Emerging Pharmacological Strategies in Obesity: From GLP-1 Agonists Through Triple Incretin Therapy to Amylin Analogs – Narrative Review

Background Obesity is one of the most prevalent chronic diseases and a growing public health burden, resulting from complex interactions between genetic, environmental, and neuroendocrine mechanisms that regulate energy homeostasis. Because lifestyle modifications alone frequently fail to maintain long-term weight reduction, modern pharmacotherapy targeting physiological pathways of appetite and metabolism has become an essential component of care. Aim This review aims to summarize the evolution of pharmacological treatments for obesity, with particular emphasis on established GLP-1 receptor agonists and emerging strategies, including dual and triple incretin receptor agonism and amylin-based therapies. It critically evaluates their efficacy, safety, current limitations, and potential future role in chronic obesity management. Materials and Methods PubMed, Google Scholar, and ClinicalTrials.gov were searched for English language sources from January 2010 to September 2026. The final search was conducted on 15th of September 2026. Earlier landmark and mechanistic sources were considered. The synthesis included 61 publications and registry records; preclinical evidence informed mechanisms only. Results Incretin-based and multi-receptor therapies have demonstrated substantial body weight reductions in clinical trials. GLP-1 receptor agonists, including liraglutide and semaglutide, reduce body weight, with cardiovascular benefits demonstrated in specific patient populations. Dual receptor agonists, including tirzepatide, mazdutide, and survodutide, and the triple receptor agonist retatrutide have also demonstrated substantial weight reductions. Retatrutide produced a mean weight reduction of 24.2% at the highest dose after 48 weeks in a phase II trial. Selected agents have shown improvements in hepatic steatosis or MASH, depending on the therapy and study population. Cagrilintide and its combination with semaglutide (CagriSema) have demonstrated weight reduction in clinical trials. The most common adverse events were gastrointestinal, generally mild to moderate, with frequency influenced by dose and dose escalation. Conclusions The pharmacological treatment of obesity has transitioned toward targeted, mechanism-based modulation of neuroendocrine pathways, demonstrating high clinical efficacy. Because treatment discontinuation frequently leads to weight regain, obesity requires sustained, chronic pharmacological management. Future therapeutic selection should be highly individualized, expanding beyond body mass index (BMI) alone to consider specific metabolic phenotypes and associated comorbidities.