Semaglutide vs Retatrutide: GLP-1 Selective vs Triple Agonist

Semaglutide and retatrutide are often grouped as “GLP-1 peptides,” but they sit at opposite ends of the incretin-agonist spectrum: semaglutide is a selective GLP-1 receptor agonist, and retatrutide is a triple agonist activating GIP, GLP-1 and glucagon receptors.

Side by side

Property	Semaglutide	Retatrutide
Receptor target	GLP-1 only	GIP + GLP-1 + glucagon
Class	Selective agonist	Triple agonist
CAS	910463-68-2	2381089-83-2
Molecular formula	C187H291N45O59	C221H342N46O68
Molecular weight	4113.6 g/mol	4757.7 g/mol
Structural anchor	Aib-8 + C18 fatty acid	C20 fatty diacid (albumin-binding)
Vial size	5 mg	10 mg
Purity	99.4%	99.5%

Mechanism differences

• Semaglutide isolates the GLP-1 pathway: appetite signaling, insulin secretion, slowed gastric emptying. Its Aib-8 substitution resists DPP-4, and the C18 chain binds albumin for a long half-life.
• Retatrutide adds GIP agonism (incretin + fat-tissue signaling, like tirzepatide) and glucagon agonism (energy expenditure via thermogenesis and lipid oxidation) on top of GLP-1.

In research, semaglutide is the clean control for GLP-1-specific effects; retatrutide is the reference compound for studying the additive energy-expenditure arm.

Trial context

Semaglutide has an extensive published evidence base (STEP/SUSTAIN programs). Retatrutide’s phase 2 data showed dose-dependent weight reduction, with the largest effects at 8-12 mg weekly, and it has advanced into the phase 3 TRIUMPH program.

Vial math comparison

Both are lyophilized research peptides stored at -20°C and reconstituted with bacteriostatic water:

• Semaglutide 5 mg + 1 mL water = 5 mg/mL stock
• Retatrutide 10 mg + 2 mL water = 5 mg/mL stock

Use the reconstitution calculator for any target dose. Also compare: semaglutide vs tirzepatide and retatrutide vs tirzepatide.