Abstract
Introduction: According to the World Obesity Atlas, overweight and obesity could affect approximately 50% of the world's adult population by 2030. Obesity treatment is complex and multidisciplinary. Pharmacological treatment with tirzepatide and retatrutide begins in secondary prevention to stop disease progression. Objective: To highlight the main clinical outcomes of tirzepatide and retatrutide in the treatment of obesity and comorbidities. Methods: The systematic review guidelines of the PRISMA platform were followed. The search was conducted from September to November 2025 in the Scopus, Embase, PubMed, Science Direct, SciELO, and Google Scholar databases. The quality of the studies was based on the GRADE instrument, and the risk of bias was analyzed according to the Cochrane instrument. Results and Conclusion: 92 articles were found. A total of 29 articles were evaluated, and 14 were included in this systematic review. Considering the Cochrane risk of bias tool, the overall assessment resulted in 18 studies with a high risk of bias and 20 studies that did not meet the GRADE and AMSTAR-2 criteria. Most studies showed homogeneity in their results, with X2 = 86.5% > 50%. It was concluded that retatrutide offers superior efficacy in weight loss compared to tirzepatide and other GLP-1 analogs, but with a higher risk of adverse events. Dual agonists offer a favorable balance between efficacy and safety. Selecting personalized treatments based on patient characteristics is recommended. Available randomized clinical trials showed that, regarding weight loss, tirzepatide (15 mg) resulted in up to 17.8% weight loss at 72 weeks, semaglutide (2.4 mg) in up to 13.9% after 68 weeks, liraglutide (3.0 mg) in up to 5.8% after 26 weeks, and retatrutide (12 mg) produced the greatest weight loss, with 22.1% after 48 weeks. The main adverse effects of retatrutide were related to gastrointestinal events compared to tirzepatide.