Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials

Sean Wharton; Adam Stefanski; Jiaxun Chen; Girish Rao; Elvis Asare Twum; Max Denning

doi:10.1111/dom.71032

. 2026 Jun 23;28(9):8347–8358. doi: 10.1111/dom.71032

Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials

Sean Wharton ¹, Adam Stefanski ², Jiaxun Chen ², Girish Rao ², Elvis Asare Twum ^2,^✉, Max Denning ²

PMCID: PMC13448879 PMID: 42338042

ABSTRACT

Aims

Orforglipron is a novel small‐molecule, once daily oral non‐peptide GLP‐1 receptor agonist. The hepatic safety profile in adults with obesity or overweight and/or type 2 diabetes (T2D) across seven orforglipron Phase 3 clinical trials was assessed.

Materials and Methods

Overall, 11 220 participants were included in this analysis (orforglipron N = 6920; pooled comparator [placebo, oral semaglutide, dapagliflozin, insulin glargine] N = 4300) for up to 104 weeks, including safety follow‐up. Eligibility criteria for these Phase 3 trials included ALT/AST < 3 × ULN in the weight management programme and ≤ 5 × ULN in the T2D programme. The main analysis sets included placebo‐controlled trials by indication for pooled orforglipron doses. Changes from baseline in hepatic analytes were assessed continuously and categorically, and screening for drug‐induced liver injury/Hy's Law was conducted. Hepatic AEs were summarised. Subgroup analyses were conducted in participants with elevated baseline aminotransferases.

Results

Orforglipron treatment was associated with mean reductions in ALT/AST. Categorical ALT/AST elevations were generally balanced between orforglipron and comparators. Six (0.1%) orforglipron‐treated participants and six (0.1%) comparator‐treated participants had ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN; however, alternative etiologies accounted for all orforglipron cases and thus did not meet criteria for drug induced liver injury/Hy's Law. The incidence of hepatic AEs was balanced between orforglipron and pooled comparators, suggesting no increased risk with orforglipron. Results were consistent in participants with normal and elevated baseline aminotransferases.

Conclusions

In this pooled analysis of orforglipron Phase 3 clinical trials, orforglipron treatment was not associated with drug‐induced liver injury, demonstrating a hepatic safety profile similar to placebo or active comparators. There were no cases consistent with drug‐induced liver injury/Hy's Law with orforglipron. Aminotransferase trajectories showed a hepatic profile consistent with the metabolic benefits of weight loss.

Keywords: ACHIEVE, ATTAIN, hepatic safety, obesity, orforglipron, type 2 diabetes

Plain Language Summary

What is the context and purpose of this research study?
- ○
  Orforglipron is an oral GLP‐1 receptor agonist taken as tablet that helps to reduce blood sugar and reduce body weight. We studied how orforglipron may affect the liver in adults with obesity, overweight, and/or type 2 diabetes who participated in the Phase 3 clinical trials.
What was done?
- ○
  Across seven trials, orforglipron up to 17.2 mg once daily was compared to placebo, oral semaglutide, dapagliflozin, or insulin glargine. We measured changes in blood liver enzymes like AST, ALT and counted how many participants developed elevated liver enzymes above a set threshold. Analysis included all participants and those with preexisting elevated liver enzymes. We also checked for Hy's law, which signals for serious medicine related liver injury. Hy's Law screening was performed, and hepatic adverse events were summarised.
What were the main results?
- ○
  Treatment with orforglipron was not associated with drug‐induced liver injury, and no participant met the Hy's Law criteria. Additionally, ALT and AST levels improved over time with orforglipron, which coincides with the significant weight loss and metabolic improvements previously reported in these trials. Overall, the liver safety profile of orforglipron was comparable to placebo and other comparator medicines, including peptide GLP‐1 receptor agonist semaglutide.
What is the originality and relevance of this study?
- ○
  Findings from this analysis suggest that orforglipron was safe in adults with overweight, obesity, or type 2 diabetes—even in those with mildly to moderately elevated liver enzyme levels, which is commonly seen in MASLD. These findings support the need for dedicated studies on people with MASLD or metabolic dysfunction‐associated steatohepatitis (MASH).

1. Introduction

Glucagon‐like peptide 1 (GLP‐1) receptor agonists are the cornerstone of contemporary management for obesity and an important part of type 2 diabetes (T2D) treatment. Beyond glycaemic control and body weight reduction, GLP‐1 receptor agonists have demonstrated cardiorenal benefits and consistent reductions in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), with histological improvement in metabolic dysfunction‐associated steatohepatitis (MASH) and metabolic dysfunction‐associated steatotic liver disease (MASLD) [1, 2, 3, 4, 5, 6]. Because MASLD affects 65%–81% of adults with T2D and 70% of adults with overweight or obesity [7, 8], characterisation of hepatic safety across a range of baseline hepatic function is an important aspect in the development of any GLP‐1 receptor agonist‐based therapy for these populations.

Most approved GLP‐1 receptor agonists are peptides, administered subcutaneously and predominantly cleared by proteolysis and renal elimination [9]. Oral small‐molecule GLP‐1 receptor agonists are structurally distinct with different pharmacological characteristics.

Orforglipron is a once‐daily, oral small‐molecule, (non‐peptide) GLP‐1 receptor agonist [10, 11], approved for weight management and under investigation for T2D [12, 13, 14, 15, 16, 17, 18, 19]. The Phase 3 development programme enrolled participants in 20 countries across North America, Latin America, Europe and Asia regions, representative for a global population. In the weight management (WM) Phase 3 trials (ATTAIN‐1/‐2), in people with obesity or overweight with a weight‐related complication, orforglipron at all doses studied resulted in significant mean body weight reductions ranging from 5.5% to 12.4% following 72 weeks of treatment, compared with placebo [13, 14]. Furthermore, in the T2D Phase 3 programme (ACHIEVE‐1/‐2/‐3/‐4/‐5), in adults on various background therapies, orforglipron at all doses studied resulted in significant reductions in HbA1c versus comparators over 40–52 weeks of treatment. In these trials, orforglipron was compared with placebo, dapagliflozin, oral semaglutide and insulin glargine, including in participants with high cardiovascular risk in ACHIEVE‐4, where glycaemic benefits persisted through 104 weeks of therapy [15, 16, 17, 18, 19].

