Glucagon-like peptide-1–based pharmacological treatment of obesity: a narrative review

Purpose: Obesity is a chronic, complex disease influenced by genetic, biological, and environmental factors, requiring integrated treatment approaches. Since lifestyle modification alone often fails to achieve sustained weight loss, pharmacological interventions are essential for long-term management.Current Concepts: Glucagon-like peptide-1 (GLP-1) receptor agonists and related co-agonists have transformed obesity and type 2 diabetes treatment. Agents including liraglutide and semaglutide, plus the dual glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonist tirzepatide, induce substantial weight loss (approximately 10% to 25%) through appetite suppression and enhanced satiety while improving glycemic control. Beyond weight reduction, these therapies demonstrate clinically meaningful cardiovascular and renal benefits, some appearing at least partly independent of weight loss, suggesting direct organ-protective effects. The therapeutic scope of GLP-1–based agents has expanded to multiple obesity-related complications, including heart failure with preserved ejection fraction, metabolic dysfunction–associated steatohepatitis, obstructive sleep apnea, osteoarthritis, and peripheral vascular disease. Current success has accelerated development of next-generation therapies targeting greater efficacy, improved tolerability, and novel delivery platforms, including oral formulations and small-molecule nonpeptide agonists.Discussion and Conclusion: This review summarizes established and emerging GLP-1–based therapies for obesity, focusing on mechanisms of action, clinical efficacy from pivotal trials, cardiovascular outcomes, and safety considerations. We discuss strategies to optimize pharmacokinetics and tolerability, advances in multi-receptor agonism, and key safety issues relevant to clinical practice. Four decades after GLP-1 discovery, these therapies represent a major advance in comprehensive metabolic disease management and may redefine obesity treatment and its associated comorbidities beyond original diabetes and weight loss indications.