Triple vs dual agonism: what the third receptor changes
Every row cites its source. Where a cell reflects our own reading of the evidence rather than an external source, the row says so.
| Dimension | Triple | Dual | Source |
|---|---|---|---|
| Receptors engaged | GIP + GLP-1 + glucagon (balanced GCGR/GLP-1R, greater GIPR activity in vitro) | GIP + GLP-1 | source |
| Primary weight mechanism | Reduced intake (GIP/GLP-1) PLUS increased energy expenditure (glucagon), shown in obese mice | Reduced intake; appetite regulation via brain incretin receptors | source |
| Human evidence for the added mechanism | Largely preclinical per a 2026 IUPHAR review; dedicated human energy-expenditure trial completed, results not posted | Extensive labeled human data for the dual mechanism | source |
| Liver fat | MASLD substudy: liver fat -82.4% (12 mg) at 24 weeks; 86% reached normal liver fat | Reductions reported in this class; no equivalent published substudy with these magnitudes | source |
| Cost of the third receptor (signals) | Dose-dependent heart-rate increase peaking at week 24; highest adverse-event risk in network meta-analysis | GI-led profile per approved labels | source |
| Structural understanding | Cryo-EM structures of retatrutide at all three receptors published 2024 | Established structural literature for incretin receptors | source |
| Regulatory maturity | No approved triple agonist exists; retatrutide is investigational | Tirzepatide approved since 2022 | source |