Semaglutide, a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist, improved the type 2 diabetes mellitus treatment and obesity by its glucose-lowering and weight loss effects. Although the subcutaneous route provides high bioavailability and stable pharmacokinetics, the development of oral semaglutide makes a significant advancement in peptide therapeutics. However, oral delivery remains limited by an absolute bioavailability of only approximately 0.4-1% under optimized fasting conditions with restricted water intake, whereas systemic exposure is essentially absent in the fed state because plasma semaglutide concentrations remain below the limit of quantification. This extremely low exposure reflects peptide degradation within the gastrointestinal tract, poor epithelial permeability, gastric physiological constraints, and presystemic metabolism. The combination with sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC) helps in gastric absorption by increasing the local gastric microenvironmental pH, thereby reducing acid-induced peptide unfolding, suppressing pepsin activation, maintaining semaglutide predominantly in its absorbable monomeric form by limiting oligomer formation, and enhancing transcellular uptake. But the oral form of semaglutide is constrained by narrow dose limits, considerable pharmacokinetic variability that, despite large fluctuations in individual absorption, produces relatively stable steady-state exposure because semaglutide's approximately one-week half-life and extensive albumin binding buffer day-to-day differences in absorption. This review examines semaglutide pharmacokinetics, focusing on mechanistic challenges to oral bioavailability and formulation approaches to address this. We assess emerging methods such as nanotechnology-based formulations, other permeation enhancers, enzyme inhibitors and device-based delivery systems for their abilities to improve absorption and efficacy. Furthermore, clinical efficacy and patient adherence as well as research opportunities are considered. Continual development of these technologies may emerge as a solution to enhance bioavailability, decrease dosing frequency and expand the range of uses of oral peptide therapies.
