Glucagon‑Like Peptide‑1–Based Agonists as Novel Targets In Obesity Management: Mechanistic Pathways and Adverse Effects

Abstract

Obesity is a persistent, recurring condition resulting from dysregulated gut-brain-adipose signaling and disrupted energy balance. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have proven to be highly effective pharmacotherapies, facilitating an average weight reduction of 10–25% in individuals with obesity through coordinated effects on hypothalamic appetite pathways, mesolimbic reward systems, gastrointestinal motility, pancreatic islet activity, and hepatic–adipose metabolism. They may lower the risk of serious cardiovascular events and protect the kidneys in people at high risk, which supports GLP-1-based therapy as a key part of lowering the risk of cardiometabolic disease. However, GLP-1/GIP agonism is also linked to a specific set of negative side effects, such as nausea, vomiting, diarrhea, and constipation that get worse with higher doses, as well as a higher risk of gallbladder disease, pancreatitis, and gastrointestinal problems. This mini‑review emphasize on the mechanistic pathways linking GLP‑1/GIP agonism to weight loss and cardiometabolic benefits and examines the pathophysiologic basis of key adverse effects to guide individualized use of semaglutide and tirzepatide in endocrinology and obesity practice.

Keywords: Glucagon-like peptide-1 receptor agonists, Obesity, Semaglutide, Tirzepatide