Oral PCSK9 Inhibitor Enlicitide Versus Oral Nonstatin Therapies: A Phase 3 Randomized Clinical Trial

Area of Science:

• Cardiovascular Medicine
• Pharmacology
• Clinical Trials

Background:

• Many adults struggle to reach target low-density lipoprotein cholesterol (LDL-C) levels with statin therapy alone.
• Additional lipid-lowering medications are often necessary.
• Enlicitide is an oral proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor with demonstrated LDL-C lowering effects.

Purpose of the Study:

• To evaluate the efficacy of enlicitide compared to other oral nonstatin lipid-lowering therapies.
• To assess enlicitide's effectiveness in statin-treated adults at high risk for atherosclerotic cardiovascular disease (ASCVD).

Main Methods:

• Phase 3, randomized, double-blind, active-comparator trial involving 301 adults.
• Participants received enlicitide, bempedoic acid, ezetimibe, or a combination of bempedoic acid and ezetimibe daily for 56 days.
• Primary endpoint: mean percentage change in LDL-C from baseline to day 56.

Main Results:

• Enlicitide demonstrated superior LDL-C reduction (-64.6%) compared to bempedoic acid (-6.3%), ezetimibe (-27.8%), and the combination (-36.5%) (all P < 0.001).
• Greater reductions in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C) were observed with enlicitide.
• Adverse event rates were similar across all treatment groups.

Conclusions:

• Enlicitide significantly outperformed other oral nonstatin therapies in reducing LDL-C, ApoB, and nonHDL-C.
• Enlicitide shows promise as an effective add-on therapy for patients with hypercholesterolemia not achieving LDL-C goals on statins.
• This study supports enlicitide's potential role in managing cardiovascular risk.