Key Points
• In the phase 3 CORALreef Add-on trial, oral enlicitide decanoate added to background statin therapy produced a significantly greater reduction in LDL-C at Day 56 than bempedoic acid, ezetimibe, or bempedoic acid plus ezetimibe.
• Mean LDL C reduction at Day 56 was 64.6% with enlicitide, compared with 6.3% for bempedoic acid, 27.8% for ezetimibe, and 36.5% for bempedoic acid plus ezetimibe.
• Enlicitide was generally well tolerated, with 2% discontinuation due to adverse events, no deaths, and no serious adverse events reported in the enlicitide arm.
Most patients treated with statins alone still do not reach guideline recommended LDL C goals. Injectable PCSK9 monoclonal antibodies produce powerful lipid lowering but remain underused, creating interest in an oral PCSK9 inhibitor that could be easier to implement in routine practice. Enlicitide works by disrupting PCSK9 binding to the LDL receptor through the same general pathway targeted by monoclonal antibodies.
CORALreef Add-on was a randomized, double blind, active comparator phase 3 presented at ACC 2026 with simultaneous publication in JACC and registered at ClinicalTrials.gov as NCT06450366, In patients with prior ASCVD or at elevated risk for a first major ASCVD event who remained above LDL C targets on statins, the trial tested whether oral enlicitide, a macrocyclic peptide inhibitor of PCSK9, could outperform established oral non-statin options. This trial enrolled 301 participants treated with stable background statin therapy. Patients were randomized in a 2:1:1:2 ratio to enlicitide 20 mg once daily, bempedoic acid 180 mg once daily, ezetimibe 10 mg once daily, or bempedoic acid plus ezetimibe for 56 days. Mean baseline LDL C across groups was about 92 mg/dL, and roughly half of participants had a prior major ASCVD event.
The primary endpoint was percent change in LDL-C from baseline on Day 56. Enlicitide reduced LDL C by 64.6%, compared with 6.3% for bempedoic acid, 27.8% for ezetimibe, and 36.5% for the combination of bempedoic acid plus ezetimibe. The between group differences versus enlicitide were 56.7 percentage points, 36.0 percentage points, and 28.1 percentage points, respectively, with P < 0.001 for all comparisons. Key secondary lipid endpoints also favored enlicitide. On Day 56, ApoB fell by 54.6% with enlicitide versus 5.4%, 20.2%, and 27.7% with the comparator regimens, while non-HDL C fell by 58.0% versus 5.2%, 25.1%, and 31.8%, respectively. Enlicitide also reduced Lp(a) by 26.2%, whereas Lp(a) rose by 8.1% with bempedoic acid, was unchanged with ezetimibe, and increased by 10.4% with the combination arm.
LDL C goal attainment was markedly higher with enlicitide. By Day 56, 81.2% of enlicitide treated participants achieved LDL C below 70 mg/dL with at least a 50% reduction, and 78.2% achieved LDL C below 55 mg/dL with at least a 50% reduction. The corresponding rates were just 2.0% and 2.0% with bempedoic acid, 8.0% and 8.0% with ezetimibe, and 22.0% and 20.0% with bempedoic acid plus ezetimibe. Safety and tolerability were broadly similar across groups. At least one adverse event occurred in 40% of participants receiving enlicitide, compared with 38% for bempedoic acid, 36% for ezetimibe, and 45% for combination therapy. Serious adverse events occurred in 0% of the enlicitide group, while discontinuation due to an adverse event occurred in 2%. No deaths were reported in any treatment arm. The investigators also reported high adherence to study medication and dosing instructions across groups.
Overall, CORALreef Add-on showed that oral enlicitide decanoate produced substantially greater LDL C lowering than commonly used oral non-statin comparators when added to statin therapy, while remaining generally well tolerated. The findings strengthen the case for oral PCSK9 inhibition as a potential new option for patients who remain above LDL C goals despite statin treatment.