Oral Versus Injectable Incretin-Based Anti-Obesity Therapies: An Integrated Computational and Evidence-Based Comparison of Orforglipron, Semaglutide, and Tirzepatide.

Incretin-based agents are transforming obesity pharmacotherapy, and orforglipron, the first oral non-peptide GLP-1 receptor agonist to complete phase 3 testing, invites direct comparison with the injectable agents semaglutide and tirzepatide. We integrated clinical trial evidence, including the direct head-to-head SURMOUNT-5 trial, independently verified molecular descriptors, a fully specified drug-target-disease network with permutation-tested hub significance, hypergeometric pathway enrichment, and multi-criteria decision analysis (MCDA) across four weighting schemes with formal sensitivity analysis. Tirzepatide produced significantly greater weight loss than semaglutide under randomized, head-to-head conditions (20.2% vs. 13.7% at week 72) and ranked highest under balanced, efficacy-, and safety-dominant MCDA models once a composite ADMET score misapplied to two large peptides was removed. Orforglipron's lipophilicity exceeds the Lipinski ceiling, showing that its oral absorption reflects deliberate chemistry rather than default small-molecule developability; it nonetheless ranked highest under an accessibility-dominant model driven by oral feasibility and manufacturing scalability. These rankings were stable under Monte Carlo sensitivity analysis for three of four weighting schemes, with the balanced model comparatively fragile. Tirzepatide's cardiovascular evidence has also advanced, with SURPASS-CVOT reporting non-inferiority to dulaglutide. No single agent dominates every criterion; treatment selection should match the clinical priority the individual patient weights most heavily.