# Enlicitide: An Oral Pill That Cuts “Bad” Cholesterol by More Than Half — What a Major Clinical Trial Found

In a large international clinical trial called CORALreef Lipids, researchers tested a new daily pill called enlicitide (en-li-SY-tide) in people with high cholesterol and heart disease risk. After 24 weeks of treatment, participants who took enlicitide saw their "bad" LDL cholesterol drop by an average of 57.1%, while those who took a placebo saw a slight increase of 3.0% — a highly significant difference reaching -55.8 percentage points after adjustment. The oral medication, which blocks a liver protein known as PCSK9, continued to show strong cholesterol-lowering effects through 52 weeks, with a safety profile that appeared similar to placebo. If approved, enlicitide could become the first oral PCSK9 inhibitor, offering a pill alternative to currently available injectable therapies.

# Enlicitide: An Oral Pill That Cuts “Bad” Cholesterol by More Than Half — What a Major Clinical Trial Found

## Table of Contents

- Key Points
- Why This Research Matters
- How the Study Was Conducted
- Key Findings: LDL Cholesterol Reduction at 24 Weeks
- Additional Lipid Improvements at 24 and 52 Weeks
- Safety and Tolerability
- What This Means for Patients
- Study Limitations
- Recommendations for Patients
- Frequently Asked Questions
- Source Information

## Key Points

- In a phase 3 trial of 2,909 adults, enlicitide lowered LDL cholesterol by 57.1% at 24 weeks versus a 3.0% increase with placebo.
- Enlicitide is an investigational oral PCSK9 inhibitor, offering a potential daily-pill alternative to injectable PCSK9 drugs.
- More than two-thirds of enlicitide-treated patients reached the strict LDL goal of under 55 mg/dL plus a 50% reduction.
- The drug also reduced non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) by significant amounts at 24 weeks.
- Adverse events appeared similar to placebo over 52 weeks, but effects on heart attacks or strokes are not yet proven.

## Why This Research Matters

For decades, clinical trials have shown that lowering low-density lipoprotein (LDL) cholesterol — often called "bad" cholesterol — helps prevent heart attacks, strokes, and other cardiovascular events. Benefits are seen even in people who start with LDL levels well below 70 mg/dL (1.8 mmol/L). Because of this, modern clinical guidelines recommend that the highest-risk patients aim for LDL cholesterol levels of 55 mg/dL (1.4 mmol/L) or lower.

Yet despite these recommendations, **more than half of patients still do not reach their target LDL levels**. Many are already taking statins, the first-line cholesterol-lowering drugs, but they may need additional help.

The most powerful non-statin therapies currently available work by inhibiting a liver protein called proprotein convertase subtilisin–kexin type 9, or **PCSK9**. When PCSK9 is blocked, more LDL receptors remain on liver cells, allowing the liver to remove more LDL cholesterol from the blood.

Two forms of PCSK9 inhibitors already exist: injectable monoclonal antibodies and a small interfering RNA (a type of genetic medicine) that is also given by injection. Studies have shown these injectable drugs reduce cardiovascular events in high-risk patients. However, despite their proven benefit, PCSK9 inhibitors are **infrequently used in clinical practice**. One major reason is that they must be injected.

This trial was designed to evaluate a new option: **enlicitide decanoate**, an oral macrocyclic peptide that blocks PCSK9 from binding to LDL receptors. Previous phase 1 and phase 2 studies showed short-term LDL reductions, but longer-term data were needed. The CORALreef Lipids trial set out to provide those longer-term results.

## How the Study Was Conducted

### Trial Design and Oversight

CORALreef Lipids was a **phase 3, multinational, double-blind, randomized, placebo-controlled trial**. It was conducted at 168 sites in 14 countries. “Double-blind” means neither the patients nor the research team knew who was receiving the active drug and who was receiving the placebo — a design that prevents bias.

The trial was sponsored by MSD (Merck & Co.), based in Rahway, New Jersey. It was designed by the sponsor in collaboration with a scientific advisory committee, and an independent data and safety monitoring board provided oversight. The trial protocol was approved by an institutional review board or independent ethics committee at each participating site. All participants gave written informed consent.

Data were collected at participating sites and analyzed by representatives of the sponsor, who vouched for the accuracy and completeness of the data. Academic authors interpreted the data. The first author drafted the manuscript with editorial support from a medical writer employed by the sponsor.

