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Retatrutide vs Tirzepatide vs Semaglutide: What the 2026 Research Actually Shows
One hormone, two hormones, three hormones. Here is how the best-known metabolic peptides differ: how they work, what the clinical trials found, and where each one stands today.
Key takeaways
- One, two or three hormones. Semaglutide activates the GLP-1 receptor; tirzepatide adds GIP; retatrutide adds GIP and glucagon.
- Headline trial results: about 15% average weight loss for semaglutide (68 weeks), about 21% for tirzepatide 15 mg (72 weeks) and up to 28.7% for retatrutide 12 mg (68 weeks, TRIUMPH-4).
- Not a fair race yet. These numbers come from different trials, populations and durations. Only a few true head-to-head studies exist.
- Same main side effects: nausea, diarrhoea, constipation and vomiting, mostly during dose escalation. Retatrutide trials also reported dysesthesia (abnormal skin sensations).
- Regulatory status (Oct 2026): semaglutide and tirzepatide are approved medicines; retatrutide is still investigational (Lilly plans to file in Q1 2027); CagriSema is under FDA review.
01The short answer
If you only read one part of this guide, read this table. It shows what each compound targets, the headline result from its best-known obesity trial, and where it stands with regulators today.
| Compound | Receptors targeted | Developer | Headline trial result | Status (Oct 2026) |
|---|---|---|---|---|
| Semaglutide | GLP-1 | Novo Nordisk | −14.9% at 68 weeks (STEP 1, 2.4 mg) | Approved |
| Tirzepatide | GLP-1 + GIP | Eli Lilly | −20.9% at 72 weeks (SURMOUNT-1, 15 mg) | Approved |
| CagriSema (cagrilintide + semaglutide) | Amylin + GLP-1 | Novo Nordisk | −22.7% at 68 weeks (REDEFINE 1) | Under FDA review |
| Retatrutide | GLP-1 + GIP + glucagon | Eli Lilly | −28.7% at 68 weeks (TRIUMPH-4, 12 mg)* | Investigational |
*Efficacy estimand (participants who stayed on treatment). The treatment-regimen figure, which counts everyone randomised, was 23.7%. More on why trials report two numbers below.
02How incretin peptides work
All four compounds copy hormones your gut and pancreas already make after a meal. The natural versions are broken down within minutes. The research versions are engineered, usually with a fatty-acid side chain that binds to albumin in the blood, so a single weekly dose stays active for days.
GLP-1
Released by the gut after eating. It boosts glucose-dependent insulin release, slows stomach emptying and signals fullness to the brain.
GIP
The other incretin hormone. Adding it to GLP-1 action appears to strengthen weight and glucose effects; exactly why is still being studied.
Glucagon
Usually raises blood sugar, but it also increases energy expenditure and fat burning in the liver. Paired with GLP-1 and GIP, the glucose effect is balanced out.
Amylin
Released with insulin by the pancreas. It promotes satiety and slows gastric emptying. Cagrilintide is a long-acting amylin analogue.
Receptor map: which pathway each compound activates.
03Semaglutide: the single-agonist benchmark
Semaglutide is the compound that started the current wave of metabolic research. It shares about 94% of its sequence with human GLP-1, and its fatty-acid chain gives it a half-life of roughly one week.
In STEP 1, 1,961 adults with overweight or obesity (without diabetes) received 2.4 mg once weekly or placebo for 68 weeks. Average weight change was −14.9% versus −2.4% with placebo. Semaglutide is sold as Ozempic for type 2 diabetes and Wegovy for weight management.
Because it acts on only one receptor, semaglutide is the natural control arm when a study wants to isolate what GIP, glucagon or amylin activity adds on top of GLP-1.
04Tirzepatide: the dual GIP/GLP-1 agonist
Tirzepatide is a single molecule built on the GIP sequence that activates both GIP and GLP-1 receptors. Its half-life is about five days.
In SURMOUNT-1 (2,539 adults, 72 weeks), average weight change was −15.0% (5 mg), −19.5% (10 mg) and −20.9% (15 mg), compared with −3.1% on placebo.
It is also one of the few compounds with true head-to-head data:
Tirzepatide is marketed as Mounjaro for type 2 diabetes and Zepbound for weight management.
