Oral PCSK9 Inhibitor Delivers Significant Lipid Reductions in High-Risk Patients

Novel drug enlicitide decanoate lowers LDL by over 60% compared to other lipid-lowering therapies

Apr. 8, 2026 at 1:51pm

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In a clinical trial, the oral PCSK9 inhibitor enlicitide decanoate (Merck) lowered LDL cholesterol by more than 60% at 56 days in high-risk patients with atherosclerotic cardiovascular disease or at intermediate-to-high risk, compared to other lipid-lowering drugs like ezetimibe and bempedoic acid. The drug also demonstrated significant reductions in other lipid markers like non-HDL, apolipoprotein B, and lipoprotein(a).

Why it matters

The ability of enlicitide to deliver large lipid reductions in an oral formulation is significant, as many patients prefer taking pills over injectable medications. This could help increase the use of potent lipid-lowering therapies and further reduce cardiovascular risk in high-risk populations.

The details

In the CORALreef AddOn trial, researchers randomly assigned 301 statin-treated patients with a history of ASCVD or at high risk to receive either enlicitide 20 mg daily, bempedoic acid, ezetimibe, or a combination of bempedoic acid and ezetimibe. At 56 days, LDL declined 64.6% in the enlicitide group, significantly more than the 36.5% reduction seen with the bempedoic acid/ezetimibe combination, 27.8% with ezetimibe alone, and just 6.3% with bempedoic acid alone. Enlicitide also led to greater reductions in other lipid markers compared to the other treatments.

  • The CORALreef AddOn trial results were presented at the American College of Cardiology Scientific Session in April 2026.
  • An on-treatment analysis of data from the CORALreef Lipids and CORALreef HeFH trials also showed enlicitide lowered LDL by 60% at 52 weeks compared to placebo.

The players

Alberico L. Catapano, MDHc, PhD

Professor and director of the Center of Epidemiology and Preventive Pharmacology at ICCS MultiMedica and the University of Milan, and lead investigator of the CORALreef AddOn trial.

Ann Marie Navar, MD, PhD

Associate professor of medicine (cardiology) at UT Southwestern Medical School, and presenter of the on-treatment analysis of the CORALreef Lipids and CORALreef HeFH trials.

Merck

The pharmaceutical company that developed the oral PCSK9 inhibitor drug enlicitide decanoate.

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What they’re saying

“Many patients like to take oral drugs, or don't like to be injected. So I think [enlicitide] is a good option, and that will promote even more the use of lipid-lowering drugs, and reduce cardiovascular risk across the world.”

— Alberico L. Catapano, Professor and director, Center of Epidemiology and Preventive Pharmacology at ICCS MultiMedica and the University of Milan

“Enlicitide provided significant and sustained LDL cholesterol lowering through week 52. Those who remained on treatment had a 64% placebo-corrected reduction at week 24 and 60% at week 52. The high degree of self-reported adherence to dosing instructions is corroborated by the demonstrated and sustained LDL lowering that we observed in this on-treatment analysis.”

— Ann Marie Navar, Associate professor of medicine (cardiology) at UT Southwestern Medical School

What’s next

The first outcome trial for enlicitide is currently ongoing, and results will be available in the future. Once those results are published, the drug is expected to be approved and made available to patients.

The takeaway

The ability of the oral PCSK9 inhibitor enlicitide to deliver substantial LDL reductions of over 60% compared to other lipid-lowering therapies could significantly expand access to potent cholesterol-lowering treatments, especially for patients who prefer taking pills over injectable medications. This could have a major impact on reducing cardiovascular risk in high-risk populations.