The science
Semaglutide, tirzepatide, and retatrutide are all incretin-based research compounds. Each one expands the receptor profile of the last — and changes what the molecule can do.
Pure GLP-1 agonist. Drives appetite suppression and slowed gastric emptying. The compound that proved incretin therapy worked at scale.
Adds GIP (glucose-dependent insulinotropic polypeptide) to the GLP-1 backbone. Better appetite reduction and metabolic flexibility than semaglutide in head-to-head trials. Generally better GI tolerability.
Adds the glucagon receptor — which raises energy expenditure rather than just suppressing appetite. The Phase 2 results show the largest weight loss reported by any incretin compound to date, with effects continuing past the 48-week mark.
Side-by-side. Numbers from published Phase 2 / Phase 3 trial results.
| Compound | Targets | Weight loss | Status |
|---|---|---|---|
| Semaglutide | GLP-1 | ≈ 15% in 68 weeks | FDA-approved (2017 / 2021) |
| Tirzepatide | GLP-1 + GIP | ≈ 21% in 72 weeks | FDA-approved (2022 / 2023) |
| Retatrutide | GLP-1 + GIP + Glucagon | ≈ 24% in 48 weeks (Phase 2) | Phase 3 (Eli Lilly) |
Trial references: STEP-1 (semaglutide, NEJM 2021), SURMOUNT-1 (tirzepatide, NEJM 2022), Jastreboff et al. (retatrutide Phase 2, NEJM 2023). Weight-loss figures are approximate mean change in body weight at top trial dose; individual research results vary.
GLP-1 agonists work primarily by suppressing appetite. They tell the brain you're full and slow down stomach emptying so you eat less.
Adding GIP (the second receptor) sharpens that effect and improves metabolic markers. Patients on tirzepatide consistently lose more weight than on semaglutide, with comparable or better tolerability.
The glucagon receptor is the new variable. Glucagon raises energy expenditure — your body burns more — rather than just reducing intake. Retatrutide combines all three. Phase 2 readouts show the largest weight loss reported by any incretin compound studied to date, and the curve was still trending downward at the trial endpoint.
For research, the practical question is which receptor profile fits the protocol. Single-target work? Semaglutide. Established dual-agonist? Tirzepatide. Frontier triple-target work? Retatrutide.
Both compounds, third-party tested, shipped monthly.