05Retatrutide: the triple agonist
Retatrutide (developed by Eli Lilly, sometimes called "GGG" or "triple G") adds glucagon-receptor activity to GIP and GLP-1. The idea: GIP and GLP-1 reduce appetite, while glucagon raises energy expenditure. Its trial results are the strongest published for any obesity compound so far.
Phase 2 (2023)
In a 48-week study of 338 adults, the 12 mg dose produced an average weight change of −24.2%, published in the New England Journal of Medicine.
Phase 3: the TRIUMPH program
| Trial | Population | Length | Weight change | Notable findings |
|---|---|---|---|---|
| TRIUMPH-4 | 445 adults with obesity and knee osteoarthritis | 68 wk | −26.4% (9 mg), −28.7% (12 mg) vs −2.1% placebo | 58.6% on 12 mg lost ≥25% of body weight; large drops in knee-pain scores |
| TRIUMPH-2 | 1,152 adults with type 2 diabetes and obesity | 80 wk | −12.7% (4 mg), −19.1% (9 mg), −20.8% (12 mg) vs −4.0% | A1C fell 1.4–1.6 points from 7.7% |
| TRIUMPH-3 | 1,949 adults with severe obesity and heart disease | 80 wk | −21.6% (9 mg), −22.6% (12 mg) vs −3.2% | 12 mg: triglycerides −37%, hsCRP −51%, systolic BP −9.3 mmHg |
People with type 2 diabetes typically lose less weight on every incretin drug, which is why TRIUMPH-2's numbers look lower. Lilly says it plans to submit retatrutide to the FDA in Q1 2027. Until then, it is not an approved medicine anywhere.
06CagriSema: adding amylin to GLP-1
CagriSema is not a single molecule. It combines cagrilintide (a long-acting amylin analogue) with semaglutide, both at 2.4 mg in Novo Nordisk's trials.
- REDEFINE 1 (68 weeks): −22.7% with the combination, versus −16.1% with semaglutide alone, −11.8% with cagrilintide alone and −2.3% with placebo. The combination clearly beat either part alone.
- REDEFINE 4 (84 weeks, open label): −23.0% for CagriSema versus −25.5% for tirzepatide 15 mg. The trial missed its goal of showing CagriSema was non-inferior.
- Status: submitted to the FDA in December 2025, with a decision expected by late 2026.
For labs studying how the amylin and GLP-1 pathways interact, a pre-combined blend saves preparing and matching two separate stocks. See our Cagrilintide 5 mg + Semaglutide 5 mg blend.
07Side effects and safety signals
All of these compounds share a class profile, but each has its own details. Select a compound:
Shared, mostly gastrointestinal
Nausea, diarrhoea, constipation, vomiting and reduced appetite are the most reported effects in every trial. They are most common while the dose is being increased, which is why all of these trials start low and step up every four weeks.
Dysesthesia and dose-related dropouts
In TRIUMPH-4, dysesthesia (unusual skin sensations such as tingling or sensitivity) was reported by 8.8% on 9 mg and 20.9% on 12 mg, versus 0.7% on placebo. Most cases were mild.
Discontinuation due to adverse events was 12.2% (9 mg) and 18.2% (12 mg) versus 4% on placebo. Lilly noted that some participants stopped because of perceived excessive weight loss, and that dropouts tracked with lower starting BMI.
Label warnings for semaglutide and tirzepatide
The approved products carry a boxed warning about thyroid C-cell tumours seen in rodents, plus warnings on pancreatitis, gallbladder problems, low blood sugar when combined with other glucose-lowering drugs, and kidney problems linked to dehydration. Long-term safety data for retatrutide and CagriSema are still being collected.
08Can you compare them directly?
Not really, at least not from headline numbers. Three things make cross-trial comparisons misleading:
- Different people. TRIUMPH-4 enrolled people with a starting BMI of about 40; STEP 1 and SURMOUNT-1 had lower average BMIs; diabetes trials always show smaller losses.
- Different lengths. 48, 68, 72, 80 and 84 weeks. Weight keeps falling for many months, so longer trials tend to look better.
