Orforglipron
An oral small-molecule GLP-1 receptor agonist, approved on April 1, 2026 as Foundayo for weight management. It is not a peptide; it is here because it is sold, searched and compared alongside the peptide GLP-1 drugs.
Orforglipron activates the GLP-1 receptor like semaglutide but is a small molecule taken once a day as a tablet, with or without food (label). In its phase 3 obesity trial the top dose cut body weight by 11.2% at 72 weeks against 2.1% on placebo. Its label carries the class's thyroid warning even though it does not act on the rodent receptor.
What is it?
Every GLP-1 drug before orforglipron was a peptide. Peptides are broken down in the gut, so most are injected. Orforglipron is a small molecule, C48H48F2N10O5, designed to activate the same receptor. Its discovery paper showed how: it binds a pocket in the upper part of the receptor that peptides do not use, acts as a partial agonist biased towards G-protein signalling, and depends on a tryptophan found only in the primate receptor, which is why it has no effect in rats or mice. It is not a peptide, and our encyclopedia marks it as such.
FDA approved it on April 1, 2026 as Foundayo (NDA 220934) for long-term weight management in adults with obesity, or overweight with at least one weight-related condition, alongside diet and activity. The label starts at 0.8 mg once daily and steps up at intervals of at least 30 days through 2.5, 5.5, 9 and 14.5 mg to a maximum of 17.2 mg, taken with or without food. Those tablet strengths are not the doses printed in the trials, which used capsules of 3 to 36 mg: a 429-person study showed each tablet is bioequivalent to its capsule, so the 36 mg trial dose corresponds to the 17.2 mg tablet.
The obesity evidence is large. In ATTAIN-1, 3,127 adults without diabetes lost 7.5%, 8.4% and 11.2% of their weight over 72 weeks on the three doses against 2.1% on placebo; at the top dose 54.6% lost at least 10%. In ATTAIN-2, 1,613 adults with obesity and type 2 diabetes lost 5.1% to 9.6% against 2.5%. In ATTAIN-MAINTAIN, people who had already lost weight on tirzepatide or semaglutide injections kept most of the loss after switching to orforglipron (74.7% and 79.3% of it, against 49.2% and 37.6% on placebo).
In type 2 diabetes it lowered HbA1c by 1.2 to 1.5 points in early disease (ACHIEVE-1), beat oral semaglutide head to head over 52 weeks (-1.91 against -1.47 points at the top doses), beat dapagliflozin (-1.56 against -0.81) and lowered HbA1c 0.8 to 1.1 points more than placebo when added to titrated insulin glargine without raising the risk of clinically significant hypoglycaemia. The type 2 diabetes indication was not part of the April 2026 approval; a 2026 profile reports submissions in the EU, Japan and Canada.
Its safety profile is the class's: mostly mild-to-moderate gastrointestinal effects during dose escalation, with 5% to 10% stopping for adverse events in the obesity trials. A pooled analysis of seven phase 3 trials and 6,920 treated people found no drug-induced liver injury. The label warns of pancreatitis, severe gastrointestinal reactions, kidney injury from dehydration and hypoglycaemia with insulin or sulfonylureas, and carries the boxed thyroid C-cell warning: rodent tumours are a GLP-1-receptor effect, orforglipron is not active in rodents and caused none, but the relevance to people is undetermined, so it is contraindicated with a personal or family history of medullary thyroid carcinoma or MEN 2.
Mechanism of Action
Orforglipron activates the GLP-1 receptor from an unusual position. Its effects in people are those of the class; its chemistry is not.
A small molecule at a peptide receptor
It binds a pocket formed by the receptor's extracellular domain, a loop and several transmembrane helices, a site GLP-1 itself does not use (2020 structure).
Partial and biased
It is a partial agonist that favours G-protein signalling over beta-arrestin recruitment, which may explain part of its profile.
Primate-only
It relies on a tryptophan found only in the primate receptor, so it does not act in rats or mice, the reason it produced no rodent thyroid tumours.
Once daily by mouth
77% to 79% of an oral dose is absorbed, peak levels come 4 to 8 hours after a dose, and a 29- to 49-hour half-life gives steady state in about a week; it is cleared by CYP3A4 and leaves in faeces.
Published Research
PubMed returns 143 records for orforglipron or its codes. Our evidence set holds 40 papers; 31 name it in their titles and have an abstract, and 14 are carded below: 11 studies in people, including every phase 3 programme trial with published results, 2 laboratory studies and 1 review. It is a new drug, so its evidence is recent and almost all company-sponsored.
