The global burden of obesity is high with more than 600 million adults estimated to be living with obesity worldwide. First line treatment for obesity is lifestyle intervention including diet, exercise, and behavioral therapy. While effective in many patients, lifestyle intervention is often not sustainable, and many patients regain weight after initial weight loss. Significant progress has recently been made in pharmacotherapeutic options for obesity treatment with the approval of the GLP-1 receptor agonist (GLP-1Ra) class of anti-obesity medications. Injectable GLP-1R liraglutide and semaglutide (Novo Nordisk) are showing promising weight loss, with multiple oral small molecule GLP-1Ra’s in later stage clinical development offering patients the convenience of a once daily pill as well as a means to offset some of the supply burden associated with peptide manufacture. While efficacious and generally well tolerated, there remains significant unmet need to support those patients who require an additional degree of weight loss and to mitigate the gastrointestinal side effects observed for some taking GLP-1Ra. Several approaches are being pursued to combine mechanisms that function cooperatively with GLP-1 including incretin (GIP and GCGR modulators) as well as other entero-pancreatic hormones (e.g., amylin and PYY agonists) to enhance the therapeutic profile of GLP-1Ra monotherapy. Similar to the evolution of GLP-1R agonist monotherapy, the next horizon is the development of oral small molecule-based GLP-1R combinations providing additional optionality for patients and physicians. The recent success of Lilly’s dual GLP-1R/GIPR agonist peptide tirzepatide (Zepbound) in the SURMOUNT obesity trials for chronic weight management is a testament to the abundance of opportunity in this space. This presentation will highlight recent pre-clinical anti-obesity combination data, an effort aimed at ultimately providing optimal efficacy for obesity patients.