Peptide Name
Retatrutide (LY3437943)
Updated February 2026
Retatrutide Dosing Protocol
Complete retatrutide research dosing protocol with phase-by-phase titration schedule (1 mg to 12 mg), reconstitution math, side effect profile, and trial references.
Half-life
~6 days
Dose range
1 mg to 12 mg weekly
Status
Phase 3 investigational
Developer
Eli Lilly and Company
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Quick Reference Card
Category / Class
Metabolic - Triple Agonist (GLP-1 / GIP / Glucagon)
Half-Life
~6 days
Dosing Frequency
Once weekly (subcutaneous injection)
Dose Range
1 mg - 12 mg per week
Common Vial Sizes
5 mg, 10 mg, 20 mg, 30 mg
Route of Administration
Subcutaneous (SubQ)
Regulatory Status
Investigational - Phase 3 clinical trials (TRIUMPH program). Not FDA-approved as of February 2026.
Developer
Eli Lilly and Company
Key Stat
Phase 2: Up to 24.2% body weight reduction at 48 weeks (12 mg). Phase 3 (TRIUMPH-4): Up to 28.7% at 68 weeks.
What Is Retatrutide?
Retatrutide (LY3437943) is an investigational peptide developed by Eli Lilly that functions as a triple receptor agonist - simultaneously activating receptors for three metabolic hormones: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon. This triple mechanism sets it apart from earlier compounds like semaglutide (GLP-1 only) and tirzepatide (GLP-1 + GIP dual agonist).
Structurally, retatrutide is a 39-amino acid single-chain peptide engineered from a GIP peptide backbone and conjugated to a C20 fatty diacid moiety. This acylation enables albumin binding in the bloodstream, extending its half-life to approximately 6 days and supporting once-weekly dosing.
Retatrutide is currently being evaluated in Eli Lilly's TRIUMPH Phase 3 clinical trial program across multiple indications including obesity, type 2 diabetes, knee osteoarthritis, obstructive sleep apnea, cardiovascular outcomes, and metabolic dysfunction-associated steatotic liver disease (MASLD). In December 2025, TRIUMPH-4 reported that participants lost up to an average of 28.7% of their body weight at 68 weeks. Seven additional Phase 3 readouts are expected throughout 2026, with potential FDA approval in 2027 if outcomes remain positive.
Retatrutide is not FDA-approved and is currently available only through clinical trials. All information on this page is for educational and research reference purposes only.
How Retatrutide Works: Triple Receptor Agonism
Retatrutide's efficacy stems from simultaneous activation of three receptor targets, each contributing complementary metabolic effects.
3-Panel Pathway Infographic
GLP-1 Receptor (Glucagon-Like Peptide-1)
Activation slows gastric emptying, increases satiety signaling to the brain, and stimulates glucose-dependent insulin secretion. This is the same pathway targeted by semaglutide (Ozempic/Wegovy) and is a core mechanism behind appetite suppression.
GIP Receptor (Glucose-Dependent Insulinotropic Polypeptide)
GIP receptor activation enhances insulin sensitivity, improves adipose tissue metabolism, and may contribute to appetite regulation through central nervous system signaling. Retatrutide is notably potent at GIP receptors, approximately 8.9x more potent than endogenous human GIP.
Glucagon Receptor (GCGR)
This is the key differentiator from dual agonists like tirzepatide. Glucagon receptor activity increases fatty acid oxidation, energy expenditure, and thermogenesis. In clinical research, this component has been associated with substantial liver fat reductions, including up to 82% relative liver-fat reduction in a MASLD substudy published in Nature Medicine.
Retatrutide has a deliberately engineered potency ratio: GIP receptor activity at roughly 8.9x endogenous GIP, GLP-1 receptor activity at approximately 0.4x endogenous GLP-1, and glucagon receptor activity at roughly 0.3x endogenous glucagon. The combined result is a metabolic profile that can reduce intake, improve glucose handling, and increase energy expenditure across multiple pathways.
Retatrutide Dosing Protocol & Titration Schedule
Phase 1 - Initiation
Weeks 1-4
1 mg once weekly
Starting dose to assess initial tolerance. Minimal metabolic effects expected at this dose.
Phase 2 - Early Escalation
Weeks 5-8
2 mg once weekly
First meaningful dose increase. GI side effects (nausea) may begin.
Phase 3 - Mid Escalation
Weeks 9-12
4 mg once weekly
Appetite suppression typically becomes noticeable. Weight loss begins accelerating.
Phase 4 - High Escalation
Weeks 13-16
6 mg once weekly
TRIUMPH Phase 3 added this intermediate step (not present in Phase 2 trials).
Phase 5 - Therapeutic Range
Weeks 17-20
9 mg once weekly
Phase 3 target dose. Significant weight loss expected.
