Clinical Context

Many adults receiving statin therapy do not achieve recommended LDL-C targets and require additional lipid-lowering strategies. Oral nonstatin therapies such as ezetimibe and bempedoic acid are widely used, although their lipid-lowering effects may be modest in some individuals.

Enlicitide offers a potential oral alternative with more substantial LDL-C reduction, and this phase 3 trial evaluated its efficacy and safety compared with established oral nonstatin therapies.

Study Design

This phase 3, randomized, double-blind, active-comparator trial was conducted across 35 sites in 8 countries between July 2024 and March 2025.

Participants: 301 adults with hypercholesterolemia

Mean age: 64.4 years

Female: 37.2%

Baseline LDL-C: 91.6 mg/dL

ASCVD present: 44.2%

Duration: 56 days

Participants received enlicitide 20 mg, bempedoic acid 180 mg, ezetimibe 10 mg, or a combination of bempedoic acid and ezetimibe once daily, with continued background statin therapy. Study completion was 99.0%, with adherence above 98%.

Lipid-Lowering Efficacy

Primary Endpoint: LDL-C Reduction

Enlicitide achieved a mean LDL-C reduction of −64.6% (95% CI −68.3 to −60.9) at day 56. In comparison, LDL-C reduction was −6.3% with bempedoic acid, −27.8% with ezetimibe, and −36.5% with combination therapy.

Between-group differences in LDL-C reduction ranged from −28.1% to −56.7% in favor of enlicitide (all P < 0.001).

LDL-C reduction approached maximal levels by day 21 and remained stable through day 56, with consistent effects across subgroups.

Secondary Lipid Effects and Goal Attainment

Enlicitide also produced greater reductions in multiple lipid parameters compared with all comparators:

• ApoB reduction difference: −47.5% to −26.8%
• nonHDL-C reduction difference: −51.2% to −25.8%
• Lp(a) reduction difference: −40.3% to −26.2%

These lipid changes translated into higher LDL-C goal attainment at day 56:

• 81.2% achieved LDL-C <70 mg/dL with ≥50% reduction
• 78.2% achieved LDL-C <55 mg/dL

Goal attainment with comparator therapies remained ≤22%.

Safety Profile

Adverse event rates were similar across treatment groups:

• Enlicitide: 40%
• Bempedoic acid: 38%
• Ezetimibe: 36%
• Combination therapy: 45%

Discontinuations due to adverse events were low, with 2% reported in the enlicitide group.

No serious adverse events or deaths were reported with enlicitide. No cases of drug-induced liver injury or new-onset or worsening diabetes mellitus were observed.

Study Limitations

• Short treatment duration of 56 days limits long-term assessment
• A modest sample size of 301 participants
• Predominantly older, white population may limit generalizability
• Lower-than-expected LDL-C reduction with bempedoic acid

Clinical Perspective

Enlicitide demonstrated greater reductions in LDL-C and other atherogenic lipids compared with oral nonstatin therapies. LDL-C reduction occurred early and remained sustained through the treatment period, with a higher proportion of participants achieving guideline-recommended targets. 

Comparable short-term safety and tolerability across treatment groups support its potential role as an oral add-on option in patients who remain above LDL-C targets despite statin therapy.

Key Takeaway

Enlicitide achieved significantly greater LDL-C reduction and higher target attainment compared with oral nonstatin therapies, with a similar short-term safety profile, supporting its potential as a novel oral option in lipid management.

Author

Vivek Pathak is Founder and Editorial Lead at MedApt, a physician-focused platform covering clinical updates, congress insights, and expert perspectives.