Tirzepatide: How a Dual GIP/GLP-1 Peptide Agonist Emerged as a New Approach to Type 2 Diabetes

Narrative review summarizing preclinical data, phase 1, and phase 2 clinical trial results for tirzepatide in type 2 diabetes, along with an overview of the planned SURPASS phase 3 clinical trial program.

GLP-1 receptor agonists like semaglutide were already transforming diabetes treatment, but tirzepatide's dual-receptor approach takes the concept further. By harnessing both incretin pathways simultaneously, tirzepatide has since shown in the completed SURPASS trials even greater glucose lowering and weight loss than single-target GLP-1 drugs. This review captured the state of knowledge just before those landmark phase 3 results, documenting the scientific rationale that led to one of the most significant diabetes drugs in recent history.

Tirzepatide represented a paradigm shift in metabolic medicine — proving that targeting multiple incretin receptors simultaneously could produce dramatically better outcomes than targeting one alone. This dual-agonist approach has since expanded to triple agonists (like retatrutide) and has reshaped how pharmaceutical companies think about metabolic drug design. The SURPASS trials, previewed in this review, would go on to show unprecedented HbA1c reductions and weight loss, leading to tirzepatide's approval as both Mounjaro (diabetes) and Zepbound (weight loss).

This review was published before the SURPASS phase 3 trial results were available, so it relies on early-phase data only. Long-term efficacy, safety, and cardiovascular outcomes were unknown at the time of publication. The review does not include head-to-head comparisons with GLP-1 agonists from controlled trials.