Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial.

Summary

In statin-treated adults with HeFH, the oral PCSK9 inhibitor enlicitide produced large, durable LDL-C reductions (~59% at 24 weeks; ~62% vs placebo at 52 weeks), along with significant decreases in non-HDL-C, apolipoprotein B, and lipoprotein(a). Safety and discontinuation rates were similar to placebo over 52 weeks.

Key Findings

• At 24 weeks, LDL-C decreased by 58.2% with enlicitide vs increased 2.6% with placebo (between-group difference −59.4% [95% CI, −65.6% to −53.2%]; P<.001).
• At 52 weeks, mean LDL-C change was −55.3% with enlicitide vs +8.7% with placebo (between-group difference −61.5% [95% CI, −69.4% to −53.7%]; P<.001).
• Enlicitide reduced non-HDL-C (−52.3% vs +2.1%), apolipoprotein B (−48.2% vs +1.8%), and lipoprotein(a) median (−24.7% vs −1.6%) at week 24, all P<.001.
• Adverse events, serious adverse events, and discontinuations due to adverse events were similar between groups.

Clinical Implications

If approved, an oral PCSK9 option could simplify access and adherence in HeFH, enabling combination therapy (with statins/ezetimibe) to reach guideline LDL-C and apoB targets; outcome trials remain necessary.

Limitations

• Surrogate lipid endpoints without cardiovascular outcome data.
• Population limited to HeFH on background lipid therapy; generalizability to broader dyslipidemia populations is uncertain.

Future Directions

Conduct cardiovascular outcome trials, evaluate long-term safety and adherence, assess efficacy across non-HeFH populations and in combination regimens, and study effects on hard outcomes and Lp(a)-driven risk.