### Trial Population

To participate, adults had to be at least 18 years old and meet one of these two sets of criteria:

-
**Established disease group:** A history of a major atherosclerotic cardiovascular disease event and an LDL cholesterol level of **55 mg/dL or higher**. Major events included acute coronary syndrome, coronary revascularization, heart attack (myocardial infarction), ischemic stroke, cerebrovascular arterial revascularization, and peripheral artery disease with a history of acute limb ischemia, revascularization, or major amputation (meaning amputation of all or part of an arm or leg, not just fingers or toes).
-
**At-risk group:** Intermediate-to-high risk for a first atherosclerotic cardiovascular event and an LDL cholesterol level of **70 mg/dL or higher**. This risk was defined by any of the following: heterozygous familial hypercholesterolemia (an inherited form of very high cholesterol), diabetes mellitus, stable angina, a previous transient ischemic attack (mini-stroke), symptomatic peripheral artery disease, or age 40 or older with a predicted 10-year cardiovascular risk of at least 7.5% by the American Heart Association and American College of Cardiology Pooled Cohort Equation (or an equivalent calculator), or a coronary-artery calcium score of at least 100 Agatston units (a marker of plaque in the heart arteries).

Participants were required to be on a **stable dose of appropriate lipid-lowering therapy** for at least 30 days before screening, including at least a moderate- or high-intensity statin, unless they had a documented history of unacceptable side effects from statins.

People were excluded if they were actively receiving or had recently received a PCSK9 inhibitor, had uncontrolled high blood pressure or diabetes, had active liver disease, or had a triglyceride level of 400 mg/dL (4.52 mmol/L) or higher at screening.

### Trial Procedures

Participants were randomly assigned in a **2:1 ratio** to receive either enlicitide decanoate at a dose of 20 mg daily or a matching placebo daily for 52 weeks. The enlicitide formulation included an excipient (a non-active ingredient) called **sodium caprate**, which acts as a permeation enhancer to help the drug be absorbed in the digestive tract. The placebo did not contain sodium caprate.

Randomization was stratified (balanced) according to three factors:

- Renal function (estimated glomerular filtration rate, or eGFR, of ≥60 vs. <60 mL/min/1.73 m²)
- Baseline statin use
- Geographic region

Participants were told to take the pill in the morning on an empty stomach and to **withhold food and beverages other than water for 30 minutes** after taking it. Study visits occurred at baseline and at weeks 4, 8, 16, 24, 36, and 52. After the 52-week treatment period, participants completed an 8-week safety follow-up or could choose to enroll in a separate open-label extension study (ClinicalTrials.gov number NCT06492291).

### End Points (Outcome Measures)

The **primary end point** was the mean percent change in LDL cholesterol level from baseline to week 24. Key secondary end points were tested in a specific order:

- Mean percent change in LDL cholesterol level from baseline to week 52
- Mean percent change in non–high-density lipoprotein (non-HDL) cholesterol level from baseline to week 24
- Mean percent change in apolipoprotein B level from baseline to week 24
- Percent change in lipoprotein(a) — an inherited risk factor — from baseline to week 24

Other secondary end points included achieving an LDL cholesterol level of **less than 70 mg/dL** along with a 50% or greater reduction from baseline, and achieving an LDL level of **less than 55 mg/dL** along with a 50% or greater reduction.

Safety end points included adverse events, discontinuation due to adverse events, and two prespecified topics of clinical interest: **new or worsening diabetes mellitus** and **drug-induced liver injury**.

### Laboratory Methods

Throughout the trial, LDL cholesterol levels were calculated using the Martin–Hopkins equation. At baseline, LDL cholesterol was also directly measured by beta quantification in all participants. During follow-up, beta quantification was used if the calculated LDL level was 40 mg/dL (1.03 mmol/L) or lower, if data were missing, or if triglycerides were 400 mg/dL or higher. Central laboratories in five locations performed all measurements.

### Statistical Analysis

The planned sample size was 2,760 participants, designed to provide at least 1,500 participants exposed to enlicitide for about 52 weeks. The researchers estimated that, assuming a standard deviation of 25%, a true -50 percentage-point difference between groups in the mean percent change in LDL, and 5% discontinuation by week 24, the trial would have **more than 99% statistical power** at a one-sided alpha of 0.025 for the primary end point.

The primary analysis used an analysis of covariance (ANCOVA) model with treatment, renal function, and geographic region as fixed effects and baseline LDL cholesterol as a covariate. Missing data (including data from participants who died) were handled with a “washout imputation” approach, in which missing values were imputed based on changes observed in the placebo group — a conservative method. A nonparametric bootstrap approach with 1,000 samples was used for statistical inference. For the lipoprotein(a) endpoint, a stratified Wilcoxon test was used, with multiple imputation for missing data.

