Research progress and future prospects of small-molecule glucagon-like peptide-1 receptor agonists (GLP-1RAs)

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are key agents in the treatment of type 2 diabetes mellitus (T2DM) and obesity. Small-molecule GLP-1RAs offer the advantage of oral administration while demonstrating efficacy comparable to that of peptide drugs. Despite synthetic challenges and solubility issues, compounds such as Pfizer’s PF-06882961 (Danuglipron), Eli Lilly’s LY3502970 (Orforglipron), and Hengrui Pharma’s HRS-7535 have shown potential to reduce glycosylated hemoglobin A1c (HbA1c) levels and body weight in Phase I-II trials, with mild to moderate gastrointestinal adverse effects, suggesting that they may be promising therapeutic options in the future.