John Giacona: And with that we'll move to section 3, Fundamentals: Personalizing Lipid Lowering Treatment Beyond Statin Therapy. And I will pass it back to Laura Ross.

[0:39:22]

Fundamentals II: Personalizing Lipid-Lowering Treatment Beyond Statin Therapy

Laura Ross: Thanks, John. So now Viet has taught us why cholesterol is important, who should benefit from treatments, now I get to talk about how do we get patients there.

[0:39:37]

What’s New From the 2022 ACC ECDP on the Role of Nonstatin Therapies to Reduce ASCVD Risk?

And I think it's prudent to go back to that Expert Consensus Decision Pathway in 2022 to add some of the therapies that weren't there when the guidelines came out in 2018. So they really build on it because since that time we had bempedoic acid come out. This is a single dose that does come in a combination tablet with ezetimibe, so it can really help with pill burden. We had the addition of evinacumab, another monoclonal antibody that attacks a different pathway, and that's important to help lower cholesterol in homozygous familial hypercholesterolemia. And also the addition of inclisiran, a twice a year injection in the clinic that can really help with compliance as well. So we have many tools to discuss today.

[0:40:21]

Thresholds for Initiation of Nonstatin Therapy in ASCVD

And 1 thing that's new is when do we start some of these nonstatin therapies? It's really important, I think, to talk about why do we have this 50% reduction and an LDL target? Like it's hard enough to keep track of 1 thing, right. Well, if you have a patient at very high risk, they've had multiple events and let's just say their LDL is 54. Does that mean we shouldn't start treatment? No. It means we should try to get a 50% reduction because what they were doing was not working, clearly, if they had an event. So that's where that threshold and the absolute number come into play.

And this is just a reminder of what Viet said, if they have had an event of ASCVD, but they're not at very high risk, so blockage somewhere, but not 2 of those other risk factors, less than 70, and if they are high risk and their baseline LDL is over 190 less than 70—but not everyone has access to genetic testing, although we will share shortly here a website where you can have patients get free testing for FH—under 70. But I think, and I don't think I'll find anyone to argue with me on this call, the lower the better. So if they had an over 190, there's something wrong with how they're making cholesterol. It may be under 55 if you don't have access to testing is reasonable. And really adding a nonstatin therapy to get that 50% reduction and get that LDL to goal.

[0:41:41]

Many LDL-C–Lowering Tools at Your Disposal

So there's over 30 steps to making cholesterol. And I won't bore you with all of them, but we'll highlight this picture to really look at the pathways that we have therapeutics to intervene on. So although almost every cell in our body makes the cholesterol it needs, the cholesterol our brain needs, it makes. It's up there for 4-5 years. It is not related to the cholesterol we check in a blood draw, that that our liver makes. But that stays around for 4-5 days. So it's the best we got. We're not going to be checking cholesterol in brains anytime soon but it tells us what's the risk of that extra transported cholesterol being toxic to the artery wall.

And bempedoic acid and statins slow the production of cholesterol in the liver. Now the liver is very greedy. It wants to have more cholesterol. So when we stop the production or slow it down, it will send out more LDL receptors to suck it out of the bloodstream and that is how it lowers cholesterol.

Now, ezetimibe works a little differently. It blocks the absorption of cholesterol at the intestinal border, the Niemann-Pick receptors. So that's just another pathway that we have or different angle we can help get to optimize their LDL to goal.

And then on the far right, you'll see our PCSK9 medications, inclisiran or PCSK9 monoclonal antibodies. These drugs, we’ll go into more detail, help slow down the recycling of the LDL receptor. So if we stop the recycling, you have even more receptors available to suck cholesterol out of the bloodstream. And so we've got all these tools at our disposal.

But we're first going to talk about ezetimibe. This is a great go-to medication. It was the first to become generic, the first nonstatin medication that had positive cardiovascular outcome trials in combination with a statin.

[0:43:18]

IMPROVE-IT: Ezetimibe Efficacy

So this was a double-blind, randomized trial of over 18,000 patients who were hospitalized with acute coronary syndrome, very high risk. And some of them were on lipid lowering therapy and some were not. So what they accepted as LDL is a little bit different, but they put everyone on simvastatin 40 mg and a placebo, or simvastatin 40 and ezetimibe 10. The IMPROVE-IT trial showed there was a significant improvement in the 3-point major adverse cardiac events, and at 7 years, there was about a 2% absolute risk reduction.

