Multiple phase 3 trials assessing interventions to reduce lipoprotein(a) (Lp[a]) are currently underway. At the recent American College of Cardiology 75th Annual Scientific Session & Expo (ACC.26), researchers presented data addressing the role of Lp(a) reduction as a component of primary and secondary risk reduction for cardiovascular disease (CVD) in patients with elevated Lp(a) levels.

Following these presentations, featured expert Christie M. Ballantyne, MD, was interviewed by Conference Reporter Associate Editor-in-Chief Mona Shah, PharmD. Clinical perspectives from Dr Ballantyne on these findings are presented here.

So, you have identified a high Lp(a) level. What do you do about it? General risk factor management is very important. Lp(a) is one type of atherogenic lipoprotein. Unfortunately, statins do not lower Lp(a). However, they do lower the other ApoB-containing lipoproteins, so you try to lower the patient’s low-density lipoprotein cholesterol (LDL-C), and you want to start earlier. “Lower for longer” is the general principle.

The new guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) Joint Committee on Clinical Practice Guidelines recommend considering the addition of a PCSK9 inhibitor for secondary prevention in very high-risk individuals with an Lp(a) that is over 50 mg/dL (125 nmol/L) and an LDL-C level that is still above target. These recommendations were based on data from 2 large outcomes trials of evolocumab and alirocumab. Both showed that people needing secondary prevention with high Lp(a) had the highest risk of events. They also had the greatest absolute benefit with PCSK9 therapy.

The oral agent enlicitide, another PCSK9 inhibitor, is also in development, and there were data presented at ACC.2026 on this therapy. An on-treatment analysis by Ann Marie Navar, MD, PhD, and colleagues presented at the meeting did report a reduction in Lp(a) levels from baseline after 8 weeks of therapy. Alberico Catapano, PhD, also presented data showing that the addition of enlicitide to statin therapy provided greater reductions in both LDL-C and Lp(a) as compared with ezetimibe, bempedoic acid, or the combination of ezetimibe plus bempedoic acid.

Multiple therapies designed to lower Lp(a) specifically are currently being studied in outcomes trials. The first is pelacarsen, which is being studied in Lp(a)HORIZON, an ongoing secondary prevention trial, and we hope to hear the results toward the latter part of 2026. Olpasiran is an siRNA that is being studied in the 2 OCEAN(a) trials. The first is a secondary prevention trial that is fully enrolled and ongoing. The second is a primary prevention trial in high-risk individuals, and it is recruiting now. Lepodisiran is also an siRNA that is being studied for primary and secondary prevention in the fully enrolled ACCLAIM-Lp(a) trial, and there is an oral Lp(a) inhibitor called muvalaplin that is being studied in another large outcomes trial (ie, MOVE-Lp[a]) for both secondary and high-risk primary prevention. Finally, phase 1 data on SRSD216, another siRNA, from Patrick Yue, MD, et al were presented at the ACC.26 meeting with promising results.

There are multiple other Lp(a) inhibitors with programs in development, and gene editing is also being examined as a therapeutic approach. So, there is a lot going on in this field, and hopefully we will have targeted therapies that specifically lower Lp(a).

How should we approach primary prevention in patients with elevated Lp(a) levels? The first thing to do is assess risk. You can use a risk assessment tool such as the PREVENT Risk Calculator (American Heart Association) to look at 10- and 30-year CVD, atherosclerotic CVD, or heart failure risk. If the patient’s risk is extremely low, you may have a little less concern about an elevated Lp(a) level. However, if the patient’s family history is significant, I would still be worried. When I have a patient with very high Lp(a) and a significant family history, I will also look at imaging studies to help risk stratify further. If they are a little older (ie, men >40 years and women >45 years), a coronary artery calcium score can be useful.

I remind people that assessing CVD risk is like multiplying multiple risk factors, including Lp(a). So, a patient might have a high Lp(a), but if they have a low LDL-C level, a healthy lifestyle, a normal body weight, normal blood sugar and HbA_1c levels, a low CRP level, no family history, a good exercise regimen, and a normal high-density lipoprotein cholesterol level, that person is not going to have a high risk just from the elevated Lp(a) level alone, unless it is extremely elevated. So, there is this issue of focusing on keeping everything good, in terms of keeping up with a healthy diet, exercise, and a healthy lifestyle.