The pivotal CORALreef Lipids study has shown that **enlicitide decanoate**, an oral PCSK9 inhibitor developed by **Merck**, successfully met all primary and key secondary endpoints for treating hypercholesterolemia in adults at increased risk for atherosclerotic cardiovascular disease. Announced on **September 2, 2025**, the trial indicated that treatment with enlicitide led to statistically significant reductions in low-density lipoprotein cholesterol (**LDL-C**) compared to placebo after **24 weeks**.
In addition to lowering LDL-C, enlicitide also demonstrated reductions in non-high-density lipoprotein cholesterol (**non-HDL-C**), apolipoprotein B (**ApoB**), and lipoprotein(a) [LP(a)]. Importantly, the study reported no significant differences in adverse events, including serious ones, between the treatment and placebo groups.
Groundbreaking Results and Future Potential
Dr. **Ann Marie Navar**, an associate professor of medicine in the division of cardiology at **UT Southwestern Medical Center**, who led the study, remarked, “These data add to the growing body of evidence supporting the safety and efficacy profile of enlicitide to lower LDL cholesterol and other key atherogenic lipids including ApoB and Lp(a).” She emphasized the potential for enlicitide to help more patients achieve guideline-recommended lipid goals, ultimately reducing atherosclerotic cardiovascular risk.
Enlicitide is particularly noteworthy as it may be the first oral PCSK9 inhibitor that lowers LDL-C through the same biological mechanism as existing injectable monoclonal antibody PCSK9 inhibitors, but in a convenient daily pill form. This small molecule macrocyclic peptide binds to PCSK9, inhibiting its interaction with LDL receptors, thereby enhancing the body’s ability to remove LDL-C from the bloodstream.
The CORALreef Lipids trial was a **phase 3 randomized, placebo-controlled, double-blind study** involving **2760 participants** who had previously been treated with stable lipid-lowering therapies, including statins or had experienced statin intolerance. The primary objective was to assess whether enlicitide decanoate was superior to placebo in reducing LDL-C, measured by mean percent change from baseline at week 24. Key secondary endpoints included changes in LDL-C at week 52 and in other key atherogenic lipids at week 24.
Participants were randomly assigned in a **1:1 ratio** to receive either enlicitide decanoate at a dose of **20 mg** or a placebo, administered daily for up to **52 weeks**. Blood samples were collected at baseline and week 24 to evaluate the percentage of participants achieving LDL-C levels below **55 mg/dL** and those with a **50%** reduction from baseline, along with mean percent changes in LDL-C, non-HDL-C, and ApoB.
Ongoing Investigations and Implications
The safety and efficacy of enlicitide continue to be evaluated through the **CORALreef Clinical Trial program**, which encompasses a broader series of phase 3 clinical trials. Dr. **Dean Y. Li**, president of **Merck Research Laboratories**, noted, “This is the third Phase 3 trial to demonstrate clinically meaningful and statistically significant LDL-C lowering for enlicitide.” He further stated that if approved, enlicitide could transform the management of LDL levels, providing patients with a new option to help meet their treatment goals.
As the medical community anticipates further developments, the results from the CORALreef Lipids study mark a significant step forward in the fight against hypercholesterolemia and related cardiovascular risks.