Oral PCSK9 Inhibitor Enlicitide Versus Oral Nonstatin Therapies: A Phase 3 Randomized Clinical Trial.
Level 2 - randomized trial
Individual randomized, double-blind, active-comparator phase 3 trial
PubMed 42017875 · doi:10.1016/j.jacc.2026.03.036
What was done
In a phase 3, multicenter, double-blind trial (CORALreef AddOn), 301 statin-treated adults (mean age 64.4 years, 37% female, 98% receiving moderate- to high-intensity statin) with LDL-C >=55 mg/dL and prior ASCVD, or LDL-C >=70 mg/dL with intermediate-to-high risk, were randomized (2:1:1:2) to once-daily 20 mg enlicitide (n = 101), 180 mg bempedoic acid (n = 50), 10 mg ezetimibe (n = 50), or 180 mg bempedoic acid plus 10 mg ezetimibe (n = 100) for 56 days. The primary endpoint was mean percentage change in LDL-C from baseline to day 56; secondary endpoints were percentage changes in ApoB and nonHDL-C, along with adverse events (AEs) and discontinuations.
What was found
A total of 298 participants (99.0%) completed the trial. Mean percentage change in LDL-C from baseline to day 56 was -64.6% (95% CI: -68.3% to -60.9%) with enlicitide, -6.3% (95% CI: -13.5% to 0.8%) with bempedoic acid, -27.8% (95% CI: -32.3% to -23.4%) with ezetimibe, and -36.5% (95% CI: -40.8% to -32.2%) with bempedoic acid plus ezetimibe (P < 0.001 for enlicitide vs each comparator). Reductions in ApoB and nonHDL-C were also significantly greater with enlicitide (all P < 0.001). Proportions of participants with AEs and AE-related discontinuations were similar across treatment arms.
Why it matters
This study provides head-to-head evidence that the oral PCSK9 inhibitor enlicitide achieves substantially greater lipid lowering (~65% LDL-C reduction) than existing oral nonstatin therapies or their combination when added to statin therapy.
Limits
The trial duration was short (56 days), which does not evaluate long-term safety, durability, or adherence. The study evaluated surrogate lipid biomarkers rather than clinical cardiovascular outcomes. The sample size was modest (n = 301 total, with only 50 participants in two comparator arms), and women were underrepresented (37%).
Cited by
- supports Enlicitide (MK-0616) is an oral PCSK9 inhibitor developed by Merck.