What is the risk of ileus with tirzepatide (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist) use?

Risk of Ileus with Tirzepatide Use

Tirzepatide can cause gastrointestinal disorders including severe constipation and small bowel obstruction/ileus progression, though specific percentage data on ileus occurrence is not explicitly provided in current guidelines. 1

Gastrointestinal Side Effects of Tirzepatide

• Tirzepatide, as a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, is associated with significant gastrointestinal adverse effects 1
• Common gastrointestinal side effects include nausea, vomiting, diarrhea, and esophageal reflux 1
• Constipation is specifically listed as one of the gastrointestinal adverse events that can occur with tirzepatide use 1, 2
• The FDA label for tirzepatide (Mounjaro) specifically mentions "ileus" as a postmarketing adverse reaction, indicating it has been reported during post-approval use 3

Mechanism Behind Ileus Risk

• GLP-1 receptor activation delays gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone 1
• This effect is mediated through the vagus nerve, as GLP-1 receptors located on the myenteric plexus activate pathways that inhibit vagal activity on the gut 1
• These effects lead to reduced phasic gastric contractions, delayed gastric emptying, and increased gastric volumes 1
• The dual action of tirzepatide on both GLP-1 and GIP receptors may contribute to its pronounced effects on gastrointestinal motility 1, 4

Frequency and Severity of Gastrointestinal Effects

• Gastrointestinal adverse events with tirzepatide are dose-dependent: 39% (95% CI, 35%-43%) for 5 mg, 46% (95% CI, 42%-49%) for 10 mg, and 49% (95% CI, 38%-60%) for 15 mg 5
• While specific percentages for ileus are not provided in the available evidence, gastrointestinal disorders including "severe constipation and small bowel obstruction/ileus progression" are listed as possible safety concerns 1
• The risk appears to be similar to that seen with other GLP-1 receptor agonists like semaglutide and liraglutide, which share the same warning about ileus risk 1
• Gastrointestinal adverse events are the most common reason for discontinuation of tirzepatide therapy 5

Clinical Implications and Monitoring

• Healthcare providers should monitor for potential consequences of delayed absorption of oral medications in patients taking tirzepatide 1
• Special caution is needed with medications that have a narrow therapeutic index (e.g., warfarin) 1
• Patients with pre-existing gastrointestinal motility disorders may be at higher risk for developing ileus 1
• Case reports have documented severe gastrointestinal complications in patients taking tirzepatide, including a case of duodenal ulcer perforation 6
• Gastrointestinal adverse effects tend to decrease gradually over time with continued use 2

Perioperative Considerations

• There is concern about increased risk of pulmonary aspiration during anesthesia in patients taking GLP-1 receptor agonists due to delayed gastric emptying 1
• Multiple case reports document regurgitation and aspiration events in patients taking GLP-1 receptor agonists despite appropriate fasting periods 1
• Consideration should be given to the timing of tirzepatide administration in relation to surgical procedures requiring general anesthesia 1

While the exact percentage of patients who develop ileus with tirzepatide is not specified in the current guidelines or research, it is recognized as a potential serious adverse effect that requires monitoring. The overall gastrointestinal adverse event profile is substantial (39-49% depending on dose), with constipation and potential progression to ileus being specifically mentioned as safety concerns.