Enlicitide: The First Oral PCSK9i for Lowering Low-Density Lipoprotein Cholesterol

This article describes pharmacology, pharmacokinetics, safety, and efficacy data of enlicitide, the first Food and Drug Administration (FDA)-approved oral proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i).

PubMed, Embase, Web of Science, and Cochrane were searched through July 17, 2026.

Clinical trials published in English were included. Relevant information from the methodology and results was extracted.

Enlicitide received FDA approval on July 16, 2026, based on results from phase 2 and 3 trials showing a 57.1% to 64.6% reduction in low-density lipoprotein-cholesterol (LDL-C) and reduced other atherogenic lipid particles at 24 weeks in patients with hypercholesterolemia, including those with heterozygous familial hypercholesterolemia, while maintaining a favorable adverse effect profile. Enlicitide represents the fifth FDA-approved agent targeting PCSK9, having similar efficacy to other agents in class while having a novel macrocyclic peptide formulation with permeation enhancers, allowing for oral administration.Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs:As PCSK9is continue to be at the forefront of dyslipidemia guidelines, the approval of an oral agent is paramount in ensuring patient access. Enlicitide mirrors LDL-C lowering compared with existing PCSK9is and surpasses LDL-C lowering compared with non-statin options such as bempedoic acid and ezetimibe. Confirmation of cardiovascular outcomes data with enlicitide will solidify its role in reducing atherosclerotic cardiovascular disease risk.

Enlicitide significantly lowered LDL-C similar to existing PCSK9is with few adverse effects. The oral formulation provides an essential option for LDL-C lowering, especially in patients adverse to injections.