Peptide education
Enlicitide
Lipfendra · enlicitide decanoate · MK-0616
Enlicitide is an oral peptide drug that blocks PCSK9, a protein involved in clearing LDL cholesterol from the blood. Lipfendra is FDA-approved to lower LDL cholesterol in adults with high cholesterol.
Enlicitide lowered LDL cholesterol in large randomized studies and is supplied as a once-daily oral tablet. The label has specific instructions for taking it on an empty stomach.
Overview
Quick answer
The approval is for lowering LDL cholesterol. The CORALreef trials measured changes in cholesterol, while cardiovascular outcome benefits mentioned in the label come from trials of statins or antibody PCSK9 inhibitors.
Who is Lipfendra for?
The US label covers adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia, alongside diet and exercise.
How is the tablet taken?
The label specifies 20 mg once daily on an empty stomach in the morning, with water, black coffee, or plain tea. The tablet is swallowed whole; food and other drinks are delayed for at least 30 minutes.
What did CORALreef Lipids find?
In adults with prior or elevated risk of cardiovascular disease, mean observed LDL cholesterol changes at 24 weeks were -57.1% with enlicitide and +3.0% with placebo. The adjusted difference was -55.8 percentage points; unlike the observed group means, it comes from a model that accounts for missing data.
Does it prevent heart attacks or strokes?
The CORALreef Lipids trial's primary outcome was LDL cholesterol, not heart attacks or strokes. The label describes cardiovascular outcome evidence for statins and antibody PCSK9 inhibitors separately.
Evidence
Evidence snapshot
The label includes adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia.
The trial included 2,909 participants in its intention-to-treat population; 1,935 received enlicitide and 969 received placebo. It measured LDL cholesterol change at 24 weeks and followed treatment for 52 weeks.
A separate placebo-controlled trial studied adults with heterozygous familial hypercholesterolemia on lipid-lowering treatment.
CORALreef Lipids and HeFH establish LDL cholesterol change, not an enlicitide-specific reduction in heart attacks or strokes.
Claims
Common claims vs evidence
| Claim | Human evidence | Mechanistic evidence | Verdict |
|---|---|---|---|
| Enlicitide lowers LDL cholesterol. | In CORALreef Lipids, the adjusted difference versus placebo in mean LDL cholesterol change was -55.8 percentage points at 24 weeks. Participants had prior cardiovascular disease or elevated risk of a first event. | Enlicitide blocks PCSK9 from binding LDL receptors, leaving more receptors available to remove LDL cholesterol. | Supported by randomized trials and the adult product label. |
| Enlicitide has proven it prevents cardiovascular events. | CORALreef Lipids and HeFH measured lipid endpoints. The prescribing information discusses event reduction demonstrated with statins or antibody PCSK9 inhibitors, not an enlicitide cardiovascular outcomes result. | LDL lowering and enlicitide-specific cardiovascular outcomes are distinct findings. | |
| The tablet can be taken the same way as any other oral medicine. | The label specifies an empty stomach and a wait before food or most beverages. Taking enlicitide after a meal reduced exposure in the pharmacokinetic study described in the label. | Food timing is part of the labeled administration instructions. |
Bottom line
Main takeaway
Lipfendra lowers LDL cholesterol and is taken as a tablet rather than an injection.
Take the tablet on an empty stomach in the morning and follow the label's 30-minute food and beverage interval.
CORALreef Lipids assessed LDL cholesterol at 24 weeks in adults with established or elevated cardiovascular risk.
Identity
What it is
Enlicitide is a macrocyclic peptide that binds PCSK9. By preventing PCSK9 from promoting the breakdown of LDL receptors in the liver, it increases the receptors available to clear LDL cholesterol.
Lipfendra is a film-coated tablet containing enlicitide as its decanoate form. The formulation includes sodium caprate, which helps absorption.
Use context
Routes, doses, and cycle patterns
Lipfendra is taken once daily. The label's empty-stomach instructions matter because food changes how much enlicitide reaches the bloodstream.