Orforglipron is primarily metabolised through the liver and is an in vitro inhibitor of hepatic transporters (OATP1B, BSEP, MRP2) [20]. The hepatic safety was closely monitored in all clinical trials investigating this molecule [13, 14, 15, 16, 17, 18, 19]. Herein, we present an integrated analysis of the hepatic safety of orforglipron observed in adults with obesity or overweight and/or T2D from the Phase 3 clinical trials [13, 14, 15, 16, 17, 18, 19]. Assessments included continuous and categorical changes in hepatic analytes, drug‐induced liver injury (DILI) screening with Hy's Law adjudication, and treatment‐emergent hepatic and biliary disorders; in the overall population and in a subgroup of participants with elevated baseline aminotransferases, suggestive of MASLD.

2. Methods

2.1. Trial Design and Participants

Study designs, full inclusion and exclusion criteria and primary results are published and summarised in Table S1 [13, 14, 15, 16, 17, 18, 19]. Briefly, the orforglipron Phase 3 development programme was comprised of two parallel programmes, one in WM (placebo‐controlled ATTAIN‐1/‐2 trials assessing orforglipron in addition to diet and exercise) and one in T2D (placebo‐controlled [ACHIEVE‐1/‐5 trials] and open‐labelled, active comparator‐controlled including dapagliflozin 10 mg, oral semaglutide 7 and 14 mg and insulin glargine [ACHIEVE‐2/‐3/‐4 trials]) [13, 14, 15, 16, 17, 18, 19]. Orforglipron capsule doses ranged from 1 to 36 mg. Capsule doses were later demonstrated to be bioequivalent to tablet doses ranging from 0.8 to 17.2 mg, which are reported herein [21]. Trial durations were 72 weeks in the WM Phase 3 programme and ranged from 40 to over 104 weeks across the T2D Phase 3 programme [13, 14, 15, 16, 17, 18, 19]. Participants were excluded from the trials if they had acute or chronic hepatitis, including a history of autoimmune hepatitis, signs and symptoms of any other liver disease other than nonalcoholic fatty liver disease (i.e., MASLD), or ALT/AST ≥ 3× the upper limit of normal (ULN) for the WM programme, > 5 × ULN for T2D, alkaline phosphatase (ALP) ≥ 1.5 × ULN, or total bilirubin (TBIL) level ≥ 1.5 × ULN (except for known cases of Gilbert's syndrome) [13, 14, 15, 16, 17, 18, 19]. The higher aminotransferase cutoff in the T2D programme was prespecified to enhance generalisability to a population with a high background prevalence of MASLD [15, 16, 17, 18, 19].

2.2. Procedure

In the orforglipron Phase 3 clinical trials, hepatic safety was monitored through systematic assessment of (1) adverse event (AE) reporting, (2) monitoring of hepatic analytes and (3) adjudication of cases meeting pre‐specified criteria, as described in the sections below.

2.3. AE Reporting

AE and serious AEs (SAEs) were reported in a spontaneous, non‐solicited manner by investigators who provided their own assessment of severity and drug‐relatedness. SAEs were AEs defined as serious according to International Conference on Harmonisation Good Clinical Practice guidelines. Additional information on the search strategy used is in the Supporting Information.

2.4. Hepatic Analyte Assessment

ALT, AST, ALP, gamma‐glutamyltransferase (GGT), TBIL and direct bilirubin (DBIL) were assessed at site visits every 4 weeks during dose escalation and every 8 weeks thereafter in the T2D Phase 3 programme (with the exception of ACHIEVE‐4, approximately every 12 weeks) and every 12 weeks in the WM Phase 3 programme. Additional unscheduled visits were permitted as deemed necessary by study investigators. Blood samples were analysed by central testing as well as local testing when necessary for immediate participant management. Respective central and local laboratory reference ranges were used when evaluating hepatic enzymes.

2.5. Adjudication

Cases meeting the criteria below were independently reviewed by two blinded safety physicians employed by the sponsor from another therapeutic area, with training and experience in hepatic event adjudication. If they were unable to reach a consensus, a hepatologist acted as the tiebreaker:

ALT ≥ 5 × ULN
AST ≥ 5 × ULN
ALP ≥ 3 × ULN
ALP ≥ 2 × ULN and TBIL ≥ 2 × ULN
ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN
Discontinued study intervention due to a hepatic‐related event, or
Serious hepatic‐related event

Causality was assigned using a modified US Drug‐Induced Liver Injury Network classification [22, 23]. For participants of interest, individual profiles were reviewed, including timing of the event relevant to study drug initiation, interruption and/or discontinuation, the changes in hepatic labs over time, the results of a comprehensive hepatic evaluation including diagnostic labs and imaging, and the temporal association with potential alternative causes.

2.6. Endpoints

Prespecified hepatic safety assessments included percent change from baseline over time in ALT and AST with post hoc assessment in a subgroup of participants with elevated baseline aminotransferases defined as ALT or AST ≥ 1.5 × ULN. Abnormal postbaseline categories of hepatic analytes were summarised (i.e., ALT and AST ≥ 3 × ULN, ≥ 5 × ULN and ≥ 10 × ULN; ALP ≥ 2 × ULN and ≥ 3 × ULN; and TBIL ≥ 2 × ULN, ≥ 5 × ULN, ≥ 8 × ULN) and shift of maximum baseline to maximum postbaseline ALT and AST was assessed from all Phase 3 trials. Hepatocellular DILI was assessed using an evaluation of Drug‐Induced Serious Hepatotoxicity (DILI screening plot) of peak postbaseline TBIL versus peak postbaseline ALT or AST (whichever was higher), including central and local laboratory analytes, with quadrants defined at 3 × ULN (aminotransferases) and 2 × ULN (bilirubin) [24, 25]. Cholestatic DILI was characterised analogously using peak postbaseline ALP 2 × ULN versus peak postbaseline TBIL 2 × ULN [24]. Hy's Law cases were defined as ALT or AST ≥ 3 × ULN concurrent with TBIL ≥ 2 × ULN, in the absence of cholestasis (ALP < 2 × ULN) and after exclusion of alternative aetiologies [25]. Hepatic‐related treatment‐emergent adverse events (TEAEs) and gallbladder‐related TEAEs were summarised separately in the overall population. Hepatic‐related TEAEs were also analysed in participants with elevated baseline aminotransferases.

