Lipfendra (enlicitide decanoate): FDA approval, pivotal trial and safety
Approved
Type
New molecular entity · Oral
FDA-approved use
To reduce low-density lipoprotein cholesterolWording from FDA's list of novel approvals.
FDA review
Priority review
Company
Merck
Application
NDA 220848
Specialty
Cardiology
At a glance
Lipfendra is the first oral PCSK9 inhibitor, approved to lower LDL cholesterol in adults with hypercholesterolemia, including heterozygous familial hypercholesterolemia. It is not a statin and was tested on top of statins: in CORALreef Lipids it lowered LDL cholesterol by about 56% more than placebo at 24 weeks. Its approval rests on LDL lowering; cardiovascular outcome data for enlicitide itself are not yet available.
What it is and how it works
PCSK9 is a protein that tags LDL receptors on liver cells for destruction. Enlicitide is a macrocyclic peptide, taken by mouth, that binds PCSK9 and stops it attaching to the receptors, so more receptors stay on the cell surface to clear LDL from the blood. The injectable PCSK9 antibodies evolocumab and alirocumab work the same way.
2,904 treated adults with a past atherosclerotic cardiovascular event and LDL cholesterol of 55 mg/dL or higher, or at risk of a first event with LDL of 70 mg/dL or higher; 97% on a statin; mean age 63, mean LDL 96 mg/dL.
Compared with
Placebo, on top of lipid-lowering therapy.
Primary endpoint
Mean percent change in LDL cholesterol from baseline to week 24.
Result
LDL cholesterol changed by -57.1% with enlicitide versus +3.0% with placebo: an adjusted difference of -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001).
Other results
LDL lowering held at week 52, and non-HDL cholesterol, apolipoprotein B and lipoprotein(a) fell significantly more than with placebo at week 24 (P<0.001 for all).
Safety in the trial
Adverse events did not appear to differ between groups.
Phase 3, randomized (2:1), double-blind, placebo-controlled, 52 weeks, at 59 sites in 17 countries.
Patients
303 adults with heterozygous familial hypercholesterolemia on at least a moderate-intensity statin (82% high intensity; 64% also on ezetimibe); mean LDL 119 mg/dL.
Compared with
Placebo
Primary endpoint
Mean percent change in LDL cholesterol at week 24.
Result
LDL cholesterol changed by -58.2% versus +2.6%: difference -59.4% (95% CI, -65.6% to -53.2%; P<0.001).
Other results
At week 52 the difference was -61.5% (95% CI, -69.4% to -53.7%). Lipoprotein(a) fell a median 24.7% versus 1.6%.
Safety in the trial
Adverse events, serious adverse events and discontinuations similar between groups.
How does Lipfendra (enlicitide decanoate) compare with the alternatives (Statins, Ezetimibe, Evolocumab or alirocumab) for its approved use (to reduce low-density lipoprotein cholesterol)? Summarize head-to-head and indirect evidence, efficacy, safety and where each fits, with citations.
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Safety signals
In both phase 3 trials, adverse events, serious adverse events and stops for adverse events were similar with enlicitide and placebo. See the label for the full safety information.
What it competes with
Statins remain first line, and ezetimibe is the usual next step. For further lowering, the alternatives are injectable PCSK9 antibodies, inclisiran and bempedoic acid; the antibodies and bempedoic acid have cardiovascular outcome trials, which enlicitide does not yet have.
StatinsFirst line; enlicitide is added to them, not used instead.
EzetimibeOral add-on with smaller LDL lowering.
Evolocumab or alirocumabInjectable PCSK9 antibodies with cardiovascular outcome data.
InclisiranTwice-yearly injection that reduces PCSK9 production.
Bempedoic acidOral option with outcome data in statin-intolerant patients.
Bottom line for clinicians
For patients on a statin who need more LDL lowering and would rather take a pill than an injection, enlicitide gives PCSK9-antibody-level LDL reductions of about 55% to 60%. It adds to statins rather than replacing them, and until outcome data for enlicitide are available, its benefit on heart attacks and strokes is inferred from LDL lowering.
Dosing, contraindications and full warnings are in the prescribing information.
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Last updated October 27, 2026 by 2 Minute Medicine.
For healthcare professionals. A summary of public FDA documents and published trials, not medical advice. Check the full prescribing information before prescribing.
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