Abstract
Incretins are gut hormones involved in maintaining metabolic homeostasis in the human body, and disorders of the incretin system are recognized as contributing to the pathobiology of metabolic dysfunction and obesity. Incretin polyagonists are transforming the landscape of obesity treatment by offering potent, non-surgical alternatives to bariatric procedures. Acting on multiple incretin and related receptors, these novel pharmacological agents harness the synergistic effects of gut hormones such as glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide, and glucagon to achieve unprecedented weight loss and metabolic improvements. Recent clinical trials demonstrate that dual and triple agonists can produce weight reductions comparable to, or in some cases approaching, those seen with bariatric surgery, while simultaneously improving glycemic control, lipid profiles, liver fat, and cardiovascular risk factors. Unlike conventional monotherapies, these polyagonists address the complexity of energy homeostasis and metabolic dysfunction in obesity, with some agents displaying a favorable side effect profile and thereby enhancing patient tolerability. Practical considerations, such as ease of administration, cost, long-term safety, and accessibility, remain evolving challenges; yet, incretin polyagonists have rapidly gained prominence in clinical guidelines for the management of obesity and type 2 diabetes mellitus. As evidence mounts regarding their efficacy, safety, and potential to modify cardiometabolic disease risk, incretin polyagonists emerge as promising alternatives, especially for patients unable or unwilling to undergo bariatric surgery. Ongoing research will further define their long-term role, comparative effectiveness, and optimal integration into multidisciplinary obesity care. This review discusses the current evidence-base for optimal use of incretin polyagonists as an alternative to bariatric surgery.