Orforglipron
Also known as: LY3502970, Foundayo, Non-peptide oral GLP-1 receptor agonist, Small-molecule GLP-1 agonist
Overview
Orforglipron (brand name Foundayo, formerly LY3502970) is a first-in-class oral, non-peptide, small-molecule GLP-1 receptor agonist developed by Eli Lilly (originally discovered by Chugai Pharmaceutical and licensed by Lilly in 2018). It received FDA approval on April 1, 2026, for chronic weight management in adults with obesity or overweight with weight-related comorbidities — becoming the first approved GLP-1 pill that can be taken at any time of day without food or water restrictions. This differentiates it sharply from oral semaglutide (Rybelsus), which requires fasting and minimal water intake. Although not a peptide itself, orforglipron competes directly in the GLP-1 therapeutic space and represents a major advance in patient convenience. Phase 3 ATTAIN-1 showed 11.2% mean weight loss at 72 weeks (36 mg dose), and ATTAIN-2 showed 9.6% weight loss in patients with T2D. Lilly has submitted for regulatory approval in >40 countries.
Mechanism of Action
Orforglipron activates GLP-1 receptors through a non-peptide allosteric mechanism, enabling oral bioavailability without food restrictions. It enhances glucose-dependent insulin secretion, suppresses glucagon, slows gastric emptying, and engages hypothalamic satiety pathways. As a small molecule, it avoids proteolytic degradation in the GI tract and does not require absorption enhancers. This represents the first proof of concept that a small molecule can achieve full agonism of a complex peptide hormone receptor with clinical-grade efficacy.
Potential Benefits
- FDA-approved April 1, 2026 (brand name Foundayo) for obesity/overweight
- First GLP-1 pill with no food or water restrictions — taken any time of day
- ATTAIN-1: 11.2% mean weight loss at 72 weeks (36 mg); 54.6% of patients lost ≥10%
- ATTAIN-2: 9.6% mean weight loss in T2D patients at 72 weeks (36 mg)
- ATTAIN-MAINTAIN: Maintains near-full weight loss after transitioning from Wegovy/Zepbound
- Up to 1.66% HbA1c reduction in T2D (Phase 2)
- No liver toxicity signal (unlike some small molecule drugs)
- Cardiovascular biomarker improvements (blood pressure, lipids)
- Lower GI burden than oral semaglutide (no fasting/water restrictions)
- Potential applications in sleep apnea, hypertension, osteoarthritis, PAD (trials ongoing)
Research Dosage Notes
The following reflects doses used in published research studies. This is not medical advice.
Consult published research literature for study-specific protocols.
Routes of Administration
Oral (Tablet) Moderate (small molecule oral bioavailability; no food/water restrictions required)
Once-daily oral tablet at any time of day without food restrictions. This distinguishes it from oral semaglutide, which requires 30-minute fasting and limited water. FDA-approved as Foundayo tablets (6 mg, 12 mg, 36 mg).
Read our full Routes of Administration Guide for detailed comparison of all delivery methods.
Stacking Protocols
Popular research stacks involving Orforglipron:
Metabolic Health Stack
Combines Orforglipron with MOTS-c (mitochondrial metabolism) and AOD-9604 (lipolysis) for metabolic optimization.
Explore our complete Peptide Stacking Guide for more combinations and safety considerations.
Reconstitution
| Storage | Refrigerate at 2-8°C after reconstitution. Do not freeze reconstituted solution. |
|---|
Typical vial sizes: 5 mg. Add bac water slowly down the side of the vial, swirl gently — do not shake. Use insulin syringe for precise dosing.
Need exact syringe measurements?
Amino Acid Sequence
N/A — non-peptide small molecule (not an amino acid sequence)
Side Effects & Safety
- Nausea (most common; dose-dependent; primarily during titration)
- Vomiting
- Diarrhea
- Constipation
- Decreased appetite
- GI adverse events generally mild to moderate, resolving with titration
- No significant liver toxicity (important safety differentiator for small molecules)
- Thyroid C-cell tumor risk in animal models (class effect warning, as with all GLP-1 RAs)
- Not for use with other GLP-1 receptor agonist medicines
Safety & Contraindications
This information is for educational purposes only. Consult a qualified healthcare provider before using any peptide.
MTC/MEN2
Boxed warning for medullary thyroid carcinoma. Contraindicated in patients with personal or family history of MTC or MEN2.
Severe Renal Impairment
Limited data in patients with eGFR <30 mL/min. Use with caution and monitor.
Pancreatitis History
Discontinue if acute pancreatitis is suspected. Has not been studied in patients with a history of pancreatitis.
Pregnancy & Lactation
Contraindicated in pregnancy. Discontinue at least 2 months before planned conception due to long washout period.
Drug Interactions
- Insulin/sulfonylureas: Risk of hypoglycemia. Consider reducing insulin or sulfonylurea dose when initiating orforglipron.
- Oral contraceptives: May reduce effectiveness of oral contraceptives due to delayed gastric emptying. Use backup contraception during dose escalation.
FDA Safety Information
FDA approved April 1, 2026 as Foundayo. First non-peptide oral GLP-1 receptor agonist. Carries standard GLP-1 RA boxed warning for thyroid C-cell tumors.
Pharmacokinetics
| Half-Life | ~24 hours (supports once-daily dosing without food restrictions) |
|---|---|
| Storage | Room temperature; oral tablet — no refrigeration required |
Synergistic Compounds
The following compounds have been studied alongside Orforglipron for potential complementary or synergistic effects:
Learn More
References & Further Reading
- FDA approves Lilly's Foundayo (orforglipron) — the only GLP-1 pill for weight loss that can be taken any time of day without food or water restrictions
- Orforglipron: A Comprehensive Review of an Oral Small-Molecule GLP-1 Receptor Agonist
- What to Know About Orforglipron — Eli Lilly Official Page
- The pharmacological basis for nonpeptide agonism of the GLP-1 receptor
- Orforglipron, a novel non-peptide oral daily GLP-1 receptor agonist — Meta-analysis
- ATTAIN-MAINTAIN Phase 3 topline results — orforglipron maintains weight loss after Wegovy/Zepbound