Oral PCSK9 Inhibitor Enlicitide Lowers LDL by 57% at 24 Weeks

Adults with a history of or at risk for a first atherosclerotic cardiovascular disease (ASCVD) event who received the oral proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor enlicitide had significantly lower low-density lipoprotein (LDL) cholesterol levels at 24 weeks compared with placebo.¹

The phase 3 multinational, double-blind, randomized, placebo-controlled CORALreef Lipids (NCT05952856) trial is published in the New England Journal of Medicine.

“The percentage of participants with LDL cholesterol levels that reached the guideline-recommended targets was higher with enlicitide than with placebo, and safety outcomes did not appear to differ between the groups,” wrote the researchers of the study. “The degree to which the reduction in LDL cholesterol levels with enlicitide will translate into a reduction in cardiovascular events is being tested in the ongoing CORALreef Outcomes trial, with a projected completion date of December 2029 (NCT06008756).”

Merck’s enlicitide decanoate represents a new class of lipid-lowering therapy designed to expand options beyond injectable PCSK9 inhibitors.² Unlike currently approved PCSK9 inhibitors, which are administered by injection, enlicitide is taken orally—a formulation that could improve patient convenience and adherence.

This trial was conducted at 168 sites in 14 countries.² Adults aged 18 years or older were eligible if they had a history of a major ASCVD event with an LDL cholesterol level of 55 mg/dL or higher or were at intermediate-to-high risk for a first ASCVD event with an LDL cholesterol level of 70 mg/dL or higher.¹ Participants were required to be on stable lipid-lowering therapy, including at least a moderate- or high-intensity statin, unless they had documented intolerance.

Participants were randomly assigned in a 2:1 ratio to receive enlicitide 20 mg daily or matching placebo for 52 weeks. Randomization was stratified according to renal function, baseline statin use, and geographic region. The primary end point was the mean percent change in LDL cholesterol from baseline to week 24. Key secondary end points included the mean percent change in LDL cholesterol at week 52 and the mean (SD) percent change in non–high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B, as well as the percent change in lipoprotein(a) at week 24.

A total of 2912 participants underwent randomization; after exclusions, 2909 were included in the intention-to-treat population. Of these, 1935 received enlicitide and 969 received a placebo.

The mean baseline LDL cholesterol level was 95.0 (38.8) mg/dL in the enlicitide group and 98.3 (39.2) mg/dL in the placebo group. At week 24, the mean LDL cholesterol level was 38.7 (35.6) mg/dL with enlicitide and 98.6 (42.5) mg/dL with placebo. The mean percent change from baseline to week 24 was −57.1% (95% CI, −61.8 to −52.5) with enlicitide and 3.0% (95% CI, 0.9-5.1) with placebo, for an adjusted between-group difference of −55.8 percentage points (95% CI, −60.9 to −50.7; P < .001).

At week 52, the adjusted between-group difference in LDL cholesterol reduction was −47.6 percentage points (95% CI, −52.7 to −42.5; P < .001). At week 24, the adjusted between-group differences were −53.4 percentage points for non-HDL cholesterol (95% CI, −55.5 to −51.2; P < .001) and −50.3 percentage points for apolipoprotein B (95% CI, −52.1 to −48.5; P < .001). The median between-group difference in percent change in lipoprotein(a) was −28.2 percentage points (95% CI, −30.3 to −26.0; P < .001).

An LDL cholesterol level below 70 mg/dL with a reduction of 50% or more from baseline was observed in 70.3% of participants in the enlicitide group and 1.5% in the placebo group. An LDL cholesterol level below 55 mg/dL with a reduction of 50% or more from baseline occurred in 67.5% and 1.2% of participants, respectively.

There were no apparent differences between groups in the incidence of adverse events, serious adverse events, discontinuations due to adverse events, or deaths.

However, the researchers acknowledged several limitations. LDL cholesterol reductions were observed in a clinical trial setting rather than routine clinical practice. The prespecified data-handling rule for certain beta-quantification–derived LDL cholesterol values led to underestimation of baseline levels and treatment effect in a small number of participants. Follow-up was limited to 52 weeks, long-term durability and cardiovascular outcomes remain unknown, missing data from participants who died were imputed, and the trial was not powered to detect rare adverse events.

Despite these limitations, the researchers believe the study found that once-daily oral enlicitide resulted in significantly greater reductions in LDL cholesterol, non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) compared with placebo over 52 weeks in adults with or at risk for ASCVD and elevated LDL cholesterol levels, with no apparent differences in adverse events.

“Among participants who had a history of or were at risk for a first atherosclerotic cardiovascular disease event, treatment with the oral PCSK9 inhibitor enlicitide resulted in significantly lower LDL cholesterol levels than placebo at 24 weeks,” wrote the researchers.

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. doi:10.1056/NEJMoa2511002

2. Merck’s investigational oral PCSK9 inhibitor enlicitide decanoate met all primary and key secondary end points in adults with hypercholesterolemia in pivotal CORALreef Lipids study. Merck. News release. September 2, 2025. Accessed February 11, 2026. 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/