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

Clinical Snapshot

Key Findings

• P Value: All pairwise comparisons of enlicitide vs each comparator: P<0.001

• Effect Size: Enlicitide achieved approximately 28–58 percentage points greater LDL-C reduction compared with active comparators. Reductions in ApoB and nonHDL-C were also significantly greater with enlicitide (all P<0.001). Proportions of AEs and discontinuations due to AEs were similar across all treatment arms.

• Primary Outcome: Mean percentage change in LDL-C from baseline to day 56: Enlicitide -64.6% vs bempedoic acid -6.3% vs ezetimibe -27.8% vs bempedoic acid + ezetimibe -36.5%; enlicitide superior to all comparators (all P<0.001)

• Nnt Or Sensitivity: NNT for cardiovascular outcomes cannot be calculated from this surrogate-endpoint trial. Based on established Mendelian randomisation and statin trial data, each 1 mmol/L (~38.7 mg/dL) reduction in LDL-C reduces major cardiovascular events by approximately 22% (relative risk reduction). A 64.6% LDL-C reduction on top of background statin therapy would be expected to produce substantial absolute risk reduction in very high-risk patients, but this requires confirmation in a dedicated cardiovascular outcomes trial.

• Confidence Interval: Enlicitide: 95% CI -68.3% to -60.9%; Bempedoic acid: 95% CI -13.5% to 0.8% (crosses zero); Ezetimibe: 95% CI -32.3% to -23.4%; Combination: 95% CI -40.8% to -32.2%

Abstract

BACKGROUND: Many adults fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals on statin monotherapy, requiring additional nonstatin lipid-lowering medication. Enlicitide, an oral proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, lowered LDL-C by 60% compared with placebo; its efficacy compared with other oral nonstatin therapies has yet to be examined. OBJECTIVES: This study assessed the efficacy of enlicitide, a novel oral PCSK9 inhibitor, vs other oral nonstatin therapies. METHODS: In this phase 3, randomized, double-blind, active-comparator trial, statin-treated adults aged ≥18 years with LDL-C ≥55 mg/dL and a previous major atherosclerotic cardiovascular disease (ASCVD) event, or LDL-C ≥70 mg/dL if at intermediate to high risk for a first event, were randomized in 2:1:1:2 fashion to 20 mg enlicitide (n = 101), 180 mg bempedoic acid (n = 50), 10 mg ezetimibe (n = 50), or 180 mg bempedoic acid plus 10 mg ezetimibe (n = 100) once daily for 56 days. The primary endpoint was mean percentage change in LDL-C from baseline to day 56; secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C). Safety endpoints included overall adverse events (AEs) and discontinuations due to AEs. RESULTS: Among 301 randomized participants (mean age 64.4 years, 37% female, 98% receiving moderate- to high-intensity statin), 298 (99.0%) completed the trial. The mean percentage change in LDL-C from baseline to day 56 was -64.6% (95% CI: -68.3% to -60.9%) with enlicitide, -6.3% (95% CI: -13.5% to 0.8%) with bempedoic acid, -27.8% (95% CI: -32.3% to -23.4%) with ezetimibe, and -36.5% (95% CI: -40.8% to -32.2%) with bempedoic acid plus ezetimibe; enlicitide was superior to each comparator (all P < 0.001). Reductions in ApoB and nonHDL-C were also greater with enlicitide (all P < 0.001). Proportions of participants with AEs and discontinuations due to AEs were similar across treatment arms. CONCLUSIONS: In statin-treated adults with a history of a major ASCVD event or at increased risk for a first event, enlicitide achieved greater reductions in LDL-C, ApoB, and nonHDL-C than other oral nonstatin therapies, demonstrating its potential role as an important add-on option when LDL-C goals are not met with the use of statins alone. (A Study to Evaluate the Efficacy and Safety of Enlicitide Decanoate [MK-0616, Oral PCSK9 Inhibitor] Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia [MK-0616-018] [CORALreef AddOn; NCT06450366).