Enlicitide Meaningfully Lowers LDL-C at 24 Weeks in Patients At Risk for ASCVD Events

Full results from the phase 3 CORALreef Lipids (NCT05952856) clinical trial have been published by investigators in The New England Journal of Medicine, highlighting significant reductions in low-density lipoprotein cholesterol (LDL-C) and other markers of atherosclerotic cardiovascular disease (ASCVD) when patients were treated with enlicitide decanoate (enlicitide, Merck & Co), an oral proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor.^1,2

Topline Results: Enlicitide Demonstrates Significant LDL-C Reductions

The study enrolled a total of 2904 participants aged 18 years and older with a history of a major ASCVD event and an LDL-C level of 55 mg per deciliter or higher, or who were at immediate-to-high risk for a first ASCVD event and harbored LDL-C of 70 mg per deciliter or higher. Individuals were also required to have been taking a stable dose of lipid-lowering therapy at least 30 days prior to screening, including at least a moderate- or high-intensity statin.¹

Individuals were randomly assigned to receive either enlicitide 20 mg (n = 1935) or placebo (n = 969). Enlicitide led to a mean percent change in LDL-C levels of approximately –57.1% (95% CI, –61.8 to –52.5) at week 24, compared with 3.0% (95% CI, 0.9 to 5.1) with placebo. This represents an adjusted between-group difference of –55.8% (95% CI, –60.9 to –50.7; P < .001), an achievement of the study’s primary end point.¹

“With a nearly 60% reduction in LDL-C when given on top of background therapy, this offers a great option for patients who are above goal and need additional nonstatin therapy,” Ann Marie Navar, MD, PhD, an associate professor of internal medicine and member of the Division of Cardiology at UT Southwestern Medical School and study investigator in the CORALreef Lipids trial, said in an interview with Pharmacy Times.^1,3

Major Indicators of ASCVD Besides LDL-C Also Reduced, With Positive Safety

Key secondary end points were also investigated, including change in non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein B (ApoB), and lipoprotein(a) [Lp(a)]. Non–HDL-C was reduced by about 53.4% from baseline to week 24 (95% CI, –55.5 to –51.2; P < .001); ApoB was reduced by 50.3% from baseline to week 24 (95% CI, –52.1 to –48.5; P < .001); and Lp(a) was reduced by 28.2% from baseline to week 24 (95% CI, –30.3 to –26.0; P < .001).¹

In a critical development, the investigators observed an LDL-C level of less than 70 mg per deciliter with an accompanying reduction of 50% or more from baseline in over 70% of participants in the enlicitide group, compared with 1.5% of those in the placebo group. Furthermore, an LDL-C level of less than 55 mg per deciliter, with a reduction of 50% or more from baseline, was observed in 67.5% of enlicitide patients and 1.2% of placebo patients. These points demonstrate significant LDL-C lowering in patients who are at risk of developing ASCVD.¹

Safety was deemed to be similar between the enlicitide and placebo groups regarding the incidence of any adverse events (AEs), serious AEs, trial discontinuation due to AEs, or death.¹

What to Know in Advance of Approval

Enlicitide has the potential to transform the treatment paradigm of high cholesterol and cardiovascular prevention. As a PCSK9 inhibitor, enlicitide as an adjunct to statin use could deliver more significant lipid lowering compared with standard treatment regimens. Its oral nature makes it a more convenient and reasonable option for patients to consistently adhere to and take the medication, compared with currently available PCSK9 injectables.^1,3,4

“There is the hope that this can be more deployable to a broader patient population, as far as an option that can fit the scheme of how patients usually take their maintenance medications,” Joseph Saseen, PharmD, BCPS, BCACP, CLS, professor and associate dean for clinical affairs in the Department of Clinical Pharmacy at the University of Colorado Anschutz Skaggs School of Pharmacy and Pharmaceutical Sciences, said in an interview with Pharmacy Times.⁴

The potential of enlicitide to revolutionize cholesterol treatment led to it being granted a national priority voucher from the FDA. The voucher, awarded under the Commissioner’s National Priority Voucher pilot program, is designed to accelerate the review and approval processes for enlicitide, which could help address the national problem of increased cardiovascular risk and increase access to effective therapies.⁵

REFERENCES

1. Navar AM, Mikhailova E, Catapano AL, et al. A placebo-controleld trial of the oral PCSK9 inhibitor enlicitide. N Engl N Med. 2026;394:529-539. doi:10.1056/NEJMoa2511002

2. Halpern L. New enlicitide decanoate data show significant LDL-C reductions in at-risk patients. Pharmacy Times. Published November 19, 2025. Accessed February 5, 2026. https://www.pharmacytimes.com/view/new-enlicitide-decanoate-data-show-significant-ldl-c-reductions-in-at-risk-patients

3. Saseen JJ, Halpern L. Expert: Debunking cholesterol myths and the rise of oral PCSK9 inhibitors. Pharmacy Times. Published February 4, 2026. Accessed February 5, 2026. https://www.pharmacytimes.com/view/expert-debunking-cholesterol-myths-and-the-rise-of-oral-pcsk9-inhibitors

4. Navar AM, Halpern L. Q&A: How oral PCSK9 inhibitors will revolutionize pharmacists’ role in cholesterol control. Pharmacy Times. Published January 22, 2026. Accessed February 5, 2026. https://www.pharmacytimes.com/view/q-a-pharmacists-role-in-the-era-of-oral-pcsk9-inhibitors-for-cholesterol-control

5. Halpern L. FDA grants national priority vouchers to enlicitide decanoate, sacituzumab tirumotecan. Pharmacy Times. Published January 7, 2026. Accessed February 5, 2026. https://www.pharmacytimes.com/view/fda-grants-national-priority-vouchers-to-enlicitide-decanoate-sacituzumab-tirumotecan