2.7. Statistical Analyses

Data from all participants who received at least one dose of study drug were used for these analyses (i.e., safety population). The main analyses sets included (1) pooled placebo‐controlled WM Phase 3 trials (ATTAIN‐1/−2 trials), (2) pooled placebo‐controlled T2D Phase 3 trials (ACHIEVE‐1/‐5 trials) and (3) pooled placebo‐ and active‐comparator‐controlled WM and T2D Phase 3 trials.

Changes from baseline in ALT and AST were analysed in pooled placebo‐controlled trials by indication and in ACHIEVE‐2 (vs dapagliflozin), ACHIEVE‐3 (vs oral semaglutide) and ACHIEVE‐4 (vs insulin glargine) using a mixed model repeated measures (MMRM) analysis, using log transformation, with the following fixed effects: treatment group, visit, and treatment‐by‐visit interaction, and with baseline value included as a covariate. Missing data were implicitly handled by the MMRM model, which was based on the missing at random assumption. No explicit imputation methods for missing data were employed. Treatment comparisons were not adjusted for multiplicity. Baseline and postbaseline maximum ALT, AST, ALP and TBIL from pooled WM and T2D Phase 3 trials were used for the analyses of abnormal postbaseline categories and DILI. TEAEs potentially related to hepatic injury were identified using the Drug‐Related Hepatic Disorders Standardised MedDRA Query (version 28.1) and were descriptively summarised by pooled orforglipron groups and pooled comparators groups from all trials. For percentage of participants with events, the study size adjusted percentage was provided to adjust for different randomisation ratios across trials.

Statistical analyses were done with SAS (version 9.4) and R (version 3.5 and later).

3. Results

3.1. Exposure to Study Drug and Baseline Characteristics

In the orforglipron Phase 3 clinical trials, 11 220 randomised participants received at least one dose of study drug (orforglipron, placebo, or active comparators [dapagliflozin 10 mg, oral semaglutide 7/14 mg, insulin glargine]), with a mean total study drug exposure of 13238.5 patient‐years. Of these, 6920 participants received orforglipron (mean drug exposure 7829.5 patient‐years) and 4300 participants received active comparator or placebo (mean drug exposure 5409.0 patient‐years), with a combined exposure of 14811.7 patient‐years (pooled orforglipron: 8889.1 patient‐years; pooled comparators: 5922.6 patient‐years). Baseline demographics and clinical characteristics from the total population of each trial are presented in Table 1.

TABLE 1.

Baseline demographics and clinical characteristics.

Parameters	ATTAIN‐1 (N = 3127)	ATTAIN‐2 (N = 1613)	ACHIEVE‐1 (N = 559)	ACHIEVE‐2 (N = 962)	ACHIEVE‐3 (N = 1698)	ACHIEVE‐4 (N = 2749)	ACHIEVE‐5 (N = 546)
Age, years	45.1 ± 12.1	56.8 ± 10.7	53.4 ± 11.8	56.1 ± 11.5	53.9 ± 11.1	63.1 ± 9.9	60.2 ± 10.1
Female sex, n (%)	2009 (64.2)	757 (46.9)	269 (48.1)	474 (49.3)	825 (48.6)	1032 (37.5)	257 (47.1)
Race, n (%)
American Indian or Alaska Native	11 (0.4)	5 (0.3)	143 (25.6)	243 (25.3)	334 (20.0)	285 (10.4)	2 (0.4)
Asian	884 (28.6)	279 (17.3)	245 (43.8)	171 (17.8)	202 (12.1)	232 (8.5)	140 (25.6)
Black or African American	267 (8.6)	105 (6.5)	24 (4.3)	20 (2.1)	65 (3.9)	227 (8.3)	53 (9.7)
White	1746 (56.5)	1143 (70.9)	145 (25.9)	500 (52.0)	1029 (61.5)	1914 (69.9)	319 (58.4)
Native Hawaiian or other Pacific Islander	3 (0.1)	6 (0.4)	NA	NA	NA	3 (0.1)	1 (0.2)
Multiple	181 (5.9)	45 (2.8)	1 (0.2)	27 (2.8)	42 (2.5)	77 (2.8)	23 (4.2)
Ethnicity, n (%)
Hispanic or Latino	1175 (37.6)	488 (30.3)	223 (39.9)	458 (47.6)	1234 (72.7)	1276 (46.4)	226 (41.4)
Not Hispanic or Latino	1923 (61.5)	1084 (67.2)	335 (59.9)	495 (51.5)	455 (26.8)	1472 (53.5)	319 (58.4)
Not reported	29 (0.9)	41 (2.5)	1 (0.2)	9 (0.9)	9 (0.5)	1 (0.0)	1 (0.2)
HbA1c, %	5.6 ± 0.3	8.05 ± 0.75	8.0 ± 0.9	8.1 ± 1.04	8.3 ± 1.1	8.2 ± 1.0	8.5 ± 0.95
In mmol/mol	38.1 ± 3.7	64.4 ± 8.2	63.8 ± 9.7	65.5 ± 11.4	67.1 ± 12.0	66.4 ± 10.8	69.4 ± 10.4
Body weight, kg	103.2 ± 22.1	101.4 ± 22.5	90.2 ± 23.1	89.9 ± 21.8	97.0 ± 22.3	90.9 ± 20.0	85.2 ± 19.2
BMI, kg/m²	37.0 ± 6.5	35.6 ± 6.6	33.0 ± 7.5	32.6 ± 6.6	35.1 ± 7.1	32.6 ± 6.2	30.8 ± 6.1
Waist circumference, cm	112.4 ± 14.5	115.6 ± 14.6	107.3 ± 16.1	107.1 ± 15.0	112.3 ± 15.3	109.2 ± 14.2	104.5 ± 14.2
eGFR, ml/min/1.73 m² ^a	92.7 ± 18.6	82.8 ± 21.5	83.6 ± 22.4	87.2 ± 20.0	90.6 ± 19.6	69.1 ± 23.9	78.8 ± 23.4
Obesity duration, years	13.5 ± 10.9	18.1 (12.6)	NA	NA	NA	NA	NA
Diabetes duration, years	NA	8.5 ± 6.6	4.4 ± 5.4	8.0 ± 6.7	8.7 ± 6.5	12.0 ± 8.4	15.0 ± 8.3
ALT (U/L)	22.8 (58.2)	25.8 (56.7)	24.8 (61.6)	25.6 (59.3)	26.2 (63.9)	21.4 (51.6)	20.8 (49.0)
AST (U/L)	20.2 (36.3)	21.8 (43.9)	21.9 (46.3)	22.1 (47.6)	21.4 (49.8)	20.0 (39.0)	19.7 (38.1)

