Current Insights, Advantages and Challenges of Small Molecule Glucagon-like Peptide 1 Receptor Agonists: A Scoping Review

Type 2 diabetes mellitus (T2DM) is a prevalent chronic condition with significant morbidity and mortality, largely due to its vascular complications. The emergence of novel pharmacological agents, particularly glucagon-like peptide-1 receptor agonists (GLP-1RAs), has revolutionized T2DM management by addressing glycemic control and comorbidities such as cardiovascular and renal diseases. Traditionally, GLP-1RAs require subcutaneous injection, presenting challenges in patient adherence and limiting combination therapy options. Recent advancements have introduced orally available small-molecule GLP-1RAs, which retain the physiological benefits of peptide-based GLP-1RAs, such as promoting insulin secretion, reducing appetite, and improving weight loss. These small molecules offer enhanced tissue permeability, extended half-lives, and the potential for fixed-dose combinations, addressing limitations of injectable formulations. This review explores the preclinical and clinical progress of small-molecule GLP-1RAs, highlighting their potential to redefine diabetes care by improving convenience, adherence, and accessibility for patients.