As oral glucagon-like peptide-1 receptor agonists (GLP-1 RAs) inch closer to mainstream clinical use, understanding their tolerability at different doses is becoming a practical priority for prescribers. A network meta-analysis published in Endocrinology, Diabetes and Metabolism evaluated the gastrointestinal (GI), hepatic, and pancreatic safety profile of orforglipron (OFG), an oral small-molecule GLP-1 RA, across its full dose range in adults with and without type 2 diabetes (T2DM).

The analysis searched PubMed, Embase, Scopus, and Web of Science following PRISMA guidelines. It included randomized controlled trials (RCTs) enrolling adults with and without T2DM who received orforglipron at doses of 3, 12, 24, 36, or 45 mg.

Findings

• All OFG doses increased GI adverse events compared with placebo.
• The most pronounced effects were seen with the 45 mg dose, which was associated with higher odds of Nausea (OR 11.48; 95% CI 6.52-20.21), Vomiting (OR 11.48; 95% CI 6.52-20.21) and Diarrhea (OR 3.99; 95% CI 2.07-7.70).
• Discontinuation due to GI adverse events were also observed with OFG 45 mg dose (OR 10.22; 95% CI 4.99-20.94).
• None of the OFG doses increased pancreatitis risk (p>0.05).
• 24 mg OFG dose reduced alanine aminotransferase (ALT) levels (MD –11.19 IU/L; 95% CI, −19.18 to −3.21).
• 24 mg OFG dose increased lipase levels (MD +28.52 IU/L; 95% CI 12.02-45.01).
• 45 mg OFG dose increased pancreatic amylase levels (MD +18.20 IU/L; 95% CI 9.49-26.91).
• Aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels were similar between the groups. 

Overall, oral orforglipron was associated with dose-dependent GI adverse events, while hepatic and pancreatic safety findings remained consistent with the established GLP-1 RA class profile.