Key Points
- Three receptors: Retatrutide targets GLP-1, GIP, and glucagon receptors
- Phase 2 results: Up to 24% weight loss at 48 weeks (vs. ~17% for semaglutide)
- Glucagon paradox: Adding a "sugar-raising" hormone actually enhances weight loss
- Phase 3 ongoing: Larger trials will determine if benefits hold up
- Not yet approved: Likely 2026-2027 for potential FDA decision
The Evolution: Single → Dual → Triple
| Generation | Drug | Receptors | Max Weight Loss |
|---|---|---|---|
| Single Agonist | Semaglutide (Ozempic/Wegovy) | GLP-1 only | ~15-17% |
| Dual Agonist | Tirzepatide (Mounjaro/Zepbound) | GLP-1 + GIP | ~21-22% |
| Triple Agonist | Retatrutide (Phase 3) | GLP-1 + GIP + Glucagon | ~24% (Phase 2) |
The Three Receptors: What Each Does
1. GLP-1 Receptor
The foundation of current obesity medications:
- Reduces appetite via brain signaling
- Slows gastric emptying
- Increases insulin secretion (glucose-dependent)
- Cardiovascular protection
2. GIP Receptor
The "twincretin" addition in tirzepatide:
- Enhances insulin secretion
- May amplify GLP-1 effects on appetite
- Improves fat tissue metabolism
- Reduces GI side effects (compared to GLP-1 alone)
3. Glucagon Receptor
The surprising addition—glucagon traditionally raises blood sugar:
- Increases energy expenditure
- Promotes fat breakdown in liver
- Reduces food intake (separate mechanism from GLP-1)
- Improves fatty liver disease
The Glucagon Paradox
Adding glucagon agonism seems counterintuitive—glucagon raises blood sugar. Here's why it works:
The Science
Yes, glucagon raises glucose by stimulating the liver to release stored sugar. This is how glucagon rescue works in hypoglycemia.
But glucagon also:
- Increases metabolic rate (energy expenditure)
- Promotes lipolysis (fat breakdown)
- Reduces appetite via central mechanisms
- Improves liver fat metabolism
The balance: When combined with GLP-1 and GIP (which enhance insulin), the glucose-raising effect is counteracted while the metabolic benefits are preserved.
Phase 2 Trial Results
Clinical Data
Retatrutide Phase 2 Results (2023)
Population: 338 adults with obesity (BMI ≥30 or ≥27 with comorbidity)
Duration: 48 weeks
Key results at highest dose (12mg):
Duration: 48 weeks
Key results at highest dose (12mg):
- Mean weight loss: 24.2%
- Proportion losing ≥15%: 87%
- Proportion losing ≥20%: 73%
- Proportion losing ≥25%: 54%
For context: STEP 1 (semaglutide 2.4mg) achieved 14.9% at 68 weeks.
24%
weight loss at 48 weeks (12mg)
87%
achieved ≥15% weight loss
54%
achieved ≥25% weight loss
Potential Advantages of Triple Agonism
1. Greater Weight Loss
- Phase 2 suggests ~24% vs. ~17% for semaglutide
- More patients reaching clinically meaningful thresholds
- Potentially approaching bariatric surgery results
2. Enhanced Liver Benefits
- Glucagon agonism particularly effective for fatty liver
- May exceed current GLP-1 effects on MASH
- Phase 2 showed dramatic liver fat reduction
3. Increased Energy Expenditure
- Glucagon increases metabolic rate
- May partially offset metabolic adaptation to weight loss
- Could mean less weight regain
Safety Considerations
Phase 2 Safety Data
- GI side effects: Similar to other GLP-1s (nausea, vomiting, diarrhea)
- No major safety signals: In Phase 2 (larger trials will provide more data)
- Glucose: Did not cause hyperglycemia despite glucagon component
- Heart rate: Some increase (needs monitoring in Phase 3)
Theoretical Concerns
- Glucagon and glucose: Need to ensure balance is maintained in diabetic patients
- Liver effects: Glucagon activates liver; need long-term safety data
- Muscle mass: Does increased metabolic rate affect lean mass preservation?
Phase 3 Program
Eli Lilly is running the TRIUMPH Phase 3 program:
| Trial | Population | Status |
|---|---|---|
| TRIUMPH-1 | Obesity without diabetes | Ongoing |
| TRIUMPH-2 | Obesity with type 2 diabetes | Ongoing |
| TRIUMPH-3 | Obesity maintenance | Planned |
| TRIUMPH-4 | Cardiovascular outcomes | Planned/Ongoing |
Timeline and Availability
- Phase 3 completion: Expected 2025-2026
- Potential FDA submission: 2026
- Potential approval: 2026-2027 (if trials successful)
- Brand name: Not yet announced
How It Compares
| Feature | Semaglutide | Tirzepatide | Retatrutide |
|---|---|---|---|
| Receptors | GLP-1 | GLP-1 + GIP | GLP-1 + GIP + Glucagon |
| Max weight loss | ~17% | ~22% | ~24% (Phase 2) |
| FDA approved | Yes (2021) | Yes (2023) | No (Phase 3) |
| Dosing | Weekly | Weekly | Weekly (expected) |
| Liver fat effect | Good | Better | Potentially best |
Other Triple Agonists in Development
Retatrutide isn't alone—other companies are pursuing triple agonism:
- Eli Lilly: Retatrutide (most advanced)
- Novo Nordisk: Exploring combinations
- Hanmi Pharmaceutical: HM15211 (early stage)
- Others: Various academic and biotech programs
The Bottom Line
Retatrutide represents the next evolution in metabolic medications: triple agonism targeting GLP-1, GIP, and glucagon receptors simultaneously. Phase 2 results showed remarkable 24% weight loss at 48 weeks, exceeding what's been achieved with current medications. The addition of glucagon agonism—counterintuitive since glucagon raises blood sugar—appears to enhance weight loss through increased energy expenditure and fat metabolism, while the GLP-1 and GIP components prevent glucose elevation. If Phase 3 trials confirm these results and safety profile, retatrutide could become the most effective pharmaceutical weight loss treatment ever approved. However, it's still investigational—FDA approval is likely 2026-2027 at earliest if trials succeed. For now, semaglutide and tirzepatide remain the proven options.
Sources
- Jastreboff AM, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity. N Engl J Med. 2023.
- Rosenstock J, et al. Retatrutide Phase 2 in Type 2 Diabetes. Lancet. 2023.
- Coskun T, et al. Retatrutide, a GGG Triagonist. Cell Metab. 2022.
- Finan B, et al. A Rationale for Glucagon-Based Obesity Therapy. Nat Rev Drug Discov. 2016.
- Müller TD, et al. Glucagon-Like Peptide 1 (GLP-1). Mol Metab. 2019.
- Nauck MA, D'Alessio DA. Tirzepatide, a Dual GIP/GLP-1 Receptor Agonist. Lancet. 2022.
- Wilding JPH, et al. STEP 1 Trial. N Engl J Med. 2021.
- Jastreboff AM, et al. SURMOUNT-1 Trial. N Engl J Med. 2022.
- ClinicalTrials.gov. TRIUMPH Program Registration. 2024.
- Eli Lilly. Retatrutide Press Releases. 2023-2024.
- Day JW, et al. A New Glucagon and GLP-1 Co-Agonist. Nat Chem Biol. 2009.
- Ambery P, et al. Glucagon Receptor Agonism in NAFLD. Cell Metab. 2018.