Orforglipron

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 (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 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]

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