Enlicitide: The first oral PCSK9 inhibitor approved for treatment of hypercholesterolemia

Hypercholesterolemia, and particularly elevated low-density lipoprotein cholesterol (LDL-C), is a major causal factor in atherosclerotic cardiovascular disease (ASCVD) and contributes substantially to coronary heart disease, ischemic stroke, and peripheral artery disease. Statins remain the cornerstone of lipid-lowering therapy, while ezetimibe and injectable proprotein convertase subtilisin/kexin 9 (PCSK9) targeted agents are added when further LDL-C reduction is required. However, concerns about injections, cost, accessibility, and treatment inertia have limited the use of existing PCSK9 therapies, creating a need for potent oral alternatives. Enlicitide, approved by the US Food and Drug Administration in July 2026, is the first approved oral PCSK9 inhibitor. This macrocyclic peptide blocks the interaction between circulating PCSK9 and hepatic LDL receptors, thereby increasing receptor recycling and LDL-C clearance. In the phase III CORALreef Lipids and CORALreef HeFH trials, once-daily enlicitide reduced LDL-C by approximately 60%, and the effect was maintained for up to 52 weeks. Adverse event rates were generally similar to those observed with a placebo. Nevertheless, those trials primarily evaluated LDL-C reduction rather than cardiovascular outcomes, and their duration was insufficient to establish long-term safety. The ongoing CORALreef Outcomes trial will determine whether enlicitide-mediated LDL-C reduction translates into fewer major cardiovascular events and will help define its long-term clinical role.