Oral Incretin-Based Therapies for Weight Management

This paper aims to review the current development of oral incretin-based therapies for treatment of overweight and obesity, and outline the efficacy of upcoming therapeutic candidates as well as their safety profiles. Clinical recommendations are provided regarding the role of oral incretin-based therapies for treatment of overweight and obesity.

Until recently, almost all incretin-based therapies have been injectable formulations due to limitations in absorption and bioavailability. Recently, novel techniques have emerged to overcome these barriers, with two agents (oral semaglutide and orforglipron) having obtained FDA approval; multiple other candidates are currently in development. Semaglutide is a peptide GLP-1 receptor agonist and orforglipron is a small-molecule biased GLP-1 receptor agonist approved for treatment of obesity; oral semaglutide is additionally approved for secondary cardiovascular risk reduction. In phase 3 trials, oral semaglutide and orforglipron have demonstrated clinically significant weight loss efficacy of > 10% with an adverse-event profile consistent with the GLP-1 class. Differences in formulations of novel oral agents result in differences in administration guidelines and potential risk of adverse events; with particular concern of drug-induced liver injury observed with first generation small-molecule incretin therapies. Overall, oral incretin-based therapies offer a promising new and potentially more accessible option for patients with overweight or obesity.