OnePin Peptide Library · Metabolic
Retatrutide
Reta · Tri-G · GGG
Retatrutide (LY3437943) is a first-in-class triple agonist peptide targeting GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors simultaneously. Developed by Eli Lilly, it produced the most dramatic weight loss results of any obesity peptide in Phase 2 trials, with participants losing up to 24.2% of body weight at 48 weeks at the highest dose. The triple agonist mechanism addresses appetite suppression (GLP-1), insulin sensitivity and fat metabolism (GIP), and energy expenditure and hepatic fat reduction (glucagon). Retatrutide represents the next generation beyond dual agonists like tirzepatide.
Any time of day, with or without food. Once weekly.
Start here. Every protocol below is ordered lowest-first. Begin at the smallest effective dose, hold about a week to assess tolerance, and step up only if needed.
How it works
Retatrutide activates three receptor systems simultaneously. GLP-1 receptor activation suppresses appetite via hypothalamic signaling, slows gastric emptying, and enhances glucose-dependent insulin secretion. GIP receptor activation improves insulin sensitivity, enhances lipid metabolism in adipose tissue, and may reduce inflammation. Glucagon receptor activation increases hepatic energy expenditure, promotes lipolysis, reduces hepatic fat accumulation, and increases thermogenesis. The glucagon component is what distinguishes retatrutide from tirzepatide (GLP-1/GIP only) and semaglutide (GLP-1 only), and is believed to account for the superior weight loss results through increased energy expenditure.
Retatrutide activates three receptor systems simultaneously. GLP-1 receptor activation suppresses appetite via hypothalamic signaling, slows gastric emptying, and enhances glucose-dependent insulin secretion. GIP receptor activation improves insulin sensitivity, enhances lipid metabolism in adipose tissue, and may reduce inflammation. Glucagon receptor activation increases hepatic energy expenditure, promotes lipolysis, reduces hepatic fat accumulation, and increases thermogenesis. The glucagon component is what distinguishes retatrutide from tirzepatide (GLP-1/GIP only) and semaglutide (GLP-1 only), and is believed to account for the superior weight loss results through increased energy expenditure.
What to expect
Weeks 1-4: Appetite suppression noticeable. Nausea common during titration. Initial weight loss primarily from reduced caloric intake. Slow titration minimizes side effects.
Weeks 4-12: Consistent weight loss. GI side effects typically improve. Body composition changes visible. Blood glucose improvements if metabolically impaired.
Weeks 12-48: Significant cumulative weight loss. Phase 2 showed 17-24% body weight loss depending on dose. Hepatic fat reduction. Metabolic markers improve substantially.
Evidence
The honest take
Most potent weight loss peptide
SupportedConfirmed by Phase 2 data. 24.2% body weight loss exceeds semaglutide (15-16%) and tirzepatide (20-22%). Triple agonist mechanism provides additive weight loss.
Glucagon receptor activation specifically targets hepatic fat. Phase 2 data showed significant liver fat reduction. Promising for NASH/NAFLD.
Glucagon component increases basal metabolic rate. This distinguishes retatrutide from GLP-1-only agents that primarily reduce intake.
Interactions & stacking
What's safe to combine, and what belongs in a separate pin.
Safe & synergistic
Keep separate
Side effects & safety
Commonly reported
- Nausea (most common, dose-dependent)
- Diarrhea
- Decreased appetite
- Vomiting during titration
- Constipation
Less common & notes
- Gastroparesis (delayed gastric emptying) with chronic use.
- Pancreatitis risk (class effect).
- Gallbladder issues with rapid weight loss.
- Heart rate increase.
- Monitor thyroid (GLP-1 class has thyroid C-cell tumor signal in rodents).
- Contraindicated with personal/family history of medullary thyroid carcinoma or MEN2.
- Oral contraceptives may be less reliable during dose initiation and escalation: delayed gastric emptying (GLP-1 / amylin) can reduce oral drug absorption - Tirzepatide carries an FDA label warning to use a backup or non-oral method for 4 weeks after starting and after each dose increase.
Pharmacokinetics
Storage. Refrigerate at 2-8C. Protect from light. Stable for 28 days after reconstitution. GLP-1 class peptides are generally stable. Do not freeze after reconstitution.
Regulatory status
Investigational drug (Eli Lilly). Phase 3 trials ongoing. Not yet FDA-approved. Available through compounding pharmacies. WADA status: Not specifically listed but metabolic modulators may fall under S4.
Put it to work
Calculate, log & track
Open Retatrutide straight into OnePin with your vial and dose pre-filled, then let it handle the syringe math and remind you before the vial runs out.
Open Retatrutide in the app →Go deeper
The guide & community
The complete Retatrutide walkthrough, real protocol discussion and coaching live inside the BlessUp community on Skool.
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