Is Oral Semaglutide a Good Fit for Patients After Metabolic Bariatric Surgery? A Biopharmaceutical Mechanistic Perspective

Currently, GLP-1RAs are peptide drugs, typically administered by injection due to insufficient absorption, and only one GLP-1RA, semaglutide, is available as an orally administered drug. To overcome the absorption challenges of oral peptides, this drug product contains the absorption enhancer SNAC. As the tablet is eroded in the stomach, SNAC neutralizes the acidic gastric environment, thereby protecting the semaglutide from enzymatic degradation. Then, SNAC fluidizes the stomach lipidic membrane to increase semaglutide transcellular permeability across the gastric epithelium. It is necessary to realize that the use of such a unique drug product, that relies solely on the stomach for absorption, is expected to be affected by the extreme gastric anatomy/physiology changes post-MBS. Hence, we analyzed the key mechanisms that may affect the bioavailability of oral semaglutide post-MBS. Several mechanisms appear to potentially reduce oral semaglutide absorption post-MBS, including decreased inner gastric surface area, decreased gastric contractility, and faster gastric emptying. Hence, the effectiveness of the complex formulation, that relies solely on the stomach for the SNAC activity and semaglutide absorption, may be severely hampered post-MBS; clinicians should be aware of the potential malabsorption of oral GLP-1RA post-MBS, and preferably consider subcutaneous therapy until specific pharmacokinetic/clinical data are available.