Oral PCSK9 Inhibitor Enlicitide Demonstrates Nearly 60% LDL-C Reduction in Landmark Trial
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A new oral medication, enlicitide decanoate (enlicitide), developed by Merck & Co., has shown significant promise in lowering “bad” cholesterol and reducing the risk of cardiovascular disease. Full results from the phase 3 CORALreef Lipids (NCT05952856) clinical trial, published in The New England Journal of Medicine, reveal substantial reductions in low-density lipoprotein cholesterol (LDL-C) and other key markers of atherosclerotic cardiovascular disease (ASCVD).
The study, conducted between 2025 and 2026, enrolled 2,904 participants aged 18 and older, all with a history of a major ASCVD event or at high risk for a first event. All participants were already taking lipid-lowering therapy, including a statin, prior to the trial. Participants were randomly assigned to receive either 20 mg of enlicitide or a placebo.
The results were striking. At week 24, enlicitide led to a mean percent change in LDL-C levels of approximately –57.1% (95% CI, –61.8 to –52.5), compared to just 3.0% (95% CI, 0.9 to 5.1) with the placebo. This translated to an adjusted between-group difference of –55.8% (95% CI, –60.9 to –50.7; P < .001), successfully meeting the study’s primary endpoint.
“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,” stated a study investigator from UT Southwestern Medical School.
Beyond LDL-C: Broad Impact on Cardiovascular Risk Markers
The benefits of enlicitide extended beyond LDL-C reduction. Key secondary endpoints also showed significant improvements in other crucial indicators of ASCVD. Non–high-density lipoprotein cholesterol (non–HDL-C) decreased by approximately 53.4% (95% CI, –55.5 to –51.2; P < .001), while apolipoprotein B (ApoB) was reduced by 50.3% (95% CI, –52.1 to –48.5; P < .001). Notably, lipoprotein(a) [Lp(a)]—a genetically determined risk factor for cardiovascular disease—was reduced by 28.2% (95% CI, –30.3 to –26.0; P < .001).
The data also revealed a substantial proportion of patients in the enlicitide group achieving clinically significant LDL-C levels. Over 70% of participants taking enlicitide achieved an LDL-C level of less than 70 mg per deciliter with a 50% or greater reduction from baseline, compared to only 1.5% in the placebo group. Furthermore, 67.5% of enlicitide patients reached an LDL-C level below 55 mg per deciliter with a similar reduction, versus 1.2% of those receiving the placebo.
Safety Profile and Future Implications
Importantly, the safety profile of enlicitide appeared comparable to placebo, with no significant differences observed in the incidence of adverse events, serious adverse events, trial discontinuation due to adverse events, or death. This positive safety profile, combined with the dramatic lipid-lowering effects, positions enlicitide as a potentially transformative therapy.
As a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, enlicitide works by enhancing the liver’s ability to remove LDL-C from the bloodstream. Its oral formulation offers a significant advantage over currently available PCSK9 inhibitors, which require injections. “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,” explained a professor of clinical pharmacy at the University of Colorado Anschutz Skaggs School of Pharmacy and Pharmaceutical Sciences.
The potential of this novel treatment has already garnered attention from regulatory bodies. The Food and Drug Administration (FDA) has granted enlicitide a national priority voucher, designed to expedite the review and approval process, recognizing its potential to address the growing national problem of cardiovascular risk and improve access to effective therapies. .
The arrival of enlicitide could fundamentally change the treatment landscape for high cholesterol and cardiovascular prevention, offering a convenient and highly effective option for patients who need additional lipid-lowering therapy beyond statins.
