Efficacy and safety of semaglutide and tirzepatide in the therapy of obesity and type 2 diabetes – current state of knowledge

Abstract

Background. The diabesity epidemic (obesity and type 2 diabetes) requires a shift from a glucocentric to a holistic approach, making weight reduction a clinical goal equal to glycemic control. Incretin-based therapies (semaglutide, tirzepatide) represent a breakthrough due to their pleiotropic effects. Aim. This study analyzes their efficacy, safety, molecular mechanisms, and cardio/nephroprotection in light of recent trials and guidelines. Material and methods. PubMed and Google Scholar were searched (2018–2026) using MeSH terms: obesity, type 2 diabetes, GLP-1/GIP agonists. The analysis included phase III trials (STEP, SURPASS, SURMOUNT), meta-analyses, and guidelines of the Polish Diabetes Association (PTD 2026), the Polish Association for the Study of Obesity (PTLO 2024), and the American Diabetes Association (ADA). Case reports and early-phase studies were excluded. Results. Diabesity is linked to an incretin deficit. GLP-1 and dual GIP/GLP-1 receptor agonists mimic the incretin effect, modulating appetite and enhancing insulin sensitivity. This facilitates sustained weight loss and multi-organ protection. Evidence from STEP and SURPASS trials highlights robust cardioprotection, nephroprotection, and reduced hepatic steatosis in MASLD. By targeting cerebral reward centers, these agents address hedonic hunger, improving long-term metabolic health. Conclusions. Incretin therapy is revolutionizing treatment. Semaglutide and tirzepatide achieve high weight reduction (>20%) and lower the risk of MACE, renal failure, and hepatic steatosis. Latest PTD (2026) and PTLO (2024) guidelines recommend their early implementation in primary care to combat obesity and its complications.