Enlicitide Offers a New Oral Option for Managing High Cholesterol

In the randomized, double-blind, placebo-controlled, phase 3 CORALreef Lipids (NCT05952856) clinical trial, enlicitide decanoate, an oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, demonstrated significant and clinically meaningful reductions in low-density lipoprotein cholesterol (LDL-C). The study focused on the safety, efficacy, and tolerability of the treatment among individuals with hypercholesterolemia on a moderate- or high-intensity statin.^1,2

Clogged arteries, Cholesterol plaque in artery. 3d illustration - Image credit: Rasi | stock.adobe.com

“This is the third phase 3 trial to demonstrate clinically meaningful and statistically significant LDL-C lowering for enlicitide,” Dean Y. Li, MD, PhD, president of Merck Research Laboratories, said in a news release. "The advent of injectable PCSK9 inhibitors has enabled a new approach to controlling LDL-C and reducing the risk of atherogenic cardiovascular events.”¹

Understanding Hypercholesterolemia & Enlicitide

Hypercholesterolemia is a disorder that induces high levels of LDL-C in the blood, which causes fat to build up in the arteries. This buildup increases an individual’s risk for heart attack, stroke, and atherosclerosis, which is the leading cause of cardiovascular disease. Additionally, hypercholesterolemia impacts nearly 86 million US adults and accounts for 85% of cardiovascular deaths.^1,3

Enlicitide can offer further treatment options for hypercholesterolemia as the potential first oral PCSK9 inhibitor designed to lower LDL-C using the same biological mechanism as approved monoclonal antibody-based injectable PCSK9 inhibitors. As a novel small molecule peptide, enlicitide binds to PCSK9 and inhibits the interactions of PCSK9 with LDL receptors, according to the study authors.¹

“Enlicitide, designed to deliver antibody-like efficacy, is the first oral macrocyclic peptide PCSK9 inhibitor with clinically meaningful and statistically significant LDL-C lowering in phase 3 trials. If approved, it has the potential to change the way we think about managing LDL levels, giving patients the possibility of a new option to help them meet their treatment goals,” Li said in the news release.¹

CORALreef Lipids Trial Design and Results

The CORALreef Lipids study is currently marked as the largest phase 3 trial evaluating the effectiveness of enlicitide. The study included participants who had high LDL cholesterol and a history or increased risk of major cardiovascular events. All participants were already being treated with moderate- or high-intensity statins or were unable to tolerate statins during the study.¹

The primary end point of the study was to compare enlicitide and a placebo at lowering LDL-C by measuring the average percentage change from the start of the study to week 24. Key secondary end points assessed the change in LDL-C at week 52 and the other non-high-density lipoprotein cholesterol (HDL-C), apolipoprotein B, and lipoprotein(a) at week 24.¹

The results demonstrated that enlicitide met all primary and secondary end points, achieving statically significant and clinically meaningful reduction in LDL-C compared to placebo at week 24.¹

“These data add to the growing body of evidence supporting the safety and efficacy profile of enlicitide to lower LDL cholesterol and other key atherogenic lipids, including ApoB and Lp(a),” Ann Marie Navar, MD, PhD, a lead trial investigator of the study and associate professor of medicine in the division of cardiology at UT Southwestern Medical Center, said in the news release.¹

In terms of adverse events, the study authors noted that there were no notable differences in the number of participants who experienced adverse events or serious adverse events between the enlicitide and placebo groups. However, very few individuals stopped treatment due to adverse events in both groups.¹

“Enlicitide has the potential to help more patients achieve guideline-recommended lipid goals and ultimately reduce atherosclerotic cardiovascular risk, which is currently being evaluated in an ongoing cardiovascular outcomes trial,” Navar concluded.¹

REFERENCES

1. Merck’s investigational oral PCSK9 inhibitor enlicitide decanoate met all primary and key secondary endpoints in adults with hypercholesterolemia in pivotal CORALreef Lipids study. Merck. News release. September 2, 2025. Accessed September 3, 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/

2. A study of enlicitide decanoate (MK-0616 Oral PCSK9 Inhibitor) in adults with hypercholesterolemia (MK-0616-013) CORALreef Lipids. Merck Sharp & Dohme LLC. Updated September 3, 2025. Accessed September 3, 2025. https://clinicaltrials.gov/study/NCT05952856?id=NCT05952856&rank=1

3. Cleveland Clinic. Hypercholesterolemia. News release. Updated August 1, 2022. Accessed September 3, 2025. https://my.clevelandclinic.org/health/diseases/23921-hypercholesterolemia