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Phase IIIVendors pendingFacts verified · 2026-05-25

Retatrutide

Also known as GLP3-R, retatrutide, ly3437943, reta, triple-agonist (gip/glp-1/gcgr) · Wikipedia

Retatrutide (LY3437943) is a once-weekly subcutaneous triple agonist of the GIP, GLP-1, and glucagon receptors developed by Eli Lilly. In its 48-week Phase 2 obesity trial (NEJM 2023), the 12 mg dose produced mean weight reductions of approximately 24%, the largest effect size reported for any pharmacotherapy in late-stage development at the time. The molecule adds glucagon receptor activity to the dual-incretin scaffold pioneered by tirzepatide, an approach intended to increase energy expenditure and hepatic fat oxidation while preserving the appetite-suppressing and glycemic effects of GIP/GLP-1 co-agonism. Retatrutide is currently in the Phase 3 TRIUMPH program for obesity, type 2 diabetes, metabolic dysfunction-associated steatohepatitis (MASH), and obesity with established cardiovascular disease. It is not approved by any regulator and is available only as a research chemical outside of formal trials.

24%

weight

loss

48 wk

trial

duration

12 mg

max

dose

Phase 3

TRIUMPH

NEJM 2023

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Mechanism of action

Retatrutide (LY3437943) is a synthetic, fatty-acid-acylated single-peptide triple agonist at the GIP, GLP-1, and glucagon receptors. GLP-1 receptor activation drives glucose-dependent insulin secretion, glucagon suppression, slowed gastric emptying, and central appetite suppression via hypothalamic (POMC) and brainstem (NTS, area postrema) circuits.

Retatrutide (LY3437943) is a synthetic, fatty-acid-acylated single-peptide triple agonist at the GIP, GLP-1, and glucagon receptors. GLP-1 receptor activation drives glucose-dependent insulin secretion, glucagon suppression, slowed gastric emptying, and central appetite suppression via hypothalamic (POMC) and brainstem (NTS, area postrema) circuits. GIP receptor co-activation enhances insulin sensitivity in adipose tissue, may modulate central nausea, and contributes additively to weight loss. Glucagon receptor activation, the differentiating mechanism, increases hepatic fatty-acid oxidation, raises resting energy expenditure, and reduces hepatic steatosis but partially opposes incretin-mediated glycemic effects, requiring careful receptor balancing. The molecule is engineered with relative receptor potencies biased toward GIP and GLP-1 to maintain net glycemic benefit; structural studies (Wu et al., 2024, Nature Comms) show distinct binding modes at each receptor. Net clinical effects include weight reduction, HbA1c lowering, ~80% reduction in liver fat (Sanyal et al., Nature Med 2024), modest LDL-C and triglyceride increases attributable to glucagon agonism, and dose-dependent increases in heart rate.

Pharmacokinetic properties

Half-life

~6 days subcutaneous (supports once-weekly dosing)

Routes

subcutaneous

Bioavailability

Fatty-acid acylation enables albumin binding and sustained exposure; not orally bioavailable. Steady-state reached after approximately 4 weeks.

Amino-acid sequence

39-amino-acid GIP-based backbone with fatty-acid acylation; see Coskun et al., 2022, Cell Metab 34:1234-1247 and Wu et al., 2024 (structural insights at GLP-1R/GIPR/GCGR) for full sequence and modifications.

Use & research dosing

Appetite ControlWeight LossMetabolic SupportLiver Fat Reduction

Phase 2 obesity dosing (Jastreboff et al., NEJM 2023) initiated at 2 mg subcutaneously once weekly and escalated by 2 mg every 4 weeks up to maintenance doses of 4, 8, or 12 mg weekly. Mean weight reductions at 48 weeks were approximately 17.5%, 22.8%, and 24.2% at the 4, 8, and 12 mg doses respectively (placebo-subtracted). The Phase 2 T2D trial (Rosenstock et al., Lancet 2023) used similar 0.5-12 mg dose ranges. Retatrutide is not FDA-approved and has no labeled human dose. Research-grade self-experimentation protocols commonly reported online mirror the trial titration (e.g., 2 mg/week start, escalated every 4 weeks), though there is no validated guidance and slower titration is often used to limit nausea. No dose has been established for renal or hepatic impairment.

Research-use framing only. SavePeptides sells nothing for human consumption. Doses above reflect reported research / self-experimentation ranges, not clinical recommendations.

Editorial perspective

Retatrutide is the most potent weight-loss agent in late-stage development as of 2026, with Phase 2 mean weight loss of ~24% at 48 weeks at the 12 mg dose (Jastreboff et al., NEJM 2023). The MASLD Phase 2a (Sanyal et al., Nature Medicine 2024) reported ~82% reduction in liver fat and >85% resolution of steatosis at higher doses. Phase 3 TRIUMPH-3 (obesity with established CVD, NCT05882045) has a primary completion date of April 2026; TRIUMPH-1, TRIUMPH-2, and TRIUMPH-4 (obesity, T2D, MASH variants) are ongoing. Eli Lilly has guided to FDA NDA submission in late 2026 with potential approval in 2027-2028. Glucagon-receptor activity differentiates retatrutide from semaglutide and tirzepatide, contributing to higher energy expenditure and liver-fat reduction but also requiring monitoring of heart rate, LDL-C, and triglycerides.

— SavePeptides editorial desk · last updated 2026-05-25

Cautions & contraindications

Before researching this compound, note:

  • Theoretical risk of thyroid C-cell tumors based on class effect of GLP-1 receptor agonists (rodent data)
  • Avoid in personal or family history of medullary thyroid carcinoma
  • Avoid in multiple endocrine neoplasia syndrome type 2 (MEN2)
  • History of pancreatitis (no signal in Phase 2 but warrants monitoring per class)
  • Pregnancy and breastfeeding (no human data; animal reproductive toxicity expected)
  • Severe GI side effects (nausea, vomiting, diarrhea) common during titration and dose-related
  • Dose-dependent increases in resting heart rate (5-9 bpm at 12 mg)
  • Dysesthesia / skin tingling reported at higher doses
  • Modest increases in LDL-C and triglycerides attributable to glucagon receptor agonism
  • Small transient HbA1c increase reported early in non-diabetic participants before weight loss accrues
  • Risk of acute kidney injury from dehydration with severe GI losses
  • Long-term safety beyond ~1 year not yet characterized; cardiovascular outcomes pending TRIUMPH-3 readout

Research foundation

The papers behind the page.

  1. [01]https://www.nejm.org/doi/full/10.1056/NEJMoa2301972
  2. [02]https://pubmed.ncbi.nlm.nih.gov/37385280/
  3. [03]https://www.nature.com/articles/s41591-024-03018-2
  4. [04]https://clinicaltrials.gov/study/NCT05882045
  5. [05]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11255275/

Facts verified

2026-05-25

Confidence

high

What this means

  • trial data exclusively from single sponsor (Eli Lilly)
  • Phase 3 TRIUMPH readouts pending through 2026-2027
  • no FDA-approved label exists; dosing inferences are from Phase 2 data only

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Vendor data coming soon

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Research-use disclaimer.

SavePeptides surfaces vendor, pricing, and coupon information for research compounds. These products are not intended, approved, or recommended for human consumption. Our content is informational only and does not constitute medical advice.