The phase 3 CORALreef Lipids trial, a multinational, double-blind, randomized, placebo-controlled study published in the New England Journal of Medicine on February 4, 2026, assessed the efficacy and safety of enlicitide decanoate, an investigational oral macrocyclic peptide inhibitor of proprotein convertase subtilisin/kexin type 9 (PCSK9). Enlicitide targets PCSK9 to increase hepatic LDL receptor availability and reduce circulating LDL cholesterol (LDL-C), offering a convenient oral alternative to injectable monoclonal antibodies.
The trial enrolled 2909 adults (mean age 63 years, 39.3% women; baseline mean LDL-C 96.1 ± 38.9 mg/dL) with a history of major ASCVD events (LDL-C ≥55 mg/dL) or at risk for first events (LDL-C ≥70 mg/dL), most on moderate- or high-intensity statins. Participants were randomized 2:1 to enlicitide 20 mg once daily or placebo for 52 weeks.
The primary endpoint was the mean percent change in LDL-C from baseline to week 24: -57.1% (95% CI, -61.8 to -52.5) with enlicitide versus +3.0% (95% CI, 0.9 to 5.1) with placebo, yielding an adjusted between-group difference of -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001). This robust reduction was sustained at week 52. Key secondary endpoints also favored enlicitide significantly (P<0.001 for all): greater reductions in non-HDL cholesterol and apolipoprotein B at week 24, and in lipoprotein(a) levels. Notably, 70.3% of enlicitide-treated participants achieved both ≥50% LDL-C reduction and LDL-C <70 mg/dL, with many reaching <55 mg/dL.
Safety profiles were similar between groups, with no apparent increase in adverse events, serious adverse events, or discontinuations due to treatment-related issues. The trial was not powered to detect rare events, but overall tolerability supported further development. Enlicitide provides antibody-like LDL-C lowering efficacy in an oral formulation, addressing adherence barriers with injectable PCSK9 therapies. These results position enlicitide as a potential game-changer for patients requiring intensive lipid lowering beyond statins, particularly those with established ASCVD or high residual risk. Longer-term cardiovascular outcome trials will be needed to confirm clinical event reduction benefits.