ATTAIN-1: obesity without diabetes, 3,127 adults
Once-daily orforglipron 6, 12 or 36 mg or placebo for 72 weeks: weight fell 7.5%, 8.4% and 11.2% against 2.1%. At 36 mg, 54.6% lost at least 10%, 36.0% at least 15% and 18.4% at least 20%. Adverse events led to stopping in 5.3% to 10.3% against 2.7%, mostly gastrointestinal.
ATTAIN-2: obesity with type 2 diabetes, 1,613 adults
Over 72 weeks weight fell 5.1%, 7.0% and 9.6% on 6, 12 and 36 mg against 2.5% on placebo, and HbA1c and every cardiometabolic measure improved. Discontinuation for adverse events was 6.1% to 9.9% against 4.1%; ten deaths (six and four) were judged unrelated.
ATTAIN-MAINTAIN: switching from injections
People who had lost weight on tirzepatide or semaglutide in SURMOUNT-5 were randomised to orforglipron or placebo. At 52 weeks those from tirzepatide kept 74.7% of their loss against 49.2%, and those from semaglutide 79.3% against 37.6%. The trial had no arm that stayed on the injections.
Phase 2 in obesity, 272 adults
Doses of 12 to 45 mg or placebo for 36 weeks: weight fell 9.4% to 14.7% against 2.3%, and 46% to 75% lost at least 10% against 9%. Gastrointestinal events occurred mainly during dose escalation and led 10% to 17% to stop.
ACHIEVE-1: early type 2 diabetes, 559 adults
Over 40 weeks HbA1c fell 1.24, 1.47 and 1.48 points on 3, 12 and 36 mg against 0.41 on placebo, and weight 4.5% to 7.6% against 1.7%. No severe hypoglycaemia occurred; adverse events led 4.4% to 7.8% to stop against 1.4%.
Head to head with oral semaglutide, 1,698 adults
In type 2 diabetes on metformin, over 52 weeks HbA1c fell 1.71 and 1.91 points on orforglipron 12 and 36 mg against 1.23 and 1.47 on oral semaglutide 7 and 14 mg; each orforglipron dose was superior to its comparator.
Against dapagliflozin, 962 adults
In type 2 diabetes on metformin, over 40 weeks HbA1c fell 1.23, 1.50 and 1.56 points on orforglipron 3, 12 and 36 mg against 0.81 on dapagliflozin 10 mg; every dose was non-inferior and better.
ACHIEVE-5: added to insulin glargine, 546 adults
Added to titrated insulin glargine for 40 weeks, orforglipron lowered HbA1c by 1.58 to 1.88 points against 0.79 on placebo and weight by 2.6% to 5.4% against a 0.2% gain, without raising the risk of clinically significant hypoglycaemia.
Liver safety across seven phase 3 trials
Among 11,220 participants (6,920 on orforglipron) followed for up to 104 weeks, ALT and AST fell on average; six people on orforglipron and six on comparators had combined enzyme and bilirubin rises, all with other causes. No case met criteria for drug-induced liver injury.
Tablets vs capsules: why the label doses differ
In 429 healthy adults, capsules of 1, 3, 6, 12, 24 and 36 mg were bioequivalent at steady state to tablets of 0.8, 2.5, 5.5, 9, 14.5 and 17.2 mg, with similar safety. The trials used capsules; Foundayo is the tablets.
Absolute bioavailability and elimination
In two phase 1 studies using radiolabelled orforglipron, oral bioavailability was 79.1%, 87% of a dose was recovered in faeces and 0.2% in urine.
Phase 1a: first doses in 92 people
Single doses of 0.3 to 6 mg gave a half-life of 24.6 to 35.3 hours, lengthening to 48.1 to 67.5 hours after four weeks of daily dosing; exposure was roughly dose-proportional, gastrointestinal effects were most common, and weight fell by up to 5.4 kg in four weeks.
How a non-peptide activates the GLP-1 receptor
The discovery paper: LY3502970 (OWL833) is a potent, selective partial agonist biased to G-protein signalling. A high-resolution structure showed it bound in a unique upper pocket, and its dependence on the primate-specific Trp33 explains its species selectivity.
Orforglipron: first approval
A profile of the April 2026 US approval for long-term weight management. It reports submissions in the EU (weight management and type 2 diabetes), Japan (weight management) and Canada (type 2 diabetes), and phase 3 trials in sleep apnoea, hypertension, stress urinary incontinence, osteoarthritis pain and peripheral arterial disease.
Dosing Data
Orforglipron is dosed by label as Foundayo tablets. The trial doses (3 to 36 mg) were capsules; the tablets that carry the same exposure are 0.8 to 17.2 mg, so trial figures should not be read as tablet doses.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the Foundayo label and the trials above.
