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 WADA's 2026 or 2027 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" — so S0 captures it by default and it is off-limits in drug-tested sport. 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. VialWise is a research and educational reference, not medical advice — consult a licensed professional.

⚠️ 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)
9. World Anti-Doping Agency. World Anti-Doping Code International Standard Prohibited List 2027 (effective 1 January 2027). PDF: wada-ama.org/sites/default/files/2026-09/2027list_en_final_clean_26_august_2026_2.pdf. Retatrutide is not named. S0 (Non-Approved Substances) keeps its 2026 wording and adds "peptides" to its examples.

• 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