Enlicitide Decanoate: Research & Studies
Scientific evidence, clinical trials, and research findings
๐TL;DR
- โข3 clinical studies cited
- โขOverall evidence level: high
- โข6 research gaps identified
Research Studies
A Placebo-Controlled Trial of the Oral PCSK9 Inhibitor Enlicitide
Navar AM, Mikhailova E, Catapano AL, et al. (2026) โข New England Journal of Medicine
Phase 3 CORALreef Lipids trial in 2,909 adults with ASCVD or high risk, randomized 2:1 to enlicitide 20 mg daily or placebo across 168 sites.
Key Findings
- 55.8% placebo-adjusted LDL-C reduction at week 24 (primary endpoint)
- 47.6% placebo-adjusted LDL-C reduction sustained at week 52
- Significant reductions in non-HDL-C, apoB, and Lp(a)
- Safety profile comparable to placebo
Limitations: No cardiovascular outcomes data; 52-week duration
Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia
Ballantyne CM, et al. (2026) โข JAMA
Phase 3 CORALreef HeFH trial in 303 adults with HeFH at 59 sites in 17 countries.
Key Findings
- 58.2% LDL-C reduction with enlicitide vs 2.6% increase with placebo at week 24
- Significant reductions in apoB and non-HDL-C
- Adverse events in 64% enlicitide vs 62% placebo
- Serious adverse events in 10% enlicitide vs 12% placebo
Limitations: Relatively small sample size (n=303); cardiovascular outcomes not assessed
Phase 2b Randomized Trial of the Oral PCSK9 Inhibitor MK-0616
Ballantyne CM, Banka P, Mendez G, et al. (2023) โข Journal of the American College of Cardiology
Phase 2b dose-ranging trial of MK-0616 at 6, 12, 18, 30 mg daily vs placebo in 381 adults with hypercholesterolemia.
Key Findings
- Dose-dependent LDL-C reductions from 41.2% (6 mg) to 60.9% (30 mg) at week 8
- All doses significantly reduced LDL-C vs placebo (P<0.001)
- Well tolerated across all dose groups
Limitations: 8-week treatment duration; short follow-up period
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๐Research Gaps & Future Directions
- โขCardiovascular outcomes data from CORALreef Outcomes trial (19,000+ participants)
- โขLong-term safety beyond 52 weeks of continuous treatment
- โขEfficacy in homozygous familial hypercholesterolemia
- โขHead-to-head comparison with injectable PCSK9 inhibitors (evolocumab, alirocumab)
- โขReal-world adherence and persistence with oral vs injectable PCSK9 inhibition
- โขEffects in statin-intolerant patients as monotherapy
Research Overview#
Enlicitide decanoate (MK-0616) has been evaluated in a robust clinical development program that includes a Phase 2b dose-ranging trial (JACC 2023) and two Phase 3 pivotal trials (NEJM and JAMA 2026). The evidence consistently demonstrates that this oral macrocyclic peptide achieves LDL cholesterol reductions comparable to injectable PCSK9 monoclonal antibodies, with a safety profile indistinguishable from placebo.
The evidence level is classified as high based on Phase 3 RCTs published in the NEJM and JAMA, involving nearly 3,600 participants across the published trials. A cardiovascular outcomes trial (CORALreef Outcomes) enrolling over 19,000 participants is ongoing and will provide the definitive evidence for clinical benefit.
CORALreef Lipids Trial (Phase 3)#
Navar et al., NEJM 2026 (DOI: 10.1056/NEJMoa2511002)#
The CORALreef Lipids trial was the pivotal Phase 3 study establishing the efficacy and safety of enlicitide in the broad ASCVD risk population.
Study Design:
- Multinational, double-blind, randomized, placebo-controlled trial
- 2,909 adults with ASCVD or high ASCVD risk, on stable lipid-lowering therapy including at least moderate-intensity statin (or documented statin intolerance)
- Randomized 2:1 to enlicitide 20 mg daily or placebo
- 168 sites; stratified by renal function, baseline statin use, and region
- Primary endpoint: percent change in LDL-C at week 24
Key Results:
| Endpoint | Enlicitide | Placebo | Difference |
|---|---|---|---|
| LDL-C change at week 24 | -57.1% | +3.0% | -55.8 pp |
| LDL-C change at week 52 | -47.6% | -- | Sustained |
| Non-HDL-C at week 24 | Significant | -- | P<0.001 |
| Apolipoprotein B at week 24 | Significant | -- | P<0.001 |
| Lipoprotein(a) at week 24 | Significant | -- | P<0.001 |
Post-hoc reanalysis: Excluding biologically implausible LDL values, the reduction was 59.7% at 24 weeks and 52.4% at 52 weeks.
