Written by Mirjam Boros, Radcliffe Cardiology
A new oral proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor, enlicitide, has demonstrated a significant reduction in low-density lipoprotein cholesterol (LDL-C) levels in patients with or at risk of atherosclerotic cardiovascular disease (ASCVD), according to results from the CORALreef Lipids trial.¹
Mechanism of Action
Enlicitide is an orally administered PCSK9 inhibitor. By blocking PCSK9, it increases the number of LDL receptors on the liver, which enhances the clearance of LDL-C from the bloodstream. This offers a new route of administration compared to existing injectable PCSK9 inhibitor therapies.
Methodology
CORALreef Lipids was a multinational, double-blind, randomised, placebo-controlled trial involving adults with a history of a major ASCVD event and an LDL-C level of ≥55mg/dL, or those at risk for a first ASCVD event with an LDL-C level of ≥70mg/dL. A total of 2,909 participants were randomised in a 2:1 ratio to receive either 20mg of enlicitide or placebo daily for 52 weeks. The primary endpoint was the mean percentage change in LDL-C level from baseline to week 24.¹
Results
At 24 weeks, participants receiving enlicitide experienced a mean LDL-C reduction of 57.1%, compared to a 3.0% increase in the placebo group. This represents a placebo-adjusted between-group difference of -55.8 percentage points (95% CI, -60.9 to -50.7; p<0.001).¹
Significant improvements were also observed in key secondary endpoints. The reduction in LDL-C was sustained at 52 weeks, and there were significant reductions in non-high-density lipoprotein (non-HDL) cholesterol, apolipoprotein B, and lipoprotein(a) levels at 24 weeks compared to placebo (p<0.001 for all comparisons). The incidence of adverse events was similar between the enlicitide and placebo groups.¹
In Practice
The results suggest that enlicitide is a highly effective oral agent for lowering LDL-C. An oral PCSK9 inhibitor could help overcome potential barriers to adherence associated with injectable therapies, offering a convenient and potent option for managing dyslipidaemia in high-risk patients, often on top of existing statin therapy.²
Next Steps
While these lipid-lowering results are promising, data on clinical outcomes are needed. Merck is sponsoring a large cardiovascular outcomes study, the CORALreef Outcomes trial, to evaluate the efficacy of enlicitide in reducing cardiovascular events, with results anticipated in 2029.²
This study was funded by MSD.
Disclaimer
The information presented in this article is for educational purposes only. Any quotes included reflect the opinions of the individual quoted, and do not necessarily reflect the views of the publisher. The publisher does not guarantee the accuracy or completeness of the content and accepts no responsibility for any errors, or any consequences arising from its use.
References
1. Navar AM, Mikhailova E, Catapano AL, et al. A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide. N Engl J Med 2026;394:529-539. https://doi.org/10.1056/NEJMoa2511002
2. Mandrola JM. Feb 06, 2026 This Week in Cardiology Podcast. Medscape. Feb 06, 2026. https://www.medscape.com/viewarticle/1003240