Retatrutide vs Tirzepatide vs Semaglutide: A Research Comparison
Three generations of incretin research peptides
All three are peptides - short chains of amino acids, the building blocks that make up proteins. A receptor is like a lock on the surface of a cell, and these peptides act like keys that fit those locks. The main difference is how many of these locks each one can turn. Semaglutide turns one (called GLP-1), tirzepatide turns two (GLP-1 and GIP), and retatrutide turns all three (GLP-1, GIP and glucagon). These are the three most studied peptides in this area of research. Each newer one acts on one more receptor than the last. For researchers, the question is not which one is “best” - it is which receptor profile matches the pathway they want to study.
This page compares them by which receptors they act on, because that is what really sets them apart in the lab. It does not cover human dosing or results in people, which are outside what these research reagents are for.
Side-by-side receptor comparison
| Property | Semaglutide | Tirzepatide | Retatrutide (LY3437943) |
|---|---|---|---|
| GLP-1 receptor agonism | ✓ | ✓ | ✓ |
| GIP receptor agonism | ✗ | ✓ | ✓ |
| Glucagon receptor agonism | ✗ | ✗ | ✓ |
| Receptor targets | 1 | 2 | 3 |
| Research generation | First generation | Second generation | Third generation (triple) |
| Primary research axis | Insulin secretion, satiety signalling | Added GIP-mediated insulin potentiation | Added glucagon-mediated energy expenditure |
Each one builds on the last. Tirzepatide does what semaglutide does (acts on GLP-1) and adds a second receptor, GIP. Retatrutide does both of those and adds a third, glucagon. In animal studies, the glucagon receptor has been linked to how the liver handles sugar and how much energy the body burns. These are research observations only, not therapeutic effects.
What the clinical trials reported
The figures below summarise what separate published human clinical trials reported. They are third-party trial findings, cited for scientific reference only - not effects of Velox Peptides products, and not outcomes a reader should expect or attempt. The trial doses are stated only as facts of each trial's design. Because each compound was studied in a different trial, these are not direct head-to-head results.
| Compound | Trial | Avg body-weight reduction reported | Receptors |
|---|---|---|---|
| Semaglutide | STEP-1 (Wilding et al., NEJM 2021) | ~14.9% at 2.4 mg over 68 weeks | GLP-1 |
| Tirzepatide | SURMOUNT-1 (Jastreboff et al., NEJM 2022) | ~22.5% at 15 mg over 72 weeks | GLP-1 / GIP |
| Retatrutide | TRIUMPH-1 Phase 3 (Eli Lilly, May 2026) | 28.3% at 12 mg over 80 weeks | GLP-1 / GIP / Glucagon |
In retatrutide's TRIUMPH-1 Phase 3 trial, Eli Lilly's topline announcement (21 May 2026) also reported average reductions of 25.9% on 9 mg and 19.0% on 4 mg at 80 weeks, with a 104-week extension reporting up to 30.3% in participants with a starting BMI of 35 or above who continued. That trial enrolled 2,339 adults with obesity or overweight plus at least one weight-related comorbidity and without diabetes, randomised 1:1:1:1 to once-weekly subcutaneous retatrutide or placebo.[4][5]
Average body-weight reduction in published clinical trials
Semaglutide - single GLP-1 agonist
Semaglutide is a GLP-1 receptor agonist (an “agonist” is something that switches a receptor on). It acts on just one receptor. In lab and animal studies, switching on the GLP-1 receptor has been linked to the release of insulin (the hormone that controls blood sugar) when sugar is present, to food moving more slowly out of the stomach, and to appetite signals in the brain. Because it is the simplest of the three, researchers often use semaglutide as a baseline or starting point when they want to look at the GLP-1 pathway on its own, without GIP or glucagon getting involved.
Tirzepatide - dual GLP-1 / GIP agonist
Tirzepatide acts on two receptors, GLP-1 and GIP. Researchers got interested in hitting both at once because studies suggest the two pathways may work together and boost each other, rather than just doing the same job twice.[2] If a study wants to look at how the GIP receptor changes the way GLP-1 signals, tirzepatide is the two-receptor option that sits in the middle - between single-receptor semaglutide and triple-receptor retatrutide.
Retatrutide - triple GLP-1 / GIP / glucagon agonist
Retatrutide (also called LY3437943) takes the two-receptor model and adds a third receptor: glucagon. On its own, switching on the glucagon receptor raises blood sugar - the opposite of what GLP-1 does. So why combine them? The idea researchers are testing is that all three together might burn more energy and affect fat handling more than two receptors alone, while the insulin released by the GLP-1 and GIP pathways at the same time helps keep blood sugar in check.[1] Because it acts on all three receptors at once, retatrutide is the go-to choice for researchers studying combined receptor effects that you cannot get from one- or two-receptor compounds. These are research observations only, not therapeutic effects.
For more on how retatrutide works, what studies have found, and how to handle it in the lab, see the full Retatrutide research overview, or view the Retatrutide product page for HPLC-verified supply details.
Choosing a compound for a research model
Which one to pick depends on the question you are asking. To study the GLP-1 pathway on its own, semaglutide is the cleanest single-receptor choice. To see how GIP changes the way GLP-1 signals, tirzepatide gives you the two-receptor case. To look at all three receptors working together - including glucagon - retatrutide is the only one of the three that fits. Velox Peptides supplies all of these compounds as HPLC-verified lyophilised (freeze-dried) reagents, each with a batch certificate of analysis (a lab report proving what is in the vial). Browse the full incretin & receptor research category for the complete range.
Semaglutide - single agonist
Activates GLP-1 only. Published trial reported ~14.9% body-weight reduction at 2.4 mg over 68 weeks.
Tirzepatide - dual agonist
Activates GLP-1 + GIP. Published trial reported ~22.5% body-weight reduction at 15 mg over 72 weeks.
Retatrutide - triple agonist
Activates GLP-1 + GIP + glucagon. Published trial reported 28.3% body-weight reduction at 12 mg over 80 weeks.
Research framing
Figures are published clinical-trial observations, not therapeutic claims. Compounds are supplied for in vitro research use only.
References
- Coskun T et al. “LY3437943, a novel triple GIP, GLP-1 and glucagon receptor agonist for glycemic control and weight loss.” Cell Metabolism, 2022. PMID: 35108511
- Finan B et al. “Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.” Science Translational Medicine, 2013. PMID: 24107776
- Jastreboff AM et al. “Triple–Hormone-Receptor Agonist Retatrutide for Obesity.” New England Journal of Medicine, 2023. PMID: 37366315
- Eli Lilly and Company. Lilly's retatrutide achieved topline weight-reduction results in the TRIUMPH-1 Phase 3 obesity trial. Press release, 21 May 2026. PR Newswire; reported in AJMC (ajmc.com) and The Pharmaceutical Journal (pharmaceutical-journal.com).
- Wilding JPH et al. “Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP-1).” N Engl J Med, 2021. PMID: 33567185. Jastreboff AM et al. “Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1).” N Engl J Med, 2022. PMID: 35658024.
