New Oral Contender Outshines Standard Add-on Therapies for LDL-C

For decades, the standard of care for lowering low-density lipoprotein cholesterol (LDL-C) has followed a predictable, albeit sometimes slow, stepwise approach: start with statins and, if goals are not met, add oral agents such as ezetimibe (Zetia; Merck) or bempedoic acid (Nexletol; Esperion Therapeutics, Inc). If those fail, patients often move to powerful, although sometimes underutilized, injectable PCSK9 monoclonal antibodies. However, results from the phase 3 CORALreef AddOn trial (NCT06450366), now published in the Journal of the American College of Cardiology, suggest a paradigm shift may be on the horizon with the emergence of enlicitide decanoate (Merck), the first oral PCSK9 inhibitor to show dramatic superiority over current oral nonstatin therapies.^1,2

A Decisive Victory in Lipid Lowering

The trial, led by Alberico L. Catapano, PhD, of the University of Milan, compared enlicitide directly against the most common oral add-on options used when statins alone are insufficient. The study randomly assigned 301 adults—all of whom were already on stable statin therapy and had either a history of a major atherosclerotic cardiovascular disease event or were at high risk for one.¹

By day 56 of the trial, participants taking 20 mg of enlicitide daily saw their LDL-C levels plummet by an average of 64.6%. In comparison, those taking ezetimibe saw a 27.8% reduction, whereas the combination of bempedoic acid and ezetimibe achieved a 36.5% reduction. Bempedoic acid alone produced a modest 6.3% reduction, a figure lower than seen in previous trials, which researchers noted might be due to the specific high-intensity statin background of this study population.¹

"Enlicitide achieved greater reductions in LDL-C, [apolipoprotein B], and non-[high-density lipoprotein]-C than other oral non-statin therapies," the investigators concluded, noting its potential to bridge the "persistent gap" in lipid management where patients fail to reach guideline-recommended goals.^1,2

Beyond the Primary Goal

Although LDL-C is the primary target, enlicitide also demonstrated a broader impact on the atherogenic profile—the collection of particles that contribute to arterial plaque. The drug significantly outperformed its competitors in reducing apolipoprotein B, which represents the total number of atherogenic particles, and non-HDL-C. Perhaps most notably for specialists, enlicitide reduced lipoprotein(a), a genetically determined risk factor that ezetimibe and bempedoic acid typically do not affect.¹

The trial also highlighted a massive difference in goal attainment. Although fewer than one-fourth of patients on the ezetimibe/bempedoic acid combination reached an LDL-C level below 70 mg/dL with at least a 50% reduction, over 81% of those on enlicitide hit that target.¹

The Crucial Role of the Pharmacist

As this new class of medication moves toward potential clinical use, the role of the pharmacist in patient education and adherence will be paramount. Unlike standard statins, enlicitide is a macrocyclic peptide that requires specific administration to be effective. Pharmacists will need to counsel patients to take enlicitide on an empty stomach in the morning, followed by a 30-minute fast from all food and beverages except water.¹

During the trial, adherence to these instructions was high (over 95%), which likely contributed to the robust efficacy results.¹ Pharmacists are uniquely positioned to ensure this success translates to the real world, where therapeutic inertia often leaves high-risk patients vulnerable.

Furthermore, the safety profile of enlicitide appears encouraging for long-term management. Adverse event rates were similar across all treatment arms (40% for enlicitide vs 45% for the combination therapy), and there were no reports of drug-induced liver injury or new-onset diabetes.¹ This safety profile, combined with the convenience of an oral pill over an injection, could significantly improve patient uptake and long-term compliance.

Closing the Treatment Gap

CORALreef AddOn suggests that enlicitide could simplify the complex stepwise escalation of lipid therapy. By providing significant efficacy in an oral format, it offers a potent tool for clinicians to "strike early and strike strong" against cumulative LDL-C exposure.^1,2

As the medical community awaits longer-term data from the ongoing phase 3 CORALreef Outcomes trial (NCT06008756)—which is currently investigating whether these lipid reductions translate into fewer heart attacks and strokes—enlicitide stands out as a promising new weapon in the fight against the global cardiovascular epidemic. For pharmacists and patients alike, the prospect of a once-daily pill that rivals the power of an injection could mark the beginning of a new era in heart health.

REFERENCES

1. Catapano AL, Mikhailova E, Navar AM, et al; CORALreef AddOn Investigators. Oral PCSK9 inhibitor enlicitide versus oral non-statin therapies: a phase 3 randomized clinical trial. JACC. Published online March 30, 2026. doi:10.1016/j.jacc.2026.03.036

2. Catapano A. Efficacy and safety of enlicitide decanoate, an oral macrocyclic peptide inhibitor of PCSK9, compared with bempedoic acid, ezetimibe, or bempedoic acid co-administered with ezetimibe in statin-treated adults with hypercholesterolemia: phase 3 CORALreef AddOn trial. Presented at: American College of Cardiology 2026 Scientific Sessions; March 29, 2026; New Orleans, LA.