Quick answer: semaglutide activates one receptor (GLP-1), tirzepatide activates two (GIP and GLP-1), and retatrutide (GLP-3 RT) activates three (GIP, GLP-1, and glucagon). In published trials, each added receptor has been associated with larger weight reduction, with the glucagon component adding an energy-expenditure mechanism the other two lack.
Three molecules, three receptor profiles
| Compound | Receptors | Structure | Development stage |
|---|---|---|---|
| Semaglutide | GLP-1 | GLP-1 analog with albumin-binding fatty acid | Approved (multiple indications) |
| Tirzepatide | GIP + GLP-1 | 39-amino-acid dual agonist | Approved (type 2 diabetes, obesity) |
| Retatrutide (GLP-3 RT) | GIP + GLP-1 + glucagon | Single-molecule triple agonist | Phase 3 |
Mechanisms
GLP-1 receptor
Activation slows gastric emptying, enhances glucose-dependent insulin secretion, suppresses glucagon release after meals, and reduces appetite through central pathways. This is the mechanism all three share.
GIP receptor
GIP is the other incretin hormone. Its role in weight regulation is still debated in the literature, with data supporting both agonism and antagonism as useful. In tirzepatide and retatrutide, GIP receptor activity is reported to improve tolerability of GLP-1 agonism and to contribute to metabolic effects.
Glucagon receptor
Glucagon receptor agonism raises hepatic glucose output, which is normally undesirable in metabolic disease. Paired with GLP-1 and GIP agonism, the glucose effect is offset while the glucagon-driven increase in energy expenditure and hepatic fat oxidation remains. That is the rationale for the triple design.
What the trials reported
- Semaglutide (STEP 1, 2021): mean body-weight reduction of roughly 15% over 68 weeks at the 2.4 mg dose.
- Tirzepatide (SURMOUNT-1, 2022): mean reductions of roughly 15% to 21% over 72 weeks across doses.
- Retatrutide (Phase 2, 2023): mean reductions of roughly 17% to 24% over 48 weeks across doses, with the trajectory not yet plateaued at study end.
These figures come from separate trials with different populations, durations, and designs. They are not head-to-head comparisons, and the retatrutide data are Phase 2 with smaller cohorts.
Adverse-event profiles
All three share the gastrointestinal profile of GLP-1 agonism: nausea, diarrhea, vomiting, constipation, mostly during escalation. Retatrutide additionally reported a dose-dependent heart-rate increase and dysesthesia at higher doses. See our separate review of retatrutide adverse events.
For the bench
All three are peptides with lipidation or structural modifications that extend their half-life. They are supplied lyophilized, stored at -20°C, and reconstituted for research in the same way as other peptides in this catalog.
Sources
- Wilding JPH et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine, 2021.
- Jastreboff AM et al. Tirzepatide Once Weekly for the Treatment of Obesity. New England Journal of Medicine, 2022.
- Jastreboff AM et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial. New England Journal of Medicine, 2023.
- Coskun T et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist. Cell Metabolism, 2022.
All Browse Peptides products are supplied for laboratory research use only and are not for human or veterinary use. This article summarizes published literature for research reference and is not medical advice, a protocol, or a recommendation of any kind.