Enlicitide Decanoate: Side Effects
Known side effects, contraindications, and interactions
📌TL;DR
- •3 known side effects documented
- •3 mild, 0 moderate, 0 severe
- •1 contraindications listed
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Side Effects Severity Chart
Among the most commonly reported adverse events in the CORALreef trials, occurring at similar rates in enlicitide and placebo groups. Not considered treatment-related.
Reported at comparable rates in treatment and placebo groups. Likely related to underlying ASCVD risk population characteristics and concomitant statin use rather than enlicitide.
Mild GI events (nausea, diarrhea) reported in some patients. Rates were similar between enlicitide and placebo groups in Phase 3 trials.
⛔Contraindications
- •Known hypersensitivity to enlicitide or any excipient
⚠️Drug Interactions
- •No clinically significant drug interactions have been identified. Enlicitide has been safely co-administered with statins (moderate and high intensity), ezetimibe, and other lipid-lowering therapies in clinical trials.
- •As a macrocyclic peptide, enlicitide is not expected to interact with cytochrome P450 enzymes or drug transporters, reducing the risk of drug-drug interactions.
Community-Reported Side Effects
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View community protocolsSafety Overview#
Enlicitide has demonstrated a safety profile that is essentially indistinguishable from placebo across the CORALreef Phase 3 clinical program. In the CORALreef HeFH trial, adverse events occurred in 64% of enlicitide patients vs 62% of placebo patients, and serious adverse events occurred in 10% vs 12%, respectively. Similar safety was observed in the CORALreef Lipids trial.
This clean safety profile is consistent with the established safety record of PCSK9 inhibition as a therapeutic approach. Injectable PCSK9 antibodies (evolocumab, alirocumab) have demonstrated excellent long-term safety over years of post-marketing surveillance, providing reassurance about the target biology.
Adverse Events in Clinical Trials#
CORALreef Lipids (NEJM 2026)#
In the pivotal CORALreef Lipids trial (2,909 patients):
- Adverse events did not appear to differ between enlicitide and placebo groups
- Discontinuation due to adverse events: 3.1% (enlicitide) vs 4.1% (placebo)
- No excess in any specific adverse event category
CORALreef HeFH (JAMA 2026)#
In the CORALreef HeFH trial (303 patients):
| Category | Enlicitide (n=202) | Placebo (n=101) |
|---|---|---|
| Any adverse event | 64% | 62% |
| Serious adverse events | 10% | 12% |
| Discontinuation due to AEs | Low | Similar |
Phase 2b (JACC 2023)#
In the Phase 2b trial (381 patients, 8-week treatment + 8-week follow-up):
- Well tolerated across all four dose groups (6, 12, 18, 30 mg)
- Adverse event rates similar across all treatment arms and placebo
- No dose-dependent increase in adverse events
Safety by Organ System#
Cardiovascular#
No signal for cardiovascular adverse events has been identified. The CORALreef Outcomes trial (19,000+ participants) will definitively assess cardiovascular safety and efficacy.
Hepatic#
No clinically meaningful liver toxicity signal. Liver function monitoring is standard practice for patients on lipid-lowering therapy.
Musculoskeletal#
PCSK9 inhibition is not associated with myopathy. Any muscle symptoms are more likely related to concomitant statin use.
Neurological#
Early concerns about PCSK9 inhibitors and neurocognitive effects have not been substantiated by large clinical trials or post-marketing surveillance of injectable PCSK9 antibodies. No neurocognitive signal has been reported with enlicitide.
Immunological#
As a macrocyclic peptide rather than a monoclonal antibody, enlicitide is not expected to generate anti-drug antibodies or cause immunogenicity-related adverse events.
Comparison with Injectable PCSK9 Inhibitors#
| Safety Feature | Enlicitide | Evolocumab/Alirocumab |
|---|---|---|
| Injection site reactions | Not applicable (oral) | Common (3-10%) |
| Anti-drug antibodies | Not expected | Possible (low rates) |
| Overall AE rate | Similar to placebo | Similar to placebo |
| Serious AEs | Similar to placebo | Similar to placebo |
| Cold-chain failures | Not applicable | Risk of reduced efficacy |
Contraindications#
- Hypersensitivity: Known allergy to enlicitide or excipients
Drug Interactions#
No clinically significant drug interactions have been identified. As a macrocyclic peptide, enlicitide is not metabolized by cytochrome P450 enzymes and is not expected to affect drug transporters. It has been safely co-administered with:
- Moderate and high-intensity statins (atorvastatin, rosuvastatin)
- Ezetimibe
- Other non-statin lipid-lowering therapies
Related Reading#
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Frequently Asked Questions About Enlicitide Decanoate
What are the most common side effects of enlicitide?
In Phase 3 trials, the most commonly reported adverse events with enlicitide were upper respiratory tract infections, musculoskeletal pain, and mild gastrointestinal symptoms. Critically, these events occurred at similar rates in enlicitide and placebo groups, indicating they are likely related to the underlying patient population rather than the drug itself.
Is enlicitide safer than injectable PCSK9 inhibitors?
Enlicitide eliminates injection site reactions, which are common with injectable PCSK9 antibodies. The overall adverse event profile appears comparable to placebo, consistent with the safety record of the PCSK9 inhibitor class. As a macrocyclic peptide rather than a monoclonal antibody, enlicitide is not expected to generate anti-drug antibodies.
Does enlicitide affect liver function?
No clinically meaningful hepatotoxicity signal has been identified in clinical trials. Liver function monitoring is recommended as part of standard lipid-lowering therapy management, particularly in patients on concomitant statins.
Does enlicitide cause muscle pain?
Musculoskeletal pain was reported at similar rates in enlicitide and placebo groups. PCSK9 inhibition as a mechanism is not associated with myopathy. Any muscle symptoms in clinical trial patients are more likely attributable to concomitant statin therapy.
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Medical Disclaimer
This website is for educational and informational purposes only. The information provided is not intended to diagnose, treat, cure, or prevent any disease. Always consult with a qualified healthcare professional before using any peptide or supplement.