New horizons in obesity pharmacotherapy: a clinical and pharmacological review of incretin agonists, from liraglutide and semaglutide to retatrutide

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Abstract
This article presents a clinical and pharmacological overview of modern incretin receptor agonists used to treat obesity. It examines the evolution of therapeutic approaches, ranging from moderately effective agents (liraglutide) to highly effective long-acting formulations (semaglutide), as well as dual (tirzepatide, a GIP / GLP-1 agonist) and triple (retatrutide, a GLP-1, GIP, and glucagon agonist) agonists. The mechanisms of action, based on central appetite suppression, delayed gastric emptying, and the activation of multiple metabolic pathways, are analyzed in detail. Issues regarding safety, adverse reactions, and specific aspects of use in patients with comorbidities, such as cardiovascular disease, type 2 diabetes, and obstructive sleep apnea, are discussed. Among pharmacological agents, multi-action incretin agonists, specifically tirzepatide and retatrutide, demonstrate the greatest efficacy in weight loss (reductions of 20.9 % and 24 %, respectively, in patients receiving the maximum dose), with effects approaching those of bariatric surgery. The development of oral formulations (semaglutide, amycretin) and further investigation of combination regimens involving metformin and sodium-glucose cotransporter-2 (SGLT2) inhibitors appear to be promising. It is essential to expand the indications for use and incorporate new drugs into national clinical guidelines; this would enable a personalized approach to obesity treatment, taking into account the patient’s comorbidities and individual characteristics.

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