Human studies and product labels
Lipfendra adult label
- Purpose
- LDL cholesterol reduction in adults with hypercholesterolemia
- Context
- US prescribing label
- Route
- Oral tablet
- Amount
- 20 mg
- Frequency
- Once daily in the morning on an empty stomach
- Duration
- Ongoing lipid-lowering treatment
Swallow the tablet whole with water, black coffee, or plain tea. Wait at least 30 minutes before food or other beverages. The label permits taking it with other medications.
CORALreef Lipids
- Purpose
- LDL cholesterol reduction in adults with cardiovascular disease or elevated risk
- Context
- Randomized trial
- Route
- Oral tablet
- Amount
- 20 mg enlicitide or placebo
- Frequency
- Once daily
- Duration
- 52 weeks, with the primary LDL outcome assessed at 24 weeks
Most participants received background statin therapy.
What varies
- Food timing: wait at least 30 minutes after the dose before eating or drinking other beverages.
- Missed dose: the label says to take it when possible with the same food interval, without taking two doses on one day.
- Monitoring: the label says the LDL-lowering effect can be measured as early as four weeks after initiation.
Research
Research evidence
CORALreef Lipids and CORALreef HeFH compared enlicitide with placebo in adults needing further LDL cholesterol reduction. Their primary outcomes were changes in LDL cholesterol at 24 weeks.
| Study / evidence area | Population | Design | Product context | Main outcome | Limitations | Weight |
|---|---|---|---|---|---|---|
| CORALreef Lipids | 2,909 adults with prior or elevated cardiovascular risk in the intention-to-treat population; 1,935 received enlicitide and 969 received placebo | Randomized, double-blind, placebo-controlled trial | Enlicitide 20 mg daily or placebo, generally with background lipid-lowering therapy | Observed mean LDL cholesterol changes were -57.1% versus +3.0% at week 24. The adjusted difference was -55.8 percentage points; its model accounted for missing data. | Five randomized participants did not receive either study treatment. The primary outcome was LDL cholesterol, not a clinical cardiovascular event. | Strong for LDL reduction |
| CORALreef HeFH | 303 adults with heterozygous familial hypercholesterolemia on lipid-lowering therapy | Randomized, double-blind, placebo-controlled trial | Enlicitide 20 mg daily or placebo for 52 weeks | The label reports a placebo-adjusted LDL cholesterol difference of approximately -59 percentage points at week 24. | The trial assessed lipid endpoints rather than a cardiovascular event benefit. | Strong for LDL reduction |
Cautions
Safety and unknowns
- In the familial hypercholesterolemia study, diarrhea and dizziness were reported more often with enlicitide than with placebo. Overall adverse reaction frequencies in the broader hypercholesterolemia trial were similar.
- The label advises discontinuing Lipfendra when pregnancy is recognized unless treatment benefits outweigh potential fetal risks. Human milk exposure and effects on a breastfed infant are not known.
- Safety and effectiveness have not been established in children.
Product quality
Product identity and quality
The approved tablet contains an absorption aid and is stored in its original tightly closed bottle with the desiccant in place.
Tablet integrity
The label says to swallow the tablet whole rather than split, crush, or chew it.
Food and drinks
Food timing affects exposure, so the label specifies an empty stomach and waiting interval.
Mechanism
How it is proposed to work
Enlicitide blocks a protein that would otherwise reduce the number of LDL receptors on liver cells. More available receptors can remove more LDL cholesterol from the blood.
Enlicitide is a macrocyclic peptide that prevents PCSK9 from binding to LDL receptors.
The tablet includes sodium caprate to facilitate absorption; the label reports approximately 1% oral bioavailability.
Details
Technical details
Sources
References
- 1.
DailyMed. Lipfendra (enlicitide) prescribing information
US label for adult LDL cholesterol reduction, oral administration, study results, and safety.
- 2.
PubMed. A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide
doi:10.1056/NEJMoa2511002 PMID:41879224 NCT05952856
Randomized trial of LDL cholesterol change in adults with established or elevated risk of cardiovascular disease.
- 3.
PubMed. Enlicitide in adults with heterozygous familial hypercholesterolemia: a randomized clinical trial
doi:10.1001/jama.2025.20620 PMID:41206969 NCT05952869
Randomized trial in adults with heterozygous familial hypercholesterolemia receiving background statin treatment.
- 4.
FDA. FDA review of enlicitide benefits and risks
FDA assessment of the two placebo-controlled LDL cholesterol trials.