Background Tirzepatide, a dual glucose-dependent insulinotropic polypeptide, (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, has emerged as an effective therapy for obesity and type 2 diabetes mellitus (T2DM). Its dual-incretin mechanism may offer enhanced metabolic benefits compared with selective GLP-1 receptor agonists such as semaglutide. Methods A structured narrative review of clinical trials, real-world observational studies, and contextual cardiovascular outcome analyses was conducted. Literature was sourced from ClinicalTrials.gov and relevant scientific databases to compare tirzepatide and semaglutide across weight, glycemic, cardiometabolic, and safety outcomes. Results Across completed head-to-head randomized trials, tirzepatide consistently achieved greater reductions in body weight, and HbA1c than semaglutide in individuals with obesity or T2DM. Semaglutide, however, has the most mature evidence for cardiovascular risk reduction, as demonstrated in the SUSTAIN-6, PIONEER-6, and SELECT trials. The SURPASS-CVOT trial established cardiovascular non-inferiority for tirzepatide compared with dulaglutide, alongside improvements in cardiometabolic risk factors. Real-world studies reported heterogeneous cardiovascular outcomes. Conclusion Tirzepatide demonstrates superior metabolic efficacy in direct comparative trials, whereas semaglutide currently has the strongest evidence for cardiovascular benefit. Treatment selection should be individualized based on clinical priorities and patient characteristics.
Harbi et al. (2026) studied this question.