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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 reports of hepatotoxicity in the orforglipron type 2 diabetes trials?
No hepatic safety signal was observed for orforglipron in the phase 3 studies ACHIEVE-1, ACHIEVE-2, ACHIEVE-3, and ACHIEVE-5 in adults with type 2 diabetes. There were no reported cases of drug-related hepatotoxicity in the orforglipron phase 2 studies.
See important safety information, including boxed warning, in the attached prescribing information.
Content Overview
What Changes in Liver Enzymes Were Seen During the Orforglipron Type 2 Diabetes Studies?
- Liver Enzyme Changes in the Orforglipron Phase 3 ACHIEVE-1 Study
- Liver Enzyme Changes in the Orforglipron Phase 3 ACHIEVE-3 Study
- Liver Enzyme Changes in the Orforglipron Phase 3 ACHIEVE-2 and ACHIEVE-5 Studies
- Liver Enzyme Changes in Phase 2 Orforglipron Clinical Studies
Hepatic Exclusion Criteria in Orforglipron Type 2 Diabetes Studies
What Changes in Liver Enzymes Were Seen During the Orforglipron Type 2 Diabetes Studies?
Liver Enzyme Changes in the Orforglipron Phase 3 ACHIEVE-1 Study
ACHIEVE-1 was a 40-week, phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of once-daily oral orforglipron compared with placebo in adults with type 2 diabetes inadequately controlled with diet and exercise alone.1
During this study, there were decreases in mean
- alanine aminotransferase (ALT) levels, and
- aspartate aminotransferase (AST) levels (Changes in ALT and AST Levels in ACHIEVE-1).1
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 Above 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.1
No participant with a baseline ALT or AST ≥3x ULN shifted to a higher category during the study.1
There were no cases that met Hy’s law criteria for hepatocellular drug-induced liver injury.1
See Participants With a Maximum Post-baseline ALT or AST ≥3x Upper Limit of Normal in ACHIEVE-1 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).
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Liver Enzyme Changes in the Orforglipron Phase 3 ACHIEVE-3 Study
ACHIEVE-3 was a phase 3, 52-week, randomized, open-label trial evaluating the efficacy and safety of orforglipron (12 mg and 36 mg) compared with oral semaglutide (7 mg and 14 mg) in adults with type 2 diabetes inadequately controlled with metformin.2
Although the treatments were assigned in an open-label fashion, all investigators (including those who were involved in assessing the data), participants, and sponsor were blinded to the orforglipron dose assigned.2
During this study, there were mean decreases in AST and ALT levels from baseline to week 52 across all groups (Changes in ALT and AST Levels in ACHIEVE-3 ).2
Parameters | Orforglipron 12 mg | Orforglipron 36 mg | Semaglutide 7 mg | Semaglutide 14 mg |
ALT | ||||
Baseline, IU/L | 25.3 (0.72) | 25.8 (0.73) | 26.9 (0.76) | 27.0 (0.77) |
Change from baseline at week 52, IU/L | -6.0 (0.47) | -7.5 (0.48) | -4.2 (0.47) | -5.8 (0.44) |
Percent change from baseline at week 52, % | -22.8 (1.79) | -28.7 (1.81) | -15.9 (1.80) | -22.0 (1.69) |
AST | ||||
Baseline, IU/L | 20.7 (0.47) | 21.1 (0.48) | 21.6 (0.49) | 22.0 (0.50) |
Change from baseline at week 52, IU/L | -2.1 (0.30) | -3.3 (0.31) | -1.5 (0.33) | -2.1 (0.32) |
Percent change from baseline at week 52, % | -9.60 (1.40) | -15.31 (1.44) | -6.82 (1.54) | -10.02 (1.52) |
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; MBE = model-based estimate.
Data are MBE (SE), safety participants (safety analysis set), analysis with log-transformation.