Phase 6 - Maximum Studied Dose
Weeks 21+
12 mg once weekly
Maximum dose studied in clinical trials. 24.2% average weight loss at 48 weeks (Phase 2). 28.7% at 68 weeks (Phase 3, TRIUMPH-4).
Important Titration Notes
Titration pacing matters. In the Phase 2 NEJM trial (2023), GI side effect rates nearly doubled when participants were assigned directly to 8 mg instead of gradually titrating from 1-2 mg.
Dose flexibility: Trial protocols allowed participants to remain at the current dose for an extra 2-4 weeks when GI side effects were significant.
Phase 3 dose levels: TRIUMPH evaluates 4 mg, 9 mg, and 12 mg as target maintenance doses.
Missed dose guidance: If a scheduled dose is missed, it can be taken within 5 days. If more than 5 days have passed, skip and resume on the next scheduled injection day.
Retatrutide Reconstitution Guide
Vial Size: 5 mg
BAC Water: 1.0 mL
Concentration: 5,000 mcg/mL (5.0 mg/mL)
1 mg: 0.20 mL (20 units)
2 mg: 0.40 mL (40 units)
4 mg: 0.80 mL (80 units)
8 mg: N/A - exceeds vial
12 mg: N/A
Vial Size: 10 mg
BAC Water: 2.0 mL
Concentration: 5,000 mcg/mL (5.0 mg/mL)
1 mg: 0.20 mL (20 units)
2 mg: 0.40 mL (40 units)
4 mg: 0.80 mL (80 units)
8 mg: Requires 2 vials
12 mg: Requires 2-3 vials
Vial Size: 20 mg
BAC Water: 2.0 mL
Concentration: 10,000 mcg/mL (10.0 mg/mL)
1 mg: 0.10 mL (10 units)
2 mg: 0.20 mL (20 units)
4 mg: 0.40 mL (40 units)
8 mg: 0.80 mL (80 units)
12 mg: 1.20 mL - split draw
Vial Size: 30 mg
BAC Water: 3.0 mL
Concentration: 10,000 mcg/mL (10.0 mg/mL)
1 mg: 0.10 mL (10 units)
2 mg: 0.20 mL (20 units)
4 mg: 0.40 mL (40 units)
8 mg: 0.80 mL (80 units)
12 mg: 1.20 mL - split draw
Reconstitution Step-by-Step
- Allow the lyophilized retatrutide vial and bacteriostatic water to reach room temperature.
- Clean both vial stoppers with alcohol and allow to air dry for approximately 10 seconds.
- Draw the calculated volume of bacteriostatic water using a sterile syringe.
- Inject water slowly down the inside vial wall. Do not spray directly onto lyophilized powder.
- Gently swirl until dissolved. Do not shake. The solution should remain clear and free of visible particles.
- Label the vial with peptide name, concentration, and reconstitution date.
- Refrigerate at 2-8C (35.6-46.4F) and use within 2-4 weeks.
Retatrutide Side Effects - What Clinical Trials Show
Retatrutide's side effect profile aligns with incretin-based therapies but includes distinct signals associated with glucagon receptor activity.
Common gastrointestinal effects: In Phase 2 (NEJM), nausea occurred in up to 25% of participants at 12 mg, diarrhea up to 23%, vomiting up to 26%, and constipation up to 16%. Events were most common during escalation and usually mild-to-moderate.
Cardiovascular signal: A modest resting heart-rate increase (about 5-10 bpm) was observed, peaking near week 24 and easing by weeks 36-48. No increase in serious cardiovascular events was reported.
Dysesthesia in Phase 3: TRIUMPH-4 (December 2025) identified dysesthesia (skin sensitivity/tingling) in approximately 20.9% at the highest dose.
Liver enzymes: Temporary ALT/AST elevations were reported in a minority and were generally transient during dose increases.
Injection site reactions: Redness, itching, and nodules were observed in roughly 5-15% of participants.
Discontinuation: In Phase 2, discontinuation due to adverse events was 6-16% vs 0% in placebo. Gradual titration improved adherence.
Retatrutide Clinical Trial Results
Jastreboff et al., NEJM 2023
Phase 2 • 48 weeks
338 adults with obesity (no diabetes)
12 mg: -24.2% body weight; 8 mg: -22.8%; 4 mg: -17.5%. 100% of 8 mg and 12 mg participants lost >=5%.
TRIUMPH-4, Eli Lilly 2025
Phase 3 • 68 weeks
Adults with obesity + knee osteoarthritis
12 mg: -28.7% body weight; 9 mg: similar results. Also significant pain reduction (WOMAC -4.5 points).
Rosenstock et al., Lancet 2023
Phase 2 • 36 weeks
Adults with type 2 diabetes
Up to -16.9% weight loss. HbA1c improved by -2.2%. 82% reached HbA1c <=6.5%.
