Erin D. Michos, MD, MHS

A panel of expert cardiologists share their clinical pearls for managing patients with hyperlipidemia.

Clinical Pearls on Lipid Management

Keith C. Ferdinand, MD, FACC, FAHA, FNLA:

 I’m going to give each of you about a minute or so to give what we call a take-home message: a clinical pearl for the physicians, nurse practitioners, physician assistants, [and] pharmacists who may be listening, something that will motivate them to do better. We’ve heard from the Family Heart Foundation that we’re not recognizing these patients early enough and that those patients at high risk are not getting high-intensity statin. We heard from Dr Michos that there is a whole world of alternatives. Christie, you suggested [that] we combine these agents [to] reach lower [lipid] levels vs pushing [the dose of] a drug to toxicity level. Dr Kohli, you’ve been very persistent that education, culturally appropriate [and] literacy-appropriate education, is one of the linchpins to success.

 We’ve talked about education, but it starts with [this]: “You can prevent heart attacks and strokes.” Patients need to know their numbers; that’s an education process. We help them get there. We’re their guides to get there. One thing that is a frustration, a practical point in terms of when you use some of the nonstatin therapies, [is] the approval process. It turns out—we have fellows coming [in] every year—if you say this patient has a family history of very high cholesterol [level] and premature heart disease, [you’re] denied. You [have] to say heterozygous familial hypercholesterolemia [FH]. There’s an 

International Classification of Diseases, Tenth Revision

] code for that. Put those words in there. If you say [the patient] “has heart disease or ASCVD [atherosclerotic cardiovascular disease] with MI [myocardial infarction]”…put the right information. Have a lipid measurement within a month, [provide] the LDL [low-density lipoprotein] cholesterol [level], [and state], “It was unacceptably high; therefore, [I’m] using this agent.” Some pragmatic steps will reduce the frustration for both [patient and provider], because if the patient doesn’t get it and you don’t get it, it’s frustrating. But you can do it. It’s easier.

 Dr McGowan, thank you for your great work with the Family Heart Foundation. Can you give us some clinical pearls to help our clinicians out there do better?

 When you screen patients, and hopefully you’ll screen all your patients, [but] when you screen patients with a lipid profile, if it’s an adult person and you see an LDL [level] greater than 190 mg/dL, you want to think familial hypercholesterolemia. With that in mind, you want to have a conversation with the patient [that] this is unlikely to be chance. This is your genetics, and, therefore, your children need to be screened, your siblings need to be screened, and it’s important. People who hear that it might [affect] their children are more likely to take action. So take action. The other big thing, [because] I’m coming from the Family Heart Foundation, [is] don’t forget to measure lipoprotein(a) [Lp(a)] [level]. Don’t think it’s unactionable. I’m going to tell you one quick story about a patient of ours who’s an advocate for Lp(a). This young woman was 44 years old [with a] completely normal lipid profile. [She] did have a history of cardiac disease [and] attributed her father’s early cardiac disease to his type A behavior. She waited 18 hours with chest pain before going in and finding that she was having a cardiovascular event: a myocardial infarction. What she said to us was, “If I had known I had such a high Lp(a) [level], I would have gone in earlier.” That was important information to me. So even if you feel like there aren’t agents currently [available], as everybody else has said, you can reduce other risk factors. Measure that Lp(a) [level] and then take action. And educate your patients about it.

 There’s so much burnout in medicine. It is so hard, what we do on a day-to-day basis. But the thing that keeps me most engaged is knowing that I made an impact on somebody’s life. If you could take 2 or 3 minutes at the end of every visit, no matter what it’s for (eg, knee pain, urinary tract infection, back pain), to look at those lipid [levels and] focus on prevention, [then] you are going to have a tremendous impact on [a] number of lives out there that you won’t even realize. That will give you the highest degree of engagement: knowing their numbers, not just knowing your numbers, but knowing your patients’ numbers and phenotyping at every visit so [that] you’re delivering a personalized care plan. You’re not lumping every secondary prevention to less than 70 mg/dL or less than 55 mg/dL. You’re using your risk modifiers to reclassify that risk in an iterative fashion at every visit for your primary and secondary prevention. So if Mrs Jones had a stroke since the last time you saw her, her risk just changed. You bump her down to the next level, δ LDL of 50%, and get [her level] below those thresholds. If you can work it into your busy practice, just spend 2 minutes at the end of each visit looking at those lipid [levels] and making a little plan. It’ll be tremendous how many lives you’ve changed and how many trajectories of atherosclerosis you’ve modified.

 That’s a wonderful message. Dr Michos, you have the last take-home [message].

