Lipid-efficacy RCT · JAMA 2026
CORALreef HeFH trial
Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial.
The bottom line
In patients with heterozygous familial hypercholesterolemia already on statin therapy, adding oral enlicitide substantially and safely lowered LDL-C and other atherogenic lipid measures compared with placebo.
Primary lipid endpoint metUS status: US-approved
At a glance
- Medicine
- Enlicitide decanoate 20 mg orally once daily (n=202)
- Compared with
- Placebo (n=101)
- People
- 303
- Who took part
- Adults aged 18 years or older with heterozygous familial hypercholesterolemia on at least moderate- or high-intensity statin therapy, with LDL-C ≥55 mg/dL and history of major ASCVD or LDL-C ≥70 mg/dL without history of major ASCVD
- Design
- Phase 3, randomized, double-blind, placebo-controlled
- Follow-up
- 52 weeks
- Main question
- Mean percentage change in LDL-C level at week 24
Main result
The mean percentage change in LDL-C level at week 24 was -58.2% in the enlicitide group vs 2.6% in the placebo group (between-group difference, -59.4% [95% CI, -65.6% to -53.2%]; P < .001).
Effect on LDL cholesterol
-58.2% (enlicitide) vs 2.6% (placebo) at week 24; between-group difference -59.4% (95% CI, -65.6% to -53.2%), P<.001. At week 52: -55.3% vs 8.7%; between-group difference -61.5% (95% CI, -69.4% to -53.7%), P<.001.
Other results
At week 24, mean percentage change in non-HDL-C was -52.3% vs 2.1% (difference -53.0% [95% CI, -58.5% to -47.4%]; P<.001); apolipoprotein B was -48.2% vs 1.8% (difference -49.1% [95% CI, -54.0% to -44.3%]; P<.001); median percentage change in lipoprotein(a) was -24.7% vs -1.6% (difference -27.5% [95% CI, -34.3% to -20.6%]; P<.001).
Safety
The incidence of adverse events, serious adverse events, and study discontinuation due to adverse events was similar between groups.
In the trial's own words
“The mean percentage change in LDL-C level at week 24 was -58.2% in the enlicitide group vs 2.6% in the placebo group (between-group difference, -59.4% [95% CI, -65.6% to -53.2%]; P < .001).”
Quoted from the abstract of JAMA 2026, checked word for word against PubMed. PubMed 41206969 · Full paper (DOI)
How this medicine works, where it stands and what it costs: Enlicitide (Lipfendra)
Common questions
What did the CORALreef HeFH trial find?
In patients with heterozygous familial hypercholesterolemia already on statin therapy, adding oral enlicitide substantially and safely lowered LDL-C and other atherogenic lipid measures compared with placebo.
Who was in CORALreef HeFH?
303 people. Adults aged 18 years or older with heterozygous familial hypercholesterolemia on at least moderate- or high-intensity statin therapy, with LDL-C ≥55 mg/dL and history of major ASCVD or LDL-C ≥70 mg/dL without history of major ASCVD.
What was CORALreef HeFH's main result?
The mean percentage change in LDL-C level at week 24 was -58.2% in the enlicitide group vs 2.6% in the placebo group (between-group difference, -59.4% [95% CI, -65.6% to -53.2%]; P < .001).
How much did LDL cholesterol change in CORALreef HeFH?
-58.2% (enlicitide) vs 2.6% (placebo) at week 24; between-group difference -59.4% (95% CI, -65.6% to -53.2%), P<.001. At week 52: -55.3% vs 8.7%; between-group difference -61.5% (95% CI, -69.4% to -53.7%), P<.001.
Related trials
- CORALreef Lipids (2026)In patients with or at risk for atherosclerotic cardiovascular disease, the oral PCSK9 inhibitor enlicitide substantially lowered LDL cholesterol and other atherogenic lipid markers compared with placebo, with adverse event rates similar between groups.
- VESALIUS-CV (2026)In patients with atherosclerosis or diabetes but no prior MI or stroke, adding evolocumab to therapy significantly lowered the risk of major cardiovascular events compared with placebo, with no apparent safety concerns.
- PURSUIT (2025)In statin-treated patients with hypercholesterolemia, the oral PCSK9 inhibitor AZD0780 produced robust, dose-dependent LDL-C reductions over 12 weeks with an adverse event rate similar to placebo.
- LIBerate-HR (2024)Monthly lerodalcibep added to maximally tolerated statins substantially lowers LDL-C and helps most high-risk patients reach guideline LDL-C targets, with a safety profile similar to placebo aside from mild/moderate injection site reactions.
Get your LDL treated to a goal
Preval Health's protocols follow trials like this one. Licensed clinicians set your goal, prescribe and recheck until you reach it.
Get startedEducation only, not medical advice. Results describe the people in this trial and can differ for you. Talk with your clinician before starting or stopping any medicine. Back to all 106 trials.