Participants Reporting an ALT or AST Above the Upper Limit of Normal
As shown in Participants With a Maximum Postbaseline ALT or AST ≥3x Upper Limit of Normal in ACHIEVE-3, the orforglipron and semaglutide groups had generally similar percentages of participants with a maximum postbaseline AST or ALT level
- ≥3x ULN
- ≥5x ULN, or
- ≥10x ULN.2
Patients who shifted to a higher ALT/AST category during the study included
- 2 patients with baseline ALT ≥3x ULN (1 patient in the orforglipron 36 mg group and 1 in the semaglutide 14 mg group), and
- 1 patient with baseline AST ≥3x ULN (semaglutide 7 mg group).2
There was no case of hepatocellular drug-induced liver injury, as determined using Hy's law criteria.2
Categorya, n (%) | Orforglipron 12 mg | Orforglipron 36 mg | Semaglutide 7 mg | Semaglutide 14 mg |
ALTb | ||||
N | 419 | 420 | 425 | 424 |
≥3x ULN | 6 (1.4) | 5 (1.2) | 15 (3.5) | 8 (1.9) |
≥5x ULN | 3 (0.7) | 1 (0.2) | 2 (0.5) | 2 (0.5) |
≥10x ULN | 1 (0.2) | 1 (0.2) | 0 | 1 (0.2) |
AST | ||||
N | 419 | 421 | 425 | 424 |
≥3x ULN | 3 (0.7) | 4 (1.0) | 10 (2.4) | 1 (0.2)c |
≥5x ULN | 2 (0.5) | 1 (0.2) | 2 (0.5)c | 0 |
≥10x ULN | 0 | 1 (0.2) | 1 (0.2) | 0 |
Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal calculated based on reference range given for each patient at each measurement.
N=Number of patients with at least one postbaseline measurement for the specified parameters including results obtained from both central and local labs. Estimand guiding safety.
aCategories are not mutually exclusive; the same patient may be counted in multiple categories.
bCounts include patients with ALT ≥3x at baseline (orforglipron 12 mg, 0; orforglipron 36 mg, 2; semaglutide 7 mg, 4; semaglutide 14 mg, 2).
cOne of these participants had an AST ≥3x at baseline.
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Liver Enzyme Changes in the Orforglipron Phase 3 ACHIEVE-2 and ACHIEVE-5 Studies
No hepatic safety signal was observed for orforglipron in the phase 3 studies
- ACHIEVE-2 in adults with type 2 diabetes inadequately controlled with metformin, and
- ACHIEVE-5, in adults with type 2 diabetes inadequately controlled with titrated insulin glargine, with or without metformin and/or sodium-glucose cotransporter-2 (SGLT-2) inhibitor.3
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Liver Enzyme Changes in Phase 2 Orforglipron Clinical 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.4,5
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Hepatic Exclusion Criteria in Orforglipron Type 2 Diabetes Studies
In ACHIEVE-1 and ACHIEVE-3, 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.1,2
In both studies, participants were not excluded if they had MASLD as long as their ALT level was ≤5.0x the ULN.1,2
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Orforglipron Metabolism
Orforglipron undergoes hepatic oxidative metabolism primarily via CYP3A4, with minimal contribution of reductive metabolism of orforglipron and oxidative metabolites in the gut.6
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Enclosed Prescribing Information
References
The published references below are available by contacting 1-800-LillyRx (1-800-545-5979).
1Rosenstock J, Hsia S, Nevarez Ruiz L, et al; ACHIEVE-1 Trial Investigators. Orforglipron, an oral small-molecule GLP-1 receptor agonist, in early type 2 diabetes. N Engl J Med. 2025;393(11):1065-1076. https://doi.org/10.1056/NEJMoa2505669
2Rosenstock J, Yabe D, Cox D, et al. Efficacy and safety of once-daily oral orforglipron compared with oral semaglutide in adults with type 2 diabetes (ACHIEVE-3): a multinational, multicentre, non-inferiority, open-label, randomised, phase 3 trial. Lancet. Published online February 26, 2026. https://doi.org/10.1016/S0140-6736(26)00202-3
3Lilly's oral GLP-1, orforglipron, demonstrated superior glycemic control in two successful phase 3 trials, reconfirming its potential as a foundational treatment in type 2 diabetes. Press release. Eli Lilly and Company; October 15, 2025. Accessed October 15, 2025. https://investor.lilly.com/news-releases/news-release-details/lillys-oral-glp-1-orforglipron-demonstrated-superior-glycemic
4Frias 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
5Wharton 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
6Morse 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: April 20, 2026