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Note: Data are mean ± SD, unless otherwise indicated. ALT and AST are geometric mean (coefficient of variation).

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; BMI = body mass index; CKD‐EPI = Chronic Kidney Disease‐Epidemiology; eGFR = estimated glomerular filtration rate; HbA1c = glycated haemoglobin; NA = not applicable; SD = standard deviation.

^{^a}

The value of the eGFR was calculated according to the serum cystatin C‐based Chronic Kidney Disease Epidemiology Collaboration (CKD‐EPI) equation.

3.2. Percent Change From Baseline in Hepatic Analytes

Model‐based estimates of percent change from baseline in ALT over time are presented in Figure 1. In the WM Phase 3 programme, ALT decreased by 15.7% with orforglipron 5.5 mg, 18.4% with orforglipron 9 mg and 19.8% with orforglipron 17.2 mg, versus 8.0% with placebo at Week 72 (Figure 1A). Reductions in ALT were significantly greater with orforglipron at all doses relative to placebo, with estimated treatment difference (95% confidence intervals) of −8.4% (−11.6, −5.2) with orforglipron 5.5 mg, −11.3% (−14.4, −8.1) with orforglipron 9 mg and −12.9% (−16.1, −9.6) with orforglipron 17.2 mg (p < 0.001, all comparisons). In the placebo‐controlled T2D trials, ALT decreased by 9.3% with orforglipron 2.5 mg, 14.0% with orforglipron 9 mg and 16.1% with orforglipron 17.2 mg, versus 7.6% with placebo at Week 40 (Figure 1B). Reductions in ALT were significantly greater with orforglipron 9 and 17.2 mg relative to placebo, with estimated treatment differences of −6.9% (−13.1, −0.2); p = 0.045 and −9.1% (−15.1, −2.7); p = 0.006, respectively.

Percent change from baseline in ALT through safety follow‐up. Data are model‐based estimates (standard error) change from baseline in ALT over time from the safety population, using log transformation. Baseline values are geometric means. (A) Pooled placebo‐controlled trials for weight management (ATTAIN‐1 and ATTAIN‐2), (B) pooled placebo‐controlled trials for T2D (ACHIEVE‐1 and ACHIEVE‐5), (C) ACHIEVE‐2, (D) ACHIEVE‐3, (E) ACHIEVE‐4. Abbreviations: ALT = alanine aminotransferase; DAPA = dapagliflozin; iGlar = insulin glargine; MTD = maximum tolerated dose; OFG = orforglipron; SEMA = semaglutide; SFU = safety follow‐up; T2D = type 2 diabetes.

In ACHIEVE‐2, ALT decreased by 10.7% with orforglipron 2.5 mg, 24.2% with orforglipron 9 mg and 27.2% with orforglipron 17.2 mg, versus 18.1% with dapagliflozin 10 mg at Week 40 (Figure 1C). Reductions in ALT were significantly lower with orforglipron 2.5 mg relative to dapagliflozin 10 mg (9.0% [0.1, 18.7]; p = 0.048) and significantly greater with orforglipron 17.2 mg relative to dapagliflozin 10 mg (−11.1% [−18.0, −3.7]; p = 0.004). In ACHIEVE‐3, ALT decreased by 22.8% with orforglipron 9 mg and 28.7% with orforglipron 17.2 mg, versus 15.9% with oral semaglutide 7 mg and 22.0% with oral semaglutide 14 mg at Week 52 (Figure 1D). Reductions in ALT were significantly greater with orforglipron relative to oral semaglutide 7 mg, with estimated treatment difference of −8.2% (−13.7, −2.3); p = 0.007 with orforglipron 9 mg and −15.3% (−20.6, −9.5); p < 0.001 with orforglipron 17.2 mg. Reductions in ALT were also significantly greater with orforglipron 17.2 mg relative to oral semaglutide 14 mg (−8.6% [−14.4, −2.4]; p = 0.007). In ACHIEVE‐4, ALT decreased by 9.2% with orforglipron MTD versus 5.7% with insulin glargine at Week 104 (−3.7 [−7.4, 0.2]; p = 0.060) (Figure 1E). Overall, similar reductions in AST were observed with orforglipron (Figure S1). In participants with elevated baseline aminotransferases, reductions in ALT and AST were also observed with orforglipron groups (Figures S2–S5).

