ORAL SMALL-MOLECULE GLP-1 RECEPTOR AGONISTS FOR OBESITY: PHARMACOLOGICAL MECHANISMS, CLINICAL EVIDENCE, AND DRUG-DEVELOPMENT CHALLENGES

Obesity is a chronic, relapsing, multifactorial disease associated with type 2 diabetes mellitus, cardiovascular disorders, metabolic dysfunction-associated steatotic liver disease, and reduced quality of life. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as important pharmacological agents for weight management because they regulate appetite, enhance glucose-dependent insulin secretion, suppress inappropriate glucagon secretion, and delay gastric emptying. However, many established GLP-1 receptor agonists are peptide-based medicines administered by injection. Oral semaglutide provides an oral alternative but remains a peptide drug that requires specialized absorption-enhancing technology. The development of orally bioavailable, non-peptide small-molecule GLP-1 receptor agonists represents a distinct advancement in medicinal chemistry and pharmaceutical drug development.This review examines the physiological role of GLP-1, the pharmacological mechanisms of receptor activation, the structural and pharmacokinetic advantages of small-molecule agonists, and the clinical evidence for investigational and clinically advanced compounds, particularly orforglipron, danuglipron, and aleniglipron. It also discusses gastrointestinal adverse effects, dose optimization, long-term safety, cardiovascular outcomes, receptor-signalling selectivity, manufacturing considerations, and accessibility. Phase 3 evidence published in 2025 demonstrated significant weight reduction with orforglipron in adults with obesity without diabetes. More recent evidence from 2026 has further advanced the field. Nevertheless, results from different compounds and clinical trials cannot be directly compared without accounting for differences in study design, populations, duration, and statistical methods. Overall, small-molecule GLP-1 receptor agonists offer a promising approach to oral obesity pharmacotherapy, although sustained efficacy, tolerability, long-term outcomes, and real-world affordability remain important considerations.