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Mechanisms Underlying Gut Hormone Secretion Using the Isolated Perfused Rat Small Intestine
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The Gastrointestinal Safety of Orforglipron, a GLP-1 Receptor Agonist, in Adults With or Without Type 2 Diabetes: A

Ahmed W Hageen1, Ahmed Farid Gadelmawla2,3, Ahmad Omar Saleh4

  • 1Faculty of Medicine, Tanta University, Tanta, Egypt.

Endocrinology, Diabetes & Metabolism
|May 12, 2026
PubMed
Abstract

Insights

Orforglipron (OFG) increases gastrointestinal side effects in a dose-dependent manner. While higher doses improve liver enzymes, they also elevate pancreatic enzymes without causing clinical issues, similar to other GLP-1 RAs.

Area of Science:

  • Pharmacology
  • Gastroenterology
  • Endocrinology

Background:

  • Orforglipron (OFG) is an oral small-molecule glucagon-like peptide-1 receptor agonist (GLP-1 RA) demonstrating weight loss and glycemic benefits.
  • Systematic evaluation of OFG's gastrointestinal (GI), hepatic, and pancreatic safety profile is needed.
  • This study assesses GI adverse events (AEs), hepatic and pancreatic outcomes, and enzyme changes across various OFG doses.

Purpose of the Study:

  • To conduct a network meta-analysis of randomized controlled trials (RCTs) evaluating the GI effects of OFG.
  • To assess GI adverse events, hepatic and pancreatic outcomes, and enzyme changes associated with different OFG doses.
  • To compare the safety profile of OFG to placebo across various doses in adults with or without type 2 diabetes (T2DM).

Main Methods:

  • A frequentist network meta-analysis was performed following PRISMA guidelines.
  • Searched PubMed, Embase, Scopus, and Web of Science for relevant RCTs.
  • Employed random-effects models to calculate odds ratios (OR) and mean differences (MD) with 95% confidence intervals (95% CI).

Main Results:

  • All OFG doses significantly increased GI AEs compared to placebo, showing a dose-response relationship.
  • High-dose OFG (45 mg) markedly increased nausea, vomiting, diarrhea, and GI AE-related discontinuations.
  • Higher OFG doses reduced ALT levels and increased lipase and pancreatic amylase without clinical events; pancreatitis risk was not increased.

Conclusions:

  • Oral OFG exhibits dose-dependent GI adverse effects over 26 weeks.
  • Higher OFG doses improve ALT levels and elevate pancreatic enzymes, but without significant clinical manifestations.
  • The overall safety profile of OFG aligns with established GLP-1 RAs.
Keywords:
glucagon‐like peptide‐1 receptor agonistsliverobesityorforglipronpancreas

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