Yining Xu, Daniel J Drucker, Giovanni Traverso, Ana Beloqui
Endocrine Reviews, First published online August 4, 2025, bnaf027
https://doi.org/10.1210/endrev/bnaf027
The multiple physiological effects of gut hormones in different metabolic tissues make them attractive therapeutic targets for the treatment of metabolic diseases. Currently, only glucagon-like peptide-1 (GLP-1) receptor-based agonists and oral dipeptidyl peptidase-4 inhibitors are available on the market. Despite their positive clinical outcomes across a range of indications, these treatments present several clinical challenges, including high costs, the need for peptide injections, and requirements for repeated administration. These limitations have driven research into improved GLP-1-based therapies, such as oral small-molecule agonists and novel drug delivery strategies based on emerging GLP-1 medicines. This article describes the challenges in clinical application and development of GLP-1–based pharmacotherapies. We review the development of oral small-molecule agonists and various drug delivery technologies, including ultralong-acting injectable technologies, continuous-acting implantable pumps, smart-acting electronic devices, nutrient-induced cell therapies, and noninvasive delivery systems. We discuss the current state of research, challenges to overcome, and opportunities to improve patient compliance and clinical outcomes. Additionally, we explore how endocrinological effects and patient-oriented needs can guide the development of advanced GLP-1 medicines.
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