An experimental once-daily pill called enlicitide cut LDL cholesterol by 57% in a large Phase 3 clinical trial, a result researchers say could expand options for patients who struggle with existing cholesterol drugs. The findings, drawn from a study of 2,912 participants, were published in the New England Journal of Medicine on February 4, 2026. If the drug reaches the market, it would offer an oral alternative to today’s PCSK9 inhibitor options, which are primarily delivered by injection.
How Enlicitide Works and What the Trial Found
Enlicitide belongs to a class of drugs known as PCSK9 inhibitors, which block a protein that prevents the liver from clearing LDL cholesterol from the bloodstream. Existing PCSK9 inhibitors like evolocumab and alirocumab are effective but require injections every two to four weeks, a barrier that has limited their adoption. Enlicitide, developed by Merck Sharp and Dohme and tested in the Phase 3 CORALreef Lipids trial, is taken as a once-daily 20 mg pill, a format that could dramatically simplify treatment for millions of people with stubbornly high cholesterol.
The Phase 3 trial was randomized, double-blind, and placebo-controlled, enrolling adults already on standard lipid-lowering therapy whose LDL levels remained above target despite treatment. After 24 weeks, those taking enlicitide saw their LDL cholesterol drop by approximately 57% compared to placebo, meeting the primary endpoint and confirming the drug’s strong effect on “bad” cholesterol. Investigators also monitored secondary measures such as non-HDL cholesterol and apolipoprotein B, which tracked in the same favorable direction, although the study was not yet powered to show a reduction in actual cardiovascular events like heart attacks or strokes.
Earlier Data Signaled Strong Results at Higher Doses
The Phase 3 outcome did not emerge in isolation. A dose-ranging Phase 2b trial of the compound, then known as MK-0616, was published in the Journal of the American College of Cardiology and showed that daily oral dosing could drive LDL reductions of up to 60.9% at 30 mg after just eight weeks. In that earlier study, investigators reported that overall adverse events and discontinuation rates were similar between the drug and placebo groups, suggesting that an oral PCSK9 inhibitor could be both potent and well tolerated over the medium term.
Those Phase 2b findings, first shared publicly at the 2023 American College of Cardiology meeting and supported by the trial record for NCT05261126, helped shape the design of the Phase 3 program. Investigators opted for a 20 mg daily dose, aiming to preserve most of the LDL-lowering benefit while optimizing tolerability for longer-term use. The fact that a 57% reduction persisted at 24 weeks in a much larger and more diverse population reinforces the drug’s pharmacologic strength and supports the idea that PCSK9 can be targeted effectively with an oral small molecule rather than an injectable biologic.
Where Enlicitide Fits Alongside Statins
Statins remain the backbone of cholesterol management worldwide, and drugs such as Lipitor and Crestor have decades of evidence showing they cut the risk of heart attacks and strokes. Generic versions are inexpensive and widely accessible, so enlicitide is unlikely to replace statins as first-line therapy. Instead, it is poised to serve patients who cannot tolerate adequate statin doses because of muscle pain or other side effects, as well as those whose LDL remains elevated despite maximally tolerated statins and other oral agents like ezetimibe.
For these patients, injectable PCSK9 antibodies have been available since 2015 but have seen limited uptake due to cost, prior-authorization hurdles, and the practical challenges of self-injection. Enlicitide’s once-daily pill format directly addresses many of those barriers by fitting into the familiar routine of taking oral medications, eliminating the need for refrigeration and injection training. However, pricing will be crucial: as the Associated Press has reported, early injectable PCSK9 drugs launched at list prices around $14,000 per year before subsequent reductions, and insurers often restricted access. How Merck ultimately prices its oral PCSK9 inhibitor will determine whether it becomes a mainstream add-on for high-risk patients or remains confined to a narrow group with generous coverage.
Evidence From Academic Investigators and Remaining Unknowns
Academic lipid experts have highlighted the potential of enlicitide to change everyday practice if the LDL reductions translate into fewer cardiovascular events. Researchers at UT Southwestern Medical Center, who participated in the development program, reported that patients taking the daily pill experienced substantial drops in LDL cholesterol and noted that, if sustained, reductions of that magnitude are generally expected to lower the risk of heart attacks and strokes over time. In a detailed news release describing how the oral PCSK9 agent performed in clinical testing, the institution emphasized that the magnitude of LDL lowering seen with the drug rivals what has been achieved with injectable biologics, but in a form that is easier for patients to use.
The same UT Southwestern report, dated February 4, 2026, underscored important caveats as well. While LDL reduction is a well-established surrogate marker, regulators and clinicians will want to see dedicated outcomes trials showing that enlicitide actually reduces heart attacks, strokes, and cardiovascular deaths. Questions also remain about long-term safety beyond one or two years of continuous use, particularly in populations that may start therapy in middle age and continue for decades. Until those data are available, most guidelines are likely to position the drug as an adjunct for very high-risk patients rather than a universal option for everyone with elevated cholesterol.
A Parallel Trial Targets Genetic High Cholesterol
Merck is not relying solely on patients with garden-variety high cholesterol to define enlicitide’s role. A companion study known as CORALreef HeFH is focusing on individuals with heterozygous familial hypercholesterolemia, a genetic disorder that causes extremely high LDL levels from early life. Participants in this trial must already be on moderate or high-intensity statin therapy, reflecting current standards of care for this high-risk group. The study is designed to assess LDL changes at both 24 and 52 weeks, providing a longer window to evaluate durability of response and to watch for any emerging safety issues with extended use of the oral PCSK9 inhibitor.
Familial hypercholesterolemia affects roughly one in 250 people, and many of them struggle to reach guideline-recommended LDL targets even with multiple medications and, in some cases, injectable PCSK9 antibodies. For these patients, an effective oral agent could meaningfully reduce the treatment burden and improve adherence, especially in younger adults who may be reluctant to start lifelong injections. Investigators at UT Southwestern, which has a long history of studying inherited lipid disorders, noted in a separate summary of the enlicitide program that the genetic trial will be particularly important for clarifying how well the drug performs in people whose cholesterol is elevated not just by lifestyle but by powerful inherited mutations. If CORALreef HeFH confirms large, sustained LDL reductions without new safety concerns, enlicitide could become a cornerstone therapy for this vulnerable population, offering a convenient alternative to the injectable options that currently dominate second-line care.
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*This article was researched with the help of AI, with human editors creating the final content.
