Semaglutide vs Tirzepatide
vs Retatrutide
Every GLP-1 class fat loss compound compared side by side — clinical weight loss data, mechanism differences, titration protocols, and which one is right for your goals.
| Compound | Mechanism | Peak Weight Loss | Trial Data | Half-Life | Difficulty |
|---|---|---|---|---|---|
Semaglutide Single | GLP-1 agonist | 14.9% body weight | STEP 1 (68 wk) | 7 days | Beginner |
Tirzepatide Dual | GLP-1 + GIP agonist | 22.5% body weight | SURMOUNT-1 (72 wk) | 5 days | Intermediate |
Retatrutide Triple | GLP-1 + GIP + GCG agonist | 24%+ body weight | Phase 2 TRIUMPH (24 wk) | ~7 days | Advanced |
CagriSema Dual (GLP-1 + amylin) | GLP-1 + amylin agonist | ~15.6% body weight | REDEFINE (Phase 2) | 7 days (both) | Intermediate |
Why agonism count matters
Each additional receptor agonism adds an independent appetite and metabolic mechanism. More pathways means more total effect — but also more complexity and side effect burden.
GLP-1 receptor
Slows gastric emptying, signals satiety to the brain, stimulates insulin release
Active in: All four compounds
GIP receptor
Adds a second satiety pathway; enhances insulin response; appears to amplify GLP-1 effects rather than simply duplicate them
Active in: Tirzepatide, Retatrutide
Glucagon receptor
Raises basal metabolic rate via thermogenesis (~5–8% BMR increase); drives hepatic fat mobilization and liver fat reduction
Active in: Retatrutide only
Semaglutide
GLP-1 agonist
Peak weight loss
14.9%
Trial
STEP 1 (68 wk)
Half-life
7 days
Start dose
0.25mg/week
Most data — longest human use record
Simplest titration schedule
Well-understood side effect profile
Best starting point for GLP-1 beginners
Lower weight loss ceiling vs dual/triple agonists
No GIP or glucagon pathway activation
Tirzepatide
GLP-1 + GIP agonist
Peak weight loss
22.5%
Trial
SURMOUNT-1 (72 wk)
Half-life
5 days
Start dose
2.5mg/week
22.5% mean weight loss — best of any approved drug at launch
GIP activation adds a second appetite suppression pathway
Better metabolic markers (HbA1c, insulin sensitivity)
Weekly injection — same convenience as semaglutide
More complex titration than semaglutide
Slightly higher GI burden at equivalent doses
Retatrutide
GLP-1 + GIP + GCG agonist
Peak weight loss
24%+
Trial
Phase 2 TRIUMPH (24 wk)
Half-life
~7 days
Start dose
0.5–1mg/week
Highest weight loss in class — glucagon adds thermogenesis
Raises basal metabolic rate (~5–8%) via glucagon receptor
50–60% liver fat reduction (TRIUMPH data)
Three independent mechanisms working simultaneously
Phase 3 only — not yet an approved pharmaceutical
Most complex titration; highest GI side effect burden
Not appropriate for beginners
CagriSema
GLP-1 + amylin agonist
Peak weight loss
~15.6%
Trial
REDEFINE (Phase 2)
Half-life
7 days (both)
Start dose
0.16mg cagri + 0.25mg sema
Amylin pathway is completely distinct from GLP-1/GIP
Combined weekly injection for both components
Unique postprandial glucose and gastric emptying effects
Suitable for GLP-1 responders wanting a second mechanism
Weight loss similar to semaglutide alone — amylin adds modest incremental benefit
Requires titrating two compounds independently
Which compound should you choose?
If you…
First time using a GLP-1 peptide
→ Semaglutide 5mg
Most data, simplest titration, best starting point for tolerance assessment before stepping up.
If you…
Want maximum fat loss, experienced with GLP-1s
→ Tirzepatide 15mg
22.5% mean weight loss in SURMOUNT-1 — 7–8 percentage points more than semaglutide. Dual mechanism with manageable titration.
If you…
Want maximum possible efficacy, advanced user
→ Retatrutide 10mg
Triple agonism adds thermogenesis via glucagon receptor. Highest weight loss data in the class. Requires prior GLP-1 experience.
If you…
Plateaued on semaglutide, want second mechanism without GIP
→ CagriSema
Adds amylin pathway — completely distinct from GLP-1/GIP. Both compounds weekly-dosed for simple combination protocol.
If you…
Want fat loss AND lean mass preservation
→ Tirzepatide + CJC-1295/Ipamorelin
The Advanced Body Recomp Stack — dual-agonist fat loss paired with GH secretagogue for simultaneous body recomposition.
Want the full clinical breakdown of every GLP-1 compound?
Full Fat Loss Peptide Guide