Enlicitide Decanoate: Side Effects

Safety 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):

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#

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#

• Enlicitide overview and research guide
• Enlicitide risks and regulatory status
• Enlicitide dosing protocols