The emergence of glucagon-like peptide-1 receptor agonists (GLP-1RAs) represents a major breakthrough in the pharmacotherapy of obesity. However, their single-target mechanism has limitations. In recent years, combination strategies targeting multiple pathways and multiple targets have become a frontier in weight-loss drug development. This review systematically examines GLP-1RA-based combination weight-loss strategies, focusing on the scientific rationale and research progress in two main directions: single-agent multi-target agonists and multi-drug combination therapies. In single-agent multi-target strategies, glucagon-like peptide-1 receptor/glucose-dependent insulinotropic polypeptide receptor (GLP-1R/GIPR) dual agonists, glucagon-like peptide-1 receptor/glucagon receptor (GLP-1R/GCGR) dual agonists, glucagon-like peptide-1 receptor/amylin receptor (GLP-1R/AMYR) dual agonists, and triple agonists achieve weight loss beyond traditional single agents through synergistic regulation of appetite, energy metabolism, and lipolysis. In multi-drug combination therapy, free combinations offer flexibility, while fixed-dose combinations improve convenience and adherence. These strategies improve weight loss and metabolic outcomes, including hepatic fat and cardiometabolic parameters. In terms of safety, gastrointestinal events are the most common. However, as the number of targets increases and doses escalate, potential risks such as increased heart rate and hypoglycemia warrant attention, with particular consideration for thyroid and muscle safety during long-term use. Future research should focus on optimizing personalized treatment strategies, conducting head-to-head comparisons of agents with different mechanisms, developing oral formulations, and exploring long-term maintenance regimens to advance comprehensive obesity management.
