Peptide Comparison
SetmelanotidevsRetatrutide
Targeted MC4R agonist for rare genetic obesity caused by melanocortin pathway defects
The world's first triple-action weight loss peptide that simultaneously activates three hormone receptors—GIP, GLP-1, and glucagon—delivering unprecedented weight loss results of up to 24% body weight in clinical trials.
At a Glance
Quick
comparison
Dose Range
Setmelanotide
0.5 mg–3 mg mg
Retatrutide
1–12 mg
Frequency
Setmelanotide
Once daily
Retatrutide
Once weekly
Administration
Setmelanotide
subcutaneous injection
Retatrutide
Subcutaneous injection
Cycle Length
Setmelanotide
Ongoing/indefinite
Retatrutide
12+ weeks
Onset Speed
Setmelanotide
Moderate (1-2 weeks)
Retatrutide
Moderate (1-2 weeks)
Evidence Level
Setmelanotide
Strong human trials (Phase 3 or FDA approved)
Retatrutide
Moderate human trials (Phase 1-2)
Efficacy
Benefit
ratings
Weight Management
Metabolic Health
Quality of Life
Weight Loss Power
Appetite Control
Technical Data
Compound
specifications
Setmelanotide
Molecular Formula
C49H68N18O9S2
Molecular Weight
1,117.3 Da
Half-Life
~11 hours
Bioavailability
~79% subcutaneous bioavailability
CAS Number
920014-72-8
Retatrutide
Molecular Formula
C221H342N46O68
Molecular Weight
4731 g/mol
Half-Life
~6 days (allows once-weekly dosing)
Bioavailability
High via subcutaneous injection
CAS Number
2381089-83-2
Protocols
Dosing
tiers
Setmelanotide
Retatrutide
Applications
Best
suited for
Setmelanotide
Treating obesity caused by confirmed POMC deficiency mutations
Setmelanotide is particularly well-suited for individuals focused on treating obesity caused by confirmed pomc deficiency mutations. Research and clinical experience suggest meaningful benefits in this area when used as part of a comprehensive treatment approach.
Managing obesity from PCSK1 or LEPR genetic defects
Setmelanotide is particularly well-suited for individuals focused on managing obesity from pcsk1 or lepr genetic defects. Research and clinical experience suggest meaningful benefits in this area when used as part of a comprehensive treatment approach.
Reducing hyperphagia and body weight in Bardet-Biedl syndrome
Setmelanotide is particularly well-suited for individuals focused on reducing hyperphagia and body weight in bardet-biedl syndrome. Research and clinical experience suggest meaningful benefits in this area when used as part of a comprehensive treatment approach.
Addressing early-onset severe obesity with identified melanocortin pathway mutations
Setmelanotide is particularly well-suited for individuals focused on addressing early-onset severe obesity with identified melanocortin pathway mutations. Research and clinical experience suggest meaningful benefits in this area when used as part of a comprehensive treatment approach.
Retatrutide
Significant Obesity Management
If you need to lose a substantial amount of weight, retatrutide is showing unprecedented results. Phase 2 trials demonstrated average weight loss of 24% at the highest dose—that's nearly 60 pounds for someone weighing 250 lbs. No other medication has matched this.
Type 2 Diabetes with Obesity
Retatrutide tackles both problems at once. It dramatically improves blood sugar control (HbA1c reductions of up to 2%) while delivering major weight loss. The dual benefit makes it especially valuable for diabetics struggling with weight.
Metabolic Syndrome Warriors
If you're dealing with the cluster of issues that includes high blood sugar, excess belly fat, abnormal cholesterol, and high blood pressure, retatrutide's triple mechanism attacks multiple aspects of metabolic dysfunction simultaneously.
Fatty Liver Disease (MASLD)
Early research shows retatrutide may significantly reduce liver fat. For people with non-alcoholic fatty liver disease, this peptide offers hope through weight loss plus direct metabolic improvements that benefit liver health.
Safety Profile
Side
effects
Setmelanotide
Common
- Skin Hyperpigmentation
- Injection Site Reactions
- Nausea
- Diarrhea
Uncommon
- Hair Color Darkening and Nevus Changes
Serious
- Depression and Suicidal Ideation
Retatrutide
Common
- Nausea
- Diarrhea
- Constipation
- Decreased appetite
Uncommon
- Increased heart rate
- Injection site reactions
Serious
- Pancreatitis
- Gallbladder problems
Research Status
Safety
& evidence
Setmelanotide
Evidence Level
Strong human trials (Phase 3 or FDA approved)
FDA Status
FDA approved for this use
Safety Overview
Setmelanotide demonstrates favorable tolerability in Phase 3 trials with safety data from over 200 patients across POMC, PCSK1, LEPR-deficient, and Bardet-Biedl syndrome populations. The most common adverse effect is dose-dependent skin hyperpigmentation (>60% of patients) due to off-target MC1R activation on melanocytes—a manageable, reversible pharmacological effect rather than true toxicity. Serious psychiatric adverse events including depression and suicidal ideation require baseline mental health screening and ongoing monitoring in all patients.
Contraindications
- xKnown hypersensitivity to setmelanotide or any excipients
- xObesity not caused by POMC, PCSK1, LEPR deficiency or Bardet-Biedl syndrome
- xPatients without genetic confirmation of melanocortin pathway mutations
- xUse during pregnancy (animal studies suggest potential fetal harm)
Retatrutide
Evidence Level
Moderate human trials (Phase 1-2)
FDA Status
Research compound
Safety Overview
Retatrutide has shown a generally favorable safety profile in Phase 1 and Phase 2 clinical trials involving over 600 participants. Most side effects are gastrointestinal and tend to improve over time. The medication appears well-tolerated when doses are increased gradually. No major safety signals have emerged, but larger Phase 3 trials are still ongoing.
Contraindications
- xPersonal or family history of medullary thyroid carcinoma (MTC)
- xMultiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- xPregnancy or planning to become pregnant
- xHistory of severe pancreatitis
- xKnown allergy to GLP-1 receptor agonists
Decision Guide
Which is
right for you?
Choose Setmelanotide if...
- Treating obesity caused by confirmed POMC deficiency mutations
- Managing obesity from PCSK1 or LEPR genetic defects
- Reducing hyperphagia and body weight in Bardet-Biedl syndrome
- Addressing early-onset severe obesity with identified melanocortin pathway mutations
Choose Retatrutide if...
- Significant weight loss
- Type 2 diabetes management
- Metabolic health improvement
- Body composition optimization