A post hoc reanalysis was also performed after database lock, because some baseline beta-quantification LDL values of 0 or less were determined to be biologically impossible. In that reanalysis, beta-quantification results with LDL values of 0 or less were set to missing, and Martin–Hopkins results were used when available.

## Key Findings: LDL Cholesterol Reduction at 24 Weeks

### Participant Disposition and Baseline Characteristics

A total of **2,912 participants** were randomly assigned between August 2023 and July 2025: 1,942 to enlicitide and 970 to placebo. Three participants were enrolled at multiple sites in separate enlicitide trials and were excluded, leaving **2,909 participants in the intention-to-treat population**. Of these, 5 did not receive the assigned treatment, leaving **2,904 participants (1,935 on enlicitide and 969 on placebo)** for efficacy and safety analyses.

Completion rates were high: **94.6%** of the enlicitide group and **94.7%** of the placebo group completed the trial, including 88.4% and 88.9% who continued treatment through the end of the 52-week period. Adherence was strong, with an **overall mean adherence of 97.2%**, and it was similar in both groups.

The two groups were well balanced. The mean age was **62.8 ± 10.7 years**, and **39.3% of participants were women**. The racial and ethnic breakdown was: 53.9% White, 27.6% Hispanic or Latino, and 26.3% Asian. More than half (58.3%) had a previous major atherosclerotic cardiovascular event.

At baseline, **96.6% of participants were taking a statin** (95.4% on a moderate- or high-intensity statin), and **25.8% were taking ezetimibe or hybuthimibe** (additional cholesterol-lowering drugs).

### Primary End Point: LDL Change at Week 24

At baseline, the mean LDL cholesterol level was **95.0 ± 38.8 mg/dL (2.46 ± 1.00 mmol/L)** in the enlicitide group and **98.3 ± 39.2 mg/dL (2.54 ± 1.01 mmol/L)** in the placebo group.

By week 24, the mean LDL level had fallen to **38.7 ± 35.6 mg/dL (1.00 ± 0.92 mmol/L)** in the enlicitide group, while the placebo group’s mean was essentially unchanged at **98.6 ± 42.5 mg/dL (2.55 ± 1.10 mmol/L)**.

In the primary analysis, the mean percent change in LDL cholesterol from baseline to week 24 was:

-
**−57.1%** (95% confidence interval [CI], −61.8 to −52.5) with enlicitide
-
**+3.0%** (95% CI, 0.9 to 5.1) with placebo

After adjustment for baseline LDL cholesterol, renal function, and geographic region, the between-group difference was **−55.8 percentage points** (95% CI, −60.9 to −50.7; P<0.001). In plain language, enlicitide lowered LDL by about 56 percentage points more than placebo, a result that is statistically overwhelming (a less than 0.1% probability of happening by chance). The benefit was consistent across subgroups (as shown in Figure S3 of the supplementary material).

### Post Hoc Reanalysis

In the post hoc reanalysis that corrected for biologically impossible baseline LDL values, the between-group difference in the mean percent change in LDL cholesterol was even larger: **−59.7 percentage points** (95% CI, −62.3 to −57.1). This confirms that the main result was robust to different ways of handling unusual lab values.

## Additional Lipid Improvements at 24 and 52 Weeks

All key secondary end points also favored enlicitide, and all differences were highly significant (P<0.001 for all comparisons).

-
**LDL cholesterol at week 52:** The adjusted between-group difference was **−47.6 percentage points** (95% CI, −52.7 to −42.5; P<0.001), showing that the large LDL reduction was maintained with long-term use.
-
**Non-HDL cholesterol at week 24:** The adjusted between-group difference was **−53.4 percentage points** (95% CI, −55.5 to −51.2; P<0.001). Non-HDL reflects all the “bad” cholesterol in the blood, including LDL and other atherogenic particles.
-
**Apolipoprotein B at week 24:** The adjusted between-group difference was **−50.3 percentage points** (95% CI, −52.1 to −48.5; P<0.001). Apolipoprotein B is a protein carried on all atherogenic particles and is a very strong predictor of heart disease risk.
-
**Lipoprotein(a) at week 24:** The median between-group difference in the percent change was **−28.2 percentage points** (95% CI, −30.3 to −26.0; P<0.001). Lipoprotein(a), or Lp(a), is an inherited, genetically determined risk factor for heart disease; reducing it is considered a potential additional benefit.

