The global rise in aging populations has been accompanied by increasing rates of obesity and type 2 diabetes, both of which pose significant public health and economic challenges. This review aims to investigate the pathophysiological link between obesity and diabetes and evaluate emerging therapeutic strategies that involve glucagon-like peptide-1 receptor and melanocortin-4 receptor agonists, including their dual and triple agonist developments. A comprehensive literature review was conducted focusing on the mechanisms of glucagon-like peptide-1 receptor and melanocortin-4 receptor agonists, their clinical efficacy, and the evolution of combination therapies. Emphasis was placed on recent clinical trials and the development of oral agonist formulations to improve patient compliance. Glucagon-like peptide-1 receptor agonists, such as semaglutide and liraglutide, promote insulin secretion, suppress appetite, and result in effective weight loss and glycemic control. Semaglutide is available in both injectable and oral forms, improving accessibility. Liraglutide also reduces cardiovascular risk. Melanocortin-4 receptor agonists act via the central nervous system to reduce appetite and increase energy expenditure, with setmelanotide showing efficacy in genetic obesity. Dual and triple agonists, such as tirzepatide, simultaneously target glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon receptors, leading to enhanced metabolic outcomes. Oral drugs like rybelsus improve long-term adherence. Glucagon-like peptide-1 receptor and melanocortin-4 receptor agonists, particularly when used as dual or triple agents, represent promising therapeutic innovations for obesity and type 2 diabetes. The development of oral formulations further enhances treatment convenience and adherence, paving the way for improved clinical outcomes.
