Orforglipron, the First Non-Peptide GLP-1 Receptor Agonist in a Tablet

Orforglipron does not work in mice or rats. The molecule binds a part of the GLP-1 receptor that differs between rodents and primates, so its preclinical studies needed animals carrying the human receptor. Even so, on 1 April 2026 it became the active substance of Foundayo®, the first non-peptide medicine of this class approved by the FDA, and six months later it received a positive opinion from the European CHMP committee.

This article explains how orforglipron differs from semaglutide and tirzepatide, how it activates the receptor, what the phase II and phase III trials in more than 11,000 participants showed, and what its status is in the United States, the EU and in sport. You will find no dosing schedules for the medicine here; the FAQ at the end explains why.

In our catalogue, the compounds discussed in this article are chemical reagents intended solely for laboratory research (Research Use Only). They are not medicinal products, dietary supplements or foods, and they are not intended for use in humans or animals. What this status means is explained in our material on the legal status of research reagents.

An essential distinction: every figure on body weight and glycaemia in this article comes from clinical trials of the medicine Foundayo® (orforglipron), which is prescription-only in the United States and is used under medical supervision. Research material containing the same substance is not a substitute for a medicinal product and does not replace medical consultation. The clinical trial findings do not apply to it.

What orforglipron is

It is a small synthetic molecule, not a peptide: formula C₄₈H₄₈F₂N₁₀O₅, mass 883.0 g/mol (PubChem CID 137319706). Semaglutide and tirzepatide are chains of roughly 30 to 40 amino acids with masses above 4,000 g/mol; digestive enzymes break them down, so they are injected, and oral semaglutide needs an absorption enhancer. Orforglipron originated at the Japanese company Chugai under the code OWL833 and was developed by Eli Lilly as LY3502970 (Kawai et al., 2020, PMID 33177239).

A 2020 paper described where the molecule binds. The structure of its complex with the active GLP-1 receptor revealed a pocket in the upper part of the helical bundle, formed by the extracellular domain, extracellular loop 2 and transmembrane helices 1, 2, 3 and 7. Orforglipron is a partial agonist that favours G-protein activation over β-arrestin recruitment. Species selectivity comes from a tryptophan at position 33 of the extracellular domain, present in primates and absent in rodents (Kawai et al., 2020). That is why efficacy studies used mice with the human receptor and non-human primates.

Mechanism: low occupancy, full response

Lilly’s team completed the pharmacological profile in 2024. In binding assays orforglipron proved a high-affinity ligand (inhibition constant 1 nM), selective for the human GLP-1 receptor. In signalling assays it showed low intrinsic efficacy and negligible β-arrestin recruitment, the reverse of peptide agonists, which trigger both pathways (Sloop et al., 2024, PMID 39693407).

The most interesting result concerns receptor occupancy. In mice expressing the human GLP-1 receptor, the authors calculated what fraction of receptors must be bound to lower blood glucose in a glucose tolerance test. Low occupancy turned out to be enough for a full biological response. In rats whose receptor had been edited with CRISPR-Cas9 to respond to non-peptide agonists, orforglipron engaged the receptor in the pancreas and the brain much as peptides do, and in diet-induced obesity oral orforglipron reduced body weight, and the result was compared with subcutaneous semaglutide (Sloop et al., 2024). In practice, the molecule reaches a peptide’s effect by a different route: rather than stimulating the receptor strongly, it stimulates it weakly but does not switch it off through internalisation.

Pharmacokinetics in humans: data from the medicine’s trials

The first phase I study in 92 healthy adults showed a half-life of 24.6 to 35.3 hours after a single dose and 48.1 to 67.5 hours after 28 days of administration, dose-proportional exposure and no need for food or water restrictions; the most common adverse events were gastrointestinal (Pratt et al., 2023, PMID 37344954). Absolute oral bioavailability was measured with carbon-14 labelling: 79.1% (± 16.8 percentage points), many times the roughly 1% of oral semaglutide. The compound is eliminated mainly in the faeces (87%), 0.2% of the dose appears in urine, and the parent molecule dominates in plasma (93%) (Morse et al., 2026, PMID 40888509).

One detail matters to anyone reading the publications. The phase III trials were run with capsules, while the medicine was approved as tablets with a different content of the substance; a study in 429 people demonstrated bioequivalence between six capsule strengths and their corresponding tablets (Ma et al., 2026, PMID 41994902). The milligram figure in a Lancet paper and the figure on the label therefore describe different formulations and are not the same thing.

