Retatrutide - Study Reference

What it is

Retatrutide (LY3437943) is a once-weekly injectable peptide developed by Eli Lilly that activates three receptors at once: the GIP, GLP-1, and glucagon receptors (a "triple agonist"). In studies it has been examined for body-weight reduction in obesity, blood-sugar control in type 2 diabetes, and reduction of liver fat in metabolic-dysfunction-associated steatotic liver disease (MASLD).

How studies used it

Model: Mouse (C57BL/6-based KPCY pancreatic cancer and Lewis lung carcinoma, LLC, allograft models)
Studied for: Obesity-associated cancer progression (pancreatic and lung tumor growth), plus body-weight effect
Dose: 30 nmol/kg per dose, which is about 0.14 mg/kg per dose (retatrutide molecular weight ~4731 g/mol: 30 nmol/kg x 4731 ng/nmol = ~141,900 ng/kg = ~0.142 mg/kg)
Dosing: Every other day, starting 14 days before tumor-cell injection and continued; a separate withdrawal group was treated for 14 days only
Route: Subcutaneous
Duration: About 2 weeks of pre-treatment plus continued dosing through tumor growth (withdrawal arm: 14 days)

Effects measured: Reported a 14-fold reduction in pancreatic (KPCY) tumor volume and a 17-fold reduction in lung (LLC) tumor volume versus vehicle controls. Body weight fell by about 38% of baseline in the pancreatic model and about 41% in the lung model, plateauing after roughly 2 weeks. Anti-tumor benefit reportedly persisted after drug withdrawal despite weight regain.

Side effects: No specific adverse events were reported in the treated mice in this study.

Sources: Marathe SJ, et al. Incretin triple agonist retatrutide (LY3437943) alleviates obesity-associated cancer progression. NPJ Metab Health Dis. 2025.

Model: Human, adults with obesity (BMI >=30, or 27 to <30 with a weight-related condition); n=338, 51.8% male
Studied for: Obesity / weight loss
Dose: Mean baseline body weight in this trial was 107.73 kg (BMI 37.34). Weekly doses convert to roughly: 1 mg = ~0.009 mg/kg/week; 4 mg = ~0.037 mg/kg/week; 8 mg = ~0.074 mg/kg/week; 12 mg = ~0.111 mg/kg/week (absolute mg divided by 107.73 kg)
Dosing: Once weekly, with dose escalation (some groups started at 2 mg or 4 mg)
Route: Subcutaneous
Duration: 48 weeks

Effects measured: Mean weight change at 48 weeks: placebo -2.1%; 1 mg -8.7%; 4 mg -17.1%; 8 mg -22.8%; 12 mg -24.2%. Proportion losing >=15% of body weight: 2% placebo, 60% (4 mg), 75% (8 mg), 83% (12 mg).

Side effects: Most common adverse events were gastrointestinal (nausea, diarrhea, vomiting), dose-related and mostly mild to moderate. Dose-dependent increases in heart rate peaked at 24 weeks then declined.

Sources: Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity - A Phase 2 Trial. N Engl J Med. 2023.

Model: Human, adults with type 2 diabetes (age 18-75, baseline HbA1c 7.0-10.5%, BMI 25-50; mean baseline HbA1c 8.27%); n=281
Studied for: Type 2 diabetes (blood-sugar control) and body weight
Dose: The paper's own mean baseline body weight was not accessible to me, so this mg/kg is an estimate, not the trial's reported mean. Using an assumed ~95 kg for this BMI ~35 cohort: 0.5 mg = ~0.005 mg/kg/week; 4 mg = ~0.042 mg/kg/week; 8 mg = ~0.084 mg/kg/week; 12 mg = ~0.126 mg/kg/week. Verified absolute weekly maintenance doses were 0.5, 4, 8, and 12 mg.
Dosing: Once weekly, with various escalation schedules (comparators: placebo and dulaglutide 1.5 mg weekly)
Route: Subcutaneous
Duration: 24 weeks primary endpoint, with 36-week data also reported

Effects measured: HbA1c reduction at 24 weeks: placebo -0.01%; 0.5 mg -0.43%; 4 mg -1.30 to -1.39%; 8 mg -1.88 to -1.99%; 12 mg -2.02% (dulaglutide -1.41%). Weight change at 36 weeks: 0.5 mg -3.19%; 4 mg -7.92 to -10.37%; 8 mg -16.34 to -16.81%; 12 mg -16.94%.

