CORALreef AddOn: Enlicitide Outperforms Standard Hypercholesterolemia Drugs, With Ann Marie Navar, MD, PhD

Enlicitide has demonstrated superior efficacy in reducing low-density lipoprotein cholesterol (LDL-C), among other contributing factors, in patients with hypercholesterolemia, according to data from the CORALreef AddOn clinical trial.1

These data were presented at the American College of Cardiology (ACC) Scientific Sessions 2026 in New Orleans, Louisiana, by Alberico Catapano, PhD, research director and head of the laboratory of lipoproteins and atherosclerosis and of the lipid clinic at MultiMedica IRCCS.1

“As a clinician who takes care of patients with ASCVD or at risk for ASCVD, I’m really excited to see a pill that, when added to statin therapy, can lower LDL cholesterol by 60% or more,” Ann Marie Navar, MD, PhD, associate professor, department of internal medicine, UT Southwestern Medical Center and an investigator in the trial, told HCPLive in an exclusive interview. “When we think about guidelines recommending targets of <55 for our highest-risk patients, it’s going to take more than statins to get most of our patients to those goals. I’m excited to have an oral option.”

CORALreef AddOn was a phase 3, randomized, double-blind study evaluating the safety and efficacy of enlicitide compared to ezetimibe, bempedoic acid, or a combination in adults with hypercholesterolemia. Patients were eligible if they presented with a history of major atherosclerotic cardiovascular disease (ASCVD) event, were currently undergoing treatment with a low, moderate, or high intensity statin, or were on a stable dose of all background lipid-lowering therapies (LLTs) with no planned changes during the study, among other criteria. Patients with homozygous or heterozygous familial hypercholesterolemia or NYHA class IV heart failure, among other criteria, were excluded.2

Patients enrolled in the study were randomly assigned to either the treatment arm, consisting of enlicitide 20mg, ezetimibe-matching placebo, and bempedoic acid-matching placebo once daily orally for roughly 56 days, or 1 of 3 active comparators, including ezetimibe 10mg, bempedoic acid 180mg, or ezetimibe and bempedoic acid. The primary outcome was mean percent change from baseline in LDL-C at day 56; secondary outcomes included mean percent change in apolipoprotein B (ApoB), non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein(a), among others.2

Ultimately, 301 patients were enrolled in the study – of these, 101 were assigned to the treatment arm, 50 were assigned to both the ezetimibe and bempedoic acid arms, and 100 were assigned to the group receiving both comparators. Catapano and colleagues recorded a mean age of 64 years among the patients. All had hypercholesterolemia with either a history of a major ASCVD event or were at high risk. Fasting lipids were obtained at screening and on days 1, 21, and 56 and at treatment discontinuation.1

Catapano and colleagues noted a 65% reduction in LDL-C with enlicitide versus 6% with bempedoic acid, 28% with ezetimibe, and 37% with the combination. These results were similar across all included subgroups. Additionally, patients receiving enlicitide had a substantially greater reduction in ApoB and non-HDL-C than any comparator group. Adverse events and discontinuations, totaling 2-4%, were also similar across all groups.1

Catapano, Navar, and colleagues determined that enlicitide is superior to ezetimibe, bempedoic acid, and a combination of both. These results, on top of those from the previously concluded CORALreef Lipids and CORALreef HeFH trials, emphasize the overall efficacy of the investigative PCSK9 inhibitor. Moving forward, Navar highlights the ongoing CORALreef Outcomes trial, the results of which will reportedly influence the potential submission of a New Drug Application.1

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

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. Merck Sharp & Dohme LLC. A Study to Evaluate the Efficacy and Safety of Enlicitide (MK-0616, Oral PCSK9 Inhibitor) Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia (MK-0616-018/CORALreef AddOn). ClinicalTrials.gov Identifier: NCT06450366. Updated March 27, 2026. Accessed April 7, 2026. https://clinicaltrials.gov/study/NCT06450366