The Gastrointestinal Safety of Orforglipron, a GLP ‐1 Receptor Agonist, in Adults With or Without Type 2 Diabetes: A Network Meta‐Analysis of Randomized Controlled Trials

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BACKGROUND AND AIM: Orforglipron (OFG), an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1 RA), has demonstrated significant weight loss and glycemic benefits in adults with or without type 2 diabetes (T2DM). However, its gastrointestinal (GI), hepatic and pancreatic safety profile has not been systematically evaluated. This network meta-analysis aimed to assess GI adverse events (AEs), hepatic and pancreatic outcomes, and enzyme changes across different OFG doses. METHODS: A frequentist network meta-analysis was conducted in accordance with the PRISMA guidelines. PubMed, Embase, Scopus and Web of Science (WOS) were searched for randomized controlled trials (RCTs) that assess the GI effects of OFG in adults with or without T2DM. We considered random-effects models to express treatment effects as odds ratios (OR) and mean differences (MD) with 95% confidence intervals (95% CI). RStudio software (version 4.5.1) was used for analysis. RESULTS: All OFG doses (3, 12, 24, 36 and 45 mg) increased GI AEs compared to placebo, with a clear dose-response trend. High-dose OFG (45 mg) markedly increased nausea (OR 11.48, 95% CI: 6.52-20.21), vomiting (OR 11.48, 95% CI: 6.52-20.21), diarrhoea (OR 3.99, 95% CI: 2.07-7.70) and discontinuation due to GI AEs (OR 10.22, 95% CI: 4.99-20.94). No dose increased pancreatitis risk (p > 0.05). Higher doses significantly reduced ALT, with the most significant reduction observed at 24 mg (MD -11.19 IU/L, 95% CI: -19.18 to -3.21). Doses ≥ 12 mg increased lipase (e.g., 24 mg: +28.52 IU/L, 95% CI: 12.02-45.01) and pancreatic amylase (45 mg: +18.20 IU/L, 95% CI: 9.49-26.91), without corresponding increases in clinical events. AST and ALP levels remained similar to those of the placebo. Subgroup analyses showed consistent effects in patients with or without T2DM. CONCLUSION: Oral OFG showed dose-dependent GI adverse effects over 26 weeks. Higher doses improve ALT and elevate pancreatic enzymes without clinical manifestations. The safety profile aligns with established GLP-1 RAs.

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