Retatrutide (LY3437943) is an investigational once-weekly injectable peptide developed by Eli Lilly and Company. It is the first clinical-stage molecule to simultaneously activate three metabolic hormone receptors: glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG). This triple agonism represents the next evolution beyond dual agonists like tirzepatide (GLP-1/GIP).
Structurally, retatrutide is a single peptide conjugated to a fatty diacid moiety that enables once-weekly dosing through albumin binding. Compared to endogenous ligands, it is less potent at the GLP-1 and glucagon receptors (0.4x and 0.3x, respectively) but more potent at the GIP receptor (8.9x), creating a pharmacological profile that addresses obesity through three complementary pathways.
In a Phase 2 trial published in the New England Journal of Medicine (2023), retatrutide produced weight loss of up to 24.2% at 48 weeks at the 12 mg dose, which was at that time the highest weight loss recorded for any anti-obesity pharmaceutical agent. In December 2025, the first Phase 3 trial (TRIUMPH-4) reported 28.7% mean weight loss at 68 weeks (12 mg dose), equivalent to approximately 71.2 pounds (32.3 kg) average loss. Seven additional Phase 3 readouts are expected throughout 2026.
Critical context: Retatrutide is NOT approved by the FDA. The compound is currently in the Phase 3 TRIUMPH program, with regulatory submission and FDA review to follow. Estimated earliest approval: late 2027.
| Weeks | Dosage | Syringe units (U-100) |
|---|---|---|
| Weeks 1–4 | 1 mg | 10 units0.1 mL |
| Weeks 5–8 | 2.5 mg | 25 units0.25 mL |
| Week 9+ | 5 mg | 50 units0.5 mL |
| Weeks | Dosage | Syringe units (U-100) |
|---|---|---|
| Weeks 1–4 | 2 mg | 10 units0.1 mL |
| Weeks 5–8 | 4 mg | 20 units0.2 mL |
| Weeks 9–12 | 6 mg | 30 units0.3 mL |
| Weeks 13+ | 8 mg | 40 units0.4 mL |
| Weeks | Dosage | Syringe units (U-100) |
|---|---|---|
| Weeks 1–4 | 2 mg | 6.67 units0.07 mL |
| Weeks 5–8 | 4 mg | 13.3 units0.13 mL |
| Weeks 9–12 | 6 mg | 20 units0.2 mL |
| Weeks 13+ | 8 mg | 26.7 units0.27 mL |
| Weeks | Dosage | Syringe units (U-100) |
|---|---|---|
| Weeks 1–4 | 2 mg | 5 units0.05 mL |
| Weeks 5–8 | 4 mg | 10 units0.1 mL |
| Weeks 9–12 | 6 mg | 15 units0.15 mL |
| Weeks 13+ | 8 mg | 20 units0.2 mL |
| Weeks | Dosage | Syringe units (U-100) |
|---|---|---|
| Weeks 1–4 | 2 mg | 3.33 units0.03 mL |
| Weeks 5–8 | 4 mg | 6.67 units0.07 mL |
| Weeks 9–12 | 6 mg | 10 units0.1 mL |
| Weeks 13+ | 8 mg | 13.3 units0.13 mL |
FrequencyOnce weekly, subcutaneous.
For review — starts higher and escalates faster than the cited trial. Jastreboff et al. (NEJM 2023) began at 0.5 mg once weekly and escalated to 12 mg over 48 weeks under supervision; the schedule in the chart starts at 2 mg and reaches 8 mg in 13, and the 10 mg vial chart starts at 1 mg and reaches 5 mg by week 9. The concentration strip above the chart is calculated from the vial and water volume and is correct.
Retatrutide has genuine published human dose-ranging data, and the amounts charted here fall inside the range the Phase 2 trial covered — but that trial started at 0.5 mg and took 48 weeks to reach its top arm, where this schedule starts at 2 mg and reaches 8 mg in a quarter of the time, so the pace is flagged for review. That difference is not cosmetic: dropout for gastrointestinal effects in the trial was concentrated in the higher arms and the slow escalation is what made them tolerable. Retatrutide is investigational and approved nowhere; TRIUMPH-4 reported the first Phase 3 results in December 2025 at 12 mg once weekly over 68 weeks. Every strength is made up with the same 1 mL of bacteriostatic water, so the concentration equals the vial strength — 10, 20, 30, 40 and 60 mg/mL — and the same amount takes fewer units the stronger the vial. The 10 mg vial is the beginner strength and has its own chart, starting at 1 mg and stepping to 2.5 mg and then 5 mg: 10, 25 and 50 units. The other strengths keep the 2, 4, 6 and 8 mg schedule, which reads 10, 20, 30 and 40 units on the 20 mg vial; about 6.7, 13.3, 20 and 26.7 on the 30 mg vial; 5, 10, 15 and 20 on the 40 mg vial; and about 3.3, 6.7, 10 and 13.3 on the 60 mg vial. No amount charted on this page is higher than 12.5 mg, and every step on every strength fits inside a single 50-unit syringe.
What this evidence establishes. Retatrutide has substantial published human dose-ranging data, but it is an investigational compound that is not approved anywhere. Every dose below was reached by supervised escalation from a low starting dose over months, with dropout for gastrointestinal effects concentrated in the higher arms — the endpoint dose is not the starting dose.
Sources: Jastreboff et al., NEJM 2023 — Phase 2 trial · TRIUMPH-4 Phase 3 readout, December 2025
For educational and laboratory research purposes only. It does not provide medical advice, dosing recommendations, or instructions for human or veterinary use. Syringe units assume a U-100 syringe, on which 1 mL is 100 units and a 50-unit syringe holds 0.5 mL.
