Tirzepatide and semaglutide are among the most effective incretin-based therapies currently used in type 2 diabetes and obesity. To review direct comparative clinical evidence on tirzepatide versus semaglutide, with emphasis on glycemic efficacy, body-weight reduction, metabolic and mechanistic parameters, and tolerability. PubMed was searched from inception to March 14, 2026, without language or date restrictions, for original human studies directly comparing these agents and secondary pooled, mechanistic, exploratory, or post hoc analyses derived from direct comparative trials. Eleven eligible publications were identified, largely representing three parent comparative settings: SURPASS-2, a 28-week mechanistic phase 1 study, and SURMOUNT-5. Across the available direct comparative literature, tirzepatide generally demonstrated greater metabolic efficacy within the studied dosing and trial frameworks. In type 2 diabetes, it produced larger reductions in HbA1c and body weight, whereas in obesity without diabetes it was associated with greater weight loss and waist-circumference reduction. Mechanistic analyses also favored tirzepatide across several measures of insulin sensitivity, glucose control, and body composition. Secondary and pooled analyses further suggested more frequent achievement of combined glycemic and weight targets and more durable metabolic benefit. Both agents showed the expected incretin-related tolerability profile, with gastrointestinal adverse events predominating. The currently available direct comparative evidence suggests greater metabolic efficacy of tirzepatide, particularly with respect to HbA1c reduction and body-weight loss. However, this conclusion should be interpreted cautiously because the evidence base remains limited, includes multiple overlapping secondary analyses, and is influenced by comparator-dose selection and trial design.
Umińska et al. (Sat,) studied this question.