The first dual-receptor compound to reach this stage of investigation. It reset what the category was measuring against.
Tirzepatide
Tirzepatide, development code LY3298176, is a synthetic 39-amino-acid peptide that acts as an agonist at both the GIP and GLP-1 receptors. It is described in the literature as the first compound of the dual-incretin class. Receptor occupancy analysis characterises it as an imbalanced agonist, engaging the GIP receptor to a greater degree than the GLP-1 receptor.
Before tirzepatide, incretin research had focused on GLP-1 receptor agonism alone. The hypothesis behind adding GIP activity was that combining the two signalling pathways would act on pancreatic beta cells, adipose tissue and central appetite regulation together rather than separately. Tirzepatide established the dual-agonist approach that retatrutide subsequently extended to three receptors.
SURMOUNT-1 enrolled 2,539 participants without diabetes and reported mean weight reductions of 15.0%, 19.5% and 20.9% across dose arms at 72 weeks, against 3.1% for placebo. SURMOUNT-5 was the first head-to-head trial against semaglutide over 72 weeks. The SURPASS programme covers the type 2 diabetes indication, and a 2024 network meta-analysis in Diabetologia pooled 28 randomised trials across 23,622 participants.