Tirzepatide, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, and semaglutide, a selective GLP-1 receptor agonist, are the two most effective approved injectable pharmacotherapies for obesity. Until recently, comparisons between them rested largely on cross-trial inference. A direct head-to-head randomised trial and a rapidly expanding body of comparative real-world evidence now permit a formal appraisal. This objectives of this review are to systematically identify, appraise, and synthesise original comparative studies evaluating the efficacy and safety of tirzepatide versus semaglutide in adults with overweight or obesity. This review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement. PubMed/MEDLINE, Embase, Scopus, and Web of Science were searched up to 20 July 2026, with backward and forward citation tracking. Eligible studies were peer-reviewed original randomised or non-randomised comparative studies directly comparing subcutaneous tirzepatide with subcutaneous semaglutide in adults with overweight or obesity and reporting at least one anthropometric outcome; non-original publications were excluded. Risk of bias was assessed with RoB 2 and Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I). Substantial heterogeneity precluded meta-analysis, and findings were synthesised narratively. Of 535 records identified, 11 studies comprising approximately 62,700 analysed participants were included: one phase 3b open-label randomised active-controlled trial and 10 retrospective observational cohorts from the United States, Kuwait, Turkiye, Bangladesh, and an international federated network. Tirzepatide produced greater weight reduction than semaglutide in every study that formally tested the comparison. In the randomised trial, mean weight change at 72 weeks was -20.2% with tirzepatide versus -13.7% with semaglutide. In real-world cohorts, adjusted between-group differences ranged from approximately 2.3 to 4.4 percentage points, and the advantage was most pronounced at stringent weight-reduction thresholds. Tirzepatide was also associated with greater improvements in blood pressure and glycated haemoglobin and a lower incidence of new-onset type 2 diabetes. Gastrointestinal events predominated with both agents. The randomised trial and six cohorts were judged at low risk of bias, and four cohorts at serious risk, principally from unadjusted confounding. Tirzepatide achieves greater weight reduction than semaglutide in adults with overweight or obesity, with a broadly comparable short-term safety profile. The advantage is attenuated in routine care relative to the trial setting, and long-term head-to-head data on cardiovascular and other clinical endpoints remain absent.
