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 hypercholesterolemia who had or were at risk of atherosclerotic cardiovascular disease (ASCVD), based on newly released data from the phase 3 CORALreef Lipids trial.1

Presented at the 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.1

The editorial team at HCPLive 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 HCPLive. “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 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.2,3

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.3

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.3

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.1

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.

References

1. Astle K. Investigational daily pill lowered bad cholesterol as much as injectables. Heart.org newsroom. November 8, 2025. Accessed November 9, 2025. https://newsroom.heart.org/news/investigational-daily-pill-lowered-bad-cholesterol-as-much-as-injectables

2. 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/

3. 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.