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Metabolic

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GLP-1 / GIP / glucagon triple agonist

Retatrutide

Also known as: LY3437943, Triple G

Investigational triple-incretin agonist (GLP-1 + GIP + glucagon) with the largest weight-loss effect sizes reported to date in Phase 2. Phase 3 still enrolling.

Reviewed 2026-05-04

What it does

Retatrutide is an investigational peptide that activates three incretin receptors simultaneously: GLP-1, GIP, and glucagon. The Phase 2 obesity trial 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. Phase 3 trials for obesity, Type 2 diabetes, NASH/MASH, knee osteoarthritis-with-obesity, and cardiovascular outcomes are enrolling and have not yet read out.

Used for

Dose

Starting
1,000 mcg · once weekly
Common
6,500 mcg · once weekly
Upper
12,000 mcg · once weekly
When
MorningTriple agonist; once-weekly. Time-of-day flexible across the week — pick a consistent slot for adherence. Wednesday morning a common community pick to spread any GI side-effects across the workweek.
How long
Continuous (no on/off cycling) on / off
Site
subcutaneous
Food
any

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⚠ Caution

  • 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

Medications & conditions

  • Retatrutide with insulin or sulfonylurea — hypoglycemia riskRetatrutide is a triple GIP/GLP-1/glucagon receptor agonist. Concurrent insulin or sulfonylurea use substantially increases hypoglycemia risk; dose reductions of the concurrent agent are typically required. Do not initiate without prescriber supervision.

Will it work for me?

Establish a baseline (2–3 readings over 1–2 weeks before starting), then track at consistent intervals.

Blood markers
  • Tier 1 — Human RCTHbA1c· repeat at 3 months
  • Tier 1 — Human RCTTriglycerides· 12–24 weeks
  • Tier 1 — Human RCTLiver enzymes (ALT/AST)· 12–24 weeks
  • Tier 1 — Human RCTApoB· 12–24 weeks
  • Tier 2 — Human observationalFIB-4 score· 24+ weeksCalculated proxy (age + AST + ALT + platelets) for liver fibrosis; no registry slug — free online calculators (MDCalc).
Imaging
  • Tier 2 — Human observationalLiver fat (FibroScan CAP or MRI-PDFF)· ~24 weeksGlucagon component drives standout liver-fat reduction (~80% at 24 weeks on 12 mg) not seen with other GLPs. ~$200–300 cash. No registry slug.
Functional & psychometric
  • Tier 3 — Animal / in vitroBody weight· tracked weekly; Phase 2 magnitude ~24% at 48 weeks on 12 mgLargest weight-loss signal reported in this class to date.
  • Tier 3 — Animal / in vitroResting heart rate· track at every visitRetatrutide adds +5 to +7 bpm (vs +2 to +3 for tirzepatide); glucagon-related, peaks ~24 weeks. Monitor — this is a safety-relevant signal, not a benefit.

Your stack

Track this peptide in your protocol — dose, schedule, vials on hand, refill projection. Stays in your browser; no account needed.

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Use this peptide

Cycling

Continuous (no on/off cycling) on, off.

Taken continuously, not cycled. The rhythm is a titration ramp: Phase 2 stepped 2 mg → 4 mg → 8 mg → 12 mg every 4 weeks, with the 8–12 mg arms driving the largest weight-loss signal. The eventual clinical schedule will be set by the Phase 3 program and the label.

Sex-specific dosing
Female
Standard titration; consider extending each dose step from 4 to 6 weeks if nausea is pronounced.
Male
Standard titration (4-week steps).

GLP-class titration applied equally to both sexes in the trials. Women report more pronounced nausea during titration; extending each step from 4 to 6 weeks improves tolerance without compromising end-state efficacy. Men typically reach higher maximum doses before plateau, but absolute percentage weight loss is comparable.

Co-injection & overlap

Redundant with

  • Semaglutide Retatrutide is a triple agonist (GLP-1/GIP/glucagon) that fully occupies the GLP-1 receptor; adding semaglutide (pure GLP-1 agonist) provides no additional receptor pathway and substantially increases GI adverse-event burden.; typically run one, not both.
  • Tirzepatide Retatrutide (GLP-1/GIP/glucagon) fully occupies both GLP-1 and GIP receptors that tirzepatide (GLP-1/GIP) targets; stacking adds no novel pathway and amplifies nausea, vomiting, and gastroparesis risk.; typically run one, not both.
Reconstitution & storage
VialBAC waterConcentrationShelf life
10 mg1 mL2 mg per 20 units (10 mg/mL)14–30 days refrigerated
20 mg2 mL2 mg per 20 units (10 mg/mL)14–30 days refrigerated
30 mg3 mL2 mg per 20 units (10 mg/mL)14–30 days refrigerated
60 mg6 mL2 mg per 20 units (10 mg/mL)14–30 days refrigerated

No FDA-approved formulation exists. Research-chemical 'retatrutide' is sold as lyophilized powder; identity, purity, and bioactivity of non-trial material are unverified — flag this explicitly. The table below reflects common community reconstitution math; swirl gently, do not shake.

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.

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Nasal delivery

Not suitable for nasal delivery. Molecular weight too large for efficient nasal absorption; SQ only.

Monitoring & questions

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
Biomarkers Juno tracks
FAQ (5)

Reference

How it works

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).

Juno's take

Retatrutide is the most-hyped investigational peptide in the obesity space, and the Phase 2 numbers genuinely are striking. They're also single-program data — that's why the indication sits at Tier 2 by policy, not Tier 1, despite the headline number sounding Tier-1-adjacent. Re-evaluate when Phase 3 publishes. Anything bought outside a clinical trial is an unregulated research chemical — important not to moralize about, important not to gloss over.

EvidenceTier 2 — Human observational

Tiers are per indication. The same molecule can be Tier 1 for one use and Tier 4 for another — the tier reflects published literature, not 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.

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.

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.

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.

Citations (4)
  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