 I want to circle back to something that Dr Kohli said at the beginning about cholesterol years. This is something that might resonate with patients and other clinicians when they’re familiar with pack-years of smoking. It’s not only the magnitude of elevation; it’s the duration [that] one’s [had] that value. There’s been some modeling thinking that the theoretical onset of clinical ASCVD may be around 5000 mg/dL-years. Individuals who have had high cholesterol [level] since birth—our patients with FH—if left untreated, they’ll cross that threshold of clinical ASCVD very young in life. Whereas individuals who have favorable genetics, healthy lifestyle, or early treatment may never cross that threshold for clinical ASCVD. [And] don’t forget about those with mild to moderate hyperlipidemia. The LDL [level] is [in the] 130s mg/dL [or] 160s mg/dL. A lot of these patients are ignored. But [if] left untreated for a sufficient number of years, those individuals will have earlier onset ASCVD than their counterparts who have had lifelong low LDL [levels]. The message is [that] we want to get LDL [levels] lower for longer and get there faster.

 Wonderful message. Thanks to you all for this rich and informative discussion. And thank you for watching this 

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 Christie, where are we going with lipoprotein(a) [Lp(a)]? Have we reached the end of the road, or is there something on the horizon?

 We’re just moving, and I agree with my colleagues. I screen everybody in my personal practice. I also do cascade screening. One thing we didn’t mention but I think is very important is if you’re looking at Black individuals, [they have] the highest levels of Lp(a), and it is a risk factor. That’s underappreciated in terms of screening. It’s actionable now but with targeted therapies. I did a [postdoctoral study] in genetics, and genetics has allowed us—you mentioned Mendelian randomization [but] also rare disorders—to identify which genes are important in terms of lipoproteins in cardiovascular disease. Lp(a) jumps out there. A couple of other targets, [such as] APOC3 [apolipoprotein C3] and ANGPTL3 [angiopoietin-like 3], [there are] big programs on those. What’s cool is once you see a loss of function mutation or variant, you can make a monoclonal antibody to block it. That to me was high tech[nology], but now that’s old tech[nology]. The new tech[nology] is [that] you don’t make the protein; basically, [you use] RNA silencing approaches: antisense oligonucleotides [ASOs] and small interfering RNAs [siRNAs]. You already mentioned this, Erin, but we’ve got 2 big programs for Lp(a). One of them, the ASO [approach], has a fully enrolled outcomes trial. The siRNA [approach] is enrolling [for] the outcomes trial, and both look to be very efficacious. ASO has about 80% [reduction in Lp(a)], [and] siRNA is well over 90% reduction in Lp(a). There’s a big study called the OCEAN(a) trial [NCT05581303] that’s enrolling. These are for people who have very high levels [of Lp(a)]. It’s an opportunity if you’ve got a patient with a very high [Lp(a)] level, and there will probably be another program coming down the road soon; they can [enroll] into a study. So that’s an opportunity. It’s going to be a few years before we have the data on this, but the agents look very promising. I mentioned also some other new targets, but Lp(a) is out front, so we’re going to have some data [coming]. Stay tuned [for] that.

 If you look across the lipid world, we have data, [such as] the GOULD registry. You’ve mentioned that before. Can you tell us about that?

 We think we’re doing well, but we’re surprised to look at these registry data and see how much we’re missing the mark when it comes to our patients and their cholesterol [level control]. The GOULD registry is an outpatient registry looking at patients with ASCVD [atherosclerotic cardiovascular disease] who are on lipid-lowering therapy or PCSK9 inhibitors and following them over time to see how well we’re doing as practitioners in terms of [managing] their [elevated] lipid [levels]. It’s shocking that [for] patients with ASCVD, [two-thirds] of them [had lipid levels] above 70 mg/dL, and that was the old end zone. Now that we’ve moved the end zone down to 55 mg/dL, we’re seeing that only 15% of [patients] are getting into that end zone. In fact, 11% of [patients] didn’t even [have their lipid levels check]. So we’ve talked about the importance of knowing where we’re going, taking off our blindfold [and] knowing where we’re going by checking the lipid [levels]. If [for] 1 of 10 patients [with ASCVD] we’re not checking their lipid [levels] and [for] 2 of 10 we’re checking it once in 2 years, that’s why we’re undertreating so much, and that’s what the Family Heart [Foundation] data have shown us as well. The reasons for some of this are complex, because we talk about clinical inertia. We [also] talked about lack of knowledge. But in fact, looking longitudinally over time, even after the new guidelines came out in 2018, it didn’t change our behavior. So for some reason, even though the information is out there, our implementation of it in our practices continues to lag behind.

