GLP-1 Receptor Signaling and Oral Dysfunction: A Narrative Review on the Mechanistic Basis of Semaglutide-Related...

This review addresses the growing concern of oral side effects, particularly dry mouth, associated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) widely used for diabetes and obesity. A literature search of PubMed/MEDLINE, Scopus, Web of Science, and Google Scholar (March-September 2025) identified studies on GLP-1 receptor signaling, semaglutide pharmacology, salivary gland biology, biased agonism, β-arrestin, and cAMP pathways, and reported oral adverse effects. Of 183 records screened, 78 met inclusion criteria and were narratively synthesized across 5 mechanistic domains linking the molecular mechanisms that may underly semaglutide-induced alteration in salivary function by exploring GLP-1 receptor (GLP-1R) expression and signaling in salivary glands. The available literature data shows that different GLP-1 receptor agonists exhibit distinct patterns of GLP-1R activation, engaging the cAMP- and β-arrestin-dependent pathways to varying extents, which may thus differentially regulate exocytosis and cellular protection. Furthermore, semaglutide's strong albumin binding leads to prolonged receptor activation, and may disturb the rhythmic calcium and cAMP cross-talk essential for normal salivary secretion. Persistent stimulation may cause receptor desensitization, β-arrestin-mediated internalization, and reduced gland responsiveness. Clinical pharmacovigilance data indicate disproportionality signals, suggesting that semaglutide may be reported more frequently with oral side effects compared with other GLP-1 receptor agonists, although spontaneous-report databases cannot confirm causality. These insights underscore the need for patient counseling, preventive oral care, and further studies on receptor signaling bias, contributing to personalized approach when using GLP-1RAs.