3.3. Abnormal Postbaseline Categories for Hepatic Analytes

Incidence of abnormal postbaseline categories for hepatic analytes pooled across the seven Phase 3 orforglipron trials are presented in Table S2. Overall, 142 (2.1%) orforglipron‐treated versus 80 (1.9%) comparator‐treated participants had ALT ≥ 3 × ULN, 48 (0.7%) versus 27 (0.6%) had ALT ≥ 5 × ULN, and 16 (0.2%) versus 6 (0.1%) had ALT ≥ 10 × ULN. The majority of the orforglipron cases that met the ALT/AST ≥ 10 × ULN threshold had alternative aetiologies reported (Table S3). Furthermore, 58 (0.8%) versus 45 (1.1%) participants had AST ≥ 3 × ULN, 21 (0.3%) versus 12 (0.3%) had AST ≥ 5 × ULN, and 7 (0.1%) versus 6 (0.1%) had AST ≥ 10 × ULN, respectively. ALP ≥ 2 × ULN was reported in 34 (0.5%) versus 26 (0.6%) participants and 9 (0.1%) versus 9 (0.2%) had ALP ≥ 3 × ULN, respectively. TBIL ≥ 2 × ULN was reported in 26 (0.4) versus 13 (0.3%) participants, no cases of TBIL ≥ 3 × ULN or ≥ 8 × ULN occurred with orforglipron, whereas 6 (0.1%) comparator‐treated participants were reported for each threshold.

3.4. Shift in ALT and AST

Shifts from maximum baseline to maximum postbaseline hepatic analytes in the orforglipron Phase 3 clinical trials are presented in Table 2. The majority of patients with baseline elevations of AST or ALT shifted to a lower category or stayed within the same category. Overall, the safety was consistent among participants with normal aminotransferases and in those with elevated aminotransferases with no clinically relevant differences observed across treatment groups in percentage of participants who shifted from baseline to a higher postbaseline category of ALT or AST elevation.

TABLE 2.

Shift in ALT and AST from maximum baseline to maximum postbaseline in the orforglipron development programme.

Hepatic analyte	Treatment arm	Baseline category	Postbaseline threshold for pooled orforglipron (N = 6920) or pooled comparator (N = 4300) ^a , n (%)
Hepatic analyte	Treatment arm	Baseline category	< 1 × ULN	≥ 1× to < 3 × ULN	≥ 3× to < 5 × ULN	≥ 5× to < 10 × ULN	≥ 10× to < 20 × ULN	≥ 20 × ULN
ALT (U/L)	Pooled orforglipron	< 1 × ULN	3988 (57.6)	1116 (16.1)	41 (0.6)	16 (0.2)	6 (0.1)	0
		≥ 1× to < 3 × ULN	431 (6.2)	1134 (16.4)	49 (0.7)	12 (0.2)	4 (0.1)	0
		≥ 3× to < 5 × ULN	6 (0.1)	19 (0.3)	4 (0.1)	3 (< 0.1)	3 (< 0.1)	0
		≥ 5× to < 10 × ULN	0	1 (< 0.1)	2 (< 0.1)	0	0	0
		≥ 10× to < 20 × ULN	1 (< 0.1)	0	0	0	0	0
		≥ 20 × ULN	0	0	0	0	0	0
	Pooled comparator	< 1 × ULN	2588 (60.2)	636 (14.8)	16 (0.4)	8 (0.2)	2 (< 0.1)	1 (< 0.1)
		≥ 1× to < 3 × ULN	224 (5.2)	700 (16.3)	28 (0.7)	13 (0.3)	0	0
		≥ 3× to < 5 × ULN	1 (< 0.1)	18 (0.4)	10 (0.2)	1 (< 0.1)	0	0
		≥ 5× to < 10 × ULN	0	0	0	1 (< 0.1)	0	0
		≥ 10× to < 20 × ULN	0	0	0	0	0	0
		≥ 20 × ULN	0	0	0	0	0	0
AST (U/L)	Pooled orforglipron	< 1 × ULN	5418 (78.3)	675 (9.8)	23 (0.3)	12 (0.2)	1 (< 0.1)	0
		≥ 1× to < 3 × ULN	306 (4.4)	375 (5.4)	11 (0.2)	1 (< 0.1)	2 (< 0.1)	0
		≥ 3× to < 5 × ULN	2 (< 0.1)	10 (0.1)	1 (< 0.1)	0	0	0
		≥ 5× to < 10 × ULN	1 (< 0.1)	0	0	0	0	0
		≥ 10× to < 20 × ULN	0	0	0	0	0	0
		≥ 20 × ULN	0	0	0	0	0	0
	Pooled comparator	< 1 × ULN	3326 (77.3)	428 (10.0)	18 (0.4)	2 (< 0.1)	2 (< 0.1)	1 (< 0.1)
		≥ 1× to < 3 × ULN	162 (3.8)	281 (6.5)	12 (0.3)	2 (< 0.1)	1 (< 0.1)	0
		≥ 3× to < 5 × ULN	1 (< 0.1)	5 (0.1)	3 (0.1)	1 (< 0.1)	0	0
		≥ 5× to < 10 × ULN	0	1 (< 0.1)	0	1 (< 0.1)	0	0
		≥ 10× to < 20 × ULN	0	0	0	0	0	0
		≥ 20 × ULN	0	0	0	0	0	0

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Note: Data are n (%) from the safety population. Shift in “improved,” “stable,” and “attenuated” categories are indicated in green, yellow, and red, respectively.

Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; n = number of participants in each category; N = number of participants in the analysis population; ULN = upper limit of normal reference.

^{^a}

Post‐baseline missing data for 82 (1.2%) orforglipron‐treated participants and 53 (1.2%) comparator‐treated participants for ALT and 81 (1.2.%) orforglipron‐treated participants and 53 (1.2%) comparator‐treated participants for AST.