Medical experts discuss the importance of screening for Lp(a) and ongoing trials targeting this protein. Moreover, other new targets for the treatment of hyperlipidemia are reviewed.

Novel Targets for Lipid Level Lowering and Implementation of Lipid Therapy

Drs Michos, McGowan, and Kohli discuss Lp(a) and the development of cardiovascular disease.

The Role of Lipoprotein A in Lipid Lowering

 We’re going to switch gears [and] go to an LDL [low-density lipoprotein]–like biomarker; it’s a substance that’s a causal agent for atherosclerotic cardiovascular disease, [and] that’s lipoprotein a [Lp(a)]. Now FH is not just familial hypercholesterolemia. The [Family Heart] Foundation also embraces putting more attention on lipoprotein a…. Dr [Mary] McGowan[, MD, FNLA], you want to tell us about Lp(a)?

: Sure. Lipoprotein a…has an LDL-like particle, but it also has an [apolipoprotein] a [apo(a)]. That combination of apo(a) and LDL, in addition to oxidized phospholipids, creates a lipoprotein that is more toxic; much more of an endotoxin than LDL alone. One in 5 [persons] have an elevated lipoprotein a in the United States. Yet, based on research from the Family Heart Foundation, fewer than 1% of [individuals] have had their lipoprotein a measured. Lp(a), because it has an LDL portion, is atherogenic. The apo(a) has homology to plasminogen and it competes with plasminogen for fibrin binding. So, it looks like fibrinolysis is impaired. We see an increased risk of thrombotic issues. Then the oxidized phospholipid is really inflammatory in nature and may increase the action of osteogenic genes, making the aortic valve become more calcific. What we see with [persons] with very elevated Lp(a) is they may get into trouble with very early cardiovascular disease [and] sudden cardiovascular disease.

 There’s a number you said, and you can continue with Lp(a), but there’s a number you said [that] I don’t want our audience to miss. You said that elevated lipoprotein a may be as [common] as 20% [of the population]. So, if you’re in a classroom of 100 [persons], 20 of them might have elevated lipoprotein a?

: That’s right. Right now, we’re still in a fact-finding mission, but what would be defined as a high lipoprotein a is an Lp(a) greater than 50 mg/dL, or greater than 125 nmol/L, and nmol/L is the preferred way to measure lipoprotein a. But regardless of which way it’s measured, most labs are switching over to nmol/L; what’s high is high and increases the risk. Because so few [individuals] have had it measured, it’s not being factored in. It is recommended that everybody have a lipoprotein a measured in Europe. The European guidelines suggest that, [and] the Canadian guidelines. We have fallen short in the United States of saying everybody should be measured. In our current guideline, it’s a risk-enhancing factor. But we at the Family Heart Foundation believe that [persons] deserve to know what their lipoprotein a is.

: Dr [Erin D.] Michos[, MD, MHS], any impression on what we should be doing with lipoprotein a? Or you can discuss whether…you think it’s causal for atherosclerotic cardiovascular disease [ASCVD] and aortic stenosis.

: Well, I can touch on both. We have good genetic data that does show that lipoprotein a is causal for both ASCVD and aortic stenosis. Just like LDL, it’s not binary. Certainly the higher the value, the higher the risk. In my practice, I measure everybody at least once in their lifetime, and I hope that we move to that in the United States because elevated lipoprotein a is actionable now. Dr [Christie] Ballantyne [MD, FACC] and I [are] writing a statement about this because it hasn’t been fully adopted in the United States [as] we don’t yet have the dedicated Lp(a)-lowering therapeutics that are currently in phase 3 outcome trials. You’re going to hear more about this in a minute, but those are not FDA approved yet. So, some [individuals] are like, “Well, we don’t have [the] therapy to lower it. Why should we measure it?” Well, we absolutely have things we can do now. It’s actionable. It’s already in the guideline as a risk-enhancing factor. If somebody has elevated Lp(a), for primary prevention, this would put them in a higher-risk category where we would recommend statin therapy. Although statins don’t lower Lp(a), statins clearly lower LDL and they lower vascular risk. [Implementing] a more intensified lifestyle. Although lifestyle changes won’t lower Lp(a), they certainly lower risk. You could consider aspirin. We know [for] some subsets from the Women’s Health Study [and] ASPRE study, these primary prevention aspirin trials—although we’ve gone away [from] using aspirin in primary prevention broadly in those with genetically predicted elevated Lp(a), there did seem to be a benefit. Now in the secondary prevention population, elevated Lp(a), again, is a high-risk marker. If someone needs additional lowering, [consider] PCSK9 inhibitors and inclisiran because they can lower Lp(a) [by] about 25%. They’re not FDA approved for that indication; they’re FDA approved for LDL lowering. But I tell my patients this bonus is going to help both of those lipid biomarkers, so be thinking about that. Don’t forget there’s still a role for apheresis. If you have a very high-risk patient with clinical ASCVD (eg, multiple heart attacks) who has managed to get their LDL very well controlled, well below that 55 mg/dL threshold, but continues to have [cardiac] events and high Lp(a), [remember] it is an FDA-approved indication to do apheresis for elevated Lp(a). So, there are things we can do, and we should find these patients. If we don’t measure it, we won’t know [whether] they fall into that category of high Lp(a).

