Christie Ballantyne, MD

Triglyceride Management and Pancreatitis Risk, With Christie M. Ballantyne, MD

New results from two Phase 2 trials—SHASTA-2 and MUIR—show that plozasiran, an investigational siRNA therapy targeting hepatic APOC3, delivers a substantial reduction in triglyceride-rich lipoprotein particles (TRL-P) and drives a favorable shift in lipoprotein composition and size in patients with 

American College of Cardiology (ACC) 2025 Annual Scientific Sessions

, patients with severe hypertriglyceridemia (HTG) or mixed dyslipidemia received plozasiran 10, 25, or 50 mg subcutaneously at baseline and again at week 12. At the 25 mg dose, plozasiran significantly reduced TRL-P by ~50% in both trials.

“When you see high triglycerides, sometimes the low-density lipoprotein cholesterol (LDL-C) goes up. With nuclear magnetic resonance (NMR) data, you’re changing the particle, so you have an increase in the large particles and a reduction in small, dense LDL particles,” Christie M. Ballantyne, MD, chief of cardiovascular research at Baylor College of Medicine, told 

. “Reduction in small, dense LDL particles may be particularly atherogenic, but these triglyceride particles per particle might be worse for the common person. They have more LDL particles, but people with high triglycerides have different types of particles.”

Importantly, while total LDL-P remained stable, there was a shift toward larger LDL particles, considered less atherogenic. Small LDL-P declined by 20–22%, while large LDL-P increased up to 103% in MUIR. HDL particle concentration also improved, driven by increases in large HDL-P.

Insulin resistance also improved in both studies, by 24% in SHASTA-2 and 9% in MUIR, further supporting the cardiometabolic potential of plozasiran. Ballantyne noted that high triglyceride levels, particularly over 1000 mg/dL, pose an acute pancreatitis risk and could signal conditions like familial chylomicronemia syndrome (FCS).

In a recent analysis of 1.2 million patients, Ballantyne found more than 90% experienced triglyceride reductions with standard treatment, but about 1 in 5,500 had persistent chylomicronemia. Among those individuals, 26% developed pancreatitis, underscoring the need for close monitoring and targeted therapy.

“The other alarm feature is, if they've had a history of pancreatitis, you better worry about that patient, because it's like secondary prevention,” Ballantyne told HCPLive. “To keep it simpler, when you see the 1000 mg/dL, you know you need to have some alarms going off in terms of needing special attention.”

Relevant disclosures for Ballantyne include Arrowhead, AstraZeneca, Eli Lilly and Company, Abbott Diagnostics, NewAmsterdam, and others.

Ballantyne CM, Gaudet D, Rosenson RS, et al. Effect Of Plozasiran Targeting APOC3 On Lipoprotein Particle Number And Size Measured By NMR In Patients With Hypertriglyceridemia (Htg). Presented at: American College of Cardiology (ACC.25) Annual Scientific Session. March 29 – 31, 2025. Chicago, Il.

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Christie M. Ballantyne, MD, discusses the role of plozasiran in managing elevated triglycerides and reducing pancreatitis risk.

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.

Christie Ballantyne, MD

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