Novel pharmacotherapies for weight loss: Understanding the role of incretins to enable weight loss and improved health outcomes

Abstract Obesity and type 2 diabetes mellitus (T2D) are widespread diseases that significantly impact cardiovascular and renal morbidity and mortality. In the recent years, intensive research has been performed to assess the role of adipose tissue and body fat distribution in the development of metabolic and non‐metabolic complications in individuals with obesity. In addition to lifestyle modifications, glucagon‐like peptide‐1 receptor agonists (GLP‐1‐RA) have become a meaningful treatment expansion for the management of both disorders. In addition to improving metabolic control and reducing body weight, treatment with GLP‐1‐RAs reduces cardiovascular and renal events in individuals with obesity with and without diabetes. These important benefits of GLP‐1‐RAs have triggered new interest in other enteroendocrine and enteropancreatic peptides for treating obesity and its metabolic and non‐metabolic consequences. The first peptide dual‐agonist targeting glucose‐dependent insulinotropic polypeptide (GIP) and GLP‐1 receptors has been approved for the treatment of T2D and obesity. GIP/GLP‐1 dual‐agonism appear to provide better metabolic control and greater weight reduction compared with GLP‐1‐R mono‐agonism. Other peptide and non‐peptide co‐agonists are in clinical development for obesity, T2D, metabolic dysfunction‐associated steatotic liver disease (MASLD) and other metabolic disorders. This narrative review aims to summarize the available data on approved and emerging enteroendocrine and enteropancreatic based treatment approaches for obesity and metabolic disorders. In addition to available clinical efficacy measures, side effects, limitations and open challenges will also be addressed.