COMPOUND

Compounds / GLP-1 agonists

Orforglipron

Orforglipron (Foundayo / LY3502970)

GLP-1 agonists Oral FDA approved

First oral non-peptide small-molecule GLP-1 receptor agonist. FDA approved as Foundayo (April 1, 2026) for chronic weight management in adults: uniquely, with NO food, water, or fasting restrictions (unlike Rybelsus). Phase 3 ATTAIN-1 (NEJM 2025): -11.2% weight loss at 36mg over 72 weeks. Beat oral semaglutide head-to-head in T2D (ACHIEVE-3 Feb 2026). Solves the operational nightmare of Rybelsus's 30-min fasting window.

At a glance

Half-life
~48 h Single-dose mean t½ 24.6-35.3h; multiple-dose (steady-state) t½ 48.1-67.5h. Supports once-daily oral dosing. Tmax 4-8h post oral dose. Bioavailability ~30-40%. Food has minimal impact on AUC and Cmax (up to 24% lower with food, but tmax and t½ unchanged).
Routes
Oral
Evidence base
3 studies 3 human

Mechanism

Non-peptide small molecule that binds and activates the GLP-1 receptor through an allosteric site distinct from the orthosteric site bound by peptide GLP-1 RAs. Despite different binding mode, downstream signaling cascade (cAMP, beta-arrestin recruitment, insulin secretion) is similar to peptide GLP-1 RAs. Phase 1a established t½ 24.6-67.5h and dose-proportional PK. Key advantages of small-molecule design: oral bioavailability without absorption enhancers (no SNAC needed), no food/water restrictions, cheaper to manufacture, stable in standard tablet formulation. Pharmacological effects same as peptide GLP-1 RAs: glucose-dependent insulin secretion, glucagon suppression, gastric emptying delay, central appetite suppression. Phase 2: -8.6% to -12.6% body weight across doses. ATTAIN-1 phase 3 (n=3,127): 36mg -11.2% vs -2.1% placebo at 72 weeks.

Dosing

Any amounts shown here are reported from published studies only. 3 of 3 catalogued studies involved human subjects. COMPOUND does not publish its own dosing guidance.

Where a study reports an amount, it appears in that study's entry below, attributed to the source.

Published evidence

  1. Human RCT 2025

    Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment (ATTAIN-1)

    Jastreboff AM, Frias JP, Garcia-Salas R, et al. NEJM

    Phase 3 obesity, n=3,127, 72 weeks: 6mg -7.5%, 12mg -8.4%, 36mg -11.2% vs placebo -2.1%. 54.6% of 36mg arm had ≥10% loss; 36% had ≥15%; 18.4% had ≥20%.

    PMID 40960239

  2. Human RCT 2023

    Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1a single- and multiple-ascending-dose study

    Pratt E, Ma X, Liu R, et al. Diabetes Obes Metab

    Phase 1a healthy: t½ 24.6-67.5h depending on dose/timing. Dose-proportional PK. Well tolerated.

    PMID 37344954

  3. Human RCT 2023

    Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity

    Wharton S, Blevins T, Connery L, et al. NEJM

    Phase 2 obesity, 36 weeks: -8.6% to -12.6% across 12-45mg doses vs placebo -2.0%. Foundation for phase 3.

    PMID 37356432

Reported side effects

Nausea
Very common Moderate · Phase 3 ATTAIN-1: nausea common, comparable to injectable GLP-1s. Dose-dependent, escalation-related.
Vomiting
Common Moderate · Class GI profile.
Diarrhea
Common Mild · Class effect.
Constipation
Common Mild · Class effect.
Decreased appetite
Very common Mild · Wanted effect.
Headache
Occasional Mild · Class effect.
Hepatic enzyme elevation
Occasional Moderate · Small-molecule organ-specific concern. Phase 3 monitoring showed no major hepatotoxicity signal but FDA label may include hepatic monitoring.
Hypoglycemia
Rare Moderate · Glucose-dependent mechanism; rare unless combined with SU/insulin.
Thyroid C-cell tumors
Rare Serious · BOXED WARNING expected (class effect from rodent carcinogenicity studies on GLP-1 RAs). Contraindicated with personal/family hx of MTC or MEN-2.

Interactions

  • Insulin or sulfonylurea Synergy

    GLP-1 mechanism + insulin/SU. Hypoglycemia risk.

  • Oral medications (general) Absorption interference

    GLP-1 receptor activation slows gastric emptying, but to a lesser degree than injectable peptide GLP-1 RAs (oral small molecule has lower peak exposures despite similar AUC). May modestly affect oral drug absorption.

  • Semaglutide (SC) Redundant

    Overlapping GLP-1 agonism. Concurrent GLP-1 RA not recommended.

  • Semaglutide (Oral) Redundant

    Both are oral GLP-1 RAs: additive effects, no benefit.

Storage

Standard tablet: room temperature storage. Specifics in PI.