### Achieving Guideline-Based LDL Goals

The study also measured how many patients reached the strict LDL targets recommended for high-risk individuals:

-
**An LDL level of less than 70 mg/dL and a 50% or greater reduction from baseline:** achieved by **70.3%** of enlicitide-treated participants vs. **1.5%** of placebo-treated participants.
-
**An LDL level of less than 55 mg/dL and a 50% or greater reduction from baseline:** achieved by **67.5%** of enlicitide-treated participants vs. **1.2%** of placebo-treated participants.

These numbers demonstrate that enlicitide allowed the majority of patients to reach the very low LDL levels now recommended for people at the highest cardiovascular risk.

(Changes in HDL, or “good,” cholesterol and triglycerides were reported in the supplementary materials but were not part of the hierarchical testing in this analysis.)

## Safety and Tolerability

The researchers reported that the **incidence of adverse events did not appear to differ between the enlicitide and placebo groups**. This is reassuring for a new medication, although the results are limited by the 52-week duration of the trial.

As is standard in such studies, the trial prespecified two safety topics of special interest: **new or worsening diabetes** and **drug-induced liver injury**. The main results section of the article notes that safety analyses included all participants who received at least one dose of study medication; no detailed numbers for these specific safety topics are reported in the abstract or main summary, but they will presumably appear in future detailed safety reports or the supplementary appendix.

The study also recorded discontinuations due to adverse events, and the completion rates above (88–89% continued to the end of the 52-week treatment period) suggest that the drug was generally well tolerated.

## What This Means for Patients

This is the first phase 3 trial to show that an **oral** PCSK9 inhibitor can produce LDL reductions of the same magnitude as injectable PCSK9 drugs, which typically lower LDL by 50–60%. If enlicitide is approved by regulators, patients might soon have a pill option that is far less burdensome than injections.

The practical implications are significant:

-
**Convenience:** A daily pill can be taken at home without needles, potentially improving long-term adherence.
-
**Goal attainment:** More than two-thirds of enlicitide-treated patients reached the very strict LDL goal of <55 mg/dL with ≥50% reduction, a target that many patients today fail to achieve.
-
**Comprehensive lipid benefits:** Beyond LDL, enlicitide also reduced non-HDL cholesterol, apolipoprotein B, and Lp(a) — three additional markers that contribute to cardiovascular risk.
-
**Potential for earlier use:** An oral agent could be used alongside statins and ezetimibe without requiring patients to visit a clinic for injections. It may also be appropriate for people who are reluctant to start injectable therapy.

The current evidence is mechanistic: it shows enlicitide improves lipid levels. What we do not yet know is whether these LDL reductions will translate into fewer heart attacks and strokes. However, given the long-established causal relationship between LDL lowering and cardiovascular event reduction — supported by dozens of trials over decades — it is reasonable to expect that a 57% reduction in LDL would significantly lower risk. The FDA and other regulatory authorities will review this evidence, and longer-term cardiovascular outcome trials will be important to confirm clinical benefits.

## Study Limitations

No single trial is perfect, and this one has several limitations that patients and clinicians should keep in mind:

-
**Surrogate end point:** The primary outcome was LDL cholesterol, not heart attacks, strokes, or deaths. LDL cholesterol is an established surrogate, but the actual reduction in cardiovascular events has not yet been measured in this drug’s development program.
-
**Duration:** Twelve months (52 weeks) is longer than early-phase studies but is still relatively short for a chronic medication. Long-term safety — especially regarding diabetes and liver effects — requires more observation.
-
**No active comparator:** The trial compared enlicitide to placebo, not to injectable PCSK9 inhibitors. Head-to-head trials would be needed to know whether enlicitide performs as well as or better than the injectable options in direct comparison.
-
**Population selection:** The trial excluded people with uncontrolled hypertension or diabetes, active liver disease, and very high triglycerides. Results may not apply to those groups.
-
**Adherence requirements:** The drug must be taken on an empty stomach, with no food or beverages (other than water) for 30 minutes after the dose. This is manageable but could be challenging for some patients, and the 97% adherence seen in a clinical trial may not reflect real-world use.
-
**Data-handling complexities:** The trial used sophisticated statistical imputation methods and a post hoc reanalysis to handle unusual beta-quantification results. Although the reanalysis confirmed the primary result, such complexities highlight the need for careful interpretation.

