Tirzepatide for obesity without diabetes: mechanistic insights, clinical evidence, and future directions

Obesity and its related complications have become an important public health concern. Traditional lifestyle modification and earlier pharmacotherapies provide only limited weight reduction. There is an urgent need for more effective treatments. Tirzepatide is a novel dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 receptor agonist (GIP/GLP-1 RA). Its distinctive pharmacological mechanisms and outstanding effects on weight loss have attracted wide attention. Although initial studies on tirzepatide mainly focused on type 2 diabetes mellitus (T2DM), evidence in adults with obesity without T2DM has expanded rapidly. Available human evidence supports reduced appetite and energy intake as major contributors to weight reduction, whereas mechanisms involving central neural circuits, adipose-tissue remodeling, and biased receptor signaling remain largely preclinical or translational. In available clinical trials, tirzepatide has been shown to produce substantial weight reduction and appears to be among the most effective obesity management medications (OMMs), although most comparisons beyond SURMOUNT-5 remain indirect. Its safety profile is characterized mainly by mild-to-moderate gastrointestinal symptoms during dose escalation, while long-term and rare safety outcomes require continued evaluation. In this narrative review, we summarize the mechanisms, clinical efficacy, safety, comparative positioning, and evidence gaps relevant to long-term real-world evaluation and next-generation incretin-based therapies.