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

Summary

In a 52-week, multinational, double-blind RCT, oral enlicitide reduced LDL-C by 57% at 24 weeks versus placebo, with sustained benefit at 52 weeks and favorable effects on non-HDL-C, apoB, and Lp(a). Safety signals were comparable to placebo, supporting an oral alternative to injectable PCSK9 therapies.

Key Findings

• LDL-C change at week 24: −57.1% with enlicitide vs +3.0% with placebo; adjusted difference −55.8 percentage points (P<0.001).
• Sustained LDL-C lowering at week 52; significant reductions in non-HDL-C, apoB, and Lp(a) at week 24 (all P<0.001).
• Adverse event rates were similar between groups over 52 weeks.

Clinical Implications

For high-risk patients not at LDL-C goal or intolerant to injectables, an oral PCSK9 inhibitor may offer potent, convenient lipid lowering alongside statins/ezetimibe; outcomes trials are still needed.

Limitations

• Surrogate primary endpoint (LDL-C change) without cardiovascular outcomes.
• Follow-up limited to 52 weeks; long-term safety and adherence beyond 1 year unknown.

Future Directions

Dedicated cardiovascular outcomes trials, long-term safety, and comparative effectiveness versus PCSK9 mAbs/inclisiran and in combination with ezetimibe/statins.