The trial programme: phase II and phase III

Phase II produced two publications in 2023. In 272 adults with obesity and no diabetes, the change in body weight after 36 weeks ranged from −9.4% to −14.7% across four dose groups, against −2.3% with placebo; gastrointestinal adverse events, mild to moderate, led to discontinuation in 10 to 17% of participants (Wharton et al., 2023, PMID 37351564). In 383 people with type 2 diabetes at 45 centres, including sites in Poland, glycated haemoglobin after 26 weeks fell by up to 2.10 percentage points against 0.43 with placebo and 1.10 with dulaglutide, and body weight by up to 10.1 kg (Frías et al., 2023, PMID 37369232).

The phase III programme has two strands. ATTAIN concerns body weight. In ATTAIN-1, in 3,127 adults with obesity and no diabetes, body weight changed by −7.5%, −8.4% and −11.2% in three dose groups after 72 weeks, against −2.1% with placebo (treatment-regimen estimand); a reduction of at least 10% was reached by 54.6% of people in the highest group against 12.9% with placebo, and 5.3 to 10.3% discontinued because of adverse events against 2.7% (Wharton et al., 2025, PMID 40960239). In ATTAIN-2, in 1,613 people with obesity and type 2 diabetes, the results were smaller: −5.1%, −7.0% and −9.6% against −2.5% (Horn et al., 2026, PMID 41275875). ATTAIN-MAINTAIN tested what happens after the injections stop: participants who had previously lost weight on tirzepatide or semaglutide maintained 74.7% and 79.3% of that reduction after a year on orforglipron, against 49.2% and 37.6% with placebo (Aronne et al., 2026, PMID 42120723).

ACHIEVE concerns type 2 diabetes. ACHIEVE-1 (559 people managed with diet and exercise alone, 40 weeks): glycated haemoglobin fell by 1.24 to 1.48 percentage points against 0.41 with placebo, with no episodes of severe hypoglycaemia (Rosenstock et al., 2025, PMID 40544435). ACHIEVE-2 (962 people on metformin): superiority over dapagliflozin, but gastrointestinal adverse events in 46 to 54% against 12% and discontinuation in 15 to 20% against 6% (Welch et al., 2026, PMID 42259339). ACHIEVE-3 (1,698 people): orforglipron was non-inferior and then superior to oral semaglutide in lowering glycated haemoglobin at 52 weeks, at the price of more frequent gastrointestinal events (58 to 59% against 37 to 45%), more discontinuations (9 to 10% against 4 to 5%) and a larger rise in pulse rate (3.7 to 4.7 against 1.0 to 1.5 beats per minute) (Rosenstock et al., 2026, PMID 41765029). ACHIEVE-5 (546 people) added orforglipron to insulin glargine without raising the risk of hypoglycaemia (Giorgino et al., 2026, PMID 42251769).

ACHIEVE-4 stands apart: a cardiovascular safety trial in 2,749 people with type 2 diabetes at increased risk, with insulin glargine as the comparator. Over a median of two years, major adverse cardiovascular events (cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina) occurred in 4.2% of those on orforglipron and 5.0% of those on insulin; the hazard ratio of 0.84 with a confidence interval of 0.59 to 1.20 met the non-inferiority criterion. Clinically significant or severe hypoglycaemia was recorded in 6.8% against 19.2% (Klein et al., 2026, PMID 42815506). The wider background to this class of medicines is in our article on semaglutide and in the comparison of tirzepatide and semaglutide.

Safety: what the label and the pooled analyses say

The Foundayo® prescribing information (version of 29 July 2026) carries a boxed warning on thyroid C-cell tumours, shared by the whole class of GLP-1 receptor agonists. Here the paradox from the opening returns: the warning rests on tumours in rodents, yet orforglipron is inactive in rodents and caused no tumours in them; the FDA notes, however, that the human relevance of the phenomenon has not been determined. The medicine is contraindicated in people with a personal or family history of medullary thyroid carcinoma and in MEN 2 syndrome. The warnings cover acute pancreatitis, severe gastrointestinal reactions, acute kidney injury from volume depletion, hypoglycaemia with insulin, hypersensitivity reactions, complications of diabetic retinopathy, acute gallbladder disease and pulmonary aspiration during general anaesthesia. Adverse reactions in at least 5% of treated patients include nausea, constipation, diarrhoea, vomiting, dyspepsia, abdominal pain, headache, abdominal distension, fatigue, eructation, reflux and hair loss (FDA, 2026).

The liver was assessed in a pooled analysis of seven phase III trials in 11,220 participants: aminotransferase activity fell, the cases meeting the laboratory criteria of Hy’s law had other explanations, and the frequency of hepatic events did not differ from comparators (Wharton et al., 2026, PMID 42338042). Across all trials, gastrointestinal symptoms were the most common reason for stopping treatment, usually during dose escalation. Bear in mind that these data describe a medicine given under a physician’s supervision, in defined populations and with monitoring; they do not describe a reagent.

