Orforglipron demonstrates hepatic safety profile similar to placebo in pooled Phase 3 trials for obesity and T2D

The global prevalence of obesity and Type 2 Diabetes (T2D) continues to rise, necessitating effective and safe long-term treatment options. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have revolutionized metabolic disease management, but most are injectables. Oral small-molecule GLP-1 RAs like Orforglipron offer convenience, yet their hepatic safety, especially for long-term use in populations often with underlying metabolic dysfunction-associated steatotic liver disease (MASLD), requires rigorous evaluation. This study addresses the critical need to confirm the hepatic safety profile of Orforglipron.

This pooled analysis included 11,220 participants (Orforglipron N=6920; pooled comparator N=4300) from seven Phase 3 clinical trials, lasting up to 104 weeks with safety follow-up. Participants had obesity or overweight and/or T2D, with baseline ALT/AST <3xULN (weight management) or ≤5xULN (T2D). The main analysis compared pooled Orforglipron doses against placebo, oral semaglutide, dapagliflozin, or insulin glargine. Researchers assessed continuous and categorical changes in hepatic analytes, screened for drug-induced liver injury (DILI)/Hy's Law, and summarized hepatic adverse events (AEs). Subgroup analyses were performed for participants with elevated baseline aminotransferases.

Orforglipron treatment was consistently associated with mean reductions in ALT/AST levels. Categorical ALT/AST elevations were generally balanced between the Orforglipron group and comparators. A total of six (0.1%) Orforglipron-treated participants and six (0.1%) comparator-treated participants met initial criteria for Hy's Law (ALT or AST ≥3xULN and TBIL ≥2xULN). However, for all Orforglipron cases, alternative etiologies were identified, meaning they did not meet the definitive criteria for drug-induced liver injury. The overall incidence of hepatic AEs was balanced between Orforglipron and pooled comparators, indicating no increased risk. These findings remained consistent across subgroups, including those with normal and elevated baseline aminotransferases.

Orforglipron treatment was not associated with drug-induced liver injury, demonstrating a hepatic safety profile similar to placebo or active comparators.