## Recommendations for Patients

If you are at high risk for heart disease or have had a previous cardiovascular event, here’s what this study means for you and what you can do now:

1.
**Know your numbers.** Ask your doctor about your LDL cholesterol, non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) levels. The target LDL for high-risk patients is generally 55 mg/dL or lower.
1.
**Stay on your statin.** Statins are the bedrock of cholesterol management. In this trial, 96.6% of participants were taking a statin, and enlicitide was tested on top of statin therapy. Never stop a statin without talking to your doctor.
1.
**Recognize the “injectable” barrier.** If your doctor has suggested an injectable PCSK9 inhibitor and you are avoiding it because of needles, understand that injectable drugs are proven to reduce heart attacks and strokes. In the future, an oral option may become available, but don’t wait to address elevated LDL if it is currently above goal.
1.
**Ask about add-on therapies.** If you are still far from your LDL goal on a maximally tolerated statin, ask whether ezetimibe, an injectable PCSK9 inhibitor, or enrollment in clinical trials like the enlicitide program is appropriate for you.
1.
**Watch for study updates.** Longer-term data and cardiovascular outcome trials are needed. If enlicitide is approved, follow the official prescribing information and discuss it with your healthcare provider.
1.
**Adopt a heart-healthy lifestyle.** Medications are powerful, but they work best alongside a diet low in saturated fats, regular physical activity, weight management, smoking cessation, and control of blood pressure and diabetes.

## Frequently Asked Questions

### What is enlicitide and how does it work?

Enlicitide is an experimental daily oral pill that blocks a liver protein called PCSK9. Blocking PCSK9 leaves more LDL receptors on liver cells, allowing the liver to remove more 'bad' LDL cholesterol from the blood. It was tested as an add-on to statins in people with high cholesterol and heart disease risk.

### Who was eligible for the CORALreef Lipids trial?

Adults with either a history of major cardiovascular events and LDL ≥55 mg/dL, or intermediate-to-high risk for a first event and LDL ≥70 mg/dL. They had to be on a stable statin dose unless statins caused unacceptable side effects. People with uncontrolled blood pressure, active liver disease, or very high triglycerides were excluded.

### Will enlicitide reduce heart attacks or strokes?

Not yet known. The trial measured LDL cholesterol levels, not actual heart attacks or strokes. LDL cholesterol is an established surrogate, and the expectation is that a large LDL reduction would lower risk, but longer-term cardiovascular outcome trials are still needed to confirm clinical benefits.

### What side effects were seen with enlicitide?

The incidence of adverse events appeared similar between enlicitide and placebo over 52 weeks. The trial specifically monitored new or worsening diabetes and drug-induced liver injury, though detailed numbers were not in the main summary. About 88–89% of participants continued treatment through the full year.

### Who should not take enlicitide?

The trial excluded people with uncontrolled high blood pressure or diabetes, active liver disease, or triglycerides of 400 mg/dL or higher. Results may not apply to these groups. Always talk to your doctor about whether any new medication is safe for your specific health situation.

### My LDL is still high on a statin. Should I get a second opinion about trying the new oral PCSK9 inhibitor enlicitide instead of an injectable PCSK9 inhibitor?

A second opinion is reasonable if your LDL remains above goal despite a maximally tolerated statin and you are weighing an injectable PCSK9 inhibitor, ezetimibe, or waiting for enlicitide. In the large clinical trial, enlicitide lowered LDL by about 57% compared with placebo, and most patients reached strict LDL targets. However, that trial measured cholesterol levels, not heart attacks or strokes, and lasted only 52 weeks. An independent expert can help you decide whether these results apply to your heart risk and current treatment. Diagnostic Detectives Network provides independent expert second opinions.

## Source Information

**Original article title:** A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide

**Authors:** Ann Marie Navar, M.D., Ph.D., Elina Mikhailova, M.D., Ph.D., Alberico L. Catapano, Ph.D., Puja Banka, M.D., Dirk J. Blom, M.D., Alberto Cadena, M.D., Susan Kourpanidis, M.S., Norman E. Lepor, M.D., Kazuhisa Tsukamoto, M.D., Ph.D., Geraldine Mendizabal, M.D., Julio Nunez, M.D., Wenjuan Zhang, Ph.D., Pengfei Zhu, D.Phil., Min Zhuo, M.D., M.P.H., and Christie M. Ballantyne, M.D., for the CORALreef Lipids Investigators

**Journal:** The New England Journal of Medicine

**Publication details:** February 5, 2026, Vol. 394, No. 6, pages 529–539. DOI: 10.1056/NEJMoa2511002. ClinicalTrials.gov number: NCT05952856.

**Funding:** MSD (Rahway, NJ).

This patient-friendly article is based on peer-reviewed research published in The New England Journal of Medicine. It is intended for educational purposes and does not provide individual medical advice. Always consult a qualified healthcare professional for medical decisions.


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