New Enlicitide Decanoate Data Show Significant LDL-C Reductions in At-Risk Patients

Data presented at the 2025 American Heart Association (AHA) Scientific Sessions in New Orleans, Louisiana, from the CORALreef Lipids (NCT05952856) and CORALreef HeFH (NCT05952869) clinical trials demonstrate significant reductions in low-density lipoprotein cholesterol (LDL-C) in at-risk populations when using enlicitide decanoate (Merck & Co), a once-daily oral proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor.^1-4

CORALreef Lipids Highlights Enlicitide Decanoate’s Role in LDL-C Reductions in At-Risk Populations

The pivotal randomized, double-blind, placebo-controlled, phase 3 CORALreef lipids trial was designed to evaluate enlicitide decanoate in adults with or at risk for atherosclerotic cardiovascular disease (ASCVD) on background lipid-lowering therapies (LLTs) or those with documented statin intolerance. A total of 2912 participants were enrolled and subsequently randomized 2:1 to receive either 20 mg of once-daily enlicitide (n = 1942) or placebo (n = 970).¹

At week 24, enlicitide decanoate resulted in a statistically meaningful and clinically significant reduction in LDL-C (55.8%; 95% CI, –60.9 to –50.7, P < .001) compared with placebo, with greater reductions observed in a post-hoc reanalysis (59.7%; 95% CI, –62.3 to –57.1, P < .001). Reductions were also observed in non-high-density lipoprotein cholesterol (non-HDL-C) (53.4%; 95% CI, –55.5 to –51.2, P < .001), apoprotein B (ApoB) (50.3%; 95% CI, –52.1 to –48.5, P < .001), and lipoprotein A (Lp[a]) (28.2%; 95% CI, –30.3 to –26.0, P < .001) with enlicitide decanoate compared with placebo.¹

One year into treatment, enlicitide decanoate elicited significant reductions in LDL-C of 47.6% in the primary analysis (95% CI, –52.7 to –42.5, P < .001) and 52.4% in the post-hoc reanalysis (95% CI, –55.1 to –49.7, P < .001) compared with placebo. Importantly, 67.5% of treated patients achieve the prespecified LDL-C-lowering goal of at least 50% reduction, along with LDL-C levels less than 55 mg/dL. This can be compared with 1.2% of patients in the placebo arm achieving such reductions at week 24.¹

“Despite the availability of lipid-lowering therapies such as statins and injectable PCSK9 inhibitors, the majority of patients with ASCVD do not reach their LDL-C goal,” Ann Marie Navar, MD, PhD, a lead author of the study, said in a news release accompanying its results. “Enlicitide has the potential to help close gaps in achievement of lipid goals in patients with and at risk for cardiovascular events and ultimately help address the ongoing CV epidemic.”¹

CORALreef HeFH Demonstrates Enlicitde’s Efficacy in Patients With Extremely High LDL-C

The phase 3, randomized, double-blind, placebo-controlled, multicenter CORALreef HeFH trial shifted focus to patients with heterozygous familial hypercholesterolemia (HeFH), a genetic disorder characterized by abnormally elevated LDL-C. Patients with HeFH often face a heightened risk of premature ASCVD due to high cumulative LDL-C exposure. Since HeFH cannot be managed through lifestyle changes alone, effective cholesterol-lowering medication is necessary for these patients.²

Data from CORALreef HeFH, presented at AHA and simultaneously published in the Journal of the American Medical Association, highlights the effectiveness of enlicitide decanoate in significantly lowering LDL-C for patients with the rare condition. Enrolled patients included those with HeFH and a history or current risk for a major ASCVD event, who had previously received background LLT, including moderate- or high-intensity statins.^2,5

Over 300 patients were randomized 2:1 to receive either 20 mg of enlicitide decanoate once daily or a placebo. Patients treated with enlicitide achieved significant and meaningful reductions in LDL-C of 59.4% at week 24 compared with placebo (59.4%; 95% CI, –65.6 to –53.2, P < .001), with a similar effect size and safety profile to that observed in CORALreef Lipids.^2,5

