Novel Targets for Lipid Level Lowering and Implementation of Lipid Therapy

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

Christie M. Ballantyne, MD, FACC: 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.

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

Payal Kohli, MD, FACC: 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.

Transcript Edited for Clarity