Oral Cholesterol Pill Shows Promise, Rivaling PCSK9 Injections in Landmark Trial
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A new daily pill, enlicitide, demonstrated nearly a 60% reduction in “bad” cholesterol (LDL-C) in adults with or at risk for cardiovascular disease, offering a potential alternative to costly and inconvenient injections.
A groundbreaking study, presented at the American Heart Association (AHA) 2025 Scientific Sessions in New Orleans, reveals a significant advancement in the fight against heart disease. The investigational medication, developed by Merck, targets the PCSK9 protein – the same biological pathway as existing injectable PCSK9 inhibitors – but in a convenient once-daily pill form. Researchers suggest enlicitide could achieve comparable LDL-C reduction to injections, which can lower cholesterol by up to 70%.
The Challenge of Current Cholesterol Management
Despite advancements in lipid management, many patients struggle to reach recommended cholesterol targets. Current treatments, including statins and ezetimibe, are often insufficient, leading to the use of more potent, but less accessible, PCSK9 inhibitors. These existing inhibitors, such as alirocumab, evolocumab, and inclisiran, are administered via subcutaneous injection and carry a substantial cost, limiting their widespread adoption.
How Enlicitide Works
Enlicitide is a small-molecule macrocyclic peptide designed to block the interaction between the PCSK9 protein and LDL receptors. By preventing this interaction, more LDL receptors are available to remove low-density lipoprotein cholesterol (LDL-C) from the bloodstream. This oral mechanism of action has the potential to overcome the barriers associated with injectable biologics, offering a more patient-friendly approach.
CORALreef Lipids Trial: Key Findings
The phase 3 CORALreef Lipids trial was a double-blind, placebo-controlled study involving 2,912 adults across 168 centers in 14 countries. The participant cohort, with a mean age of 63, was comprised of individuals with a prior heart attack or stroke, or those at intermediate to high risk for a first cardiovascular event. Notably, 97% of participants had a history of statin therapy, and 26% were also taking ezetimibe.
Participants were randomized 2:1 to receive either 20 mg of enlicitide once daily (n=1935) or a placebo (n=969) for 52 weeks. After 24 weeks, those receiving enlicitide experienced a 55.8% greater reduction in LDL-C compared to the placebo group (P < .001). A subsequent analysis, excluding potentially inaccurate LDL values, showed an even more pronounced reduction of 59.7% at 24 weeks and 52.4% at 52 weeks. A chart presented at AHA 2025 demonstrated a consistent and rapid decline in mean LDL-C levels within the first four weeks of treatment.
Beyond LDL-C, enlicitide also significantly impacted other key lipid markers:
- Non–high-density lipoprotein cholesterol reduced by 53%
- Apolipoprotein B reduced by 50%
- Lipoprotein(a) reduced by 28%
The study revealed that nearly 70% of participants achieved both a 50% or greater reduction in LDL-C and a level below 70 mg/dL, with over two-thirds reaching levels below 55 mg/dL. “Results were even numerically better than what has been shown for the siRNA medication inclisiran,” one researcher stated.
Safety and Tolerability Profile
The safety profile of enlicitide appeared comparable to placebo, with adverse events (AEs) occurring in 64% and 62% of patients, respectively. Serious AEs were reported in 10% and 12% of patients, and approximately one-third of participants in each group experienced moderate to severe AEs. However, only 100 patients across both groups discontinued treatment due to these AEs. The rate of deaths was consistent between the groups at 0.7%, and no new safety concerns were identified.
What’s Next?
While these preliminary results are promising, the CORALreef outcomes trial is ongoing. This next phase will determine whether the lower LDL-C levels achieved with enlicitide translate into a reduction in major cardiovascular events. As of November 8, 2025, Merck has not yet submitted an application for enlicitide’s approval to the FDA, and a Prescription Drug User Fee Act (PDUFA) date has not been established. The potential arrival of an oral PCSK9 inhibitor could significantly broaden access to this vital class of medications, offering a new hope for millions at risk of heart disease.