However, we found that the more risk factors someone had: heart failure, diabetes, age over 75—the lower the number needed to treat would fall. So this is a great generic option for really helping optimize risk.

[0:44:05]

PCSK9 Inhibitor Monoclonal Antibodies: Impact on MACE

We also have here the PCSK9 inhibitor monoclonal antibodies. So the FOURIER trial looked at evolocumab and the ODYSSEY trials looked at alirocumab. And very similar findings; we found a significant reduction over time in major adverse cardiac events. And the difference between the 2, practically speaking, is just what's on their insurance formulary. We don't expect any further LDL lowering on 1 vs the other, or change in cardiovascular outcomes in 1 from the other. It's really what's more affordable. So I think these are great tools in our toolbox to help with patients.

[0:44:44]

FOURIER-OLE: Lower for Longer Is Better!

Now the FOURIER-OLE trial was even better. It extended that evolocumab treatment arm, and those who were on placebo got switched to the drug of evolocumab and achieved similar LDL lowering. The average LDL was 30, and the only side effect of that was less heart attacks and strokes. There were some other side effects we'll talk a little bit about, but very well tolerated because PCSK9 really just lives in the liver, so we don't see a lot of systemic side effects.

What they found though, even though patients changed to evolocumab, that the outcomes over time, that the people who had been on evolocumab the whole trial for 8 years had better outcomes than those who were switched in the middle from placebo to evolocumab. So lower for longer is better.

[0:45:33]

Many LDL-C–Lowering Tools at Your Disposal

We're going to talk about bempedoic acid. So this is a prodrug. And it is activated by an enzyme that only lives in the liver. It's not in the muscles, so very well tolerated. In fact to become part of the trial, we found that patients had to sign a paper that said they did not tolerate statins. And what they found is that when they enrolled primary prevention patients and secondary prevention patients, those who already had an event, we significantly decrease their risk of heart attacks and strokes in about a 17% to 18% drop in the LDL.

Side effects are pretty rare. There is about a 1% higher risk of gout, so we can check uric acid to make sure your patients are not in line with that. Now, sometimes uric acid will be elevated, but I have a patient who doesn't have any side effects from that. We just continue the medication. Very small risk, even smaller of tendon rupture. But most common, if patients had had a tendon rupture in the past, were on steroids or had been on a fluoroquinolone.

[0:46:52]

CLEAR Outcomes: Bempedoic Acid CVOT

So when we look at the CLEAR Outcomes trial, we found that the 4-component major adverse cardiac event rate was much lower in less than in about 16 months. And even the primary prevention patients, you can see those curves separate, that they noticed improvement in those cardiovascular outcomes. So this is a great tool for your toolbox that comes standalone if someone hasn't tolerated ezetimibe in the past or in a combination tablet.

[0:47:19]

VICTORION-INITIATE: Inclisiran First in ASCVD

So as we move to PCSK9 pathway, we're going to talk about inclisiran. So the VICTORION-INITIATE is 1 of the latest trials that looked at what happens if we just start inclisiran for higher risk patients who are on statins compared to usual care, and it was very pivotal because it significantly decreased LDL compared to the usual care with no new safety signals. So you can see patients, 81.8% of patients got their LDL under 70, compared to 22.2% in usual care. Those who were very–high risk, 71.6% got their LDL under 55, compared to just 8.9% in usual care. And statin was discontinued in 6% of patients in the inclisiran arm vs the usual care, which was 16.7%. So this really helps eliminate some of those barriers to care with, I think, compliance.

And safety concerns, we did not see any big signal in treatment related adverse events. 62.8% with inclisiran-first and 53% in usual care. Serious adverse events were actually higher in the usual care compared to the inclisiran first. And the most common is about 10% of patients will get injection site reactions, and this can be kind of a red indurated area. It's very self-limited and it's good to reassure patients that this is a known side effect. And for my patients who've had it, it doesn't even come back the next time they do an injection. It's just something that can happen and is self-limited. We do know that people can get a little immune response too, as you give this monoclonal antibody, a little runny nose, sore throat, feeling run down. About 5 to 10% of people get that, but usually it improves with each subsequent injection. And so it's a great medication for that if it only happens a few times a year.

[0:49:15]

ORION-10: Clinically Efficacy of Inclisiran in Patients With ASCVD on Maximally Tolerated Statin Therapy

And we also found that it significantly dropped the LDL, about 50% complete compared to placebo, and that those effects were prolonged over time. So this is a great tool in our toolbox.

