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. 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. 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. 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. 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).
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PubMed · 2026-06-01
PubMed · 2026-06-24
PubMed · 2026-01-01
PubMed · 2026-06-24