Enlicitide Outperformed Oral Nonstatin Comparators in Phase 3 Trial

Key Takeaways

• Enlicitide was associated with the largest LDL-C reduction and was superior to bempedoic acid, ezetimibe, and their combination over 56 days.
• ApoB, non-HDL-C, and LDL-C goal attainment also favored enlicitide across the active-comparator groups.
• Overall adverse event and discontinuation rates were similar, although the 56-day follow-up and modest sample size limit comparative safety interpretation.

In the CORALreef AddOn phase 3 trial, oral enlicitide decanoate lowered LDL-C by 64.6% over 56 days in statin-treated adults with hypercholesterolemia and produced larger reductions than bempedoic acid, ezetimibe, or their combination. Participants were adults receiving background statins who had a previous major ASCVD event with LDL-C at least 55 mg/dL, or were at intermediate to high risk for a first major ASCVD event with LDL-C at least 70 mg/dL. Secondary lipid measures also favored enlicitide, while overall adverse event and discontinuation rates were similar across groups.

CORALreef AddOn, protocol MK-0616-018, NCT06450366, randomized 301 participants, and 298 completed the 56-day trial. Eligible adults were aged 18 years or older with LDL-C at least 55 mg/dL and a previous major ASCVD event, or at least 70 mg/dL if at intermediate to high risk for a first major ASCVD event. Background statin therapy remained stable, and participants were assigned 2:1:1:2 to enlicitide 20 mg, bempedoic acid 180 mg, ezetimibe 10 mg, or both oral agents. Group sizes were 101, 50, 50, and 100, respectively, with once-daily treatment for 56 days. Mean age was 64.4 years, 37.2% were female, 98% used moderate- to high-intensity statins, mean baseline LDL-C was 91.6 mg/dL, and the primary endpoint was day-56 percentage LDL-C change.

At day 56, mean LDL-C change was -64.6% with enlicitide, with a 95% CI of -68.3% to -60.9%. The corresponding changes were -6.3% with bempedoic acid, -27.8% with ezetimibe, and -36.5% with bempedoic acid plus ezetimibe. Enlicitide was superior to each comparator, with all pairwise P values below .001. LDL-C lowering was nearly maximal by day 21 and remained stable through day 56.

Reductions in ApoB and non-HDL-C were greater with enlicitide than with each comparator, and every pairwise comparison met P below .001. For ApoB, differences versus bempedoic acid, ezetimibe, and the combination were -47.5%, -33.6%, and -26.8%, respectively. For non-HDL-C, the corresponding differences were -51.2%, -32.2%, and -25.8%. At day 56, 81.2% of enlicitide recipients achieved at least 50% LDL-C reduction with LDL-C below 70 mg/dL, versus 2.0%, 8.0%, and 22.0% in the comparator groups. For the below-55-mg/dL threshold, the corresponding rates were 78.2%, 2.0%, 8.0%, and 20.0%, showing similar movement in lipid changes and target attainment.

Overall adverse event rates were 40%, 38%, 36%, and 45% across the enlicitide, bempedoic acid, ezetimibe, and combination groups, with discontinuation rates of 2%, 4%, 0%, and 4%. Serious adverse events occurred in four bempedoic acid recipients and one ezetimibe recipient, with none in the enlicitide or combination groups, and no deaths occurred. No protocol-defined potential drug-induced liver injury or new-onset or worsening diabetes was reported, and asymptomatic accidental overdose exceeded 5% only outside the enlicitide group. In their authors’ interpretation, investigators suggested enlicitide could serve as an add-on option when statins alone do not achieve LDL-C goals. That interpretation was limited by the 56-day follow-up, modest sample size, unexpectedly low bempedoic acid LDL-C response without a definitive explanation, and a predominantly older, white study population.