Q&A: Oral PCSK9 Inhibitor Enlicitide Cuts LDL-C by 65% in Phase 3 Trial, With Ann Marie Navar, MD, PhD

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality in the US, and aggressive LDL cholesterol (LDL-C) reduction is a central pillar of prevention. Contemporary guidelines increasingly call for LDL-C targets below 55 mg/dL for patients at highest risk, yet many individuals do not reach these thresholds even with maximally tolerated statin therapy. Although add-on options such as ezetimibe, bempedoic acid, and injectable PCSK9 monoclonal antibodies can provide further LDL-C lowering, practical barriers—including access, cost, complexity of regimens, and reluctance to use injections—often limit uptake in routine primary care.

Against this backdrop, an investigational oral PCSK9-targeting agent, enlicitide, is being evaluated as a potential next step in lipid management. The CORALreef AddOn trial is the latest in a series of phase 3 studies of enlicitide, following earlier work in the CORALreef Lipids and CORALreef HeFH trials, which included patients with ASCVD or at risk for ASCVD and, in the HeFH trial, those with clinical or genetic heterozygous familial hypercholesterolemia. In CORALreef AddOn, just over 300 participants on background statin therapy were randomized in a 2:1:1:2 design to enlicitide, ezetimibe, bempedoic acid, or a fixed combination of ezetimibe plus bempedoic acid, with percent change in LDL-C as the primary endpoint. Enlicitide achieved approximately a 65% reduction in LDL-C, compared with about 37% for the ezetimibe–bempedoic acid combination, suggesting a substantially greater magnitude of LDL lowering with the oral PCSK9-targeting agent.

Because primary care clinicians are often responsible for long-term cardiovascular risk reduction, the emergence of a potent oral therapy in this class may have important implications for everyday practice. To explore the potential role of enlicitide and the CORALreef program more broadly, Patient Care Online spoke with Ann Marie Navar, MD, PhD, about the design and findings of the CORALreef AddOn trial, and what they could mean for frontline management of high-risk patients.

Q&A: Ann Marie Navar, MD, PhD, Discussing CORALreef AddOn

Q: Can you describe where the CORALreef AddOn trial fits within the broader Coral Reef program and what patient population was studied?

Ann Marie Navar, MD, PhD: Absolutely. CORALreef AddOn is the latest in a series of three phase 3 studies that we’re presenting or have presented on enlicitide. The first were the Coral Reef Lipids study and the Coral Reef HeFH study, which evaluated enlicitide in individuals with ASCVD or at risk for ASCVD. In the HeFH trial, we focused on patients who also had clinical or genetic heterozygous familial hypercholesterolemia.

In this latest study, CORALreef AddOn, we randomized patients on background statin therapy to receive enlicitide, ezetimibe, bempedoic acid, or the fixed combination of ezetimibe and bempedoic acid. The goal was to generate head-to-head data that reflect real-world choices—if you have a patient in front of you who needs more LDL lowering, what can you expect from enlicitide compared with currently available oral options?

We enrolled just over 300 individuals and used a 2:1:1:2 randomization scheme. Roughly 100 patients went to the ezetimibe–bempedoic acid combination, a similar number to enlicitide, and smaller cohorts to each monotherapy arm. The primary endpoint was change in LDL cholesterol from baseline.

Q: What were the key LDL-C–lowering results, and how do they compare with the oral therapies primary care clinicians are already using?

Ann Marie Navar, MD, PhD: We found that enlicitide reduced LDL cholesterol by about 65%, which is very consistent with what we saw in earlier phase 2 studies of the drug. In comparison, the ezetimibe plus bempedoic acid combination was the next best performer, lowering LDL-C by about 37%. So both approaches were clearly effective in reducing LDL, but the magnitude of LDL-C lowering was much greater among those randomized to enlicitide.

For clinicians, especially in primary care, that degree of LDL reduction is quite meaningful when you consider how stringent our LDL targets have become for very high–risk patients. Many of those patients will not achieve an LDL below 55 mg/dL with statins alone, and in that context, an oral agent capable of 60% or more LDL lowering on top of statins could be very impactful.

Q: From a practical standpoint, how do you see an oral PCSK9-targeting therapy fitting into day-to-day ASCVD risk management?

Ann Marie Navar, MD, PhD: As someone who takes care of patients with ASCVD or high cardiovascular risk, I’m really excited about the possibility of an oral therapy that can deliver this level of LDL reduction when added to statins. We know that not every patient is willing or able to use injectable therapies, and there are logistical hurdles—from prior authorizations to storage and administration—that can limit uptake.

An ongoing study is looking at enlicitide in combination with rosuvastatin, with the goal of developing a single pill that can help patients reach LDL-C targets more reliably. From an adherence perspective, that kind of fixed-dose combination could be a game changer—simplifying treatment regimens and potentially improving long-term control in the patients we see every day in primary care.

Q: Mechanistically, how does enlicitide compare with the PCSK9 monoclonal antibodies, and what does that suggest about cardiovascular outcomes?

Ann Marie Navar, MD, PhD: Mechanistically, enlicitide is very similar to the PCSK9 monoclonal antibodies already in use. Both approaches work by binding PCSK9 in the bloodstream and preventing it from interacting with the LDL receptor. That leads to increased LDL receptor recycling and greater clearance of LDL from the circulation.

What’s striking is that the numerical LDL-C reductions we’re seeing with enlicitide are very similar to what’s been observed with the monoclonal antibodies. We already know from large outcomes trials—like FOURIER, ODYSSEY, and more recently Vesalius—that PCSK9 inhibition can significantly reduce cardiovascular events.

The CORALreef Outcomes trial is underway now to determine the extent to which enlicitide will reduce cardiovascular events. Based on the mechanism and the LDL-lowering profile, we’re optimistic that we’ll see a meaningful benefit, but of course we need to wait for the outcomes data before drawing firm conclusions.

Q: What is the key takeaway for primary care physicians following this emerging data?

Ann Marie Navar, MD, PhD: I think the main message is that we’re moving into an era where very low LDL targets are realistic for a broader group of patients, and we may soon have an oral tool that delivers LDL-lowering in the same range as injectable PCSK9 inhibitors. For primary care physicians who are already doing the heavy lifting of cardiovascular prevention, that could provide a more accessible and acceptable option for patients who need intensive lipid lowering but are not ideal candidates for injectables.

If ongoing trials confirm a reduction in cardiovascular events comparable to what we’ve seen with other PCSK9 inhibitors, enlicitide has the potential to become an important addition to the treatment toolbox—helping more high-risk patients achieve guideline-recommended LDL levels in the context of everyday primary care practice.

References:

1. Catapano A, Mikhailova E, Navar A, et al. Efficacy and Safety of Enlicitide Decanoate, an Oral Macrocyclic Peptide Inhibitor of PCSK9, Compared With Bempedoic Acid, Ezetimibe, or Bempedoic Acid Co-administered With Ezetimibe in Statin-Treated Adults With Hypercholesterolemia: Phase 3 CORALreef AddOn Trial. Abstract presented at the American College of Cardiology Scientific Sessions 2026, New Orleans, LA. March 28-30, 2026.
2. Catapano A, Mikhailova E, Navar A. et al. Oral PCSK9 Inhibitor Enlicitide versus Oral Non-statin Therapies: A Phase 3 Randomized Clinical Trial. JACC. null2026, 0 (0). https://doi.org/10.1016/j.jacc.2026.03.036