Contraindications & Cautions
From the Foundayo label; a clinician decides.
Legal Status
Orforglipron is an approved prescription medicine in the US. The sport row below comes from the dataset.
Frequently Asked Questions
?Is orforglipron a peptide?
No. It is a small molecule (C48H48F2N10O5) that activates the GLP-1 receptor. Our encyclopedia includes it because it is compared with, and often mistaken for, the peptide GLP-1 drugs.
?Why are the Foundayo doses different from the trial doses?
The trials used capsules of 3 to 36 mg; Foundayo is tablets of 0.8 to 17.2 mg. A 429-person study showed each tablet is bioequivalent to a capsule, so the 36 mg trial dose corresponds to the 17.2 mg tablet.
?How much weight did people lose?
In ATTAIN-1, adults without diabetes lost 7.5% to 11.2% of their weight over 72 weeks on the three doses, against 2.1% on placebo.
?Does it have to be taken on an empty stomach?
No. The Foundayo label says to take it once daily with or without food.
?Why does it carry a thyroid cancer warning?
GLP-1 drugs caused thyroid C-cell tumours in rodents. Orforglipron does not act on the rodent receptor and caused none, but the label keeps the class's boxed warning because the relevance to people is undetermined.
References
- [fda-pi] Foundayo (orforglipron) tablets Prescribing Information. Eli Lilly and Company (DailyMed version of 2026-08-13, read 2026-09-28).
- [fda-pi] US FDA, Drugs@FDA: Foundayo (orforglipron) NDA 220934, approved April 1, 2026 (read 2026-09-28).
- [Human] Wharton S, et al. "Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment." N Engl J Med, 2025;393(18):1796-1806. PMID: 40960239.
- [Human] Horn DB, et al. "Orforglipron, an oral small-molecule GLP-1 receptor agonist, for the treatment of obesity in people with type 2 diabetes (ATTAIN-2): a phase 3, double-blind, randomised, multicentre, placebo-controlled trial." Lancet, 2026;406(10522):2927-2944. PMID: 41275875.
- [Human] Aronne LJ, et al. "Orforglipron for maintenance of body weight reduction: the double-blind, randomized phase 3b ATTAIN-MAINTAIN trial." Nat Med, 2026;32(7):2679-2687. PMID: 42120723.
- [Human] Wharton S, et al. "Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity." N Engl J Med, 2023;389(10):877-888. PMID: 37351564.
- [Human] Rosenstock J, et al. "Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes." N Engl J Med, 2025;393(11):1065-1076. PMID: 40544435.
- [Human] Rosenstock J, et al. "Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial." Lancet, 2026;407(10534):1147-1160. PMID: 41765029.
- [Human] Welch M, et al. "Orforglipron compared with dapagliflozin in adults with type 2 diabetes and inadequate glycaemic control with metformin (ACHIEVE-2): a multicentre, randomised, non-inferiority, open-label, phase 3 trial." Lancet, 2026;408(10550):125-140. PMID: 42259339.
- [Human] Giorgino F, et al. "Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial." JAMA, 2026;336(5):389-399. PMID: 42251769.
- [Human] Wharton S, et al. "Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials." Diabetes Obes Metab, 2026;28(9):8347-8358. PMID: 42338042.
- [Human] Ma X, et al. "Pharmacokinetic Bioequivalence of Orforglipron Tablets and Capsules in Healthy Participants With Obesity or Overweight." Diabetes Obes Metab, 2026;28(7):5803-5809. PMID: 41994902.
- [Human] Morse BL, et al. "Disposition and Absolute Bioavailability of Orally Administered Orforglipron in Healthy Participants." Clin Pharmacol Drug Dev, 2026;15(1):e1594. PMID: 40888509.
- [Human] Pratt E, et al. "Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1a, blinded, placebo-controlled, randomized, single- and multiple-ascending-dose study in healthy participants." Diabetes Obes Metab, 2023;25(9):2634-2641. PMID: 37344954.
- [In Vitro] Kawai T, et al. "Structural basis for GLP-1 receptor activation by LY3502970, an orally active nonpeptide agonist." Proc Natl Acad Sci U S A, 2020;117(47):29959-29967. PMID: 33177239.
- [Review] Shirley M. "Orforglipron: First Approval." Drugs, 2026;86(10):1735-1745. PMID: 42479349.
Sources & Citations
Every PubMed citation on this page has been checked against its record. The Foundayo label was read on DailyMed and the approval on Drugs@FDA on September 28, 2026. Grey Peptides sells nothing and links to no vendor.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.