What is the pathophysiology of GLP‑1 receptor agonist–induced small‑bowel obstruction in adults with type 2 diabetes or obesity?

Pathophysiology of GLP-1 Receptor Agonist–Related Small Bowel Obstruction

Primary Mechanism: Delayed Gastric Emptying and Reduced Intestinal Motility

GLP-1 receptor agonists cause small bowel obstruction primarily through profound slowing of gastrointestinal motility at multiple levels of the GI tract, with the most clinically significant effect being delayed gastric emptying that persists even after extended fasting periods. 1, 2

Vagal-Mediated Motility Suppression

• GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis while simultaneously increasing pyloric tone, creating a functional barrier to gastric outflow 1
• This mechanism is mediated entirely through the vagus nerves—patients who have undergone vagotomy do not experience GLP-1-induced gastric emptying delays 1
• GLP-1 receptors located on the myenteric plexus activate nitrergic and cyclic adenosine monophosphate pathways to inhibit vagal activity on the gut, leading to reduced phasic gastric contractions 1

Multi-Level Gastrointestinal Effects

• The motility suppression extends beyond the stomach to affect the entire gastrointestinal tract, including the small intestine, where GLP-1 RAs slow transit and reduce propulsive contractions 2
• This results in increased fasting and postprandial gastric volumes, reduced gastric acid secretion, and prolonged retention of gastric contents 1
• Retained gastric contents are documented even after extended fasting periods—24.2% of semaglutide users showed increased residual gastric content versus 5.1% of controls, despite 10-14 day medication discontinuation and 12-hour fasting 1, 3

Tachyphylaxis and Persistent Risk

Adaptation of Autonomic Nervous System

• Tachyphylaxis develops with continuous GLP-1 exposure, particularly affecting the vagal nervous system response 1
• Plasma concentrations of pancreatic polypeptide (a surrogate measure of vagal activity) were markedly suppressed during the first meal but significantly less after the second meal, suggesting autonomic adaptation 1
• Acute and intermittent infusions of GLP-1 RAs have more pronounced effects on delaying gastric emptying than continuous infusion, as demonstrated by scintigraphy studies 1

Critical Clinical Implication

• Despite tachyphylaxis to some gastric emptying effects, patients still experience significantly delayed gastric emptying after prolonged exposure, as confirmed by scintigraphy (the gold standard for measuring gastric emptying) 1
• This persistent delay creates aspiration risk during anesthesia and contributes to functional bowel obstruction, even in patients who have been on long-acting formulations for extended periods 1, 3

Functional vs. Mechanical Obstruction

Functional Small Bowel Obstruction Mechanism

• The combination of delayed gastric emptying, reduced small intestinal motility, and increased gastric volumes creates a functional obstruction rather than a true mechanical blockage 1, 2
• GLP-1 RAs cause gastric distension characterized by diffuse upper abdominal discomfort, early satiety, bloating, and nausea—symptoms that overlap with small bowel obstruction 4
• The long half-lives of GLP-1 RAs (particularly semaglutide and tirzepatide) mean these effects persist for weeks after discontinuation, complicating perioperative management 1, 3

Receptor Distribution and Pleiotropic Effects

• GLP-1 receptors are distributed throughout the gastric mucosa and myenteric plexus, but those in the mucosa regulate insulin secretion while those in the myenteric plexus control motility 1
• GLP-1 receptors are also found in the hippocampus, neocortex, spinal cord, and cerebellum, explaining broader neurological effects beyond simple appetite suppression 4

Clinical Evidence and Risk Quantification

Documented Aspiration and Obstruction Risk

• Retained gastric contents persist even with extended fasting periods—cases reported in patients who stopped semaglutide 4-6 days before surgery still showed significant gastric residue 1
• Increased residual gastric content was found in 24.2% of semaglutide users versus 5.1% of controls undergoing endoscopy, despite 10-14 day discontinuation and 12-hour fasting 1
• This applies to both oral and injectable formulations, as the mechanism is receptor-mediated rather than route-dependent 1

Comparative Risk Assessment

• A large retrospective cohort study of over 1.2 million T2DM patients found no increased risk of intestinal obstruction with GLP-1 RAs compared to other anti-diabetic medications (except reduced risk versus insulins) 5
• However, this population-level data may not capture functional obstructions or perioperative complications that resolve without formal diagnosis 5

Dual GIP/GLP-1 Agonist Considerations

Tirzepatide-Specific Mechanisms

• Tirzepatide binds to both GIP and GLP-1 receptors, but its affinity for the GLP-1 receptor is approximately five times less than that of endogenous GLP-1 1, 4
• Despite lower GLP-1 receptor affinity, tirzepatide still causes delayed gastric emptying, suppressed appetite, and reduced intestinal motility through its dual-receptor action 4
• The dual-hormone mechanism provides enhanced metabolic benefits including delayed gastric emptying, but this also translates to similar obstruction risk as pure GLP-1 agonists 4

Critical Perioperative Implications

Extended Discontinuation Requirements

• For elective surgery requiring anesthesia, discontinue GLP-1 RAs well in advance: 3 weeks for semaglutide/tirzepatide, 3 days for liraglutide due to delayed gastric emptying and aspiration risk 4
• Gastric ultrasound should be considered preoperatively to assess for retained gastric contents in patients on GLP-1 RA therapy 4
• The use of prokinetic medications like erythromycin may prove helpful to increase gastric emptying before procedures, though this remains an area needing further study 3

Common Pitfall to Avoid

• Do not assume standard fasting periods are adequate for patients on GLP-1 RAs—retained gastric contents persist despite extended fasting, creating significant aspiration and functional obstruction risk 1, 3