Oral PCSK9 Inhibitor Enlicitide Matches Injectables in Lowering LDL Cholesterol

A new oral medication lowered low-density lipoprotein cholesterol (LDL-C) by nearly 60% in adults with or at risk for atherosclerotic cardiovascular disease (ASCVD), according to preliminary results from the phase 3 CORALreef Lipids trial.¹

The investigational medication enlicitide (Merck) is designed to block the PCSK9 protein’s interaction with LDL receptors, the same biological target as existing PCSK9 inhibitors, but in a daily pill form.² The results suggest the oral drug can reduce LDL-C about as much as PCSK9 injections can, which can cut LDL-C by up to 70%.³

“This oral medication is set to be another powerful addition to the treatments we currently have to lower LDL cholesterol,” said Ann Marie Navar, MD, PhD, FAHA, associate professor of cardiology at the University of Texas Southwestern Medical Center and lead study author, who presented the findings at the American Heart Association (AHA) 2025 Scientific Sessions.² “Many patients struggle to reach guideline-recommended cholesterol targets despite currently available therapies.”

A Potential Oral Alternative to PCSK9 Injections?

PCSK9 inhibitors include monoclonal antibodies like alirocumab or evolocumab and small interfering RNA (siRNA) therapies like inclisiran. Although these agents have transformed lipid management for patients who do not meet LDL-C goals on statins and ezetimibe, their subcutaneous administration and high cost have limited real-world uptake.

Enlicitide is a small-molecule macrocyclic peptide that blocks PCSK9 from binding to LDL receptors, allowing more receptors to remove LDL-C from circulation. Because it is taken orally once daily, this mechanism may eliminate barriers associated with injectable biologics. As of publication, Merck has not submitted an application for enlicitide’s approval to the FDA and the drug does not yet have a Prescription Drug User Fee Act date.

Comparable LDL-C–Lowering Effects

The double-blind, placebo-controlled study enrolled 2912 adults across 168 centers in 14 countries.¹ The cohort was predominantly White (54%) and Asian (26%), with a mean age of 63 years, and 39% of participants were women.

Participants either had a prior heart attack or stroke or were at intermediate to high risk for a first cardiovascular event. Nearly all participants (97%) had a history of statin therapy, and all of them had LDL-C levels above recommended thresholds despite at least moderate- or high-intensity statin therapy; 26% were also taking ezetimibe. Participants were randomized 2:1 to receive enlicitide 20 mg once daily (n = 1935) or placebo (n = 969) for 52 weeks.

After 24 weeks, patients receiving enlicitide experienced a 55.8% greater reduction in LDL-C compared with placebo (P < .001). In a reanalysis that excluded biologically implausible LDL values, the reduction increased to 59.7% at 24 weeks and 52.4% at 52 weeks. A chart Navar presented at AHA 2025 showed a clear drop in mean LDL-C between baseline and week 4 with treatment, with seemingly consistent lowering effects.

Enlicitide also significantly reduced other atherogenic lipids:

• Non–high-density lipoprotein cholesterol reduced by 53%
• Apolipoprotein B reduced by 50%
• Lipoprotein(a) reduced by 28%

Nearly 70% of participants achieved both at least a 50% LDL-C reduction and an LDL-C below 70 mg/dL, and more than two-thirds reached levels below 55 mg/dL. “Results were even numerically better than what has been shown for the siRNA medication inclisiran,” Navar said.

Enlicitide Safety and Tolerability

The safety profile of enlicitide was comparable to placebo, with adverse events (AEs) occurring in 64% and 62% of patients, respectively, and serious AEs occurring in 10% and 12% of patients. About a third of patients from each group experienced moderate to severe AEs, but only 100 patients total discontinued treatment because of these AEs. Deaths occurred in 0.7% of each group, and no new safety signals emerged, according to Navar.

“The CORALreef outcomes trial is still ongoing and will determine if and by how much the lower LDLs achieved with enlicitide will prevent major cardiovascular events,” she said.

References

1. Navar A. 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: AHA 2025 Scientific Sessions; November 8, 2025; New Orleans, LA.
2. Investigational daily pill lowered bad cholesterol as much as injectables. News release. American Heart Association. November 8, 2025. Accessed November 8, 2025. https://newsroom.heart.org/news/investigational-daily-pill-lowered-bad-cholesterol-as-much-as-injectables
3. PCSK9 inhibitors. Cleveland Clinic. Updated February 17, 2022. Accessed November 8, 2025. https://my.clevelandclinic.org/health/drugs/22550-pcsk9-inhibitors