Orforglipron

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%. FDA approved Foundayo on April 1, 2026 as a once-daily oral GLP-1 pill for chronic weight management; label dosing uses lower tablet strengths up to 17.2 mg and adds GLP-1 class warnings plus CYP3A4/OATP1B interaction cautions. Convenience advantage over oral semaglutide is significant — no fasting, no water restrictions. ATTAIN-MAINTAIN (Phase 3b, Nature Medicine 2026): after reaching a weight plateau, orforglipron maintained ~75-79% of prior weight reduction vs ~38-49% on placebo at week 52.

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

Foundayo tablets once daily: start 0.8 mg, then 2.5 mg after >=30 days, then 5.5 mg; may escalate to 9 mg, 14.5 mg, or 17.2 mg based on response/tolerability; no food/water restrictions

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
• https://doi.org/10.1038/s41591-026-04386-7
• https://clinicaltrials.gov/study/NCT06023095
• https://pubmed.ncbi.nlm.nih.gov/41870800/
• https://pubmed.ncbi.nlm.nih.gov/41948476/
• https://doi.org/10.1007/s11906-026-01374-7
• https://doi.org/10.3390/ijms27094137
• https://doi.org/10.1007/s40675-026-00373-z
• https://www.fda.gov/news-events/press-announcements/fda-approves-first-new-molecular-entity-under-national-priority-voucher-program
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2026/220934Orig1s000lbl.pdf

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