Orforglipron

Orforglipron
Above: skeletal diagram
Below: 3D representation
Clinical data
Trade namesFoundayo
Other namesLY-3502970
AHFS/Drugs.comMonograph
License data
Routes of
administration		Oral
Drug classAntidiabetic, GLP-1 receptor agonist
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
Elimination half-life29–49 hours[2]
Identifiers
  • 3-[(1S,2S)-1-[5-[(4S)-2,2-dimethyloxan-4-yl]-2-[(4S)-2-(4-fluoro-3,5-dimethylphenyl)-3-[3-(4-fluoro-1-methylindazol-5-yl)-2-oxoimidazol-1-yl]-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
Chemical and physical data
FormulaC48H48F2N10O5
Molar mass882.974 g·mol−1
3D model (JSmol)
  • Cc1cc(-n2nc3c(c2-n2ccn(-c4ccc5c(cnn5C)c4F)c2=O)[C@H](C)N(C(=O)c2cc4cc([C@H]5CCOC(C)(C)C5)ccc4n2[C@@]2(c4noc(=O)[nH]4)C[C@@H]2C)CC3)cc(C)c1F
  • InChI=1S/C48H48F2N10O5/c1-25-18-32(19-26(2)40(25)49)60-42(58-16-15-57(46(58)63)37-11-10-36-33(41(37)50)24-51-55(36)7)39-28(4)56(14-12-34(39)53-60)43(61)38-21-31-20-29(30-13-17-64-47(5,6)23-30)8-9-35(31)59(38)48(22-27(48)3)44-52-45(62)65-54-44/h8-11,15-16,18-21,24,27-28,30H,12-14,17,22-23H2,1-7H3,(H,52,54,62)/t27-,28-,30-,48-/m0/s1
  • Key:USUWIEBBBWHKNI-KHIFEHGGSA-N

Orforglipron, sold under the brand name Foundayo, is an oral, non-peptide, small-molecule GLP-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company.[3] It was discovered by Chugai Pharmaceutical Co., then was licensed to Lilly in 2018.[3]

Orforglipron was approved for medical use in the United States in April 2026.[4][5]

Medical uses

Orforglipron is indicated in combination with a reduced-calorie diet and increased physical activity to reduce excess body weight and maintain weight reduction long term in adults with obesity or adults with overweight in the presence of at least one weight-related comorbid condition.[1]

Adverse effects

Safety and dosing trials showed that the incidence of adverse events in orforglipron-treated participants was 62–89%, mostly from gastrointestinal discomfort (44–70% with orforglipron, 18% with placebo); in patients experiencing adverse events, 96% had mild to moderate GI side effects, while approximately 4% had severe nausea or vomiting.[6] The most common side effects of orforglipon noted in clinical trials were vomiting, diarrhea, nausea, upset stomach, and constipation.[3][6][7]

Mechanism of action

Orforglipron is a small-molecule, partial GLP-1 receptor agonist affecting the activity of cyclic adenosine monophosphate (cAMP); its effects are similar to the actions of glucagon-like peptide-1 (GLP-1) for reducing food intake and lowering blood glucose levels.[3][2]

Clinical trials

The results of Phase I safety and Phase II ascending-dose clinical trials enrolling people with obesity or type 2 diabetes were published in 2023.[8][9]

The ability of orforglipron to reduce blood sugar levels and body weight was judged favorable compared to dulaglutide.[6]

Phase III ACHIEVE-1 trial

In April 2025, results from a phase III clinical trial involving 559 people with type 2 diabetes who took an oral orforglipron pill or a placebo daily for 40 weeks showed that orforglipron produced a reduction of hemoglobin A1C level by 1.3 to 1.6 percentage points from a starting level of 8%.[3][10][7]

More than 65% of participants taking the highest dose of orforglipron achieved a reduction of hemoglobin A1C level by more than or equal to 1.5 percentage points, bringing them into the non-diabetic range as defined by the American Diabetes Association.[3] People taking the highest dose of the pill lost 8% of their weight, or around 16 lb (7.3 kg), on average after 40 weeks.[3][11] In its press release, Lilly noted that the subjects' weight loss had not yet plateaued at the time the trial concluded, and suggested that this indicated that greater weight reduction would ultimately be achieved with extended therapy.[3]

Side effects were similar to those seen with other GLP-1 agonists, and no significant liver problems were observed.[3]

References

  1. ^ a b "FOUNDAYO- orforglipron tablet, film coated". uspl.lilly.com. Eli Lilly and Company. Retrieved May 20, 2026.
  2. ^ a b Kokkorakis M, Chakhtoura M, Rhayem C, et al. (January 2025). "Emerging pharmacotherapies for obesity: A systematic review". Pharmacological Reviews. 77 (1) 100002. doi:10.1124/pharmrev.123.001045. hdl:11370/466f1da9-f22c-4d9a-be24-2680d416ebf9. PMID 39952695.
  3. ^ a b c d e f g h i "Lilly's oral GLP-1, orforglipron, demonstrated statistically significant efficacy results and a safety profile consistent with injectable GLP-1 medicines in successful Phase 3 trial" (Press release). Eli Lilly and Company. April 17, 2025. Retrieved April 18, 2025.
  4. ^ "FDA Approves First New Molecular Entity Under National Priority Voucher Program". U.S. Food and Drug Administration (FDA) (Press release). April 1, 2026. Retrieved April 5, 2026.
  5. ^ "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" (Press release). Eli Lilly and Company. April 1, 2026. Retrieved April 5, 2026.
  6. ^ a b c Frias JP, Hsia S, Eyde S, et al. (August 2023). "Efficacy and safety of oral orforglipron in patients with type 2 diabetes: a multicentre, randomised, dose-response, phase 2 study". Lancet. 402 (10400): 472–483. doi:10.1016/S0140-6736(23)01302-8. PMID 37369232.
  7. ^ a b Rosenstock J, Hsia S, Nevarez Ruiz L, et al. (June 21, 2025). "Orforglipron, an Oral Small-Molecule GLP-1 Receptor Agonist, in Early Type 2 Diabetes". New England Journal of Medicine. 393 (11). doi:10.1056/NEJMoa2505669.
  8. ^ Pratt E, Ma X, Liu R, et al. (June 2023). "Orforglipron (LY3502970), a novel, oral non-peptide glucagon-like peptide-1 receptor agonist: A Phase 1b, multicentre, blinded, placebo-controlled, randomized, multiple-ascending-dose study in people with type 2 diabetes". Diabetes, Obesity & Metabolism. 25 (9): 2642–2649. doi:10.1111/dom.15150. PMID 37264711. S2CID 259022851.
  9. ^ Wharton S, Blevins T, Connery L, et al. (June 2023). "Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity". The New England Journal of Medicine. 389 (10): 877–888. doi:10.1056/NEJMoa2302392. PMID 37351564.
  10. ^ Constantino AK (April 17, 2025). "Eli Lilly's weight loss pill succeeds in first late-stage trial on diabetes patients". CNBC. Retrieved April 17, 2025.
  11. ^ Kolata G (April 17, 2025). "Daily Pill May Work as Well as Ozempic for Weight Loss and Blood Sugar". The New York Times. Retrieved April 17, 2025.
  • Clinical trial number NCT05869903 for "A Study of Orforglipron (LY3502970) in Adult Participants With Obesity or Overweight With Weight-Related Comorbidities (ATTAIN-1)" at ClinicalTrials.gov
  • Clinical trial number NCT05872620 for "A Study of Orforglipron in Adult Participants With Obesity or Overweight and Type 2 Diabetes (ATTAIN-2)" at ClinicalTrials.gov
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