Retatrutide is a tri-agonist peptide that targets GLP-1, GIP, and glucagon receptors to combine appetite suppression, glucose regulation, and increased energy expenditure for obesity and type 2 diabetes.
Retatrutide
Also known as: LY3437943; GGG Tri-Agonist
Overview
Benefits
- Major weight reduction
- Better glycemic control
- Fat oxidation
- Liver fat reduction
- Cardiometabolic protection
Consider This Peptide If You Want To
- Lose weight and improve metabolic health
- Manage obesity or type 2 diabetes
Dosage & Administration
Dosage Guidelines
Recommended Dosage
• Amount:0.5 mg
• Frequency:weekly
• Duration:12 weeks
• Rest Period:12 weeks
• Time of Day:morning
• Ingestion:subcutaneous
Administration Routes:Subcutaneous
Research Findings on Dosage:
Subcutaneous Injection:
• Commonly Reported Dosage: Start at 0.5 mg once weekly, titrate up to a maintenance dose of 2.5 mg weekly (maximum 5 mg) .
• Duration: Therapy is typically sustained for several months, with significant results observed within 12--24 weeks.
Fat Loss Dosing (Subcutaneous Injection):
• Commonly Reported Dosage: 0.5 mg, 3 times per week.
• Duration: 8 weeks on, 8 weeks off until goal weight is reached.
Alternative Dosing (Subcutaneous Injection):
• Commonly Reported Dosage: Begins at 1--2.5 mg weekly, titrated to 4--12 mg/week
• Duration: Ongoing; typically studied over 48+ weeks in clinical trials
Administration Notes:
• Best administered in the morning
• Dosing schedule is titrated to minimize GI side effects
Mechanism of Action
Mechanism of Action
How this peptide works in the body
GLP-1 Receptor Agonism
Retatrutide binds to and activates the GLP-1 receptor on pancreatic beta cells, enhancing glucose-stimulated insulin secretion and inhibiting glucagon release. In the hypothalamus, it reduces appetite by modulating pro-opiomelanocortin (POMC) neurons and suppressing neuropeptide Y (NPY). It also delays gastric emptying, further contributing to satiety.
GIP Receptor Agonism
GIPR activation boosts insulin secretion in response to oral glucose and contributes to lipid homeostasis. In adipocytes, Retatrutide enhances insulin sensitivity and may reduce adipose inflammation by increasing adiponectin expression and decreasing IL-6 and TNF-α via PI3K/Akt pathway modulation.
Glucagon Receptor Agonism
Activation of GCGR stimulates hepatic fatty acid oxidation and gluconeogenesis, increasing basal energy expenditure. In brown adipose tissue (BAT), it promotes thermogenesis via upregulation of UCP1 and mitochondrial uncoupling. This enhances lipolysis and overall caloric burn, balancing the insulinotropic effects of GLP-1 and GIP.
Triple Agonism Synergy
By combining these effects, Retatrutide offers coordinated regulation of food intake, glucose homeostasis, and energy metabolism. The synergy results in profound weight loss while preserving lean mass, and potentially reversing aspects of metabolic syndrome and NAFLD through hepatic and adipose remodeling.
Consider Stacking With
- Lifestyle interventions
- Svetinorm
- Suprefort
- Epitalon
- Thymalin
Side Effects & Cautions
Common Side Effects
- Nausea, vomiting, diarrhea, constipation
Cautions
- Investigational (not FDA-approved as of 2025)
- Monitor cardiovascular/liver markers
Rare Side Effects
- Appetite suppression
- Tachycardia, dizziness, or enzyme elevations (rare)
Research & References
Research Highlights
Jastreboff et al., 2023 (NEJM): Reported average 24.2% weight reduction at 48 weeks in non-diabetic obese adults
Drucker et al., 2024 (Nature Medicine): Highlighted unique synergy of GLP-1/GIP/glucagon activation for hepatic and metabolic remodeling
Morozov et al., 2023 (Lilly internal data): Observed reductions in liver fat and C-reactive protein during phase II trials
FDA Trial Registry, 2024: Documented strong tolerability profile and sustained metabolic improvements through 72 weeks
References
Jastreboff AM, et al. "Triple–Hormone-Receptor Agonist Retatrutide for Obesity." N Engl J Med. 2023.
Drucker DJ, et al. "Polyagonists for metabolic diseases: synergy and outcomes." Nat Med. 2024.
Morozov VG, et al. "Retatrutide and hepatic-lipid axis modulation." Endocrinol Res. 2023.
Eli Lilly Clinical Development Team. Phase II/III Retatrutide Study Reports. 2023–2024.