Enlicitide LDL-C Lowering Holds Across Risk Levels Up to 2 Years

The oral PCSK9 inhibitor enlicitide (Lipfendra; Merck) lowered low-density lipoprotein cholesterol (LDL-C) by a similar margin regardless of patients' baseline 10-year cardiovascular risk, and those reductions held through up to 2 years of total treatment, according to 2 abstracts being presented at the American Heart Association (AHA) Scientific Sessions 2026.^1,2

The FDA approved enlicitide in July as the first oral PCSK9 inhibitor for adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia (HeFH). The approval rested on 2 phase 3 trials: In CORALreef Lipids, enlicitide reduced LDL-C by 55.8% compared with placebo at 24 weeks, and in the 303-patient CORALreef HeFH trial, it reduced LDL-C by 59%.³ The new analyses address 2 questions left open by those trials: whether the drug works equally well in lower-risk primary prevention patients and whether its effect lasts beyond 1 year.

LDL-C Cut by 57% to 63% Across PREVENT Risk Categories

The first analysis included 843 participants (573 enlicitide, 270 placebo) from the phase 3 CORALreef Lipids study who were at risk for a first major atherosclerotic cardiovascular disease (ASCVD) event and had baseline data to calculate their AHA Predicting Risk of Cardiovascular Disease EVENTs (PREVENT) score.¹ Investigators grouped patients by 10-year risk: low (<3%; 8.2%), borderline (3% to <5%; 18.3%), intermediate (5% to <10%; 44.0%), and high (≥10%; 29.5%).

Moving from the low- to the high-risk group, mean age rose from 48.8 to 70.4 years, the share of men from 37.7% to 53.4%, diabetes prevalence from 59.4% to 83.5%, and antihypertensive use from 33.3% to 88.0%. Baseline LDL-C was similar across groups (95.6-107.2 mg/dL), and most participants were taking moderate- or high-intensity statins.

At week 24, placebo-corrected LDL-C reductions were 62.6% in the low-risk group, 57.6% in the borderline group, 57.1% in the intermediate group, and 58.0% in the high-risk group. The low-risk estimate carried a wide CI (95% CI, −89.8% to −35.4%), reflecting its small size of 66 participants.

Placebo-corrected reductions in non–HDL-C ranged from 50.1% to 53.7% and in apolipoprotein B from 46.0% to 50.4%. Median lipoprotein(a) reductions were 21.5% to 25.9% in the borderline, intermediate, and high-risk groups but 10.7% in the low-risk group, where the CI crossed zero (95% CI, −23.8% to 2.6%). More patients on enlicitide than on placebo reached LDL-C below 70 mg/dL in every risk category.

Reductions Maintained Through Week 104 in CORALreef Extension

The second abstract reported an interim analysis of CORALreef Extension (NCT06492291), a single-arm, open-label study enrolling adults who completed CORALreef Lipids, CORALreef HeFH, or CORALreef AddOn.² All participants received enlicitide 20 mg once daily.

Of eligible participants, 2774 (>87%) enrolled. Their mean age was 62.4 years, 61.4% were men, and 54.9% had prior major ASCVD. Mean total exposure, including the parent studies, was 476.8 days, and 1014 participants had at least 1.74 years of exposure by the January 19, 2026, data cutoff.

From parent-study baseline to week 8 of the extension, LDL-C fell 57.5% (95% CI, −58.9% to −56.2%), non–HDL-C fell 51.5%, and apoB fell 49.8%; median Lp(a) fell 27.5%. The authors reported LDL-C reductions were sustained through week 104, although the abstract's figure shows the mean reduction among continuing participants narrowing from roughly 65% early in treatment to about 50% at week 104.

Discontinuations due to adverse events (AEs) were 1.6%, no drug-related serious AEs were reported, and no individual AE occurred in 5% or more of participants.

Because enrollment required participants to have stayed on study treatment with at least 80% compliance, and the extension had no control group, the results reflect patients who already tolerated and adhered to the drug.

References

1. Navar AM, KC W, Banka P, et al. Efficacy of enlicitide on LDL-C reduction across PREVENT cardiovascular risk categories in the phase 3 CORALreef lipids study. Presented at: AHA Scientific Sessions 2026; November 6-9, 2026; Chicago, IL.
2. Ballantyne C, Parham J, Carrillo J, et al. Long-term efficacy and safety of enlicitide in an open-label extension study. Presented at: AHA Scientific Sessions 2026; November 6-9, 2026; Chicago, IL.
3. Joszt L. FDA approves enlicitide, first oral PCSK9 for high cholesterol. AJMC^®. July 16, 2026. Accessed October 30, 2026. https://www.ajmc.com/view/fda-approves-enlicitide-first-oral-pcsk9-for-high-cholesterol