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

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.