Orforglipron

Orforglipron (LY-3502970) is an oral, non-peptide, small-molecule GLP-1 receptor agonist developed as a weight loss drug by Eli Lilly and Company.^[1] It was discovered by Chugai Pharmaceutical Co., then was licensed to Lilly in 2018.^[1]

Orforglipron

Above: skeletal diagram Below: 3D representation
Clinical data
Other names	LY-3502970
Routes of administration	Oral
ATC code	None
Pharmacokinetic data
Elimination half-life	29–49 hours
Identifiers
IUPAC name 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	2212020-52-3
PubChem CID	137319706
ChemSpider	71117507
UNII	7ZW40D021M
ChEMBL	ChEMBL4446782
Chemical and physical data
Formula	C48H48F2N10O5
Molar mass	882.974 g·mol−1
3D model (JSmol)	Interactive image
SMILES 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 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 is easier to produce than existing peptide GLP-1 agonists and is expected to be cheaper.^[2]

Mechanism

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.^[1][3]

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.^[4][5]

Orforglipron has a half-life of 29 to 49 hours across the doses tested and is taken once per day by mouth without food or water restrictions.^[3]

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) having mild to moderate severity.^[6] The most common side effects of orforglipon are diarrhea, nausea, upset stomach, and constipation.^[1][6]

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, injectable dulaglutide or a placebo daily for 40 weeks showed that orforglipron produced a reduction in blood glucose levels by 1.3 to 1.6 percentage points from a starting level of 8%.^[1][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.^[1] 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.^[1][8] 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.^[1]

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

See also

• Danuglipron
• Lotiglipron