: Dr [Payal] Kohli[, MD, FACC], give us some of your insights on what we should be doing about Lp(a).

: I see a lot of South Asian patients. Race and ethnicity, and how that plays into Lp(a) measurements, is really very fascinating and an area that I think we need to explore more moving forward. We know that South Asian [patients] tend to have high levels of lipoprotein a. They have early-onset accelerated heart disease. I checked the Lp(a) as a way to sort of catapult checking their family members [and] kids. [I] use that as a way to begin the conversation and say, “Well, now we’ve found a marker that’s largely genetic, that is causally related to ASCVD, and I really think we ought to look at your children and everybody else.” I find it doesn’t just help me with the discussion that I’m having with that patient, but it helps me screen their family members as well. [It] really helps devise a plan not just for the person in front of me, but [for] all the [individuals] related to them.

 Dr [Payal] Kohli[, MD, FACC], the PCSK9 inhibitors were [addressed], and I know you’ve looked at some of the more recent data. They’ve been around a long time, and we now have data that [show] they really do work, and…for a long period…. Do you want to discuss that?

: That’s right. The FOURIER trial [NCT01764633], which was sort of [a] parent trial, [had] over 27,000 patients using evolocumab in a population with stable ASCVD [atherosclerotic cardiovascular disease], and followed [these patients] for a couple of years. The FOURIER-OLE [NCT02867813], or open-label extension study, was about 6600 patients or so from the parent trial, who then sort of stayed on the medication. This is the longest [trial] to date for a PCSK9 inhibitor. The longest [a] patient was followed [was] for 8.4 years, but the median follow-up [duration] was about 5 years. They looked at a couple of different things. They looked at, does a PCSK9 inhibitor continue to work as well as it did in the beginning? Or do you get tachyphylaxis? Do you get used to it? Does the efficacy go down? And thankfully the LDL [low-density lipoprotein] lowering effect was over 60%, just like in the parent trial. Anyone who was initially on placebo and switched to the PCSK9 inhibitor quickly dropped their LDL nice and low. Their response was still brisk. Efficacy data [were] very reassuring with respect to LDL lowering. The safety data [were] incredibly reassuring. In fact, the…adverse effects were lower in the follow-up trial; [however,] there could have been a little bit of selection bias because the [patients who] continued on it could have been the ones [who] tolerated it. But no new signals for safety emerged. What I found interesting was something that we call a legacy effect and a lag effect that showed up in this trial. The legacy effect means the [patients who] started on evolocumab and stayed on it got a head start. They got an advantage. If you look at them vs the [patients who] started on placebo and then switched to evolocumab, the [patients who] started on it earlier did better. They had a MACE [major adverse cardiovascular event] reduction that was comparable to the parent trial, [and] that sort of put them ahead of the others. That really drives home the point that we’ve all been saying. Which is start them early because you’re giving them that head start.

The lag effect showed that in the parent trial [we] did not have any cardiovascular death benefit. Think about it. When you modify the LDL, it takes a little while to modify the plaque. It takes a little while to translate into MIs [myocardial infarctions], [which] translates into death. So, 2.2 years for the parent trial was just a bit too early to see this cardiovascular death benefit. But in the follow-up, we saw a nice reduction in cardiovascular death, really showing that [if] you keep them on it, you’re reducing [the] chance of dying from heart disease.

: That’s true…. The one other issue [highlighted] with the FOURIER trial open-label extension was those individuals, all at baseline, had cardiovascular disease [and] we saw that even with this great reduction, statistically significant reduction in favor of those who were on it longer, there were still pretty high cardiac event rates. It really speaks to starting these agents even earlier.

Drs Kohli and McGowan review recently published long-term efficacy and safety data on the use of a PCSK9-inhibitor.

Erin D. Michos, MD, MHS

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