The incretin-agonist class has expanded from selective GLP-1 receptor analogues to dual and triple agonists in less than a decade. Three molecules dominate current research: semaglutide (GLP-1), tirzepatide (GLP-1/GIP), and retatrutide (GLP-1/GIP/glucagon). They are not interchangeable. This overview compares the published research signal across receptor profile, half-life, and metabolic endpoints.
Semaglutide — selective GLP-1 receptor agonist
Semaglutide is a long-acting GLP-1 receptor analogue with a fatty acid sidechain that enables albumin binding and a ~7-day plasma half-life. Phase 3 weight-loss research (STEP programme) reports approximately 14.9% body weight reduction at 68 weeks in adults with obesity (Wilding et al., NEJM 2021). It remains the longest-validated reference compound in the class.
Tirzepatide — dual GLP-1/GIP receptor agonist
Tirzepatide co-activates GLP-1 and GIP receptors with a slight imbalance favouring GIP. The SURMOUNT-1 trial showed approximately 22.5% body weight reduction at 72 weeks at the 15 mg dose (Jastreboff et al., NEJM 2022) — a step-up of roughly 7 percentage points over the strongest single-agonist data. Half-life is ~5 days.
Retatrutide — triple GLP-1/GIP/glucagon receptor agonist
Retatrutide adds glucagon receptor activation to the GLP-1/GIP backbone. The phase 2 publication (Jastreboff et al., NEJM 2023) reports 24.2% body weight reduction at 48 weeks at the 12 mg weekly dose. The glucagon arm appears to drive an additional energy expenditure increase rather than a stronger appetite suppression. Long-term safety remains under phase 3 investigation.
Side-by-side
| Compound | Receptors | Half-life | Peak weight loss (research) |
|---|---|---|---|
| Semaglutide | GLP-1 | ~7 days | ~14.9% at 68 weeks |
| Tirzepatide | GLP-1 + GIP | ~5 days | ~22.5% at 72 weeks |
| Retatrutide | GLP-1 + GIP + glucagon | ~6 days | ~24.2% at 48 weeks (phase 2) |
Mechanistic implications
Each receptor adds a distinct physiological lever. GLP-1 drives glucose-dependent insulin secretion and central appetite suppression. GIP enhances insulin response and may protect against GLP-1-driven nausea via central pathways. Glucagon receptor activation lifts resting energy expenditure and hepatic lipid oxidation. The triple agonist therefore acts on both energy intake and energy output simultaneously.
Research handling notes
All three are supplied lyophilised. Reconstitution in bacteriostatic water at 5–10 mg/mL is typical for stability studies. Refrigerate after reconstitution and use within four weeks for reliable potency data. CoA verification is non-negotiable — these molecules require accurate HPLC purity assessment and mass-spec confirmation due to their long peptide sequences and synthesis complexity.
Chempeptides supplies all three with batch-specific CoA — see the research catalogue for current availability. Research use only.