A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide.

Enlicitide decanoate 20 mg daily produced a mean percent change in LDL cholesterol of -57.1% at week 24 compared to 3.0% with placebo.

• The adjusted between-group difference was -55.8 percentage points (95% CI, -60.9 to -50.7; P<0.001).
• Enlicitide group: mean percent change -57.1% (95% CI, -61.8 to -52.5).
• Placebo group: mean percent change 3.0% (95% CI, 0.9 to 5.1).
• This was the primary end point of the trial.
• The trial duration was 52 weeks with LDL cholesterol assessed at week 24 as the primary time point.

LDL cholesterol reductions with enlicitide were sustained at week 52, representing a key secondary end point.

• The mean percent change in LDL cholesterol level at week 52 was significantly greater with enlicitide than with placebo (P<0.001).
• Week 52 LDL cholesterol change was a pre-specified key secondary end point.
• The trial enrolled participants for 52 weeks of treatment.

Enlicitide significantly reduced non-HDL cholesterol and apolipoprotein B levels compared to placebo at week 24.

• Mean percent changes in non-HDL cholesterol and apolipoprotein B levels at week 24 were significantly greater with enlicitide than with placebo (P<0.001 for both comparisons).
• These were pre-specified key secondary end points.
• Non-HDL cholesterol and apolipoprotein B reductions were assessed at week 24.

Enlicitide significantly reduced lipoprotein(a) levels compared to placebo at week 24.

• The percent change in lipoprotein(a) levels at week 24 was significantly greater with enlicitide than with placebo (P<0.001).
• Lipoprotein(a) reduction was a pre-specified key secondary end point.
• This represents a clinically notable finding as lipoprotein(a) is an independent cardiovascular risk factor.

The incidence of adverse events did not appear to differ between the enlicitide and placebo groups.

• Safety was assessed across 1935 participants receiving enlicitide and 969 receiving placebo.
• The trial was a double-blind, placebo-controlled design, supporting the validity of adverse event comparisons.
• No differential safety signal was identified for enlicitide versus placebo over 52 weeks.

The trial enrolled 2909 participants in the intention-to-treat population, randomized 2:1 to enlicitide or placebo.

• 1935 participants received enlicitide and 969 received placebo; 5 participants did not receive either treatment.
• Participants were adults with a history of a major atherosclerotic cardiovascular disease event and LDL cholesterol ≥55 mg/dL, or at risk for a first event with LDL cholesterol ≥70 mg/dL.
• The mean age of participants was 63 years, and 39.3% were women.
• The mean (±SD) LDL cholesterol level at baseline was 96.1±38.9 mg per deciliter.
• The trial was multinational, double-blind, and placebo-controlled (CORALreef Lipids, NCT05952856).