know, whether cost, again, cost is an issue, but whether or not cost is part of it, they do want to then partner to lower their LDL cholesterol.

Laura Ross: And just to piggyback off that, I would add there's no lack of information/misinformation out there. So to address that and to say we have randomized control trials that look at outcomes and tens of thousands of people, and that YouTuber or whatever, you know, doesn't go through the same rigorous activity to come up with their conclusions. And I think once we are in that perfect position as PAs and NPs to establish a relationship, start to develop that trust, so it's not uncommon that I don't – maybe I'm not able to start a medication right away if they're very hesitant to use a medication, but by the second or third visit I've planted the seed, you know, they understand I'm on their side and it's really fruitful going forward.

John Giacona: Thank you both for such good tips on how to approach patients when it comes to optimizing their lipid therapy. I feel like, Laura, we could have a whole session on misinformation from social media, especially with regard to blood pressure as well. But for the sake of time, we'll move on to the polling, and then I'll actually bring it back to you.

[0:37:33]

Poll 4

So for the audience, we'll go next to our poll 4. How would you respond to a patient like Maria who says, I've been taking my medicine but my cholesterol is still high? Does that mean it's not working?

1. It might take more time for your medicine to work. Let's keep monitoring.
2. Your results suggest we may need to add another medication to lower your cholesterol and reduce risk. Let's review the options together.
3. That happens sometimes. Try adjusting your diet further and we'll see. Or
4. You may need to stop your statin if it's not helping. That is what most patients have to do.

Excellent. Thank you guys for participating. We have 1 more poll before the next section.

[0:38:27]

Poll 5

So poll 5, take a moment to reflect on what this case brought up for you. What's an area you'd like to strengthen in your lipid management practice?

1. Enhancing patient education and adherence support.
2. Earlier diagnostic and follow up lipid monitoring
3. Integrating quality of life and lifestyle counseling into care plans, or
4. Improving shared decision making and communication.

Excellent, excellent.