Retatrutide Dosage Guide & Titration Protocol
Retatrutide dosage guide covering the investigational triple-agonist peptide's dose escalation schedule from Phase 2 trial data, reconstitution instructions, side effect profile, and comparison context with tirzepatide and semaglutide. Educational reference only — retatrutide is not yet FDA approved.
Medical Disclaimer
This guide is for educational and informational purposes only. It is not medical advice. Dosages described reflect ranges discussed in published research and clinical practice literature — they are not recommendations. Always consult a licensed healthcare provider before using any peptide. Legality and availability vary by jurisdiction.
Overview
Retatrutide (LY3437943) is an investigational triple hormone receptor agonist targeting GIP, GLP-1, and glucagon receptors simultaneously. This tri-agonist mechanism is unique among incretin-based therapies currently in development and is discussed in research literature as potentially offering enhanced weight loss through the addition of glucagon receptor activation, which may increase energy expenditure and hepatic lipid oxidation beyond what dual agonists achieve. In the Phase 2 trial published by Jastreboff et al. (2023), participants receiving the highest dose of retatrutide (12 mg) achieved a mean body weight reduction of approximately 24.2% at 48 weeks — the largest weight reduction reported for any anti-obesity medication in a randomized trial at the time of publication. Retatrutide is currently not FDA approved and is being evaluated in Phase 3 clinical trials (the TRIUMPH program). All dosage information presented here is derived from published Phase 2 trial data and is for educational reference only.
Dosing Protocols
Phase 2 Dose Escalation — Low Dose Group
The 4 mg maintenance dose group achieved approximately 17.5% mean weight loss at 48 weeks in the Phase 2 trial. Escalation began at 0.5 mg for the first 4 weeks, then 1 mg for weeks 5–8, then 2 mg for weeks 9–12, reaching the 4 mg maintenance dose at week 13.
Phase 2 Dose Escalation — Medium Dose Group
The 8 mg maintenance dose group achieved approximately 22.8% mean weight loss at 48 weeks. The titration schedule followed the same initial 0.5 → 1 → 2 → 4 mg monthly steps, with an additional escalation to 8 mg at approximately week 17.
Phase 2 Dose Escalation — High Dose Group
The 12 mg maintenance dose produced the highest weight loss observed: approximately 24.2% at 48 weeks. Titration to the 12 mg dose was reached at approximately week 21–24. Over 90% of participants in this group achieved at least 10% body weight reduction. Note: Retatrutide is investigational — not yet FDA approved.
Anticipated Phase 3 Maintenance
The TRIUMPH Phase 3 program is evaluating retatrutide at multiple doses. The exact approved dosing, if retatrutide receives regulatory authorization, may differ from the Phase 2 protocol. This information is speculative and based on publicly available clinical trial registry data.
Reconstitution & Storage
| Vial sizes | Varies by source — research-grade and compounded forms typically available in 5 mg and 10 mg lyophilized vials |
| Recommended water volume | Reconstitute with 1–2 mL bacteriostatic water depending on vial size and desired concentration. For a 10 mg vial with 2 mL BAC water, concentration is 5 mg/mL. |
| Storage | Refrigerate reconstituted solution at 36–46 °F (2–8 °C). Protect from light and temperature fluctuations. |
| Stability once reconstituted | Limited published stability data for compounded forms. General peptide handling suggests use within 28 days of reconstitution when refrigerated. Discard if solution becomes cloudy or discolored. |
Use our reconstitution calculator to determine exact syringe units for your dose.
Cycle Guidance
As an investigational compound, there are no established clinical guidelines for cycling retatrutide. The Phase 2 trial administered retatrutide continuously for 48 weeks with no off-cycle periods. Given the weight regain patterns observed with other GLP-1 and GIP receptor agonists upon discontinuation (e.g., tirzepatide SURMOUNT-4 data, semaglutide STEP 1 extension data), it is anticipated that retatrutide would similarly require continuous use for sustained weight management. No controlled data on discontinuation effects specific to retatrutide have been published as of the current date. Researchers are monitoring whether the glucagon receptor component might offer any metabolic memory effect, but this remains speculative.
Stacking Considerations
- Retatrutide should not be combined with GLP-1 receptor agonists (semaglutide, liraglutide) or dual agonists (tirzepatide) — the overlapping GLP-1 activity would increase gastrointestinal side effect burden without established benefit.
- As a triple agonist activating glucagon receptors, retatrutide has theoretical interactions with glucose-lowering medications — combining with insulin or sulfonylureas may increase hypoglycemia risk.
- The glucagon receptor activation component of retatrutide may affect hepatic glucose output and lipid metabolism differently than GLP-1-only or GIP/GLP-1 dual agonists, making drug interaction profiles potentially distinct and not yet fully characterized.
- No published data exist on combining retatrutide with metformin, SGLT2 inhibitors, or other diabetes medications, though such combinations are expected to be studied in Phase 3 trials.
Potential Side Effects
- Nausea (reported in 16–34% of participants depending on dose group, most frequently during titration)
- Diarrhea (reported in 16–22% across dose groups)
- Vomiting (reported in 9–19% across dose groups)
- Constipation (reported in approximately 12–16%)
- Decreased appetite (reported as an adverse event though it is a mechanism-related effect)
- Dyspepsia and abdominal discomfort
- Injection site reactions (erythema, pruritus — generally mild)
- Increased heart rate (small mean increase reported, consistent with GLP-1 agonist class)
- Potential hepatic effects related to glucagon receptor activation (being monitored in ongoing trials)
Contraindications & Cautions
- Personal or family history of medullary thyroid carcinoma — based on class-wide rodent thyroid C-cell findings with GLP-1 receptor agonists
- Multiple endocrine neoplasia syndrome type 2 (MEN 2)
- Known hypersensitivity to retatrutide or formulation components
- Severe hepatic impairment (glucagon receptor activation may affect hepatic function; limited safety data)
- History of pancreatitis (precautionary, consistent with GLP-1 agonist class labeling)
- Pregnancy and breastfeeding (no human safety data available for retatrutide)
- Note: As an investigational compound, the full contraindication and safety profile of retatrutide has not been established through the regulatory approval process
Related
References
- Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial (2023) — PubMed
- Retatrutide, a GIP, GLP-1 and Glucagon Receptor Agonist, for People with Type 2 Diabetes: A Randomised, Double-Blind, Placebo and Active-Comparator Controlled, Parallel-Group, Phase 2 Trial (2023) — PubMed
- GIP/GLP-1/Glucagon Triple Agonism: A New Paradigm for Anti-Obesity Pharmacotherapy (2023) — PubMed