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Orforglipron-Diabetes
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 orforglipron-related reports of hepatotoxicity?
No cases of drug-related hepatotoxicity were reported with orforglipron in either of the phase 2 studies. No hepatic safety signal was observed in the phase 3 studies ACHIEVE-1 in type 2 diabetes and ATTAIN-1 and ATTAIN-2 in obesity or overweight.
Liver Enzyme Changes in Orforglipron Clinical Studies
Liver Enzyme Changes in Phase 2 Orforglipron Clinical Studies
Liver Enzyme Changes in the Orforglipron Phase 3 ACHIEVE-1 Study
During the orforglipron phase 3 ACHIEVE-1 study in adults with type 2 diabetes, there were decreases in mean
- alanine aminotransferase (ALT) levels, and
- aspartate aminotransferase (AST) levels (Changes in ALT and AST Levels in ACHIEVE-1).3
Parametera |
Orforglipron 3 mg |
Orforglipron 12 mg |
Orforglipron 36 mg |
Placebo |
ALT |
||||
Baseline, IU/L |
26.1 (1.2) |
23.0 (1.1) |
25.0 (1.2) |
25.0 (1.2) |
Change from baseline at week 40, IU/L |
-3.6 (0.7) |
-5.3 (0.8) |
-5.3 (0.8) |
-2.0 (0.7) |
Percent change from baseline at week 40, % |
-14.6 (3.0) |
-21.5 (3.3) |
-21.5 (3.1) |
-8.1 (3.0) |
AST |
||||
Baseline, IU/L |
22.8 (0.8) |
20.7 (0.8) |
22.2 (0.8) |
21.8 (0.8) |
Change from baseline at week 40, IU/L |
-1.8 (0.5) |
-2.4 (0.5) |
-2.9 (0.5) |
-0.9 (0.5) |
Percent change from baseline at week 40, % |
-8.2 (2.4) |
-11.0 (2.3) |
-13.1 (2.4) |
-3.9 (2.4) |
Abbreviations: ALT = alanine aminotransaminase; AST = aspartate aminotransaminase; LSM = least squares mean; MMRM = mixed model for repeated measures.
Notes: Data are LSM (SE) vs placebo at week 40 from MMRM using log transformation.
aIncludes all participants who received ≥1 dose.
Participants Reporting an ALT or AST ≥3x the Upper Limit of Normal
Participants with a maximum postbaseline ALT or AST ≥3x the upper limit of normal (ULN)
- were balanced across treatment groups
- were asymptomatic, and
- had levels return to normal or near-baseline for all orforglipron participants while taking study drug.3
No participant with a baseline ALT or AST ≥3x ULN shifted to a higher category during the study.3
There were no cases that met Hy’s law criteria for hepatocellular drug-induced liver injury.3
See Participants With a Maximum Post-baseline ALT or AST ≥3x Upper Limit of Normal for information on participants with a maximum postbaseline ALT or AST ≥3x ULN.
Categorya |
Orforglipron 3 mg |
Orforglipron 12 mg |
Orforglipron 36 mg |
Placebo |
ALTb |
|
|
|
|
≥3x ULN |
4 (2.8) |
4 (2.9) |
1 (0.7) |
2 (1.5) |
≥5x ULN |
0 |
0 |
0 |
1 (1.07) |
≥10x ULN |
0 |
0 |
0 |
0 |
AST |
||||
≥3x ULN |
1 (0.7) |
0 |
0 |
1 (0.7) |
≥5x ULN |
1 (0.7) |
0 |
0 |
0 |
≥10x ULN |
0 |
0 |
0 |
0 |
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal.
aData are n (%) and categories are not mutually exclusive as the same patient may be counted in multiple categories.
bCounts include participants with ALT ≥3x ULN at baseline (2 orforglipron 3 mg participants, 1 orforglipron 12 mg participant, and 1 placebo participant).
Hepatic Exclusion Criteria in ACHIEVE-1
In ACHIEVE-1, participants were excluded if they had
- acute or chronic hepatitis, including a history of autoimmune hepatitis, signs or symptoms of any other liver disease other than metabolic dysfunction-associated steatotic liver disease (MASLD)
- an ALT or AST >5.0x the ULN
- an alkaline phosphatase ≥1.5x the ULN
- a total bilirubin ≥1.5x the ULN, except for cases of known Gilbert’s syndrome
- hepatitis B, defined as
- positive hepatitis B core antibody and positive for hepatitis B virus DNA or
- positive hepatitis B surface antigen, or
- a positive hepatitis C antibody test and were positive for hepatitis C virus RNA.3
In ACHIEVE-1, participants were not excluded if they had MASLD as long as their ALT level was ≤5.0x the ULN.3
Available Data From the Orforglipron Phase 3 Studies ATTAIN-1 and ATTAIN-2
No hepatic safety signal was observed in the orforglipron phase 3 study ATTAIN-1 in adults with obesity or overweight and at least one weight-related comorbidity.4
No hepatic safety signal was observed in the orforglipron phase 3 study ATTAIN-2 in adults with obesity or overweight and type 2 diabetes.5
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Frias 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
2Wharton 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
3Rosenstock 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;392(25):1234-1245. https://doi.org/10.1056/NEJMoa2505669
4Lilly's oral GLP-1, orforglipron, delivers weight loss of up to an average of 27.3 lbs in first of two pivotal phase 3 trials in adults with obesity. Press release. Eli Lilly and Company. August 7, 2025. Accessed August 7, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-delivers-weight-loss-average-273
5Lilly'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
Date of Last Review: August 22, 2025