Levels of circulating semaglutide determine reductions in HbA1c and body weight in people with type 2 diabetes

Glucagon-like peptide-1 receptor agonists (GLP-1RA) are used for the treatment of type 2 diabetes. Whether clinically important responses and adverse events (AEs) are dependent on the route of administration has not been determined. We demonstrate that nearly identical exposure-response pharmacodynamic relationships are determined by plasma semaglutide levels achieved through oral versus injectable administration for changes in HbA1c, body weight, biomarkers of cardiovascular risk, and AEs such as nausea and vomiting. At typical exposure levels for oral semaglutide, the estimated response is 1.58% (oral) versus -1.62% (subcutaneous) for HbA1c and 3.77% (oral) versus 3.48% (subcutaneous) reduction in body weight relative to baseline after 6 months. Increased body weight is the most important variable associated with reduced semaglutide exposure for both formulations. Hence, interindividual variation in GLP-1R responsivity or route of administration are not major determinants of GLP-1RA effectiveness in the clinic.