Ann Marie Navar, MD, PhD, is an associate professor of cardiology at the University of Texas Southwestern Medical Center.

Ann Marie Navar, MD, PhD

CORALreef Lipids: Enlicitide Reduces LDL-C in Patients With ASCVD, With Ann Marie Navar, MD, PhD

Enlicitide decanoate has demonstrated its efficacy in reducing 

low-density lipoprotein cholesterol (LDL-C)

 levels compared to placebo in patients with a history of or at risk for a major 

atherosclerotic cardiovascular disease (ASCVD)

 event, according to data from the phase 3 CORALreef Lipids trial.

Enlicitide is an oral macrocyclic peptide, designed to inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) and prevent it from binding to LDL-C receptors. In prior phase 1 and 2 trials, enlicitide demonstrated its efficacy in lowering LDL-C levels over the short term; the CORALreef Lipids trial examined the drug’s efficacy dover a 52-week period.

“My hope is that another agent that is really impressive in terms of LDL cholesterol lowering will help to actually get more clinicians to start thinking about prescribing non-statin drugs,” Ann Marie Navar, MD, PhD, associate professor, department of internal medicine, UT Southwestern Medical Center, told 

 in an exclusive interview. “Ideally, because enlicitide as a pill is easier to take, it may get over some of the provider inertia against prescribing non-statin therapy and help more people start getting to goal.”

CORALreef Lipids was a multinational, double-blind, randomized, placebo-controlled trial conducted across 168 sites in 14 countries worldwide. Patients were eligible for inclusion if they were aged ≥18 years and had a history of a major ASCVD event and an LDL-C level ≥55 mg/dL, or if they were at risk for a first ASCVD event and had an LDL-C ≥70 mg/dL. Exclusion criteria were active or recent treatment with a PCSK9 inhibitor, uncontrolled 

, active liver disease, or a triglyceride level ≥400 mg/dL at screening.

LDL-C levels were determined via a fasting lipid panel conducted at screening. Major ASCVD events were defined as acute coronary syndrome, coronary revascularization, myocardial infarction, and ischemic stroke, among others. The study’s primary endpoint was the mean percentage change in LDL-C from baseline to week 24. Key secondary endpoints included the mean change in LDL-C by week 52 and the mean percent change in levels of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B.

A total of 2912 patients were enrolled and randomly assigned in a 2:1 ratio to receive either enlicitide 20 mg or matching placebo for 52 weeks. Investigators instructed participants to take enlicitide or placebo in the morning on an empty stomach and to withhold food and beverages other than water for 30 minutes. The team conducted follow-up visits at baseline and at weeks 4, 8, 16, 24, 36, and 52.

Ultimately, 1831 participants in the enlicitide arm and 918 in the placebo arm completed the trial. Adherence to the full regimen was high and consistent across both arms, with an overall mean adherence of 97.2%. The mean LDL-C level was 95 +/- 38.8 mg/dL in the enlicitide group and 98.3 +/- 39.2 mg/dL in the placebo group. By week 24, the enlicitide group had reached a mean LDL-C level of 38.7 +/- 35.6 mg/dL, while the placebo group rose to 98.6 +/- 42.5 mg/dL. The mean percent change in the enlicitide group was -57.1% (95% CI, -61.8 to -52.5%) and 3% (95% CI, 0.9 to 5.1%) in the placebo group.

Due to the substantial treatment adherence documented in the study, investigators hope that the comparative simplicity of oral enlicitide will overcome the notorious prescription inertia present in dyslipidemia management.

“The main advantage comes in having multiple options for people, who can now choose what works for them,” Navar said. “Some people may prefer an injection, and they may be more adherent to an injection than a pill. Some people would prefer a pill over an injection. I think enabling patient choice will help with adherence, because if people are on the drug that they want to be on and the form they want to be on it in, I think they’re more likely to take it.”

Editor’s Note: Navar reports disclosures with Esperion Therapeutics, Bristol Myers Squibb, Amgen, Janssen Pharmaceuticals, Eli Lilly, Novo Nordisk, and others.

Navar AM, Mikhailova E, Catapano AL, et al. A placebo-controlled trial of the oral PCSK9 inhibitor enlicitide. New England Journal of Medicine. 2026;394(6):529-539. 

Ballantyne CM, Banka P, Mendez G, et al. Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616. J Am Coll Cardiol. 2023;81(16):1553-1564. 

Videos

Navar discusses the positive data from the phase 3 trial and emphasizes substantial treatment adherence throughout the 52-week period.

