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.1

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.1,2

“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 HCPLive 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 hypertension or diabetes, active liver disease, or a triglyceride level ≥400 mg/dL at screening.1

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.1

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 52.1

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.1

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.

References

1. 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. doi:10.1056/nejmoa2511002

2. 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. doi:10.1016/j.jacc.2023.02.018