Peptide Comparison
SetmelanotidevsSemaglutide
Targeted MC4R agonist for rare genetic obesity caused by melanocortin pathway defects
The revolutionary once-weekly GLP-1 medication that helps your body feel full faster and longer, leading to significant weight loss while also protecting your heart—FDA approved and backed by some of the largest clinical trials in obesity medicine history.
At a Glance
Quick
comparison
Dose Range
Setmelanotide
0.5 mg–3 mg mg
Semaglutide
0.25–2.4 mg
Frequency
Setmelanotide
Once daily
Semaglutide
Once weekly
Administration
Setmelanotide
subcutaneous injection
Semaglutide
Subcutaneous injection
Cycle Length
Setmelanotide
Ongoing/indefinite
Semaglutide
Ongoing/indefinite
Onset Speed
Setmelanotide
Moderate (1-2 weeks)
Semaglutide
Moderate (1-2 weeks)
Evidence Level
Setmelanotide
Strong human trials (Phase 3 or FDA approved)
Semaglutide
Strong human trials (Phase 3 or FDA approved)
Efficacy
Benefit
ratings
Weight Management
Metabolic Health
Quality of Life
Weight Loss
Appetite Control
Heart Protection
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
Semaglutide
Molecular Formula
C187H291N45O59
Molecular Weight
4113.58 g/mol
Half-Life
Approximately 7 days (168 hours)
Bioavailability
89% (subcutaneous); 0.4-1% (oral, with absorption enhancer)
CAS Number
910463-68-2
Protocols
Dosing
tiers
Setmelanotide
Semaglutide
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.
Semaglutide
People with Obesity Seeking Significant Weight Loss
If your BMI is 30 or higher (or 27+ with weight-related health conditions), semaglutide is currently one of the most effective non-surgical weight loss options available. Clinical trials show average weight loss of 15% of body weight—that's 30+ pounds for someone starting at 200 pounds.
Those Who've Struggled with Diet and Exercise Alone
Semaglutide works by changing the biological signals that drive hunger and cravings. If you've tried to lose weight through willpower alone and found yourself constantly battling hunger, this medication addresses that underlying biology rather than just telling you to eat less.
People with Type 2 Diabetes Needing Better Control
Originally developed for diabetes, semaglutide excellently controls blood sugar while also promoting weight loss—addressing two major health concerns simultaneously. It can often allow people to reduce or eliminate other diabetes medications.
Individuals at High Cardiovascular Risk
The SELECT trial proved that semaglutide reduces heart attacks, strokes, and cardiovascular death by 20% in people with obesity and existing heart disease—even without diabetes. It's one of the few weight loss medications proven to improve hard cardiovascular outcomes.
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
Semaglutide
Common
- Nausea
- Constipation or Diarrhea
- Decreased Appetite
- Vomiting
Uncommon
- Gallbladder Problems
- Hair Loss (Telogen Effluvium)
Serious
- Pancreatitis
- Thyroid Tumors (Theoretical Risk)
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)
Semaglutide
Evidence Level
Strong human trials (Phase 3 or FDA approved)
FDA Status
FDA approved for this use
Safety Overview
Semaglutide has been studied in over 20,000 participants across multiple large clinical trials, making it one of the most thoroughly researched weight loss medications available. The FDA approved it after rigorous review of safety data. While GI side effects are common (especially early on), serious side effects are rare. The SELECT trial showed it actually reduces cardiovascular events, adding a safety benefit beyond just weight loss.
Contraindications
- xPersonal or family history of medullary thyroid carcinoma (MTC)
- xMultiple Endocrine Neoplasia syndrome type 2 (MEN2)
- xHistory of serious allergic reaction to semaglutide
- xCurrent or recent pancreatitis
- xPregnancy or planning to become pregnant
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 Semaglutide if...
- Significant weight loss
- Long-term weight management
- Cardiovascular risk reduction
- Blood sugar control