Overview
Retatrutide (LY3437943) is an investigational triple hormone receptor agonist developed by Eli Lilly. It represents the next evolution in incretin-based therapy by targeting three receptors: GIP, GLP-1, and glucagon. Phase 2 trial results have generated significant excitement, demonstrating weight loss efficacy exceeding any approved medication.
The compound is currently in Phase 3 clinical trials (TRIUMPH program) with results expected in 2024-2025. If approved, it could represent a paradigm shift in obesity treatment.
Mechanism of Action
Retatrutide activates three distinct receptor pathways:
GIP Receptor (Glucose-dependent Insulinotropic Polypeptide)
- Insulin secretion enhancement
- Beta-cell function support
- Adipose tissue effects
- Ratios: Full agonist activity
GLP-1 Receptor
- Appetite suppression via hypothalamic action
- Glucose-dependent insulin release
- Gastric emptying delay
- Cardiovascular protection
Glucagon Receptor (Novel Addition)
- Increased hepatic glucose output (counterbalanced by GLP-1/GIP)
- Enhanced energy expenditure
- Increased lipid oxidation
- Potential thermogenic effects
- May help preserve or increase resting metabolic rate
The glucagon component is theorized to prevent the metabolic adaptation (reduced metabolic rate) often seen with significant weight loss.
Research Summary
Phase 2 Trial (n=338)
48-Week Results in Adults with Obesity:
| Dose | Weight Loss | ≥15% Loss | ≥20% Loss |
|---|---|---|---|
| 1mg | -8.7% | 27% | - |
| 4mg | -17.1% | 63% | 43% |
| 8mg | -22.8% | 79% | 60% |
| 12mg | -24.2% | 83% | 63% |
| Placebo | -2.1% | 4% | 2% |
Key Findings
- Metabolic Rate: Less reduction in resting metabolic rate compared to GLP-1 only treatments
- Liver Fat: 82-86% reduction in liver fat content (vs 23% placebo)
- HbA1c: 1.3-1.5% reduction in participants with prediabetes
- Blood Pressure: Systolic BP reduced by 7-10 mmHg
- Lipids: Significant improvements in triglycerides and cholesterol
Ongoing Phase 3 Trials (TRIUMPH Program)
- TRIUMPH-1: Obesity without diabetes
- TRIUMPH-2: Obesity with type 2 diabetes
- TRIUMPH-3: MASH/NASH (metabolic liver disease)
- TRIUMPH-4: Cardiovascular outcomes
Pharmacokinetics
| Parameter | Estimated Value |
|---|---|
| Half-life | ~6 days |
| Dosing frequency | Once weekly |
| Bioavailability | Under investigation |
| Time to peak | Under investigation |
| Metabolism | Proteolytic degradation |
| Steady state | ~4-5 weeks |
Note: Full PK data pending Phase 3 completion
Common Protocols
Note: Retatrutide is investigational and not approved for use. The following represents protocols from published trials only.
Phase 2 Trial Dosing
Escalation Schedule:
- Weeks 1-4: 2mg weekly
- Weeks 5-8: 4mg weekly
- Weeks 9-12: Escalate to target dose
- Maintenance: 4mg, 8mg, or 12mg weekly
Higher doses (8mg and 12mg) showed similar efficacy, suggesting 8mg may be the optimal balance of efficacy and tolerability.
Administration
Trial Protocol
- Subcutaneous injection once weekly
- Injection sites: Abdomen, thigh, upper arm
- Administered same day each week
- With or without food
Storage (Anticipated)
- Refrigeration expected for unused product
- Specific guidelines pending approval
Side Effects
Common (From Phase 2 Data)
| Effect | Incidence (12mg) |
|---|---|
| Nausea | 25% |
| Diarrhea | 23% |
| Vomiting | 16% |
| Constipation | 14% |
| Injection site reaction | 8% |
GI effects were dose-dependent and typically transient.
Notable Observations
- Discontinuation due to adverse events: 6% (12mg) vs 1% (placebo)
- GI tolerability appeared similar to tirzepatide
- No unexpected safety signals in Phase 2
Theoretical Concerns (Glucagon Component)
- Potential for hyperglycemia (mitigated by GLP-1/GIP)
- Cardiovascular effects (being studied in TRIUMPH-4)
- Bone density effects (unknown)
Interactions
Theoretical Interactions
- Insulin/sulfonylureas: Likely increased hypoglycemia risk
- Oral medications: Delayed absorption expected
- Warfarin: May require monitoring
Expected Contraindications (Pending)
- Personal/family history of MTC (based on GLP-1 class)
- MEN2 syndrome
- Severe GI disease
Note: Full interaction data pending Phase 3 completion and regulatory filing
Community Insights
Given investigational status, community experience is limited to clinical trial participants and off-label research use. The following should be considered highly preliminary.
Reported Observations
- Interest is extremely high in obesity/weight loss communities
- Some report obtaining from research chemical suppliers (not recommended)
- Anecdotal reports suggest strong appetite suppression
- "Glucagon component" discussed as potential advantage for metabolic adaptation
Anticipated Concerns
- Cost and insurance coverage (likely expensive initially)
- Supply availability
- Long-term safety data still accumulating
- Comparison to tirzepatide will be key question
References
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Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial. N Engl J Med. 2023;389(6):514-526. [PMID: 37366315]
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Rosenstock J, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet. 2023;402(10401):529-544. [PMID: 37385280]
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Eli Lilly. Press Release: Lilly's retatrutide achieved up to 24.2% body weight reduction at 48 weeks in adults with obesity in phase 2 study. June 2023.
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ClinicalTrials.gov. TRIUMPH Program (NCT05929066, NCT05872620, NCT05879042).
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Finan B, et al. Unimolecular Dual Incretins Maximize Metabolic Benefits in Rodents, Monkeys, and Humans. Sci Transl Med. 2013;5(209):209ra151.