Retatrutide

Retatrutide is a lab-made peptide studied for weight loss and type 2 diabetes — it activates three gut-hormone receptors at once (GLP-1, GIP, and glucagon, a 'triple agonist') to increase fullness, control blood sugar, and raise energy expenditure. It's given as a once-weekly injection under the skin. It's investigational and not FDA-approved; Phase 3 trials have begun reporting results, but no regulatory filing had been made as of July 2026.

Retatrutide has been studied as a once-weekly injection for obesity and type 2 diabetes. In a Phase 2 obesity trial it was associated with average weight reductions of up to about 24% at the highest dose over 48 weeks (versus about 2% on placebo), and the Phase 3 TRIUMPH-1 trial reported about 28% at 80 weeks on the dose (topline May 2026, full publication still pending). A separate Phase 3 diabetes trial (TRANSCEND-T2D-1, published in The Lancet in 2026) reported dose-dependent blood-sugar (HbA1c) and weight reductions. Nausea was the most common dose-limiting side effect. The research attributes these weight and blood-sugar changes largely to reduced appetite and food intake (greater satiety via the gut-hormone pathway these agents act on), an appetite and energy-intake mechanism measured across the trials.

Investigational (in phase 3 trials, not FDA approved)

Retatrutide is investigational and not FDA-approved for any indication. It carries a class contraindication related to a personal or family history of medullary thyroid carcinoma. It is not named on the WADA Prohibited List, but it holds no marketing approval anywhere, and S0 (Non-Approved Substances) prohibits at all times any substance "with no current approval by any governmental regulatory health authority for human therapeutic use (e.g. drugs under pre-clinical or clinical development)" — so S0 captures it by default and it is off-limits in drug-tested sport. This is the same correction applied to survodutide on 2026-09-07: the approved GLP-1 drugs are exempt from S0 because they are approved, and that exemption does not transfer to an investigational member of the family. Verified against the local archive `docs/legal/wada-2026-prohibited-list.txt` (S0 clause plus a full-text search returning no hit for retatrutide). Re-verify when the 2027 list publishes ~September–October 2026. VialWise is a research and educational reference, not medical advice — consult a licensed professional.

⚠️ For research and educational purposes only. Retatrutide is an investigational compound not approved by the FDA for any indication. Information in this entry is informational, not medical advice. Always confirm dose calculations with the in-app calculator and consult appropriate professional guidance before any protocol decisions.

⚠️ Precision matters at low doses. Small dosing errors that look trivial in absolute terms can be significant in percentage terms when starting doses are small. A one-unit mis-draw at a 5-unit dose is a 20% error; the same one-unit error at a 50-unit dose is only 2%. Always verify draws against the in-app calculator and double-check the unit count on the syringe before injecting — most acutely at the smallest draws in your titration.

Retatrutide (development code LY3437943) is a single-molecule triple agonist developed by Eli Lilly that activates the GLP-1, GIP, and glucagon receptors. The triple-receptor mechanism is the key differentiator from earlier-generation incretin therapies: GLP-1 and GIP activation drives glucose-dependent insulin release and reduced appetite, while glucagon receptor activation contributes to increased energy expenditure. The combination has produced the largest weight reductions reported to date in phase 2 incretin trials.[¹]

The foundational phase 2 obesity results published in 2023 (Jastreboff et al., NEJM; trial NCT04881760, n=338) reported least-squares mean weight reductions, after 48 weeks of subcutaneous weekly dosing, of −8.7%, −17.1%, −22.8%, and −24.2%, compared with −2.1% in the placebo arm.[¹] Liver-fat reductions in the substudy were even larger in magnitude: −81.4% to −82.4% at the and doses at 24 weeks.[¹]

The pivotal phase 3 obesity trial, TRIUMPH-1 (NCT05929066, n≈2,335), has since completed, with topline results announced by the manufacturer on May 21, 2026. In the trial, participants on the dose had mean weight reductions of −28.3% at 80 weeks, with a dose response of −17.6%, −23.7%, and −25.0% versus −3.9% on placebo; a 104-week extension reported approximately −30.3%. All dose arms met the primary and key secondary endpoints. Gastrointestinal adverse events at the high dose were reported as nausea 42.4%, diarrhea 32.0%, constipation 26.1%, and vomiting 25.3%.[⁷] These are manufacturer-announced topline figures — a full peer-reviewed TRIUMPH-1 primary publication was not yet indexed as of July 2026.

A separate phase 2 trial in adults with type 2 diabetes (Rosenstock et al., Lancet 2023) established the T2D foundation, reporting dose-dependent weight reductions from −3.19% to −16.94% ( escalation arm) at 36 weeks, alongside clinically meaningful HbA1c reductions; retatrutide outperformed the active comparator dulaglutide.[⁴]

The phase 3 T2D monotherapy trial TRANSCEND-T2D-1 (NCT06354660) is peer-reviewed and published (Bajaj et al., The Lancet 2026). Over 40 weeks at three ascending dose levels, participants in the trial had HbA1c changes of −1.69% / −1.86% / −1.94% versus −0.81% on placebo, and bodyweight changes of −11.5% / −13.9% / −15.3% versus −2.6% on placebo; gastrointestinal adverse events were reported as predominantly mild to moderate.[⁶]

The broader phase 3 TRIUMPH program also includes a cardiovascular outcomes trial, TRIUMPH-outcomes (NCT06383390, n≈10,000), which remains active with completion expected in 2029.[⁷] Retatrutide remained investigational as of July 2026, with no FDA new drug application filed.

