Retatrutide: Complete Guide

Retatrutide is a GLP-1, GIP, and glucagon triple receptor agonist — the first peptide to target all three of these metabolic hormone receptors in a single molecule. Often referred to simply as a "GLP-1/GIP/glucagon triple agonist," retatrutide represents the next evolution in incretin-based metabolic therapy. While first-generation drugs like semaglutide target only GLP-1 receptors, and second-generation drugs like tirzepatide target GLP-1 and GIP, retatrutide adds a third target — the glucagon receptor — making it the most comprehensive multi-receptor agonist in clinical development.

The compound was developed by Eli Lilly and Company and received its first major scientific attention when Phase 2 trial results were published in the New England Journal of Medicine in June 2023. The headline finding — 24.2% mean body weight loss at the 12mg dose over 48 weeks — surpassed the efficacy of every other anti-obesity medication studied in controlled trials.

Retatrutide is currently designated as LY3437943 and is in Phase 3 clinical trials for obesity, type 2 diabetes, and nonalcoholic fatty liver disease (NAFLD/NASH). It has not yet received FDA approval. For people searching for "the GLP-1/GIP/glucagon triple agonist name" — retatrutide is the compound, with the potential brand name still to be announced by Eli Lilly.

Each of retatrutide's three receptor targets contributes distinct metabolic effects:

GLP-1 Receptor Agonism

• Reduces appetite through hypothalamic signaling
• Slows gastric emptying, prolonging satiety after meals
• Enhances glucose-dependent insulin secretion
• Suppresses inappropriate glucagon secretion post-meal

GIP Receptor Agonism

• Enhances insulin sensitivity in adipose tissue
• Improves fat metabolism and lipid handling
• May improve tolerability of GLP-1 effects (reduced nausea)
• Contributes to beta-cell preservation

Glucagon Receptor Agonism

• Increases hepatic fat oxidation and energy expenditure
• Promotes glycogenolysis and gluconeogenesis (counterbalanced by GLP-1/GIP insulin effects)
• Reduces liver fat through direct hepatocyte signaling
• Increases thermogenesis and resting metabolic rate

The glucagon component is what distinguishes retatrutide from tirzepatide and is considered the primary driver of its superior efficacy. Glucagon increases energy expenditure — meaning the body burns more calories at rest — while GLP-1 and GIP reduce caloric intake and improve metabolic processing. The combination attacks obesity from both the intake and expenditure sides of the energy balance equation.

Phase 2 Obesity Trial (Published NEJM, 2023)

The pivotal Phase 2 trial enrolled 338 adults with obesity or overweight (BMI ≥30, or ≥27 with comorbidities) and tested four doses (1mg, 4mg, 8mg, 12mg) against placebo over 48 weeks:

Dose	Mean Weight Loss	≥15% Loss	≥20% Loss
Placebo	-2.1%	3%	—
1 mg	-8.7%	21%	9%
4 mg	-17.1%	67%	40%
8 mg	-22.8%	79%	60%
12 mg	-24.2%	83%	63%

At the 12mg dose, the weight loss curve had not plateaued at 48 weeks, suggesting even greater reductions might be achievable with longer treatment duration.

Liver Fat Reduction

A sub-study of the Phase 2 trial measured liver fat by MRI in participants with NAFLD. Results were striking:

• Mean relative reduction in liver fat: 82% at 8mg dose
• 86% of participants with NAFLD at baseline achieved complete resolution (<5% liver fat) by week 48
• These results significantly exceed those seen with any current NAFLD treatment

Phase 2 Type 2 Diabetes Trial

In participants with type 2 diabetes, retatrutide at 12mg reduced HbA1c by -2.02% and body weight by -16.9% over 36 weeks. These glycemic improvements were comparable to or better than existing GLP-1 receptor agonists.

Based on clinical trial protocols:

Parameter	Detail
Route	Subcutaneous injection
Frequency	Once weekly
Starting dose	Titrated from low doses (e.g., 1-2 mg)
Maintenance doses studied	4 mg, 8 mg, 12 mg weekly
Titration	Dose escalated every 4 weeks to target dose

Dose titration is essential with retatrutide (as with all GLP-1 class drugs) to minimize gastrointestinal side effects. Starting at full dose without titration significantly increases nausea, vomiting, and diarrhea.

Retatrutide is not yet commercially available. For research applications involving lyophilized peptide, use the peptide calculator for reconstitution volumes. For detailed information, visit the retatrutide dosage guide.

Side effects observed in Phase 2 clinical trials were consistent with the GLP-1 drug class:

• Nausea (26–45%): The most common side effect, typically worst during dose titration and diminishing over time
• Diarrhea (15–22%): Usually mild to moderate and transient
• Vomiting (8–18%): More common at higher doses and during titration
• Decreased appetite (10–15%): Pharmacological effect contributing to weight loss
• Constipation (8–12%): Related to slowed gastric motility from GLP-1 activation
• Injection site reactions (5–10%): Mild erythema or discomfort

Discontinuation rates due to adverse events were relatively low (5–10% across dose groups), suggesting most side effects were manageable. No serious safety signals were identified in Phase 2, though larger Phase 3 trials will provide more comprehensive safety data.

As with all GLP-1 class drugs, there are theoretical concerns about pancreatitis and thyroid C-cell tumors (observed in rodents with GLP-1 agonists). These risks will be further characterized in Phase 3. Read more in the retatrutide side effects guide.

Feature	Retatrutide	Tirzepatide	Semaglutide
Targets	GLP-1 + GIP + glucagon	GLP-1 + GIP	GLP-1 only
Max weight loss (trials)	~24%	~22%	~16%
FDA status	Phase 3 trials	Approved (Mounjaro/Zepbound)	Approved (Ozempic/Wegovy)
Liver fat reduction	~82%	~50%	~30%
Frequency	Once weekly	Once weekly	Once weekly
Developer	Eli Lilly	Eli Lilly	Novo Nordisk

Retatrutide's triple-agonist mechanism appears to provide incrementally greater weight loss and substantially greater liver fat reduction compared to dual- and single-agonist drugs. Whether these benefits are maintained in larger Phase 3 trials and whether the safety profile remains acceptable at scale are the key outstanding questions. For more context, see the peptides for weight loss guide and the complete GLP-1 guide.

Other GLP-1 Compounds

• Survodutide: A dual GLP-1/glucagon agonist (without GIP). Phase 2 data shows 18.7% weight loss and FDA Breakthrough Therapy designation for MASH (Sanyal et al., NEJM 2024).
• Mazdutide: Another dual GLP-1/glucagon agonist (Eli Lilly/Innovent), primarily trialed in China.
• Cagrilintide (CagriSema): An amylin+semaglutide combination achieving 22.7% weight loss through complementary satiety pathways.
• Liraglutide (Saxenda): The first-generation daily GLP-1 agonist (~8% weight loss).