Sanyal et al., Nature Medicine 2024
Phase 2 substudy • 48 weeks
Adults with MASLD and >=10% liver fat
Up to 82% relative reduction in liver fat at 24 weeks.
As of February 2026, the TRIUMPH Phase 3 program includes obesity (TRIUMPH-1), type 2 diabetes (TRIUMPH-2), cardiovascular outcomes (TRIUMPH-3), and osteoarthritis (TRIUMPH-4, completed December 2025), plus additional work in obstructive sleep apnea, chronic low back pain, and MASLD. Seven additional Phase 3 readouts are expected in 2026, and if outcomes remain positive, an NDA filing is projected for late 2026 with potential approval in 2027.
Storage & Handling
Lyophilized (powder, sealed)
-20C (-4F) or below (freezer)
Long-term - up to 12+ months
Lyophilized (powder, sealed)
2-8C (35.6-46.4F) (refrigerator)
Several months
Lyophilized (powder, sealed)
Room temperature (during shipping)
Stable for several weeks - peptide powders tolerate short-term temperature fluctuations
Reconstituted (solution)
2-8C (35.6-46.4F) (refrigerator)
Use within 2-4 weeks
Reconstituted (solution)
-20C (-4F) (frozen aliquots)
3-4 months
Protect reconstituted solutions from light. Avoid repeated freeze-thaw cycles, which can degrade peptide integrity. For long-term storage, use single-use aliquots before freezing. Bacteriostatic water (0.9% benzyl alcohol) is preferred for multi-dose workflows.
Retatrutide vs. Tirzepatide vs. Semaglutide
Receptor Targets
Retatrutide: GLP-1 + GIP + Glucagon (triple)
Tirzepatide: GLP-1 + GIP (dual)
Semaglutide: GLP-1 only (single)
Half-Life
Retatrutide: ~6 days
Tirzepatide: ~5 days
Semaglutide: ~7 days
Dosing Frequency
Retatrutide: Once weekly
Tirzepatide: Once weekly
Semaglutide: Once weekly
Max Studied Dose
Retatrutide: 12 mg/week
Tirzepatide: 15 mg/week
Semaglutide: 2.4 mg/week
Peak Weight Loss (Trials)
Retatrutide: -28.7% at 68 weeks (Phase 3)
Tirzepatide: -22.5% at 72 weeks (SURMOUNT-1)
Semaglutide: -15.8% at 68 weeks (STEP-1)
FDA Status (Feb 2026)
Retatrutide: Investigational - Phase 3
Tirzepatide: Approved (obesity + T2D)
Semaglutide: Approved (obesity + T2D)
Liver Fat Reduction
Retatrutide: Up to 82% reduction (substudy)
Tirzepatide: Significant reduction
Semaglutide: Moderate reduction
Unique Advantage
Retatrutide: Triple agonism increases energy expenditure via glucagon
Tirzepatide: Dual agonism balances efficacy and tolerability
Semaglutide: Longest clinical track record, CV outcomes data (SELECT trial)
Retatrutide's triple receptor mechanism may explain higher observed weight-loss outcomes and stronger liver-fat reductions versus dual and single agonists, but it remains investigational as of February 2026.
The glucagon receptor component may contribute to increased energy expenditure and stronger liver-fat reduction, but it may also explain the dysesthesia signal observed in Phase 3 that is not common with semaglutide or tirzepatide.
These compounds are not interchangeable. Reconstitution math, dose ranges, and concentration targets differ significantly.
See the tirzepatide protocol and semaglutide protocol for compound-specific guides.
Retatrutide Stacking Protocols
Stack: Metabolic Research Stack
Retatrutide + MOTS-c
Dual-pathway metabolic modulation targeting GLP-1/GIP/glucagon signaling (retatrutide) and mitochondrial signaling (MOTS-c) in preclinical research models.
MOTS-c is a mitochondria-derived peptide studied for exercise-mimetic effects and metabolic regulation. Combined with retatrutide, this stack represents a complementary multi-pathway research approach.
See the compound-specific MOTS-c protocol for additional context.
View full Metabolic Research Stack protocolFrequently Asked Questions - Retatrutide
Q1: What is the starting dose of retatrutide?
Based on clinical trial protocols (Phase 2 and Phase 3 TRIUMPH program), the starting dose of retatrutide is 1 mg administered once weekly via subcutaneous injection for the first 4 weeks. This low starting dose allows the body to adjust before escalation begins.
Q2: What is retatrutide's half-life?
Retatrutide has a half-life of approximately 6 days (ranging from 6-8 days depending on the source). This supports once-weekly subcutaneous dosing and is enabled by albumin binding from its C20 fatty diacid conjugation.
Q3: How much weight can you lose on retatrutide?
