CORALreef Lipids
(2026)Objective
To evaluate the efficacy and safety of once-daily oral PCSK9 inhibitor enlicitide over 52 weeks in adults with established ASCVD or at high risk for first ASCVD event with elevated LDL cholesterol.
Study Summary
• 67.5% achieved LDL-C <55 mg/dL with ≥50% reduction (vs 1.2% placebo)
• Also significantly reduced non-HDL-C (−53.4 pp), ApoB (−50.3 pp), and Lp(a) (−28.2 pp)
• No significant safety signal; adverse events similar between groups
Intervention
Enlicitide decanoate 20 mg oral daily (taken fasting, 30 min before food) vs matching placebo for 52 weeks
Inclusion Criteria
Adults ≥18 years with history of major ASCVD event + LDL-C ≥55 mg/dL, OR intermediate-to-high risk for first ASCVD event + LDL-C ≥70 mg/dL; on stable lipid-lowering therapy (≥moderate-intensity statin) for ≥30 days
Study Design
Arms: Enlicitide 20 mg daily vs Placebo
Patients per Arm: 1935 enlicitide, 969 placebo
Outcome
• LDL-C change at 52 weeks: adjusted difference −47.6 pp (p<0.001)
• Non-HDL-C, ApoB, Lp(a) all significantly reduced (p<0.001 for all)
• No difference in adverse events, serious AEs, or deaths
Bottom Line
Once-daily oral enlicitide 20 mg reduced LDL cholesterol by approximately 56–60 percentage points compared to placebo at 24 weeks, with 67.5% of patients achieving LDL-C <55 mg/dL with ≥50% reduction. The drug also significantly lowered non-HDL cholesterol, apolipoprotein B, and lipoprotein(a), with no apparent increase in adverse events. This oral PCSK9 inhibitor offers efficacy comparable to injectable anti-PCSK9 monoclonal antibodies.
Major Points
- First phase 3 trial of an oral PCSK9 inhibitor (enlicitide decanoate) for LDL-C lowering
- Enlicitide reduced LDL-C by 57.1% vs +3.0% increase with placebo at 24 weeks (adjusted difference −55.8 pp, p<0.001)
- Effect sustained at 52 weeks with adjusted difference of −47.6 percentage points
- Comparable LDL-C reduction to injectable PCSK9 inhibitors (alirocumab, evolocumab)
- Non-HDL-C reduced by 53.4 pp, ApoB by 50.3 pp, and Lp(a) by 28.2 pp vs placebo
- 67.5% achieved LDL-C <55 mg/dL with ≥50% reduction (vs 1.2% placebo)
- No significant differences in adverse events, serious adverse events, or deaths
- No increase in new-onset or worsening diabetes mellitus
- High adherence (97.2%) to daily oral dosing with fasting requirements
- Cardiovascular outcomes trial (CORALreef Outcomes) ongoing with projected completion December 2029
Study Design
- Study Type
- Phase 3, multinational, double-blind, randomized, placebo-controlled trial
- Randomization
- Yes
- Blinding
- Double-blind; participants and investigators blinded to treatment assignment; matching placebo (note: placebo did not contain sodium caprate excipient)
- Sample Size
- 2904
- Follow-up
- 52 weeks treatment + 8 weeks safety follow-up
- Centers
- 168
- Countries
- USA, Japan, UK, Spain, Colombia, South Africa, Argentina, China, and others (14 countries total)
Primary Outcome
Definition: Mean percent change in LDL cholesterol level from baseline to week 24
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| +3.0% (95% CI 0.9 to 5.1) | −57.1% (95% CI −61.8 to −52.5) | - (−60.9 to −50.7) | <0.001 |
Limitations & Criticisms
- Efficacy results reflect clinical trial setting rather than real-world adherence
- Protocol-prespecified data-handling rule for beta-quantification led to transformation of biologically impossible LDL-C values (≤0) to 1 mg/dL, underestimating treatment effect in primary analysis
- 52-week follow-up is short relative to lifetime lipid-lowering therapy; long-term durability unknown
- Missing data from deceased participants were imputed
- Trial not powered to detect rare adverse events
- Placebo formulation did not contain sodium caprate (permeation enhancer present in active drug), potentially affecting blinding
- Cardiovascular outcomes not assessed — awaiting CORALreef Outcomes trial (projected completion 2029)
- Requires fasting administration (30 min before food) which may affect real-world adherence
Citation
N Engl J Med 2026;394:529-39. DOI: 10.1056/NEJMoa2511002