Oral PCSK9 inhibitor · LDL cholesterol
Enlicitide is a ring-shaped (macrocyclic) peptide taken by mouth that lowers LDL cholesterol by blocking PCSK9, the same protein targeted by injectable antibody drugs. Developed by Merck as MK-0616, it was approved by the FDA in July 2026 as Lipfendra tablets.
LDL receptors on liver cells are the main route by which LDL cholesterol is removed from the blood. PCSK9 is a circulating protein that attaches to those receptors and steers them toward breakdown, leaving fewer receptors to pull LDL in. Enlicitide binds PCSK9 and keeps it from attaching to the receptor, so more receptors remain available and blood LDL falls3. Peptides are usually poorly absorbed from the gut, so enlicitide is built as a constrained ring and formulated with sodium caprate, an absorption enhancer. Even so, the label puts oral bioavailability at roughly 1 percent, and taking it after a meal roughly halved blood levels in studies3.
Human data come from Merck's CORALreef program. In CORALreef Lipids, 2,909 adults with, or at raised risk of, atherosclerotic cardiovascular disease, nearly all already on statins, were randomized 2:1 to enlicitide or placebo for 52 weeks1. At week 24, LDL cholesterol had fallen about 57 percent with enlicitide versus a 3 percent rise with placebo; non-HDL cholesterol, apolipoprotein B and lipoprotein(a) also fell more than with placebo, and adverse-event rates looked similar between groups1,3.
In CORALreef AddOn, 301 statin-treated adults were randomized for eight weeks, and enlicitide lowered LDL more than ezetimibe, bempedoic acid, or the two combined2. A separate 52-week placebo-controlled trial in 303 adults with heterozygous familial hypercholesterolemia showed a similar LDL reduction3. Whether these LDL reductions mean fewer heart attacks and strokes is still being studied in CORALreef Outcomes, a phase 3 trial of roughly 14,500 people expected to run into 20314.
The FDA approved Lipfendra in July 2026 as an adjunct to diet and exercise for reducing LDL cholesterol in adults who have hypercholesterolemia, including its heterozygous familial form (HeFH)3. A reduction in heart attacks or strokes has not yet been shown for enlicitide itself.
Per the label, adverse reactions in the main 52-week trial were about as frequent on enlicitide as on placebo, and the share who discontinued because of an adverse reaction was also similar3. In the familial hypercholesterolemia trial, diarrhea (7% vs 2%) and dizziness (9% vs 4%) were more common than with placebo. The label lists no contraindications. Once a pregnancy is recognized, the label says to discontinue enlicitide unless its benefits outweigh the potential risk to the fetus, since reducing cholesterol may harm fetal development3. Human experience beyond about a year is still limited.
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