Tirzepatide-induced pneumatosis intestinalis: a rare but clinically significant gastrointestinal adverse effect

Glucagon-like peptide 1 receptor agonists such as tirzepatide are increasingly prescribed to treat type 2 diabetes mellitus and obesity because they improve glycemic control and promote weight loss. Although gastrointestinal adverse effects such as nausea, vomiting, constipation, and delayed gastric emptying are well recognized, very rare cases of pneumatosis intestinalis have also been reported in association with this class of medications. We report the first documented histologic diagnosis of a possible tirzepatide-associated pneumatosis intestinalis.

A 55-year-old man with obesity, type 2 diabetes mellitus, hypertension, and obstructive sleep apnea underwent colonoscopy for evaluation of abdominal pain, constipation, and anal fissures. He had been receiving tirzepatide therapy for approximately 1 year and experienced a 49-pound weight loss. Colonoscopy demonstrated mucosal edema of the cecum and ascending colon.

Biopsy specimens of the colon revealed mucosal and submucosal air-filled spaces associated with foreign body-type giant cell reactions and mixed inflammatory infiltrates, including eosinophils and neutrophils, consistent with pneumatosis intestinalis. The patient lacked other recognized risk factors for pneumatosis intestinalis, and his symptoms improved following discontinuation of tirzepatide.

As the use of tirzepatide and related glucagon-like peptide 1 receptor agonists continues to increase, awareness of this rare side effect and its characteristic histologic features should facilitate prompt recognition and accurate diagnosis. Reporting these rare events remains essential to refine the safety profile of these increasingly used medications and improve our understanding of their long-term gastrointestinal effects in broader patient populations.