3.5. DILI Screening

On the hepatocellular DILI screening plot, 155 (2.3%) orforglipron‐treated participants versus 85 (2.0%) comparator‐treated participants occupied the lower right quadrant (i.e., Temple's corollary) and 21 (0.31%) versus 7 (0.16%) participants occupied the upper left quadrant (i.e., cholestasis), with 12 (57%) of the cases in the orforglipron group and 2 (29%) of cases in the comparator group reporting Gilbert's syndrome or hyperbilirubinaemia as medical history or having elevated baseline bilirubin (Figure 2). Among those with postbaseline cholestasis, the mean percent change in body weight was −15.0% in orforglipron‐treated participants and −3.9% in comparator‐treated participants (Table S4). No cases of confirmed DILI/Hy's Law occurred in any of the Phase 3 trials. Six (0.1%) orforglipron‐treated participants and 6 (0.1%) comparator‐treated participants had ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN. Alternative aetiologies were identified for all six orforglipron‐treated participants, including two cases of gallstone disease, including one case with isolated bilirubin elevation which returned to normal 3 days later (orforglipron 5.5 mg in ATTAIN‐1, n = 1; orforglipron 9 mg in ATTAIN‐2, n = 1); one case of acute hepatitis A virus infection (orforglipron 17.2 mg in ATTAIN‐1), one case with predominantly indirect hyperbilirubinaemia, which occurred more than 30 days after the elevated AST and potential alcohol‐associated liver disease (orforglipron 2.5 mg in ACHIEVE‐1); one case with predominantly indirect hyperbilirubinaemia suggesting Gilbert's syndrome with alcohol use and steatosis as confounders (orforglipron 2.5 mg in ACHIEVE‐1); and one case with normal DBIL and most likely alternative aetiology being intake of herbal medicine, and Gilbert's syndrome (orforglipron MTD in ACHIEVE‐4). A complete summary of all orforglipron‐treated participants with either ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN across the Phase 3 programme is provided in Table S5. Cholestatic DILI screening plots with quadrant distributions are shown in Figure S6.

Hepatocellular DILI screening in the orforglipron WM and T2D Phase 3 clinical trials. Results obtained from both central and local labs were included. Points do not necessarily represent values from the same blood draw. Participants were only included if they had non‐missing postbaseline values for both TBIL and ALT or AST. Abbreviations: ALT = alanine aminotransferase; AST = aspartate aminotransferase; DILI = drug‐induced liver injury; n = number of participants with at least one event in the specified category; T2D = type 2 diabetes; TBIL = total bilirubin; ULN = upper limit of normal reference; WM = weight management.

3.6. Treatment‐Emergent Hepatic Disorders

The incidence of hepatic‐related TEAEs was balanced across orforglipron and pooled comparators (315 [4.6%] vs. 187 [4.4%], respectively), with the majority of cases being hepatic enzyme abnormalities (Table 3), which was consistent in participants with elevated baseline aminotransferases (Table S6). Gallbladder and biliary tract TEAEs were reported in 105 (1.5%) versus 49 (1.1%) participants, respectively (Table S7). The difference was driven by cholelithiasis (orforglipron: 1.0%; pooled comparators 0.6%), which was the most commonly reported event. Acute cholecystitis events were similar between groups (Table S7). Serious hepatic events were reported in 5 (0.07%) orforglipron‐treated participants versus 7 (0.2%) comparator‐treated participants (Table 3) and were consistent in the subgroups of participants with elevated baseline aminotransferases (Table S6).

TABLE 3.

Summary of treatment‐emergent hepatic events in the orforglipron development programme.

	Pooled orforglipron (N = 6920)	Pooled comparator (N = 4300)
Participants with at least one event	315 (4.55)	187 (4.35)
Severe	15 (0.22)	13 (0.30)
Serious	5 (0.07)	7 (0.16)
Death	0	2 (0.05)
Leading to permanent discontinuation of study treatment	12 (0.17)	5 (0.12)
Frequently reported events occurring in > 10 participants in any group, n (adjusted %)
Gamma‐glutamyltransferase increased	69 (0.95)	32 (0.84)
Alanine aminotransferase increased	58 (0.81)	33 (0.91)
Hepatic enzyme increased	27 (0.38)	12 (0.30)
Aspartate aminotransferase increased	24 (0.34)	19 (0.54)
Hepatic function abnormal	22 (0.28)	15 (0.40)
Transaminases increased	20 (0.29)	10 (0.21)
Blood bilirubin increased	15 (0.21)	6 (0.13)
Hyperbilirubinaemia	10 (0.14)	2 (0.05)
Blood alkaline phosphatase increased	15 (0.22)	12 (0.29)
Hepatic steatosis	69 (1.05)	51 (1.23)
Metabolic dysfunction‐associated liver disease	13 (0.18)	7 (0.16)

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Note: Data are n (%) from the safety population. Adjusted % is study size adjusted percentage, calculated within each treatment group as a weighted average of within‐study percentage to adjust for different randomisation ratio when pooling across studies. Events may be classified under multiple categories.

4. Discussion

Across ~7000 orforglipron‐treated participants and 8889.1 patient‐years of exposure spanning seven Phase 3 trials, orforglipron at doses up to 17.2 mg once daily showed no signal of DILI. Similar proportions of orforglipron‐treated participants and comparator‐treated participants had ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN during the trials. No participant met criteria for DILI/Hy's Law. The distribution of participants in the Temple's corollary was balanced. Temple's Corollary is a DILI safety concept, identifying patients with significant ALT elevations (> 3 × ULN) but without significant elevated TBIL (< 2 × ULN), signifying potential hepatocellular injury. There was an imbalance in the cholestasis quadrant, with 12 (57%) of the cases in the orforglipron group and 2 (29%) of cases in the comparator group reporting Gilbert's syndrome or hyperbilirubinaemia/abnormal bilirubin as medical history or having elevated baseline bilirubin. While orforglipron is an inhibitor of some hepatobiliary transporters in vitro (at concentrations up to 0.17 μM) [20], this does not translate into clinically meaningful inhibition at therapeutic exposures (concentrations up to 0.0002 μM at the liver inlet with orforglipron 36 mg) [20] and is therefore an unlikely explanation for the numerical imbalance in cholestasis events. Rather, the imbalance most likely reflects the substantially greater weight loss in affected orforglipron‐treated participants, as marked caloric restriction and weight reduction are themselves recognised causes of cholelithiasis and altered bilirubin levels [26, 27, 28, 29, 30]. Aminotransferase elevations were broadly similar between orforglipron and comparator groups. Dose‐dependent mean reductions in ALT and AST were observed across all studies. The observed reductions in aminotransferases were consistent with the expected hepatic response to weight loss and MASLD improvement [31, 32, 33]. These reductions were most pronounced in ACHIEVE‐4, which enrolled participants with more advanced baseline cardiometabolic profile and included participants with ALT/AST up to 5 × ULN.