[0:49:29]

Updated Evidence: Ongoing Inclisiran Trials

We talked about the V-INITIATE trial, but I want to let you know they're also doing a VICTORION-1 PREVENT trial. I'm a subinvestigator on that. And it is for high risk primary prevention patients. So why wait till after they have an event, if we have evidence that treating on the front end can prevent cardiovascular events on the tail end of treatment.

The VICTORION-2P is a phase III trial. Inclisiran’s impact on major adverse cardiac events in patients who already have cardiovascular disease. And so we'll have these 2 primary and secondary prevention trials that we expect should be released in the next year or 2.

And then the V-MONO trial is looking at inclisiran monotherapy vs placebo and ezetimibe.

So most of our trials are looking at drugs added to statins. So I'm really excited to see the results of that too, knowing that not everyone can tolerate statins.

[0:50:25]

Ongoing Real-world Data Programs

So what else should we be looking at? So lipoprotein (a) Viet is going to talk more about, but we know this is an important risk factor for cardiovascular disease, and that routine measurement helps identify high risk patients. There are many emerging therapies, in particular looking at RNA therapies that can provide reduction beyond our current options of just lowering LDL. And about 20% of humans have high lipoprotein (a) levels. So if we're able to right now not significantly lower lipoprotein (a), although the PCSK9 medications can lower it about 20%, it's not as significant as these new drugs that Viet will go into, that are 80, 90, 100% lowering of lipoprotein (a). What it does do is help us know who's in a low risk bucket and who's in a higher risk bucket, because with the same LDL, the person has high lipoprotein (a) is at a much higher risk. And if right now we can't change someone's lipoprotein (a) significantly, what we should be doing is make sure their LDL is nice and low, so that we make sure they don't have as much of a risk with that.

We know that inclisiran lowers LDL significantly, 50%, and there's good adherence, and that despite all of these tools at our fingertips, lipid goals remain underachieved due to limited combination therapy use. Despite what patients may believe, we don't love prescribing new medications every time they come. And the truth is we don't. And part of that treatment inertia or just hoping things improve and we'll check it again next year just isn't panning out. We need to do better for patients.

And so how can we integrate all these therapies together? Even talking about things like icosapent ethyl, which is a pure EPA omega-3 that has been shown to have cardiovascular protection and helps lower the risk of cardiovascular disease events. How do bempedoic acid and inclisiran work together? Most of our studies have really been related to statins since they've been around for 40 years, but there's a lot of room for future research there.

[0:52:30]

Navigating Financial Access Barriers

But I'd be remiss to not talk about the financial access barriers to some of these newer medications. So I use EPIC at my clinical practice and so sometimes when I type in a medication, there'll be a big red X that my computer knows this is not on their formulary. It's not always right but it gives you kind of an idea. Sometimes the actual cost of the medication will come up. It's not a perfect system, but it gives you a ballpark idea. And for each of my patients, I give them a “Here's our plan A. If that cost isn't reasonable, here's plan B. And sometimes even plan C,” Let's say they need a 50% reduction, I'm not going to start with ezetimibe. I'll say we're going to try a medication that blocks the PCSK9 pathway. And if that is not affordable, let's try bempedoic acid. If that isn't affordable, we're going to end up with Zetia just a step therapy. Often some insurances like that, but not all of them, so it's worth trying to do what you think is best for the patient to get them to goal.

You know, talking about prior authorizations, peer to peers, doing appeals. I don't even know if it's a person anymore who says no right away. It might be a computer. So just kind of sending it back with the same information you may have submitted the first time. I've had some luck getting that approved.

And then looking for free clinics in your area. There's a website there listed under underinsured or uninsured. And then there's links at needymeds.org. Goodrx is another great website.

And then for anyone who's on Medicare, there's the HealthWell Foundation grant. If you just Google that anyone who's on Medicare has access to these buckets of money for different disease states, and they have that for people with hyperlipidemia. So many of my patients who maybe aren't uninsured but are underinsured, get kind of a credit card for a couple thousand dollars that they can use to spend down on lipid therapies, and that has been a game changer for some of these nonstatin medications.

Also looking at formularies, trying to help them apply for, for extra help and coverage gaps. You know, when it comes fall and it's time to relook at their insurance, saying, this is a medication I'm thinking about putting you on. Why don't you look for insurance that might have that on there? All tools to help, but we can't do it all alone. So utilizing your pharmacist, utilizing a care coordinator, if your clinic has that or a nurse can be really pivotal.

