Evaluating enlicitide decanoate: first oral PCSK9 inhibitor for the treatment of adults with hypercholesterolemia.

Abstract

Atherosclerotic cardiovascular disease (ASCVD) remains the leading global cause of morbidity and mortality, with elevated low-density lipoprotein cholesterol (LDL-C) as a major modifiable risk factor. Despite intensive statin therapy, many high-risk patients do not achieve increasingly stringent LDL-C goals, highlighting the need for additional lipid-lowering strategies. The development of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has significantly advanced lipid management, although currently available agents require subcutaneous administration and may be limited by adherence, accessibility, and cost. This review discusses the pharmacological profile, clinical efficacy, safety, and potential therapeutic positioning of enlicitide decanoate, the first oral PCSK9 inhibitor. Evidence from phase 2 and phase 3 CORALreef program clinical trials evaluating enlicitide in patients with hypercholesterolemia, heterozygous familial hypercholesterolemia, and established or high risk for ASCVD is summarized. Available data on enlicitide are also compared with existing lipid-lowering therapies, including statins, ezetimibe, and approved therapies targeting PCSK9. Enlicitide decanoate is a promising addition to lipid-lowering therapy, potentially expanding access to PCSK9 inhibition through oral administration. However, its definitive clinical role will depend on cardiovascular outcomes data, long-term safety, adherence in real-world practice, and cost-effectiveness compared with established injectable therapies.