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Orforglipron-Obesity
This information is provided in response to your request. Resources may contain information about doses, uses, formulations and populations different from product labeling.
Were there any reports of hepatotoxicity in the orforglipron weight management trials?
No hepatic safety signal was observed in the orforglipron phase 3 studies ATTAIN-1 and ATTAIN-2 in adults with obesity or overweight. There were no reported incidences of drug-related hepatotoxicity in the orforglipron phase 2 studies.
Content Overview
What Changes in Liver Enzymes Were Seen During the Orforglipron Weight Management Studies?
- Liver Enzyme Changes in the Orforglipron Phase 3 ATTAIN-1 Study
- Liver Enzyme Changes in the Orforglipron Phase 3 ATTAIN-2 Study
- Liver Enzyme Changes in the Orforglipron Phase 2 Studies
Hepatic Exclusion Criteria in Orforglipron Phase 2 and ATTAIN-1 Studies
What Changes in Liver Enzymes Were Seen During the Orforglipron Weight Management Studies?
Liver Enzyme Changes in the Orforglipron Phase 3 ATTAIN-1 Study
ATTAIN-1 is a phase 3, 72-week, double-blind, randomized, placebo-controlled trial comparing the efficacy and safety of orforglipron 6 mg, 12 mg, and 36 mg as monotherapy to placebo as an adjunct to healthy diet and physical activity in adults with obesity or overweight with at least one weight-related comorbidity.1
In ATTAIN-1, across orforglipron doses from baseline to week 72,
- alanine aminotransferase (ALT) levels decreased by 15.1% to 19.5%, and
- aspartate aminotransferase (AST) levels decreased by 5.8% to 7.6% across orforglipron doses (Change From Baseline to Week 72 in ALT and AST Levels in ATTAIN-1).1
Parametera |
Orforglipron 6 mg |
Orforglipron 12 mg |
Orforglipron 36 mg |
Placebo |
ALTb |
||||
Baseline, U/L |
22.9 (0.5) |
22.7 (0.5) |
22.8 (0.5) |
22.7 (0.4) |
Week 72, U/L |
19.4 (0.3) |
18.9 (0.3) |
18.4 (0.4) |
21.7 (0.3) |
Percent change from baseline at week 72, % |
-15.1 (1.5) |
-17.2 (1.4) |
-19.5 (1.6) |
-5.2 (1.4) |
ASTc |
||||
Baseline, U/L |
20.1 (0.3) |
20.3 (0.3) |
20.1 (0.3) |
20.4 (0.2) |
Week 72, U/L |
19.1 (0.2) |
19.1 (0.2) |
18.7 (0.3) |
20.4 (0.2) |
Percent change from baseline at week 72, % |
-5.8 (1.1) |
-5.8 (1.0) |
-7.6 (1.2) |
0.4 (1.2) |
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase.
aData are presented as model based estimate ± SE and were analyzed with log-transformation.
bNormal ALT range is 4 to 43 U/L for female participants and 5 to 48 U/L for male participants.
cNormal AST range is 8 to 40 U/L for male and female participants.
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Participants Reporting an ALT or AST Above the Upper Limit of Normal in ATTAIN-1
In ATTAIN-1, there was no imbalance between treatment arms in participants with a maximum postbaseline ALT or AST ≥3x or ≥5x the upper limit of normal (ULN).1
A total of 8 participants (7 Preferred Product Name-treated participants and 1 placebo-treated participant) experienced transaminase elevations ≥10x upper limit of normal (ULN). For all 7 orforglipron participants, alternative causes were identified.1
Two participants in the Preferred Product Name groups had elevated total bilirubin >2x ULN with ALT elevation >3x ULN. Both cases had alternative causes and were not associated with drug-induced liver injury.1
See Participants With a Maximum Postbaseline ALT or AST ≥3x, ≥5x, and ≥10x ULN for information on participants with a maximum postbaseline ALT or AST ≥3x ULN.
Categorya |
Orforglipron 6 mg |
Orforglipron 12 mg |
Orforglipron 36 mg |
Placebo |
ALT |
||||
≥3x ULN |
21 (2.9) |
11 (1.5) |
22 (3.1) |
21 (2.3) |
≥5x ULN |
6 (0.8) |
5 (0.7) |
9 (1.3) |
8 (0.9) |
≥10x ULN |
0 (0.0) |
2 (0.3) |
4 (0.6) |
1 (0.1) |
AST |
||||
≥3x ULN |
8 (1.1) |
4 (0.6) |
9 (1.3) |
9 (1.0) |
≥5x ULN |
4 (0.6) |
1 (0.1) |
4 (0.6) |
3 (0.3) |
≥10x ULN |
1 (0.1) |
0 (0.0) |
1 (0.1) |
0 (0.0) |
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal.
aData are n (%).
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Liver Enzyme Changes in the Orforglipron Phase 3 ATTAIN-2 Study
No hepatic safety signal was observed in the orforglipron phase 3 study ATTAIN-2 in adults with obesity or overweight and type 2 diabetes.2
Detailed ATTAIN-2 results will be presented at a future medical meeting and published in a peer-reviewed journal.2
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Liver Enzyme Changes in the Orforglipron Phase 2 Studies
Similar percentages of participants in the orforglipron and placebo arms of both phase 2 studies experienced transient increases in liver transaminases with no reported incidences of drug-related hepatotoxicity in participants receiving orforglipron.3,4
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Hepatic Exclusion Criteria in Orforglipron Phase 2 and ATTAIN-1 Studies
In ATTAIN-1, participants were excluded if they had
- acute or chronic hepatitis including a history of autoimmune hepatitis, signs and symptoms of any other liver disease other than metabolic dysfunction-associated steatotic liver disease (MASLD)
- an ALT or AST level ≥3.0x ULN
- an alkaline phosphatase level ≥1.5x ULN
- a total bilirubin level ≥1.5x ULN, except for cases of known Gilbert’s Syndrome
- hepatitis B infection, or
- a positive hepatitis C antibody and positive hepatitis C virus RNA.1,3,4
Hepatitis B infection was defined as positive hepatitis B core antibody and positive for hepatitis B virus DNA or positive hepatitis B surface antigen.1,3,4
Participants with MASLD were eligible to participate in this trial if their ALT level was <3.0x ULN.1,3,4
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Orforglipron Metabolism
Orforglipron undergoes hepatic oxidative metabolism primarily via CYP3A4, with minimal contribution of reductive metabolism oxidative metabolism of orforglipron and oxidative metabolites in the gut.5
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References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Wharton S, Aronne LJ, Stefanski A, et al. Orforglipron, an oral small molecule GLP-1R agonist for obesity treatment. N Engl J Med. 2025;393(12):1123-1135. https://doi.org/10.1056/NEJMoa2511774
2Lilly's oral GLP-1, orforglipron, is successful in third Phase 3 trial, triggering global regulatory submissions this year for the treatment of obesity. Press release. Eli Lilly and Company; August 26, 2025. Accessed August 26, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-successful-third-phase-3-trial
3Frias 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. https://doi.org/10.1016/S0140-6736(23)01302-8
4Wharton S, Blevins T, Connery L, et al; GZGI Investigators. Daily oral GLP-1 receptor agonist orforglipron for adults with obesity. N Engl J Med. 2023;389(10):877-888. https://doi.org/10.1056/NEJMoa2302392
5Morse BL, Bhattachar S, Ma X, et al. Disposition and absolute bioavailability of orally administered orforglipron in healthy participants. Clin Pharmacol Drug Dev. Published online September 1, 2025. https://doi.org/10.1002/cpdd.1594
Date of Last Review: September 09, 2025