Regulatory status

United States. Orforglipron is the active substance of Foundayo® tablets, approved by the FDA on 1 April 2026 as a new molecular entity (NDA 220934, Eli Lilly) and available on prescription; a labelling supplement was approved on 4 August 2026. The approved indication is weight reduction and the long-term maintenance of that reduction in adults with obesity, or with overweight and at least one weight-related comorbid condition, together with a reduced-calorie diet and increased physical activity; the label advises against combining it with another GLP-1 receptor agonist (Drugs@FDA, 2026; FDA, 2026). Because orforglipron is a small molecule and an approved drug, the 503A bulk substances procedure that applies to many research peptides does not arise.

European Union. On 15 October 2026 the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion recommending marketing authorisation for Foundayo® in weight management and in type 2 diabetes in adults (procedure EMEA/H/C/006632, applicant Eli Lilly Nederland B.V.). The European Commission decision that completes the procedure had not been issued by 3 November 2026, so the medicine is not yet authorised in Poland or any other EU member state (EMA, 2026). Orforglipron is absent from the EU medicines data that EMA publishes under Article 57 (data as of 9 October 2026).

Other countries. We did not check registers outside the United States and the EU. The reagent in our catalogue, GLP-1 MAX, is material for laboratory research; what a certificate of analysis says about a batch is explained in our article on reading a COA.

Anti-doping note

The WADA 2026 Prohibited List does not name orforglipron, and nor does the 2027 List that takes effect on 1 January 2027. Class S0 covers substances with no approval for human use by any governmental regulatory health authority; FDA approval removes orforglipron from it. GLP-1 receptor agonists appear in no class of the List. Semaglutide and tirzepatide are covered by the 2026 and 2027 Monitoring Program, which serves to observe patterns of use and is not a prohibition; the programme does not mention orforglipron (USADA, 2026). USADA applies the same List to athletes tested in the United States, as a signatory to the World Anti-Doping Code. What separates the Monitoring Program from a prohibition, and how the List judges research compounds, is explained in our guide to the WADA Prohibited List; WADA and the national agencies decide.

Frequently asked questions

What is orforglipron?
A non-peptide small molecule that activates the GLP-1 receptor as a partial agonist, with signalling weighted towards the G protein. It is the active substance of Foundayo® tablets, approved in the United States in April 2026.

Is orforglipron a peptide?
No. Its mass of 883 g/mol is about one fifth that of semaglutide. It has no amino acid chain, which is why it survives digestion and has 79% bioavailability without an absorption enhancer.

How does orforglipron differ from semaglutide and tirzepatide?
In structure (a small molecule rather than a peptide), route (a tablet rather than an injection), the way it activates the receptor (a partial agonist without β-arrestin recruitment) and the number of receptors: it acts only on GLP-1, whereas tirzepatide also acts on the GIP receptor.

Is Foundayo available in the EU?
As of 3 November 2026, no. The CHMP issued a positive opinion on 15 October 2026, but authorisation in the EU requires a European Commission decision, which has not yet been issued. In the United States it has been a prescription medicine since 1 April 2026.

Why do we give no dosing information for orforglipron?
The GLP-1 MAX reagent is laboratory material that is not administered to anyone, and the figures from the clinical trials describe the medicine Foundayo® in a different formulation and under medical supervision. The trial capsules and the pharmacy tablets differ even in substance content at the same exposure.

Is orforglipron prohibited in sport?
It is not on the 2026 or 2027 Prohibited List, and as an FDA-approved medicine it does not fall under class S0. Semaglutide and tirzepatide are in the Monitoring Program, which is not a prohibition. Athletes should check the current List.

Summary

Orforglipron is the first non-peptide GLP-1 receptor agonist to make the whole journey from the structure of its receptor complex to approved medicine. It binds the receptor in a different pocket from peptides, acts as a partial agonist without β-arrestin recruitment and is inactive in rodents. Phase III trials in more than 11,000 people showed body weight reduction of up to 11.2% after 72 weeks, a fall in glycated haemoglobin of about 1.5 percentage points, superiority over oral semaglutide and cardiovascular safety non-inferior to insulin, with frequent gastrointestinal symptoms. Foundayo® has been approved in the United States since 1 April 2026 and awaits a Commission decision in the EU after a positive CHMP opinion. The WADA List does not name it, and approval excludes class S0.

Product documentation

Reagent page with batch documentation: GLP-1 MAX (orforglipron). Related reagents are collected in the category compounds studied in the context of metabolism, and the overview of the whole group is our guide to fat burners. The identity and purity of each batch are confirmed by a certificate of analysis.