[0:54:51]

Responses to Perceptions of Key Barriers to PCSK9i Use

And so we've talked about how great these nonstatin medications are, sometimes alone if needed and often with a statin. But what are the perceptions of key barriers? So you can see that providers and payers line up on many of the things: the high copays charged and the inadequate or incomplete documentation, as far as why do people not prescribe them? But these bar graphs start to separate, that providers say there's excessive prior authorization and documentation requirements, but the payers are like, no, only 44% of them thought that was a problem although 72% of providers thought it was. 6% of providers said there's insufficient evidence that PCSK9 therapies are cost effective. That means that 94% of us think there's enough evidence. We would love to prescribe these for our patients, right? But 56% of payers say we don't think there's enough evidence. How convenient. So we need to keep telling them this is an effective therapy for our patients.

And then, a little more similar, insufficient evidence that PCSK9 therapies reduce risk of major cardiovascular events. More providers believe this is the case, that there is sufficient evidence, but more payers believe there's insufficient evidence. While that is going to change soon with all of the cardiovascular outcome trials that will be coming out shortly, but for payers, I think providers, we know this is enough information that lowering the LDL certainly is the way to prevent cardiovascular disease and probably how we do it isn’t important as just the fact that we do it.

[0:56:24]

Impact of Social Determinants of Health

Lastly, let's not forget about the impact of social determinants of health. So, you can have the best guidelines in the world. You can have the most beautiful clinic. You can have the perfect PAs and NPs, but only 20% of a person's health and well-being is related to access to care and quality of service. So really, it's these other components of social determinants of health that really make or break a patient's success. So keeping in mind the health behaviors like tobacco use. I always like to say when they've studied this, the number 1 thing that causes people to quit smoking is their doctor told them to. I would insert PA or NP told them to as well. So we had a fantastic primary care doctor. His clinic was closed because people loved him so much. He told patients, if you keep smoking, I will not be your doctor anymore, and I can't tell you how many patients I saw who said that was what made them quit. I don't know if all of us can do that, but it's just a sign that people really resonate with a trusted healthcare professional and that we might have more pull than we think. At least mention quitting at each visit and how can I help you? Let's set a quit date.

Diet and exercise is so important. We know that. That's a whole other talk, probably, but 150 minutes of physical activity a day, talking about substance misuse, all of these things can have an impact. And I would also put in there eating more plants, fiber, nuts, whole grains, those sorts of things that can really not just lower cardiovascular disease but help improve so many factors, including cancer risk as well.

And then there's things we don't have as much control of in our day-to-day clinic visits. Education, job status, family and social support, income, community safety. So getting involved on a larger legislative level through larger organizations like the American College of Cardiology, like the Academy of PAs and Cardiology, we are at the table trying to help improve those things for our patients.

So, John, I think that wraps up my section of the talk. Let's move on to skill building and feedback.

[0:58:16]

Skill Building and Feedback II

John Giacona: Thank you so much, Laura. We'll move right in as you said.

[0:58:23]

Patient Case 2: David, 62-Yr-Old Man

So starting with a patient case. So this is David, 62 year old man. His chief complaint is persistently elevated LDL despite adherence to high intensity statin. He has a history of MI and type 2 diabetes. His LDL remains high at 95. He expresses frustration that he's doing everything right, but his numbers are still high. His current therapy is rosuvastatin 40. His past medical history is he has ASCVD. He also has hypertension, type 2 diabetes, and of course hyperlipidemia. In terms of lifestyle, he says he follows a balanced diet and he walks daily and that he's adherent to his therapy. In recent blood work findings, his LDL was 95, which is down from 165. Non-HDL-C was at 115, ApoB was at 105, Lp(a) at 45, and hsCRP was at 2.1.

[0:59:18]

Poll 6

So audience members, with this patient in your mind, let's go to poll 6. What is the best next step in David's management? Is it:

1. Continue rosuvastatin and reinforce lifestyle modification.
2. Add ezetimibe to statin therapy.
3. Switch to a lower dose statin to improve tolerability, or
4. Add bempedoic acid or PCSK9 inhibitor based on risk and access.

Excellent. Thank you guys for participating.

