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Enlicitide (Lipfendra): an oral PCSK9 inhibitor

Clinical review pending

Enlicitide is designed to increase LDL uptake by the liver. The source describes US approval as Lipfendra and studies of efficacy and tolerability.

What is enlicitide?

Enlicitide, development code MK-0616, is a cholesterol-lowering medicine that blocks PCSK9. This protein influences how the liver removes LDL cholesterol from the blood. The source article describes enlicitide as the first oral PCSK9 inhibitor. Existing medicines targeting this pathway are injectable antibodies or an injectable RNA therapy. Enlicitide, by contrast, is a specially engineered peptide intended for a once-daily tablet. According to the source article, Merck markets it under the name Lipfendra.

How does enlicitide work?

Enlicitide binds circulating PCSK9 1, preventing it from binding to LDL receptors on liver cells. Normally, PCSK9 promotes the breakdown of these receptors. Blocking it allows more receptors to return to the cell surface and take up LDL again. The liver consequently removes more LDL cholesterol from the blood. The distinctive feature is that the peptide has been engineered to be stable enough for effective oral use.

Is enlicitide FDA-approved?

The source article reports FDA approval in 2026 under the name Lipfendra 2. It describes once-daily oral use as a PCSK9 inhibitor to lower LDL cholesterol in adults with high cholesterol. A cardiovascular outcomes trial was reportedly still underway at the time of approval. That trial investigates whether lowering LDL also leads to fewer heart attacks and strokes.

What is enlicitide prescribed for?

According to the source article, enlicitide is used alongside diet and exercise in adults with hypercholesterolemia. This includes the inherited condition heterozygous familial hypercholesterolemia, or HeFH 3. In the pivotal trials 1, it was added to existing cholesterol-lowering treatment, usually a statin, when further reduction was needed. It is intended to offer an oral option for people who would otherwise need an injectable PCSK9 inhibitor. Treatment is managed by a physician as part of an overall approach to reducing cardiovascular risk.

What side effects are possible?

In the larger phase 3 CORALreef Lipids trial, side effects occurred at similar rates with enlicitide and placebo 1. In the trial involving adults with HeFH, the following side effects were reported more often than with placebo 3:

  • Dizziness: 9% with enlicitide and 4% with placebo

  • Diarrhea: 7% with enlicitide and 2% with placebo

In both trials, similar numbers of participants in the active-treatment and placebo groups stopped treatment because of a side effect. The prescribing information linked in the source article 2 recommends discontinuing enlicitide when pregnancy is identified, unless the benefit outweighs the potential risks to the unborn child. Individual risks and other medicines should be discussed with the treating physician.

References provided in the source article

Sources: the CORALreef Lipids Phase 3 trial (Navar et al., New England Journal of Medicine, 2026, DOI: 10.1056/NEJMoa2511002 1 ) and an active-comparator Phase 3 trial (Catapano et al., Journal of the American College of Cardiology, 2026, DOI: 10.1016/j.jacc.2026.03.036 4 ), both indexed on PubMed; and the FDA approval announcement and prescribing information for Lipfendra.

Provenance and editorial review status

Adapted for Nutrient Desk from the source article. The claims and source attributions in the original text still require clinical review. This draft has not been cleared for indexing.