<p>The contemporary management of atherosclerotic cardiovascular disease (ASCVD) risk and the strategies for reducing low-density lipoprotein cholesterol (LDL-C) are changing, with a paradigm shift in therapeutic goals and pharmacologic strategies. As discussed at the recent <strong>American Heart Association (AHA) Scientific Sessions 2025</strong>, new lipid-lowering treatment strategies have been identified, providing additional options for high-risk patients and for those with specific lipid profile abnormalities or adherence issues.</p> <p><br></p> <p><em>Following these presentations, featured expert Payal Kohli, MD, FACC, was interviewed by </em>Conference Reporter<em> Associate Editor-in-Chief Mona Shah, PharmD. Clinical perspectives from Dr Kohli on these findings are presented here.</em></p>

The way we think about LDL-C management has dramatically shifted over the course of my career. We now understand the need for aggressive LDL-C lowering, and there have been major paradigm shifts across several clinical areas. These include more urgency about lowering LDL-C earlier in life, the concept of cumulative LDL-C exposure, the aim of lower LDL-C targets before patients have CV events, the adoption of earlier combination therapy, considerations regarding dosing frequency, and the idea that we may be able to alter plaque phenotypes to prevent that initial rupture and reduce inflammation.

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At the AHA Scientific Sessions 2025, Erin A. Bohula May, MD, DPhil, presented data from the phase 3 VESALIUS-CV trial demonstrating the value of aggressive LDL-C lowering in primary prevention for high-risk patients. The investigators achieved a median LDL-C level of 45 mg/dL at week 48 in high-risk patients who had not yet had a clinical CV event. The VESALIUS-CV trial challenges our thinking about whether we should be aiming for an LDL-C goal of lower than 55 mg/dL before a patient has even had a CV event.

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I found it interesting that VESALIUS-CV included patients with subclinical atherosclerosis and a calcium score of greater than 100. We have typically thought of these individuals as being generic primary prevention patients and have not been aggressive enough with treatment; this study shifts that continuum down to these high-risk patients. The clinical challenge in interpreting the VESALIUS-CV trial results will be establishing how this information regarding more aggressively treating high-risk primary prevention patients fits into the landscape of the other medications we have, especially for high-risk patients with diabetes. As a clinician, I am left wondering what to reach for first for a high-risk patient with diabetes who fits the criteria of the VESALIUS-CV trial. An SGLT2? A GLP-1? LDL-C reduction therapy? The correct answer may really be “all of the above” because we are trying to target the treatment of CV-kidney-metabolic syndrome and parallel risk pathways. This means that a lot of these problems coexist and, therefore, the therapies also need to coexist, but the clinical practicalities can be challenging.

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I was thrilled to see the results of the phase 3 CORALreef Lipids trial, which were presented by Ann Marie Navar, MD, PhD, at the meeting. This trial of the oral PCSK9 inhibitor enlicitide was conducted in 2 phenotypes of patients: (1) adults with ASCVD and an LDL-C of 55 mg/dL or higher or (2) those at intermediate to high risk of ASCVD and an LDL-C of 70 mg/dL or higher. I was pleased to learn that, at week 52, patients taking enlicitide achieved a mean LDL-C reduction of 48% from baseline, without any apparent issues related to adherence, which can be challenging for injectable medications with infrequent dosing schedules.

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Another exciting study presented at the AHA Scientific Sessions 2025 was the phase 1 clinical trial of one-time CRISPR-Cas9 gene editing therapy targeting ANGPTL3 from Stephen Nicholls, MBBS, PhD, et al. They showed a robust LDL-C reduction with a single infusion. However, a few patients had adverse outcomes. I do like where we are going with this, which is to meet patients where they are and provide options to make LDL-C reduction more convenient and more durable with fewer interventions, especially since this is an asymptomatic condition that requires lifelong treatment.

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There was also a pilot study presented at this year’s AHA meeting by Neil Keshvani, MD, on the polypill, which encourages us to ask whether we could start using dual or triple therapy from the beginning. To me, this approach could get people to their LDL-C goal much faster, and a single pill could potentially improve adherence significantly because a high pill burden can be a significant deterrent for many patients. So, I was excited to see these data.

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Finally, I was a coauthor on a study presented at the AHA Scientific Sessions 2025 looking at whether adherence to lipid-lowering therapy affected health care utilization. This retrospective cohort study used the TriNetX electronic medical records data and included adults with ASCVD or adults at risk for it, including those with familial hypercholesterolemia, diabetes, chronic kidney disease, or a calcium score of 100 or higher. The study followed more than 29,000 patients, with 90.6% prescribed lipid-lowering therapy on the index date. However, we found that 60.4% of patients were untreated during follow-up. Patients with a lack of persistent lipid-lowering therapy use tended to have higher rates of nonfatal ASCVD events and more frequent hospitalizations and Emergency Department visits. To me, this highlights a huge disconnect. We have great therapies and great science, but, at the end of the day, if patients are not taking their medication, it is a real problem, as it drives up events and health care utilization.

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It also highlights that we need to do a better job of figuring out the barriers that our patients experience. We have an increasing number of tools and new paradigms for treatment, but we need to consider patient education, public policy, and other strategies to address the clinical challenges we continue to face.