Safety: Adverse events did not differ between groups. Discontinuation due to AEs was 3.1% (enlicitide) vs 4.1% (placebo).
CORALreef HeFH Trial (Phase 3)#
Ballantyne et al., JAMA 2026 (PMID 41206969)#
This trial evaluated enlicitide specifically in patients with heterozygous familial hypercholesterolemia, a genetically defined high-risk population.
Study Design:
- Phase 3, randomized, double-blind, placebo-controlled
- 303 adults with HeFH, on existing lipid-lowering therapy
- Randomized 2:1 to enlicitide 20 mg daily (n=202) or placebo (n=101)
- 59 sites in 17 countries
- Treatment duration: 52 weeks
Key Results:
- LDL-C reduction: 58.2% with enlicitide vs 2.6% increase with placebo at week 24
- Nearly 70% of enlicitide patients achieved both a 50% LDL-C reduction and LDL-C below 70 mg/dL
- More than two-thirds reached LDL-C below 55 mg/dL
- Adverse events: 64% enlicitide vs 62% placebo
- Serious adverse events: 10% enlicitide vs 12% placebo
Phase 2b Trial#
Ballantyne et al., JACC 2023 (PMID 36889610)#
This dose-ranging trial established the pharmacological foundation for enlicitide development.
Study Design:
- Phase 2b, randomized, double-blind, placebo-controlled, multicenter
- 381 adults with hypercholesterolemia across a wide range of ASCVD risk
- Randomized 1:1:1:1:1 to MK-0616 at 6, 12, 18, or 30 mg daily or placebo
- 8 weeks treatment + 8 weeks follow-up
Dose-Response Results at Week 8:
| Dose | LDL-C Reduction vs Placebo |
|---|---|
| 6 mg | 41.2% |
| 12 mg | 55.7% |
| 18 mg | 59.1% |
| 30 mg | 60.9% |
All doses achieved statistical significance (P<0.001). The relatively flat dose-response above 12 mg suggested that near-maximal PCSK9 inhibition is achieved at moderate doses, supporting the selection of 20 mg for Phase 3.
Evidence Quality Assessment#
| Criterion | Assessment | Details |
|---|---|---|
| Study design | Phase 2b + Phase 3 RCTs | Dose-ranging followed by pivotal trials |
| Sample size | Large (2,909 in CORALreef Lipids) | Adequate for efficacy and safety assessment |
| Primary endpoint | Met in all trials | LDL-C reduction at weeks 8 and 24 |
| Durability | Demonstrated at 52 weeks | Sustained reduction in CORALreef Lipids |
| Special populations | HeFH evaluated | CORALreef HeFH in familial hypercholesterolemia |
| Safety database | Robust | No excess adverse events vs placebo |
| Peer-reviewed publication | Yes | NEJM, JAMA, JACC |
| Outcomes trial | Ongoing | CORALreef Outcomes (19,000+ participants) |
Key Research Gaps#
-
Cardiovascular outcomes: The CORALreef Outcomes trial (NCT06008756) is the critical missing piece. While LDL-C reduction is a well-validated surrogate for cardiovascular risk reduction, regulatory and clinical acceptance of enlicitide will be strengthened by positive outcomes data.
-
Long-term safety: Published data extend to 52 weeks. The effects of sustained daily oral PCSK9 inhibition over years require ongoing surveillance, particularly regarding hepatic effects, neurocognitive outcomes, and diabetes risk.
-
Head-to-head comparisons: No direct comparisons with injectable PCSK9 inhibitors (evolocumab, alirocumab) have been published. Cross-trial comparisons suggest similar LDL-C lowering efficacy.
-
Real-world adherence: A key hypothesis underlying enlicitide's development is that oral administration will improve adherence compared to injectable PCSK9 inhibitors. This hypothesis requires real-world validation.
-
Monotherapy efficacy: Most trial participants were on background statin therapy. The efficacy of enlicitide as monotherapy in statin-intolerant patients needs further characterization.
Related Reading#
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