Side effects: Mild-to-moderate gastrointestinal events (nausea, diarrhea, vomiting, constipation) reported in 35% (67/190) of retatrutide participants overall, dose-related (range ~13% to 50% across doses), versus 13% placebo and 35% dulaglutide. No severe hypoglycemia and no deaths.

Sources: Rosenstock J, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a phase 2 trial. Lancet. 2023.

Model: Human, adults with MASLD and >=10% baseline liver fat (substudy of the phase 2 obesity trial); n=98
Studied for: MASLD / liver fat reduction (and body weight)
Dose: Mean baseline body weight in this substudy was 110.2 kg (BMI 38.4). Weekly doses convert to roughly: 1 mg = ~0.009 mg/kg/week; 4 mg = ~0.036 mg/kg/week; 8 mg = ~0.073 mg/kg/week; 12 mg = ~0.109 mg/kg/week (absolute mg divided by 110.2 kg)
Dosing: Once weekly, with dose escalation
Route: Subcutaneous
Duration: 48 weeks (liver-fat primary endpoint assessed at 24 weeks)

Effects measured: Relative liver-fat reduction at 24 weeks: placebo +0.3%; 1 mg -42.9%; 4 mg -57.0%; 8 mg -81.4%; 12 mg -82.4%. Normalization of liver fat to <5% at 24 weeks: 0% placebo, 27% (1 mg), 52% (4 mg), 79% (8 mg), 86% (12 mg). Weight change at 48 weeks: placebo -0.1%; 1 mg -8.6%; 4 mg -16.3%; 8 mg -23.8%; 12 mg -25.9%.

Side effects: Transient, generally mild-to-moderate gastrointestinal events were the most frequent adverse events, more common in the 8 mg and 12 mg groups. Per-event frequencies (nausea, diarrhea, vomiting) were not itemized separately in the accessible text.

Sources: Sanyal AJ, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024.

How solid the evidence is

Honest summary: One study here is in mice (Marathe 2025, tumor and weight effects) and three are human phase 2 trials (obesity, type 2 diabetes, MASLD substudy). The mouse cancer findings are early preclinical signals only and should not be read across to humans. The three human trials are randomized and placebo-controlled but are all phase 2 (mid-stage), industry-sponsored, and authored largely by Eli Lilly employees and Lilly-funded investigators, so sponsorship bias should be assumed. Dose conversions: the obesity trial (mean baseline weight 107.73 kg, verified from ClinicalTrials.gov NCT04881760) and the MASLD substudy (mean baseline weight 110.2 kg, verified from the published full text) gave reliable mg/kg figures. The type 2 diabetes trial's own reported mean baseline body weight was not accessible in any source I could reach (abstract and ClinicalTrials.gov baseline tables report HbA1c and BMI eligibility but not weight in kg), so its mg/kg numbers are explicitly an estimate using an assumed ~95 kg, not the paper's reported mean; treat those as approximate. The originally suggested phase 1 study (Coskun 2022, PMID 35985340) was verified for title/authors/journal/year, but its indexed abstract did not carry granular per-dose and per-side-effect data, and the full text was paywalled, so I dropped it in favor of the three weight-anchored phase 2 trials to avoid reporting unverified numbers. Important: there is no established human dosing protocol for retatrutide for any use; it is an investigational drug not approved by EMA or FDA, and the weekly mg doses above are trial-defined research doses, not a recommended regimen. All measured effects are study findings, not promises of benefit; gastrointestinal side effects were consistently dose-related across the human trials.