Several features of the programme and the target population warrant discussion. First, the T2D Phase 3 programme included participants with ALT/AST up to 5 × ULN to ensure a study population representative of real‐world T2D, including East Asian countries, in which MASLD is substantially more prevalent than in the general population. Consequently, 9.3% of orforglipron‐treated participants in the T2D placebo‐controlled dataset had elevated baseline ALT, defined as ≥ 1.5 × ULN. Enrolling a population in which baseline aminotransferase elevations consistent with MASLD are well represented is a design choice. Although this increases the observed frequency of postbaseline aminotransferase elevations through a numerator effect driven by baseline abnormalities, it improves external generalizability. The population‐level mean aminotransferase reductions with orforglipron, likely related to substantial weight loss and improvement in presumed MASLD pathophysiology, suggest potential for hepatic benefit and warrant further investigation.

A thorough evaluation of hepatic safety of orforglipron is an important consideration given the need to establish compound level safety for any new molecular entity advancing towards broad clinical use. In this context, the head‐to‐head comparison in ACHIEVE‐3 between orforglipron and oral semaglutide is particularly informative, demonstrating that orforglipron's hepatic safety profile was consistent with that of an established peptide GLP‐1 receptor agonist. These findings are also consistent with the reassuring hepatic safety profile reported across the semaglutide (STEP, SUSTAIN) and tirzepatide (SURMOUNT, SURPASS) programmes, in which weight‐loss‐associated reductions in aminotransferases have been observed without a signal of DILI [34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57].

Across all Phase 3 clinical trials included in this analysis, all cases with ALT/AST ≥ 3 × ULN and TBIL ≥ 2 × ULN had robust alternative etiologies: biliary disease (the most common), acute viral hepatitis, Gilbert's syndrome with bilirubin fractionation confirming predominantly indirect hyperbilirubinaemia, and alcohol‐associated cirrhosis. The absence of confirmed cases of DILI/Hy's Law at the doses studied, in light of the overall population size studied, is a reassuring finding, given that identification of DILI/Hy's Law cases during premarketing development is recognised by FDA 2009 DILI guidance as a predictor of severe DILI in post‐marketing setting [25].

ACHIEVE‐4 enrolled the participants with the highest cardiometabolic risk across all Phase 3 clinical trials and provided the longest exposure (median treatment duration of 94 weeks and maximum study duration of 148 weeks), making it the most informative comparison against insulin glargine, an agent without an established hepatic safety signal. The magnitude of mean aminotransferase reduction in ACHIEVE‐4 was numerically greater than in the broader pool, consistent with a higher proportion of participants entering the trial with baseline aminotransferase elevations and a greater scope for improvement with weight loss and metabolic correction. Among participants with elevated baseline aminotransferases consistent with MASLD, a subgroup of particular clinical significance due to high prevalence of MASLD in T2D, the hepatic safety findings were comparable to those observed in the overall study population. The mean ALT reduction in this subgroup ranged from 36.6% to 74.8% across trials. These findings demonstrate that orforglipron was safely initiated in adults with mildly to moderately elevated baseline aminotransferases attributable to presumed MASLD and support further prospective evaluation in dedicated MASLD/MASH trials.

A numerical imbalance in cholelithiasis (1.0% versus 0.6%) was observed with orforglipron, consistent with that observed for other products with GLP‐1 receptor agonist activity, although this did not translate into a corresponding increase in cholecystitis. Cholelithiasis was not systematically evaluated at baseline or during treatment in the Phase 3 programme. The observed imbalance may, in principle, be influenced by ascertainment bias as the higher incidence of gastrointestinal AEs and elevations in pancreatic enzymes associated with GLP‐1 receptor agonists [58, 59] may have prompted more frequent abdominal imaging in the orforglipron group.

Limitations of this analysis include pooling of trials with heterogeneity in study design, comparator groups and exposure durations limit the validity of cross‐trial inferences. Therefore, the placebo‐controlled trials and active‐comparator trials of ATTAIN and ACHIEVE were analysed separately. Three out of the seven included trials utilised an open‐label design, which may have introduced bias in the identification and reporting of hepatic AEs by investigators and participants. Participants with aminotransferases > 5 × ULN or hepatic disease other than MASLD were excluded, limiting availability of data in those populations. MASLD in this population was described presumptively from cardiometabolic phenotype and baseline aminotransferase elevations; steatosis and fibrosis were not systematically evaluated. Although elevated aminotransferases indicate hepatic inflammation, it does not characterise steatosis, or fibrosis. Determining whether reduced aminotransferase levels reflect improved hepatic inflammation or disease activity needs dedicated studies assessing inflammation and fibrosis.

In conclusion, integrated data from seven Phase 3 trials including 11 220 participants demonstrated a favourable hepatic safety profile for the once‐daily oral non‐peptide GLP‐1 receptor agonist orforglipron in adults with obesity, overweight with weight‐related comorbidities and/or T2D. Mean reductions in aminotransferases, balanced incidence of categorical liver chemistry elevations versus placebo and active comparators, and the absence of confirmed cases of DILI/Hy's Law collectively support this profile.

Author Contributions

M.D., A.S., J.C., G.R. and E.A.T. contributed to the study designs. M.D., A.S. and E.A.T. provided medical oversight during the trial. J.C. was responsible for the statistical analysis. E.A.T. and M.D. are the guarantors of this work and, as such, take responsibility for the integrity of the data and the accuracy of the data analysis. All authors participated in interpretation of the data and critical review of the manuscript, had full access to the data, and approved of this manuscript to be submitted for publication.

Funding

This work was supported by Eli Lilly and Company.