Retatrutide's distinguishing feature is triple receptor agonism. Each target contributes distinct metabolic effects, and the combination addresses energy balance from multiple directions simultaneously:
Activates hypothalamic and brainstem GLP-1 receptors to reduce hunger, increase satiety, and decrease caloric intake (~30-40% reduction)
Increases resting energy expenditure, stimulates hepatic fat oxidation, and promotes lipid metabolism in the liver. The key differentiator from dual agonists.
Enhances insulin sensitivity and metabolic processing. Amplifies the effects of both GLP-1 and glucagon agonism. Most potent component (8.9x endogenous).
Glucagon receptor activation drives dramatic liver fat reduction: 82% mean relative reduction in MASLD patients (Phase 2 substudy). Steatosis resolved in >85% at 48 weeks.
GLP-1 component slows gastric emptying rate, prolonging postprandial satiety and contributing to reduced caloric intake
Reductions in non-HDL cholesterol, triglycerides, hs-CRP, and systolic blood pressure observed across Phase 2 and Phase 3 trials
Why triple agonism matters: GLP-1 reduces how much energy comes in (appetite). Glucagon increases how much energy goes out (expenditure and fat oxidation). GIP enhances the metabolic environment for both to work more effectively. The glucagon component is specifically credited with the superior liver fat reduction that distinguishes retatrutide from GLP-1 mono-agonists and GLP-1/GIP dual agonists.
Because retatrutide is investigational, its full safety profile is not yet established. The following data is derived from Phase 2 trials and the TRIUMPH-4 Phase 3 topline results. Additional safety data will emerge from the remaining Phase 3 program:
| Condition / Factor | Risk Level | Rationale |
|---|---|---|
| GI adverse events (nausea, vomiting, diarrhea) | MODERATE (expected) | Consistent with the GLP-1 class. Nausea reported in ~43%, diarrhea ~33%, vomiting ~21% (TRIUMPH-4). Most events mild-to-moderate. |
| Dysesthesia (new Phase 3 signal) | MODERATE (monitoring) | Abnormal touch sensation, tingling, or numbness reported in 20.9% of 12 mg participants in TRIUMPH-4. Not seen in Phase 2. Most cases mild; did not lead to discontinuation. Under active investigation. |
| Excessive weight loss | MODERATE | Some TRIUMPH-4 discontinuations attributed to perceived excessive weight loss. Discontinuation rates correlated with lower baseline BMI. A novel concern for this drug class. |
| Medullary thyroid carcinoma risk (class effect) | HIGH (theoretical) | GLP-1 receptor agonists carry a class-level concern for thyroid C-cell tumors based on rodent data. MTC/MEN2 history expected to be contraindicated per class labeling. |
| Pancreatitis (class effect) | MODERATE | Incretin-class risk. No pancreatitis cases reported in Phase 2 retatrutide data. Long-term Phase 3 data pending. |
| Pregnancy / breastfeeding | HIGH | No reproductive toxicology data published. Excluded from all clinical trials. Standard exclusion for investigational compounds. |
| Gallbladder disease | MODERATE | Rapid weight loss increases cholelithiasis risk. Class-level concern. Monitoring recommended. |
| Cardiovascular effects | LOW (under study) | Heart rate increases observed (class effect). TRIUMPH-3 cardiovascular/renal outcomes trial ongoing. Improvements in CV risk markers (lipids, BP, hs-CRP) observed. |
| Human safety data completeness | INCOMPLETE | Phase 2 data published. One Phase 3 trial reported (TRIUMPH-4). Seven additional Phase 3 trials pending. Full safety profile not yet established. |
| Discontinuation rates | MODERATE | 12.2% (9 mg) and 18.2% (12 mg) vs. 4.0% (placebo) in TRIUMPH-4. Some attributed to GI side effects, some to perceived excessive weight loss. |
FDA: Retatrutide (LY3437943) is NOT approved by the FDA for any indication. It is classified as an investigational new drug (IND) undergoing Phase 3 clinical evaluation.
Clinical Trials: Retatrutide is being studied across the Phase 3 TRIUMPH program for obesity/overweight, type 2 diabetes, knee osteoarthritis, obstructive sleep apnea, chronic low back pain, cardiovascular/renal outcomes, and metabolic dysfunction-associated steatotic liver disease (MASLD). The TRANSCEND program evaluates it for type 2 diabetes specifically. The SYNERGY program evaluates it for MASLD/MASH.
Manufacturer: Eli Lilly and Company (NYSE: LLY). Retatrutide is part of Lilly's incretin portfolio alongside tirzepatide (Mounjaro/Zepbound) and orforglipron (oral, under FDA review).
Timeline context: Based on current Phase 3 enrollment and expected readouts in 2026, an FDA submission could occur in late 2026 or 2027. FDA review typically takes 10-12 months. Earliest potential commercial availability is estimated at late 2027 to early 2028. These timelines are estimated and depend on Phase 3 results being positive and regulatory review proceeding on standard timelines.
Key distinction: Retatrutide's Phase 2 and early Phase 3 data are extraordinary. A 28.7% mean weight loss in a Phase 3 trial is unprecedented for any pharmaceutical agent. However, extraordinary early data does not guarantee FDA approval. The full TRIUMPH program must demonstrate consistent efficacy and acceptable safety across diverse populations. Retatrutide is a promising investigational compound, not an approved therapy.
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This profile is for educational and research purposes only. It is not medical advice, and nothing on it is a protocol, a recommendation, or an instruction for use in a person or an animal.
Athena Peptides Education does not prescribe, sell, or recommend any compound. Compounds discussed here are for laboratory research only and are not for human consumption. Always consult a qualified physician before making any decision about your health.