Rankings / Weight Loss — Incretins & Amylin
Orforglipron
Weight loss · Oral GLP-1 agonist (small molecule)
Tier B
What this is
ATTAIN-1 (n=3127, obesity, 72 wk): -11.2% mean weight loss with ≥10% loss in 54.6%. ATTAIN-2 (T2D + obesity): -10.5% at 36 mg. ACHIEVE-3 head-to-head vs oral semaglutide 14 mg: orforglipron 36 mg superior — A1c -2.2% vs -1.4%, weight -9.2% vs -5.3%. Convenience advantage over oral semaglutide is significant — no fasting, no water restrictions. Eli Lilly. Class-specific concern: ventricular arrhythmia risk in HFrEF (per GLP-1 RA class).
Mechanism
Small-molecule (non-peptide) GLP-1 receptor agonist; ~79% oral bioavailability; no food/water restrictions (unlike oral semaglutide); biased agonism — stimulates cAMP without β-arrestin recruitment, potentially reducing receptor desensitization
Dose & route
3-36 mg PO once daily; titrate up
Citations
- https://doi.org/10.1097/CRD.0000000000001139
- https://doi.org/10.1186/s40842-025-00245-5
- https://doi.org/10.1016/j.metop.2026.100463
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