Mechanistically, retatrutide is a 39-amino-acid single peptide engineered from a GIP-peptide backbone, conjugated to a C20 fatty di-acid moiety for albumin binding (the source of its ~6-day half-life). Receptor-potency profile: approximately 2.5x lower than native hormone at GLP-1, 8.9x higher than native at GIP, and 2.9x lower than native at glucagon receptor.[⁵]

A 2025 body-composition substudy reported that approximately 38% of total weight loss on retatrutide came from lean mass — comparable to other incretin therapies (the 20-40% range observed across the GLP-1 class), but with a larger absolute lean mass change because total weight loss is greater.[²] This finding is the citable basis for the stacking rationale of GH-preserving peptides during retatrutide cycles.

Commonly reported

• Nausea — most common dose-limiting side effect, typically dose-dependent
• Diarrhea
• Constipation
• Decreased appetite (often reported as a benefit; extreme cases warrant dose reduction)
• Injection site reactions
• Anhedonia (mood-flattening; reported across the incretin class)

Serious

• Severe persistent vomiting or signs of dehydration
• Acute pancreatitis symptoms (severe abdominal pain radiating to back)
• Gallbladder symptoms (right upper quadrant pain, jaundice)
• Heart rate elevations sustained at rest
• Suicidal ideation or new-onset mood changes (class warning across incretins)

Personal or family history of medullary thyroid carcinoma (MTC) or MEN2 — class contraindication for incretin therapies

History of pancreatitis

Severe gastrointestinal disease (gastroparesis especially)

Concurrent use of other GLP-1 / GIP / glucagon agonists

Pregnancy and lactation: insufficient data; investigational status means even fewer pregnancy-specific data than approved incretins

GLP-1 receptor agonist

A compound that switches on the GLP-1 receptor, the same target a natural gut hormone uses to signal fullness and help regulate blood sugar.

GIP receptor

A gut-hormone receptor that, like GLP-1, enhances insulin release and contributes to metabolic and weight effects.

Triple agonist

A compound that activates three different receptors at once (for example, the GLP-1, GIP, and glucagon receptors).

Investigational

Still being studied and not yet approved by regulators for general use.

Half-life

Roughly how long the body takes to clear half of a dose. A long half-life is why some compounds can be taken only once a week.

1. Jastreboff AM, Kaplan LM, Frías JP, Wu Q, Du Y, Gurbuz S, Coskun T, Haupt A, Milicevic Z, Hartman ML, for the Retatrutide Phase 2 Obesity Trial Investigators. (2023). Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. New England Journal of Medicine, 389(6):514–526.(PMID 37366315 · NCT04881760)
2. Effects of retatrutide on body composition in people with type 2 diabetes: a substudy of a phase 2, double-blind, parallel-group, placebo-controlled, randomised trial. (2025). The Lancet Diabetes & Endocrinology, 13(8):674–684.(PMID 40609566 · NCT04867785)
3. Eli Lilly and Company press release (2023). Lilly's phase 2 retatrutide results published in The New England Journal of Medicine show the investigational molecule achieved up to 17.5% mean weight reduction at 24 weeks in adults with obesity and overweight. investor.lilly.com. Manufacturer source for the 17.5%-at-24-weeks figure.
4. Rosenstock J, Frias JP, Jastreboff AM, et al. (2023). Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. The Lancet, 402(10401):529–544.(PMID 37385280 · NCT04867785)
5. Triple Agonism Based Therapies for Obesity. (2025). Current Cardiovascular Risk Reports, 19(1):18.(PMID 40741227)
6. Bajaj HS, et al. (2026). Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. The Lancet, 407(10546):2402–2413.(PMID 42250575 · NCT06354660)
7. Eli Lilly and Company press release (May 21, 2026). TRIUMPH-1 phase 3 topline results: retatrutide associated with 28.3% mean weight reduction at 80 weeks in adults with obesity. investor.lilly.com.(NCT05929066)
8. Panou T, et al. (2026). Retatrutide in type 2 diabetes mellitus and obesity: an overview. Expert Review of Clinical Pharmacology, 19(4):313–339.(PMID 41785010)

• CJC-1295 / Ipamorelin Blend — discussed together in this entry's stacks section
• BPC-157 / TB-500 Blend — discussed together in this entry's stacks section
• Tesamorelin — discussed together in this entry's stacks section
• Amycretin — same mechanism class
• CagriSema — same mechanism class
• Dulaglutide — same mechanism class