As oral glucagon-like peptide-1 receptor agonists (GLP-1 RAs) become more widely studied for obesity and type 2 diabetes management, understanding dose-related safety profiles remains important. A network meta-analysis published in Endocrinology, Diabetes and Metabolism evaluated gastrointestinal (GI), hepatic, and pancreatic safety outcomes associated with oral orforglipron across multiple dose ranges in adults with or without type 2 diabetes mellitus (T2DM).

The analysis followed PRISMA guidelines and included randomized controlled trials evaluating orforglipron doses of 3, 12, 24, 36, and 45 mg. Random-effects models were used to assess GI adverse events, hepatic and pancreatic outcomes, and enzyme changes compared with placebo.

Findings

• GI adverse events increased across all orforglipron doses compared with placebo, demonstrating a dose-response relationship.
• The 45 mg dose 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 was more common with the 45 mg dose (OR, 10.22; 95% CI, 4.99–20.94).
• No orforglipron dose increased pancreatitis risk (p>0.05), despite elevations in pancreatic enzymes.
• The 24 mg dose reduced alanine aminotransferase (ALT) levels (MD, −11.19 IU/L; 95% CI, −19.18 to −3.21) and increased lipase levels (MD, +28.52 IU/L; 95% CI, 12.02–45.01).
• Pancreatic amylase levels increased with the 45 mg dose (MD, +18.20 IU/L; 95% CI, 9.49–26.91), while AST and ALP levels remained similar to placebo.

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