GLP-1 and GIP medicines: what do the signals mean?

Start with the signal

A hormone or medicine carries information to cells that have the relevant receptor and downstream machinery. The response depends on more than the name of the receptor: tissue, timing, exposure and other inputs shape what happens.1

One target and two targets

Semaglutide is described as a GLP-1 receptor agonist. Tirzepatide is described as a GIP and GLP-1 receptor agonist. These labels describe pharmacology; they do not by themselves establish that one medicine is better for every outcome or person.23

What human comparisons measure

SURPASS-2 compared three specified tirzepatide doses with semaglutide 1 mg in 1,879 adults with type 2 diabetes taking metformin. At 40 weeks, the tirzepatide groups had greater average reductions in glycated haemoglobin (HbA1c), its primary outcome. Participants and clinicians knew the treatment assigned; this open-label design, the population and the particular doses limit what can be generalised.

SURMOUNT-5 asked a different question: in 751 adults with obesity or overweight and a weight-related condition, but without type 2 diabetes, it compared the maximum tolerated doses of weekly tirzepatide and semaglutide for 72 weeks. Average weight change was −20.2% and −13.7%, respectively; gastrointestinal adverse effects were common in both groups. The trial was open-label and funded by Eli Lilly, the maker of tirzepatide. These group averages are not a prediction for an individual or proof that two receptors alone caused the difference. For other outcomes and treatment context, see tirzepatide and semaglutide.46

Where the mechanism stops

A receptor diagram cannot tell you the size of a clinical effect, how durable it is, whether harms outweigh benefits for a particular use, or how an unapproved formulation behaves. Those questions require appropriately designed human evidence and current product records.45

What the label adds

The US prescribing information for Zepbound (tirzepatide) adds practical limits that a receptor comparison cannot: nausea, vomiting and diarrhoea can occur, and severe gastrointestinal reactions are a warning for tirzepatide. Tirzepatide also delays gastric emptying, which may affect absorption of some oral medicines. For one important example, see tirzepatide, semaglutide and the contraceptive pill. These are label-level safety considerations, not a reason to change treatment without the prescribing team.5