Conflicts of Interest

S.W. reported receiving nonfinancial support from Eli Lilly and Company during the conduct of the study and personal fees from Abbvie, Amgen, AstraZeneca, Bausch Health Canada, Boehringer Ingelheim, Eli Lilly and Company, i2o Therapeutics, Merck, Metsera, NGX, Novo Nordisk, and Regeneron outside the submitted work, served on an advisory board for Boehringer Ingelheim, holds a leadership role for Obesity Canada and Obesity Society, and has received medical writing support from Boehringer Ingelheim, Eli Lilly and Company, and Novo Nordisk. A.S., J.C., G.R., E.A.T. and M.D. are employees and shareholders of Eli Lilly and Company. The sponsor (Eli Lilly and Company) designed and oversaw the conduct of the trials included in this analysis. The trial site investigators were responsible for data collection, with site monitoring, data collation, and data analysis and medical writing support provided by the sponsor.

Supporting information

Table S1: Overview of the orforglipron Phase 3 clinical trials.

Table S2: Summary of abnormal postbaseline categories for hepatic analytes.

Table S3: Details for orforglipron participants who met postbaseline ALT or AST threshold of ≥ 10 × ULN in the orforglipron Phase 3 clinical trials.

Table S4: Percent body weight change in participants with postbaseline cholestasis.

Table S5: Orforglipron‐treated participants with ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN.

Table S6: Treatment‐emergent hepatic adverse events in the orforglipron Phase 3 clinical trials in participants with elevated baseline aminotransferases.

Table S7: Summary of treatment‐emergent gallbladder and biliary tract disorders in the orforglipron Phase 3 clinical trials.

Figure S1: Percent change from baseline in AST.

Figure S2: Percent change from baseline in ALT through safety follow‐up in participants with baseline ALT ≥ 1.5 × ULN.

Figure S3: Percent change from baseline in AST through safety follow‐up in participants with baseline ALT ≥ 1.5 × ULN.

Figure S4: Percent change from baseline in ALT through safety follow‐up in participants with baseline AST ≥ 1.5 × ULN.

Figure S5: Percent change from baseline in AST through safety follow‐up in participants with baseline AST ≥ 1.5 × ULN.

Figure S6: Cholestatic DILI screening in the orforglipron Phase 3 clinical trials.

DOM-28-8347-s001.docx^{(1.3MB, docx)}

Acknowledgements

This work was supported by Eli Lilly and Company. The authors thank Chrisanthi A. Karanikas, Seán Curley and Vedashree S (Eli Lilly and Company) for their writing and editorial contributions.

Wharton S., Stefanski A., Chen J., Rao G., Twum E. A., and Denning M., “Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials,” Diabetes, Obesity and Metabolism 28, no. 9 (2026): 8347–8358, 10.1111/dom.71032.

Handling Editor: Richard Donnelly

Data Availability Statement

Lilly provides access to all individual participant data collected during the trial, after anonymisation, with the exception of pharmacokinetic or genetic data. Data are available to request 6 months after the indication studied has been approved in the US and EU and after primary publication acceptance, whichever is later. No expiration date of data requests is currently set once data are made available. Access is provided after a proposal has been approved by an independent review committee identified for this purpose and after receipt of a signed data sharing agreement. Data and documents, including the study protocol, statistical analysis plan, clinical study report, blank or annotated case report forms, will be provided in a secure data sharing environment. For details on submitting a request, see the instructions provided at www.vivli.org.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Table S1: Overview of the orforglipron Phase 3 clinical trials.

Table S2: Summary of abnormal postbaseline categories for hepatic analytes.

Table S3: Details for orforglipron participants who met postbaseline ALT or AST threshold of ≥ 10 × ULN in the orforglipron Phase 3 clinical trials.

Table S4: Percent body weight change in participants with postbaseline cholestasis.

Table S5: Orforglipron‐treated participants with ALT or AST ≥ 3 × ULN and TBIL ≥ 2 × ULN.

Table S6: Treatment‐emergent hepatic adverse events in the orforglipron Phase 3 clinical trials in participants with elevated baseline aminotransferases.

Table S7: Summary of treatment‐emergent gallbladder and biliary tract disorders in the orforglipron Phase 3 clinical trials.

Figure S1: Percent change from baseline in AST.

Figure S2: Percent change from baseline in ALT through safety follow‐up in participants with baseline ALT ≥ 1.5 × ULN.

Figure S3: Percent change from baseline in AST through safety follow‐up in participants with baseline ALT ≥ 1.5 × ULN.

Figure S4: Percent change from baseline in ALT through safety follow‐up in participants with baseline AST ≥ 1.5 × ULN.

Figure S5: Percent change from baseline in AST through safety follow‐up in participants with baseline AST ≥ 1.5 × ULN.

Figure S6: Cholestatic DILI screening in the orforglipron Phase 3 clinical trials.

DOM-28-8347-s001.docx^{(1.3MB, docx)}

Data Availability Statement

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PERMALINK

Hepatic Safety of Orforglipron in Adults With Obesity or Overweight and/or Type 2 Diabetes: A Pooled Analysis of the Orforglipron Phase 3 Clinical Trials

Sean Wharton

Adam Stefanski

Jiaxun Chen

Girish Rao

Elvis Asare Twum

Max Denning

ABSTRACT

Aims

Materials and Methods

Results

Conclusions

Plain Language Summary

1. Introduction

2. Methods

2.1. Trial Design and Participants

2.2. Procedure

2.3. AE Reporting

2.4. Hepatic Analyte Assessment

2.5. Adjudication

2.6. Endpoints

2.7. Statistical Analyses

3. Results

3.1. Exposure to Study Drug and Baseline Characteristics

TABLE 1.

3.2. Percent Change From Baseline in Hepatic Analytes

FIGURE 1.

3.3. Abnormal Postbaseline Categories for Hepatic Analytes

3.4. Shift in ALT and AST

TABLE 2.

3.5. DILI Screening

FIGURE 2.

3.6. Treatment‐Emergent Hepatic Disorders

TABLE 3.

4. Discussion

Author Contributions

Funding

Conflicts of Interest

Supporting information

Acknowledgements

Data Availability Statement

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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