Enlicitide
The first PCSK9 inhibitor taken as a pill: a macrocyclic peptide that lowered LDL cholesterol by more than half in phase 3
Enlicitide is a macrocyclic peptide from Merck that binds PCSK9, the protein that marks LDL receptors for destruction, so more receptors stay on liver cells to clear LDL cholesterol. It is a daily tablet rather than an injection. In its phase 3 trial of 2,909 adults on statins, it lowered LDL cholesterol by about 56% more than placebo. FDA approved it as Lipfendra on July 15, 2026.
What is it?
PCSK9 is a liver protein that binds LDL receptors and sends them to be destroyed; fewer receptors means more LDL cholesterol left in the blood. The earlier PCSK9 medicines are injected antibodies. Enlicitide is a macrocyclic peptide engineered to bind PCSK9 and survive being swallowed. According to its label it is minimally metabolised, is cleared mainly by the kidneys' filtration, and has an effective half-life of about 14 hours.
In CORALreef Lipids, 2,909 adults already taking statins, with atherosclerotic disease or at high risk, saw LDL cholesterol fall 57.1% at week 24 against a 3.0% rise on placebo. In people with heterozygous familial hypercholesterolaemia, the fall was 58.2% against a 2.6% rise, sustained at week 52. Against other oral add-ons it lowered LDL by 64.6% in 56 days, compared with 27.8% for ezetimibe and 36.5% for bempedoic acid plus ezetimibe.
FDA approved it as Lipfendra on July 15, 2026, for adults with hypercholesterolaemia including the familial form, alongside diet and exercise. The recommended dose is one 20 mg tablet each morning on an empty stomach, with water, black coffee or plain tea, and nothing else for 30 minutes. The label lists no contraindications; diarrhoea and dizziness were the commonest adverse reactions in the familial trial. It has no EU authorisation yet.
At a Glance
Every value in this table is printed from the Grey Peptides dataset, the same record the compound explorer and comparison tool read, so the three can never disagree.
Half-Life: How Much Remains
The dataset records a half-life of effective half-life about 14 hours; terminal about 244 hours (label) for Enlicitide. After each half-life, half of what was in the circulation is gone, so about 3% remains after five. Real clearance varies with the person, the dose, the route and kidney or liver function; this is arithmetic on a published figure, not a dosing tool.
Published Research
These are the trials behind enlicitide, read from their PubMed abstracts.
CORALreef Lipids: 2,909 adults on statins
LDL cholesterol changed by -57.1% at week 24 on enlicitide against +3.0% on placebo, a between-group difference of -55.8 percentage points; mean baseline LDL was 96.1 mg/dL.
Heterozygous familial hypercholesterolaemia: 303 adults
On background statins (and ezetimibe in 64.4%), LDL fell 58.2% at week 24 against a 2.6% rise on placebo (difference -59.4%), and 55.3% against an 8.7% rise at week 52.
Against oral non-statin add-ons
In 301 statin-treated adults, LDL fell 64.6% in 56 days on enlicitide against 6.3% on bempedoic acid, 27.8% on ezetimibe and 36.5% on both combined; adverse events were similar across arms.
Phase 2b dose-finding
In 380 treated participants, LDL fell by 41.2%, 55.7%, 59.1% and 60.9% against placebo at week 8 on 6, 12, 18 and 30 mg; adverse events occurred at similar rates to placebo.
Side Effects & Contraindications
Reported Side Effects
From the Lipfendra label and the trials above.
Contraindications & Cautions
From the label; a clinician decides.
Legal Status
Enlicitide is an FDA-approved prescription medicine.
Frequently Asked Questions
?What is enlicitide?
An oral PCSK9 inhibitor from Merck, sold as Lipfendra: a macrocyclic peptide that helps the liver clear LDL cholesterol. It is taken as one 20 mg tablet a day.
?How much does it lower LDL cholesterol?
In its phase 3 trial of 2,909 adults on statins, by about 56 percentage points more than placebo at 24 weeks; in familial hypercholesterolaemia, by about 59 points.
?How do you take it?
One tablet each morning on an empty stomach, swallowed whole with water, black coffee or plain tea, then nothing else for at least 30 minutes.
References
- [fda-pi] Merck Sharp & Dohme. LIPFENDRA (enlicitide) tablets, US prescribing information: indication, dosage (20 mg once daily on an empty stomach), no contraindications, mechanism and pharmacokinetics (effective half-life about 14 hours, terminal about 244 hours), CORALreef trials. DailyMed version effective July 15, 2026; read September 30, 2026.
- [pubmed] Navar AM, et al. "A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide." N Engl J Med, 2026;394(6):529-539. PMID: 41879224.
- [pubmed] Ballantyne CM, et al. "Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial." JAMA, 2026;335(2):129-139. PMID: 41206969.
- [pubmed] Catapano AL, et al. "Oral PCSK9 Inhibitor Enlicitide Versus Oral Nonstatin Therapies: A Phase 3 Randomized Clinical Trial." J Am Coll Cardiol, 2026;88(3):340-352. PMID: 42017875.
- [pubmed] Ballantyne CM, et al. "Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616." J Am Coll Cardiol, 2023;81(16):1553-1564. PMID: 36889610.
- [fda] FDA. Drugs@FDA (openFDA): LIPFENDRA NDA 220848, approved July 15, 2026; and FDA, Novel Drug Approvals for 2026 (content current as of September 28, 2026). Read September 30, 2026.
- [other] European Medicines Agency. Medicines register: no entry for enlicitide. Read September 30, 2026.
Sources & Citations
Every study on this page was read from its PubMed record; indications, dosing and pharmacology come from the FDA label on DailyMed. Approval details come from Drugs@FDA, FDA's Novel Drug Approvals for 2026 and EMA's register, read September 30, 2026. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Consult a licensed healthcare provider before making health decisions.