Glucagon-like peptide-1 receptor analogues and beyond: emerging obesity pharmacotherapies

Obesity is a chronic disease associated with multiple health risks. Multimodal treatments including lifestyle interventions, pharmacotherapies and bariatric surgery should be the standard of care for obesity management. Bariatric surgery remains the most effective treatment yielding to sustainable weight loss (WL) of about 20-30%. Having understood better the role of the gut-brain axis on appetite, the field of obesity pharmacotherapy has been advancing rapidly. The recent approvals for glucagon-like peptide-1 (GLP-1) receptor agonist (RA) semaglutide 2.4 mg and the dual GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) agonist tirzepatide as treatments for obesity have raised the bar for WL efficacy for the emerging obesity pharmacotherapies. Combining GLP-1 RA and other entero-pancreatic hormones including GIP, glucagon or amylin receptor agonists (RAs) as well as GIP receptor antagonists have shown promising data in early phases of clinical trials, with some progressing to phase III clinical trials. Notably, the combinations of GLP-1 RA, GIP and glucagon RA (retatrutide) have shown WL efficacy closing on to that observed in bariatric surgery. While entero-pancreatic hormone-based therapies have been the centre of attention for obesity pharmacotherapies, non- entero-pancreatic hormone treatments also hold promise. In this review, we present the future pharmacotherapies for weight management in people with obesity, focusing on entero-pancreatic hormone-based molecules.