Bibliography

1. Kawai T, Sun B, Yoshino H, 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. doi:10.1073/pnas.2014879117. PMID: 33177239
2. Sloop KW, Cox AL, Wainscott DB, et al. The pharmacological basis for nonpeptide agonism of the GLP-1 receptor by orforglipron. Sci Transl Med. 2024;16(778):eadp5765. doi:10.1126/scitranslmed.adp5765. PMID: 39693407
3. Pratt E, Ma X, Liu R, 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. doi:10.1111/dom.15184. PMID: 37344954
4. Morse BL, Bhattachar S, Ma X, et al. Disposition and Absolute Bioavailability of Orally Administered Orforglipron in Healthy Participants. Clin Pharmacol Drug Dev. 2026;15(1):e1594. doi:10.1002/cpdd.1594. PMID: 40888509
5. Ma X, Li YG, Raha S, et al. Pharmacokinetic Bioequivalence of Orforglipron Tablets and Capsules in Healthy Participants With Obesity or Overweight. Diabetes Obes Metab. 2026;28(7):5803-5809. doi:10.1111/dom.70783. PMID: 41994902
6. Wharton S, Blevins T, Connery L, et al. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med. 2023;389(10):877-888. doi:10.1056/NEJMoa2302392. PMID: 37351564
7. Frias JP, Hsia S, Eyde S, et al. Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study. Lancet. 2023;402(10400):472-483. doi:10.1016/S0140-6736(23)01302-8. PMID: 37369232
8. Wharton S, Aronne LJ, Stefanski A, et al. Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist for Obesity Treatment. N Engl J Med. 2025;393(18):1796-1806. doi:10.1056/NEJMoa2511774. PMID: 40960239
9. Horn DB, Ryan DH, Kis SG, 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. doi:10.1016/S0140-6736(25)02165-8. PMID: 41275875
10. Aronne LJ, Horn DB, le Roux CW, 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. doi:10.1038/s41591-026-04386-7. PMID: 42120723
11. Rosenstock J, Hsia S, Nevarez Ruiz L, 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. doi:10.1056/NEJMoa2505669. PMID: 40544435
12. Welch M, Forst T, Jia W, 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. doi:10.1016/S0140-6736(26)00800-7. PMID: 42259339
13. Rosenstock J, Yabe D, Cox D, 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. doi:10.1016/S0140-6736(26)00202-3. PMID: 41765029
14. Klein KR, Wysham C, Tuttle KR, et al. Cardiovascular safety of orforglipron versus insulin glargine in adults with type 2 diabetes at increased cardiovascular risk (ACHIEVE-4): a phase 3, event-driven, randomised, open-label, non-inferiority, active comparator trial. Lancet. 2026;408(10564):1557-1570. doi:10.1016/S0140-6736(26)01865-9. PMID: 42815506
15. Giorgino F, D’Souza S, Ludwig L, et al. Orforglipron Added to Titrated Insulin Glargine in Type 2 Diabetes: The ACHIEVE-5 Randomized Clinical Trial. JAMA. 2026;336(5):389-399. doi:10.1001/jama.2026.9512. PMID: 42251769
16. Wharton S, Stefanski A, Chen J, 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. doi:10.1111/dom.71032. PMID: 42338042
17. U.S. Food and Drug Administration. Drugs@FDA: NDA 220934, FOUNDAYO (orforglipron) tablets, Eli Lilly and Co; original approval 1 April 2026, supplement 3 (labelling) 4 August 2026. accessdata.fda.gov (accessed 3 November 2026)
18. U.S. Food and Drug Administration. FOUNDAYO (orforglipron) tablets, prescribing information, version of 29 July 2026 (sections 1, 3, 4, 5, 6). accessdata.fda.gov (accessed 3 November 2026)
19. European Medicines Agency. Foundayo (orforglipron): CHMP opinion adopted 15 October 2026, European Commission decision pending; EMEA/H/C/006632. ema.europa.eu (accessed 3 November 2026)
20. European Medicines Agency. Article 57 product data (data as of 9 October 2026): no entry for orforglipron. ema.europa.eu (accessed 3 November 2026)
21. National Center for Biotechnology Information. PubChem Compound Summary, CID 137319706, orforglipron. pubchem.ncbi.nlm.nih.gov (accessed 3 November 2026)
22. World Anti-Doping Agency. The 2026 Prohibited List and the 2026 Monitoring Program. wada-ama.org (accessed 3 November 2026)
23. U.S. Anti-Doping Agency. Athlete Advisory: What’s New on the 2027 WADA Prohibited List? (6 October 2026). usada.org (accessed 3 November 2026)