In the Phase 2 trial (NEJM, 2023), participants on 12 mg lost an average of 24.2% body weight at 48 weeks. In Phase 3 TRIUMPH-4 (December 2025), weight loss reached up to 28.7% at 68 weeks. Results were dose-dependent.
Q4: How do you reconstitute retatrutide?
Add bacteriostatic water to the lyophilized vial based on vial size and target concentration. For a 10 mg vial, 2.0 mL BAC water yields 5,000 mcg/mL. Inject water down the vial wall, gently swirl, do not shake, refrigerate at 2-8C, and use within 2-4 weeks. Calculator: https://www.peppal.app/calculator
Q5: Is retatrutide FDA-approved?
No. As of February 2026, retatrutide is not FDA-approved. It remains investigational and is being evaluated in Eli Lilly's TRIUMPH Phase 3 program.
Q6: What are the most common side effects of retatrutide?
Most common side effects are gastrointestinal: nausea (up to 25%), diarrhea (up to 23%), vomiting (up to 26%), and constipation (up to 16%), usually during dose escalation. Phase 3 TRIUMPH-4 also identified dysesthesia in about 20.9% at the highest dose.
Q7: How does retatrutide compare to tirzepatide and semaglutide?
Retatrutide is a triple agonist (GLP-1 + GIP + glucagon), tirzepatide is dual (GLP-1 + GIP), and semaglutide is single (GLP-1). Retatrutide has shown greater trial weight loss but remains investigational, while tirzepatide and semaglutide are FDA-approved.
Q8: What vial sizes does retatrutide come in?
Research-grade retatrutide is commonly available in 5 mg, 10 mg, 20 mg, and 30 mg vial sizes. Vial size affects reconstitution math and doses per vial.
Q9: How much bacteriostatic water should I add to a retatrutide vial?
It depends on vial size and target concentration. Common mixes: 5 mg + 1.0 mL = 5,000 mcg/mL; 10 mg + 2.0 mL = 5,000 mcg/mL; 20 mg + 2.0 mL = 10,000 mcg/mL; 30 mg + 3.0 mL = 10,000 mcg/mL. Calculator: https://www.peppal.app/calculator
Q10: What is the maximum dose of retatrutide studied in clinical trials?
The maximum weekly dose studied is 12 mg. In Phase 2, 12 mg reached -24.2% at 48 weeks, and in Phase 3 TRIUMPH-4 up to -28.7% at 68 weeks.
Q11: How should reconstituted retatrutide be stored?
Store reconstituted retatrutide at 2-8C, protected from light, and use within 2-4 weeks. Lyophilized powder is generally stored at -20C for long-term stability. Avoid repeated freeze-thaw cycles.
Q12: What is the TRIUMPH clinical trial program?
TRIUMPH is Eli Lilly's Phase 3 program for retatrutide, including obesity (TRIUMPH-1), type 2 diabetes (TRIUMPH-2), cardiovascular outcomes (TRIUMPH-3), and osteoarthritis (TRIUMPH-4), plus additional indications such as sleep apnea, low back pain, and MASLD.
Sources & Research
- Jastreboff AM, Kaplan LM, Frias JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. New England Journal of Medicine, 2023 DOI: 10.1056/NEJMoa2301972.
- Rosenstock J, Frias JP, Jastreboff AM, et al. 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. The Lancet, 2023 DOI: 10.1016/S0140-6736(23)01053-X.
- Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine, 2024 DOI: 10.1038/s41591-024-03018-2.
- Eli Lilly and Company. Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial. Press Release, December 11, 2025 Link.
- Karras SN, Koufakis T, Papakonstantinou E, et al. Retatrutide-A Game Changer in Obesity Pharmacotherapy. Metabolites, 2025 PMC Article.
- Ali F, et al. Efficacy and safety of retatrutide, a novel GLP-1, GIP, and glucagon receptor agonist for obesity treatment: a systematic review and meta-analysis of randomized controlled trials. Baylor University Medical Center Proceedings, 2025 PMC Article.
- Sattar N, et al. Effects of once-weekly subcutaneous retatrutide on weight and metabolic markers: A systematic review and meta-analysis of randomized controlled trials. Obesity Reviews, 2024 PMC Article.
- Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism, 2022 DOI: 10.1016/j.cmet.2022.07.013.
- ClinicalTrials.gov — (NCT05929066), (NCT05931367), (NCT07035093), (NCT07232719).
- Wikipedia - Retatrutide. Link.
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View protocolDisclaimer & Affiliate Disclosure
Disclaimer: The information on this page is for educational and research reference purposes only. Retatrutide is an investigational compound not approved by the FDA. No compounds discussed on this site are intended for human consumption. This is not medical advice. Consult a qualified healthcare professional before considering any peptide protocol. Protocol data is compiled from published clinical trials, peer-reviewed literature, and community research documentation.
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