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.
Orforglipron does not appear to increase the risk of drug-induced liver injury compared to other treatments in adults with obesity or type 2 diabetes.
Where it sits
this study against the rest of the orforglipron (ly-3502970) corpusSummary and findings
The study assessed the hepatic safety profile of orforglipron in adults with obesity or overweight and/or type 2 diabetes across seven Phase 3 clinical trials. A total of 11,220 participants were included, with 6,920 receiving orforglipron and 4,300 receiving pooled comparators. The results indicated no increased risk of drug-induced liver injury with orforglipron treatment compared to comparators.
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.