[1:00:08]

Let’s Discuss: When to Escalate, Turning Risk Into Action

So let's have a brief discussion before I pull the faculty back in. So really, with this patient, the question is when to escalate, right? We need to turn risk into action. So what is happening in this patient? Similar to previous, this patient has residual LDL-driven atherogenesis, despite him being on statin therapy. In this case, statin alone is insufficient for his LDL target. He was at 95. Goal in this patient is less than 70 for very high risk. And you know, we may need complementary LDL-C lowering mechanism.

And so what are some things we can do? With every patient, we always want to assess LDL goals per the 2022 ACC Expert Consensus pathway. So we know he needs to be less than 70. Some next steps are considering adding nonstatin therapy. So we have lots of choices: Zetia, bempedoic acid, PCSK9 or inclisiran. And then with every patient reinforcing adherence, you know, following up with regular lipid panels and then putting the patient in the driver's seat.

[1:01:22]

Faculty Discussion

And so at this point, I'll invite Viet and Laura back in so that we can we can get their ideas and their and their insights into how can we approach this patient and in terms of framing, add on therapy, as advancement and not necessarily escalation?

Viet Le: Yeah. Great. Just a quick correction. For very high risk ASCVD, this is less than 55 mg per deciliter. So, this individual, you know, started at 165 on a high intensity statin, is doing the lifestyle, doing the things, doing the things. And so I always celebrate that and say, please keep doing the things. And you can see that even doing the things, we still need to support reduction in LDL cholesterol.

And then again, reframing this as, “Let me just tell you, you're very high risk. What does that mean?” Event rates are much higher for an individual who has had an event. Yes, he's 62. He's not 65. But like I said, hypertension, diabetes. And those are 2 extra risk factors. Again not uncommon and happens quite frequently as either the driver of coronary disease or then as add on that they accrue with age. And so as we reframe that, as we discuss look, you know, I wouldn't just put 1 extra gallon in the fuel tank. I kind of want to fill the fuel tank. And so I want to get you to where you're going, which is a healthier life. So let's do everything we can to support reduction of risk and not have any unforced errors where we're not doing optimally the things that you need to make sure we don't have an extra event.

“David, you're only 62. Let's make sure that you get out further along before another event.”

Laura Ross: Agreed. Yeah. Great points. And I think 1 question I can see in the chat – and we'll have lots of time, so keep entering those questions – that was just about side effects too, really addressing what are their fears of side effects. What I wanted to say that I forgot, but I'll say now, is that inclisiran isn't even detectable in the bloodstream after 48 hours. So I have a lot of patients, you know, my record is I have a patient who has 44 adverse drug reactions. And she was like, “If I feel unwell for 6 months, like, I'm coming after you, Laura.” And I'm like, “No, wait, it's not detectable after 48 hours.” And so the it kind of goes in and tells the cell machinery to go to sleep so that it doesn't even make PCSK9. And that effect lasts for 6 months, just in time for their next injection. So that is a great way to deliver that message.

I have other patients who are like, I just my stomach's, you know, kind of touchy. I don't want to swallow more pills. I'm like, great. Maybe a PCSK9 inhibitor is good for you. Maybe they're really hesitant to take an injection, very fearful of that. And so we talk about, well, maybe bempedoic acid and ezetimibe in the combination pill is better.

So there's lots of ways to talk about these different pathways, trying to address their concerns. And really at the end, beginning and end of each of my visit, I say, I'm on your team. I want to figure out how can we get to that finish line of not having a heart attack or stroke, or minimizing that and optimizing your risk factors, and then really letting them know you define what the cost is reasonable. I don't decide that. And so, I think when they feel that you're part of the team, we can really be successful together.

John Giacona: Excellent points. Excellent points. Okay, so let's move on to poll 7.

[1:04:56]

Poll 7

So knowing all that you know from Viet and Laura, how would you explain the role of nonstatin therapy to your patient, David?

1. It’s a backup option when statins don’t work
2. Cholesterol is targeted through a different pathway to help you reach your goal
3. The medication will replace your statin, so you don’t need to take both
4. It’s mostly for people who can’t tolerate statins

Excellent. Thank you guys for continuing to engage.

[1:05:46]

Poll 8

So poll 8, take a moment to reflect on what this case brought up for you. What's 1 way you can strengthen personalized lipid care in your practice?

1. Using nonstatins earlier for patients not at LDL goal 
2. Improving communication about therapy rationale and adverse effects
3. Streamlining follow-up and lipid monitoring
4. Addressing cost, access, and adherence barriers proactively

Excellent. Thank you guys.