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GLP-1 / GIP / glucagon triple agonist

Retatrutide

Also known as: LY3437943, Triple G

Tier 2 — Human observationalReviewed 2026-05-04

Investigational triple-incretin agonist with the largest weight-loss effect sizes reported to date in a Phase 2 trial. Phase 3 still pending.

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Overview

Retatrutide is an Eli Lilly investigational peptide that activates the GLP-1, GIP, and glucagon receptors. The Phase 2 obesity trial (Jastreboff et al., NEJM 2023) reported mean body-weight reductions of approximately 24% at the highest dose at 48 weeks — the largest figure reported for any pharmacologic in this class to date. The Phase 3 TRIUMPH/SYNCHRONIZE program (obesity, T2D, NASH/MASH, knee osteoarthritis-with-obesity, cardiovascular outcomes) is enrolling and not yet read out as of this entry's review date. Until those trials publish, retatrutide is a Tier 2 indication for weight loss and T2D — strong-but-unreplicated single-program human data.

Mechanism

Single-molecule agonist at three incretin/metabolic receptors. Adds glucagon receptor agonism on top of GLP-1 + GIP. The glucagon arm is hypothesized to drive additional energy expenditure and hepatic fat reduction beyond what dual incretin agonists achieve, but is also the most likely source of differentiated side effects (glucose excursions, heart rate elevation).

Evidence by indication

We classify each indication separately. The same peptide can be Tier 1 for one use and Tier 4 for another. Tiers reflect the published literature, not the strength of community framing.

Weight management (obesity / overweight with comorbidity)

Tier 2high confidence

Phase 2 trial (n=338, 48 weeks) reported ~24% mean body weight reduction at 12 mg vs 2.1% on placebo. Single program, single sponsor, not yet replicated. Phase 3 SYNCHRONIZE-1 and TRIUMPH-1 are ongoing; expect to upgrade to Tier 1 if Phase 3 reproduces the effect at the safety profile observed in Phase 2.

Jastreboff AM et al. 2023Eli Lilly and Company et al. 2025

Type 2 diabetes

Tier 2high confidence

Phase 2 T2D trial (Rosenstock et al., Lancet 2023) showed HbA1c reductions of 1.6–2.0% at higher doses, comparable to or exceeding tirzepatide in cross-trial comparison. Phase 3 readout pending.

Rosenstock J et al. 2023

MASH / NAFLD

Tier 2medium confidence

Phase 2 substudy reported reductions in liver fat fraction of ~80% at 24 weeks at higher doses. Dedicated Phase 2/3 MASH trial is enrolling under the SYNCHRONIZE program.

Sanyal AJ et al. 2024

Cardiovascular outcomes

Tier 3high confidence

TRIUMPH-Outcomes is an enrolling Phase 3 cardiovascular outcomes trial. No outcomes data published as of review date. Mechanistic plausibility from semaglutide SELECT, but mechanism is not evidence.

No primary citations are anchored to this indication — the tier reflects the absence of usable literature, not a missing reference.

Studied dose ranges

The ranges below come from published trial protocols where available, and from documented self-experimenter consensus where the literature does not include human dose-finding work. The notes flag which is which.

1,000–12,000 mcgonce weekly · subcutaneous

Phase 2 trial titrated 2 mg / 4 mg / 8 mg / 12 mg arms with 4-week step-ups. The 8 mg and 12 mg arms drove the largest weight-loss signal. Clinical dosing schedule will be set by the Phase 3 program and the eventual label.

Contraindications

  • Personal or family history of medullary thyroid carcinoma (class warning extrapolated from GLP-1/GIP rodent data)
  • Multiple Endocrine Neoplasia syndrome type 2 (class warning)
  • Pregnancy and breastfeeding (no human safety data; investigational compound)
  • Severe gastroparesis or active GI motility disorders
  • Active substance-use issues affecting nutritional intake
  • Investigational status: outside of clinical trials, retatrutide is not available through any FDA-approved channel — anything sold as 'retatrutide' through research-chemical vendors is unregulated

Reported side effects

  • Nausea, vomiting, diarrhea (dose-dependent, peaks during titration)
  • Decreased appetite (intended, can cause undereating)
  • Constipation
  • Heart rate elevation of approximately 5–7 bpm at higher doses (likely glucagon-related; flagged in Phase 2)
  • Transient mild glucose excursions in non-diabetic subjects (glucagon-related)
  • Injection site reactions
  • Long-term safety not yet characterized — investigational compound

Reconstitution & storage

No FDA-approved formulation exists. Compounded or research-chemical 'retatrutide' is sold as lyophilized powder, typically 5–10 mg vials. Reconstitution practices mirror tirzepatide community math: a 10 mg vial in 2 mL bacteriostatic water = 5 mg/mL, so a 4 mg dose ≈ 80 units on a U-100 syringe. Identity, purity, and bioactivity of non-trial retatrutide are unverified — flag this explicitly.

Storage. Lyophilized: refrigerate 2–8 °C. Reconstituted: refrigerate 2–8 °C, use within ~30 days based on tirzepatide-class stability data. No manufacturer guidance exists outside the trial.

Open the peptide calculator → to compute exact draw volumes for your specific vial and BAC water choice.

Editorial note

DRAFT — pending Wayne's review. Retatrutide is the most-hyped investigational peptide in the obesity space; resist the pull to call it Tier 1 before Phase 3 reads out. Single-program data, however striking, is Tier 2 by policy. Anything bought outside a clinical trial is an unregulated research chemical — call this out without moralizing. Re-tier when SYNCHRONIZE / TRIUMPH publish.

Citations

  1. [1]
    Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial
    Jastreboff AM, Kaplan LM, Frías JP, et al. · New England Journal of Medicine · 2023 · PMID 37356684
    Phase 2 obesity efficacy and safety; primary anchor for the weight-loss indication.
    View source
  2. [2]
    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
    Rosenstock J, Frias J, Jastreboff AM, et al. · Lancet · 2023 · PMID 37356680
    Phase 2 T2D efficacy and safety; anchor for the diabetes indication.
    View source
  3. [3]
    Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial
    Sanyal AJ, Kaplan LM, Frias JP, et al. · Nature Medicine · 2024 · PMID 38912744
    Phase 2a hepatic fat reduction; anchor for the MASH/NAFLD indication.
    View source
  4. [4]
    TRIUMPH and SYNCHRONIZE Phase 3 program for retatrutide (clinicaltrials.gov registration set)
    Eli Lilly and Company · ClinicalTrials.gov · 2025
    Status of ongoing Phase 3 program referenced for the cardiovascular and confirmatory weight-loss indications.
    View source