- Two ways to count. The efficacy estimand only counts people who stayed on treatment; the treatment-regimen estimand counts everyone. The first number is always higher. TRIUMPH-4's 28.7% becomes 23.7% using the second method.
The only direct comparisons so far favour tirzepatide over semaglutide (SURMOUNT-5) and over CagriSema (REDEFINE 4). No published head-to-head trial has yet tested retatrutide against tirzepatide.
09Choosing a compound for your research
The right compound depends on the question your study is asking:
Isolating GLP-1
Use semaglutide as the single-pathway reference or control arm.
The GIP contribution
Compare tirzepatide against a GLP-1-only arm.
Energy expenditure and liver fat
Retatrutide's glucagon activity makes it the tool for studying these.
Amylin synergy
Use the cagrilintide + semaglutide blend.
Whichever you choose, your results are only as good as your material. Before you order, read our guides on how to verify peptide purity with a COA and how to reconstitute and store peptides so the compound stays stable through your experiment.
Retatrutide
5 · 10 · 15 · 20 · 30 mgTriple GIP/GLP-1/glucagon receptor agonist.
View productTirzepatide
5 · 10 mgDual GIP/GLP-1 receptor agonist.
View productCagrilintide + Semaglutide
5 mg + 5 mgAmylin analogue + GLP-1 agonist blend.
View productResearch-grade metabolic peptides, made easy
Lyophilised, lot-numbered vials of the compounds in this guide, packed for stable shipping and sold for laboratory research.
FAQFrequently asked questions
Is retatrutide FDA approved?
No. As of October 2026 retatrutide is an investigational compound. Eli Lilly has reported positive Phase 3 results and plans to submit it to the FDA in the first quarter of 2027. It is not approved as a medicine in any country.
What is the difference between retatrutide and tirzepatide?
Both come from Eli Lilly and both activate GIP and GLP-1 receptors. Retatrutide also activates the glucagon receptor, which is thought to increase energy expenditure. Tirzepatide is an approved medicine (Mounjaro, Zepbound); retatrutide is not.
Which peptide produced the most weight loss in trials?
Retatrutide has the highest published averages (up to 28.7% at 68 weeks in TRIUMPH-4). However, no head-to-head trial against tirzepatide has been published, and its trial populations differ, so a direct ranking is not yet possible.
Is CagriSema the same as semaglutide?
No. CagriSema combines semaglutide with cagrilintide, a long-acting amylin analogue. In REDEFINE 1 the combination produced more weight loss (22.7%) than semaglutide alone (16.1%).
Why do trials report two different weight-loss numbers?
The efficacy estimand counts only participants who kept taking the drug as planned; the treatment-regimen estimand includes everyone randomised, including people who stopped. The second number is lower and closer to real-world use.
How should these research peptides be stored?
Lyophilised (powder) vials are best kept frozen at −20 °C, away from light and moisture. Once reconstituted, keep the solution at 2–8 °C and use it promptly, or split it into aliquots and freeze. See our reconstitution and storage guide.
REFSources
- Wilding JPH et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med 2021. nejm.org
- Jastreboff AM et al. Tirzepatide once weekly for the treatment of obesity (SURMOUNT-1). N Engl J Med 2022. nejm.org
- Aronne LJ et al. Tirzepatide as compared with semaglutide for the treatment of obesity (SURMOUNT-5). N Engl J Med 2025. ACC summary
- Jastreboff AM et al. Triple-hormone-receptor agonist retatrutide for obesity: a phase 2 trial. N Engl J Med 2023. nejm.org
- Healio. Retatrutide confers up to 28.7% weight loss and reduction in knee osteoarthritis pain (TRIUMPH-4), Jan 2026. healio.com
- Eli Lilly press release. Retatrutide successful in two additional Phase 3 obesity trials (TRIUMPH-2, TRIUMPH-3), Jul 23, 2026. biospace.com
- Novo Nordisk press release. CagriSema REDEFINE 4 head-to-head results, Feb 23, 2026. biospace.com
- Drugs.com. CagriSema FDA approval status and REDEFINE 1 results. drugs.com
Keep reading
We write plain-English guides to the peptide research literature and lab handling, and we cite primary sources so you can check every claim yourself.
