Where each compound stands in October 2026
Semaglutide engages one receptor, GLP-1. Tirzepatide engages two, GIP and GLP-1. Retatrutide engages three: GIP, GLP-1 and glucagon. Semaglutide and tirzepatide are approved medicines with large phase 3 programmes behind them. Retatrutide remains investigational.
Eli Lilly has now reported several positive phase 3 trials for retatrutide. TRIUMPH-1 appeared in NEJM, and TRIUMPH-2, in adults with obesity and type 2 diabetes, appeared in The Lancet on the same day. In its 29 September release Lilly said it plans to submit a Biologics License Application to the FDA in the first quarter of 2027. No regulator has approved retatrutide.
| Retatrutide | Tirzepatide | Semaglutide | |
|---|---|---|---|
| Receptors | GIP, GLP-1, glucagon | GIP, GLP-1 | GLP-1 |
| Backbone | 39 residues on a GIP peptide backbone | 39 residues based on the GIP sequence | 31 residues, modified human GLP-1 |
| Albumin-binding chain | C20 fatty diacid | C20 fatty diacid on Lys20 | C18 fatty diacid on Lys26 |
| Reported half-life | About 6 days | About 5 days | About 1 week |
| Status, October 2026 | Investigational; FDA filing planned for Q1 2027 | Approved | Approved |
| Pivotal obesity trial cited here | TRIUMPH-1, 80 weeks, NEJM 2026 | SURMOUNT-1, 72 weeks, NEJM 2022 | STEP 1, 68 weeks, NEJM 2021 |
How the three molecules are built
Semaglutide starts from human GLP-1. Its FDA label lists three changes: position 8 modified to resist DPP-4 (aminoisobutyric acid replaces alanine), position 34 changed so that only one fatty acid attaches (arginine replaces lysine), and lysine 26 linked through a hydrophilic spacer to a C18 fatty diacid. The diacid binds albumin, which slows renal clearance and gives a half-life of about one week.
Tirzepatide is a 39-residue peptide based on the GIP sequence, with aminoisobutyric acid at positions 2 and 13 and lysine 20 attached to a C20 fatty diacid. Its label gives a half-life of about 5 days.
Retatrutide also sits on a 39-residue GIP-derived backbone with a C20 fatty diacid (Coskun et al., Cell Metabolism, 2022). In the phase 2 report (Jastreboff et al., NEJM, 2023) it was 8.9 times as potent as native GIP at the human GIP receptor, 0.4 times as potent as native GLP-1 at the GLP-1 receptor and 0.3 times as potent as native glucagon at the glucagon receptor. Its half-life is about 6 days.
What the trials report
Each trial below compared one drug with placebo, except SURMOUNT-5. Figures are mean percentage change in body weight, taken from the highest-dose arm where a trial tested several.
- Semaglutide, STEP 1 (NEJM, 2021): -14.9% at 68 weeks against -2.4% with placebo.
- Tirzepatide, SURMOUNT-1 (NEJM, 2022): -20.9% at 72 weeks against -3.1%.
- Tirzepatide against semaglutide, SURMOUNT-5 (NEJM, 2025): -20.2% with tirzepatide and -13.7% with semaglutide at 72 weeks. This is the only randomised head-to-head trial among the three.
- Retatrutide, phase 2 (NEJM, 2023): -24.2% at 48 weeks against -2.1%.
- Retatrutide, TRIUMPH-1 (NEJM, 2026): -25.0% at 80 weeks against -3.9%, in 2,339 adults with obesity and without diabetes.
Lilly's press releases for TRIUMPH-1 quote 28.3% for the same arm. That figure uses an efficacy estimand, which estimates the effect had participants stayed on treatment; the NEJM figure uses an estimand that also counts participants who stopped. Compare like with like when you read these numbers.
Semaglutide also has a cardiovascular outcomes result. In SELECT (NEJM, 2023), it reduced major adverse cardiovascular events against placebo in people with cardiovascular disease and overweight or obesity without diabetes, with a hazard ratio of 0.80. Retatrutide's TRIUMPH-3, in adults with severe obesity and cardiovascular disease, was a weight-loss trial; Lilly reported its MACE counts as pre-specified analyses, and neither hazard ratio reached significance.
Is retatrutide better or stronger than tirzepatide?
The trials above cannot answer that. Each ran in a different population, for a different length of time, against its own placebo group. Cross-trial comparisons mix the drug effect with those differences.
The direct test is TRIUMPH-5 (NCT06662383), a double-blind phase 3 trial of retatrutide against tirzepatide in about 800 adults with obesity, with percent change in body weight at 80 weeks as the primary outcome. ClinicalTrials.gov lists primary completion as estimated for November 2026, and no results have been posted. Until it reports, "retatrutide vs tirzepatide" has no head-to-head answer.
Why add glucagon at all
Glucagon raises hepatic glucose output, which looks like the opposite of what an incretin drug should do. The case for adding it rests on two published lines of work. Coskun and colleagues found that retatrutide increased energy expenditure in diet-induced obese mice and that blocking the glucagon receptor prevented the increase. In a substudy of the phase 2 trial (Sanyal et al., Nature Medicine, 2024), liver fat fell by 86.0% at 48 weeks in the highest-dose arm, and 93% of those participants reached normal liver fat (below 5%).
GIP carries its own open question. Tirzepatide and retatrutide activate the GIP receptor, while maridebart cafraglutide blocks it and still produces weight loss when paired with GLP-1 agonism. Reviewers describe this as an unresolved paradox.
Choosing a compound for a study
- GLP-1 signalling on its own: semaglutide, the single-receptor reference, backed by the STEP and SELECT trials.
- GIP and GLP-1 interaction: tirzepatide, with SURMOUNT-5 as a published comparison against semaglutide.
- Glucagon-receptor effects, such as energy expenditure or hepatic lipid handling: retatrutide, which puts all three receptors on one molecule with one exposure profile. Combining separate agonists would give each receptor its own pharmacokinetics and make timing a confounder.
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Sourcing
Ashraf and colleagues (JAMA Network Open, 2024) bought semaglutide from online sellers that claimed 99% purity; LC-MS measured 7% to 14% purity and content 29% to 39% above the label. An independent laboratory assays every Encodex lot, by HPLC for purity and by mass spectrometry for identity. The certificate for the lot printed on your vial is available on request, and the /verify page checks the lot number. Our guide on how to read a certificate of analysis explains each figure.
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