Positive reductions in non-HDL-C (53.0%; 95% CI, –58.5 to –47.4, P < .001), ApoB (49.1%; 95% CI, –54.0 to –44.3, P < .001), and Lp(a) (27.5%; 95% CI, –34.3 to –20.6, P < .001) were observed in patients treated with enlicitide compared with placebo. There was also a significant proportion of patients (67.3%) treated with enlicitide who achieved at least a 50% reduction in LDL-C with LDL-C levels less than 55 mg/dL at week 24, compared with 1.0% in the placebo arm.^2,5

Investigators observed LDL-C reductions as early as week 4 of the trial, which were maintained through 1 year of treatment. At the 1-year mark, enlicitide decanoate led to major reductions in LDL-C of 61.5% compared with placebo (95% CI, –69.4 to –53.7, P < .001).^2,5

“As the potentially first approved oral PCSK9 inhibitor, enlicitide was designed to provide efficacy similar to anti-PCSK9 monoclonal antibodies and may be an important new treatment option to help adults with HeFH reach their guideline-recommended LDL-C goal,” Christie M. Ballantyne, MD, lead author of CORALreef HeFH, said in a news release. “Lowering elevated LDL-C levels helps reduce the risk of atherosclerotic cardiovascular disease.”²

Pharmacists should continue to monitor the regulatory path of enlicitide decanoate and prepare themselves for its likely approval. If the FDA approves enlicitide decanoate, patients with hypercholesterolemia and HeFH will have a convenient and effective new treatment option to reduce their LDL-C. Its oral formulation will allow for better adherence and more significant proportions of patients who achieve their LDL-C goals and lower their ASCVD risk.

REFERENCES

1. Merck’s enlicitide decanoate, an investigational oral PCSK9 inhibitor, significantly reduced LDL-C in phase 3 CORALreef Lipids trial. News Release. Merck. Released November 8, 2025. Accessed November 19, 2025. https://www.merck.com/news/mercks-enlicitide-decanoate-an-investigational-oral-pcsk9-inhibitor-significantly-reduced-ldl-c-in-phase-3-coralreef-lipids-trial/

2. Merck’s enlicitide decanoate, an investigational oral PCSK9 inhibitor, significantly reduced LDL-C in adults with heterozygous familial hypercholesterolemia (HeFH) in phase 3 CORALreef HeFH trial. News Release. Merck. Released November 9, 2025. Accessed November 19, 2025. https://www.merck.com/news/mercks-enlicitide-decanoate-an-investigational-oral-pcsk9-inhibitor-significantly-reduced-ldl-c-in-adults-with-heterozygous-familial-hypercholesterolemia-hefh-in-phase-3-coralreef-hefh-tr/

3. A study of enlicitide decanoate (MK-0616 oral PCSK9 inhibitor) in adults with hypercholesterolemia (MK-0616-013) CORAlreef Lipids. ClinicalTrials.gov Identifier: NCT0592856. Last Updated September 10, 2025. Accessed November 19, 2025. https://clinicaltrials.gov/study/NCT05952856

4. A study of enlicitide decanoate (MK-0616 oral PCSK9 inhibitor) in adults with heterozygous familial hypercholesterolemia (MK-0616-017) CORAlreef HeFH. ClinicalTrials.gov Identifier: NCT0592869. Last Updated May 13, 2025. Accessed November 19, 2025. https://clinicaltrials.gov/study/NCT05952869

5. Ballantyne CM, Gellis L, Tardif J, et al. Efficacy and safety of oral PCSK9 inhibitor enlicitide in adults with heterozygous familial hypercholesterolemia: A randomized clinical trial. JAMA. Published Online: November 9, 2025. Accessed November 19, 2025. doi:10.1001/jama.2025.20620