CORALreef Lipids: Enlicitide Lowers LDL-C as Much as Injectables, With Ann Marie Navar, MD, PhD

An oral, once-daily dose of PCSK9 inhibitor enlicitide has proven its efficacy by substantially reducing LDL cholesterol compared to placebo in patients with 

, based on newly released data from the phase 3 CORALreef Lipids trial.

American Heart Association’s Scientific Sessions 2025

 in New Orleans, Louisiana, by Ann Marie Navar, MD, PhD, an associate professor of cardiology at the University of Texas Southwestern Medical Center and lead study author, this study could revolutionize LDL-C reduction and provide an entirely new pathway to cardiovascular event prevention.

 sat down with Navar to discuss the implications of these groundbreaking data.

“From a clinician perspective, I think it’s safe to say that enlicitide is as effective in lowering LDL-C as injectable monoclonal antibody PCSK9 inhibitors,” Navar told 

. “They’re actually a bit numerically greater than the reductions we saw with SIRNAs, and that’s already been shown previously for the monoclonal antibodies. This is not a surprise because the way that enlicitide works is very similar to how the monoclonal antibodies do.”

CORALreef Lipids was a phase 3 randomized, double-blind, placebo-controlled trial evaluating the efficacy, safety, and tolerability of enlicitide in patients with hypercholesterolemia and a history of major ASCVD events, or an increased risk for a first event. Specifically, the trial included patients with either ASCVD and an LDL-C ≥55 mg/dL or a risk of ASCVD and an LDL-C ≥70 mg/dL. Patients were also required to be treated with stable lipid-lowering therapies, including ≥1 statin, for ≥30 days.

The study’s primary endpoints included percent change from baseline in LDL-C at week 24, the percent of participants with adverse events (AEs), and the percent of participants with discontinuations due to AEs. Investigators also included multiplicity-controlled secondary endpoints of percent change from baseline in LDL-C at week 52 and in non-HDL-C, ApoB, and Lp(a) at week 24, as well as the percent of participants achieving protocol-defined LDL-C goals.

Ultimately, Navar and colleagues included 2909 patients, who were then randomly assigned in a 2:1 ratio to either enlicitide 20 mg or placebo daily for 52 weeks. The enlicitide group included 1940 patients, while 969 were assigned to placebo. Mean age was 63 years, and 58% of patients had prior ASCVD, while 95% were on moderate or high intensity statin therapy.

After 24 weeks of daily treatment, Navar and colleagues found an LDL-C reduction of up to 60% in patients receiving enlicitide, which was sustained at 52 weeks. Additionally, patients saw a 53% reduction in non-HDL, a 50% reduction in ApoB, and a 28% reduction in Lp(a). In total, 7 in 10 patients taking enlicitide had a ≥50% reduction in LDL-C and achieved an LDL <70 mg/dL. More than 2/3 of patients reduced their LDL-C by ≥50% and achieved levels below 55 mg/dL.

Navar also discussed the issue of treatment adherence, given the difficulty in keeping patients consistently following medication advice with lipid-lowering therapies.

“I think having more options for patients is going to allow people to choose the therapy that’s going to work the best for them,” Navar said. “For people who are doing great on an injectable and are able to stick with it and are happy with it, they don’t need to switch to a pill. But for somebody who may be reluctant to start an injectable or who wouldn’t be as adherent, then maybe they’ll be better off with the pill.”

Editor's Note: Navar reports disclosures with Janssen Pharmaceuticals, Amgen, Bristol Myers Squibb, and Esperion Therapeutics, Inc.

Astle K. Investigational daily pill lowered bad cholesterol as much as injectables. 

 November 8, 2025. Accessed November 9, 2025. 

https://newsroom.heart.org/news/investigational-daily-pill-lowered-bad-cholesterol-as-much-as-injectables

Merck. Merck’s Investigational Oral PCSK9 Inhibitor Enlicitide Decanoate Met All Primary and Key Secondary Endpoints in Adults with Hypercholesterolemia in Pivotal CORALreef Lipids Study. September 2, 2025. Accessed November 9, 2025. 

https://www.merck.com/news/mercks-investigational-oral-pcsk9-inhibitor-enlicitide-decanoate-met-all-primary-and-key-secondary-endpoints-in-adults-with-hypercholesterolemia-in-pivotal-coralreef-lipids-study/

Navar A, Mikhailova E, Catapano A, et al. Efficacy and Safety of Enlicitide, an Oral PCSK9 Inhibitor, for Lowering LDL Cholesterol in Adults with or At-Risk for ASCVD: The Phase 3 CORALreef Lipids Trial. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.

Navar discusses the groundbreaking results of this phase 3 trial, as well as the implications of an oral PCSK9 inhibitor for treatment adherence and persistence.

Ann Marie Navar, MD, PhD

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