Oral PCSK9 Inhibitor Enlicitide Lowers LDL Cholesterol In Phase 3 Trial

Key Takeaways

• Enlicitide was associated with a marked week 24 LDL cholesterol reduction, while placebo showed little change over the same interval.
• Week 52 LDL cholesterol and week 24 non-HDL cholesterol, apolipoprotein B, and lipoprotein(a) also favored enlicitide over placebo.
• Adverse event incidence did not appear to differ between groups, and longer-term data remain needed.

In a 52-week phase 3 trial, the oral PCSK9 inhibitor enlicitide lowered LDL cholesterol by an adjusted 55.8 percentage points more than placebo. The randomized, placebo-controlled comparison enrolled adults with established atherosclerotic cardiovascular disease or elevated risk for a first event. Treatment continued for 52 weeks, with lipid measures assessed at prespecified time points. Findings focused on lipid lowering during follow-up rather than clinical cardiovascular events.

This multinational, double-blind, randomized, placebo-controlled phase 3 trial assigned participants in a 2:1 ratio to enlicitide 20 mg daily or placebo for 52 weeks. Eligibility included adults with a history of a major atherosclerotic cardiovascular disease event and LDL cholesterol of at least 55 mg/dL. It also included adults at risk for a first atherosclerotic cardiovascular disease event and LDL cholesterol of at least 70 mg/dL. The intention-to-treat population included 2909 participants, with 1935 assigned to enlicitide and 969 to placebo, while 5 did not receive assigned treatment. Mean age was 63 years, 39.3% were women, and baseline LDL cholesterol was 96.1±38.9 mg/dL. The prespecified primary end point was mean percent change in LDL cholesterol from baseline to week 24.

At week 24, mean LDL cholesterol changed by −57.1% with enlicitide and by 3.0% with placebo. That corresponded to an adjusted between-group difference of −55.8 percentage points, with a 95% confidence interval from −60.9 to −50.7. The comparison met statistical significance with P<0.001. The New England Journal of Medicine report also described significantly greater effects with enlicitide for week 52 LDL cholesterol and for week 24 non-HDL cholesterol, apolipoprotein B, and lipoprotein(a). Together, these findings showed a consistent lipid-lowering pattern across the primary and key secondary end points.

Over the study period, adverse event incidence did not appear to differ between the enlicitide and placebo groups. The finding does not establish definitive safety equivalence between treatments. Longer-term data remain needed, and the 52-week trial did not establish cardiovascular outcome benefit or broader real-world effectiveness. Within this phase 3 population, enlicitide lowered LDL cholesterol more than placebo at 24 weeks.