What gastrointestinal (GIT) problems can be exacerbated by Glucagon-like peptide-1 (GLP-1) receptor agonists, such as exenatide (exenatide) or liraglutide (liraglutide), in patients with pre-existing gastrointestinal issues like gastroparesis, inflammatory bowel disease, or irritable bowel syndrome?

Gastrointestinal Conditions That Can Be Problematic with GLP-1 Receptor Agonists

GLP-1 receptor agonists should be used with extreme caution or avoided entirely in patients with gastroparesis, as these medications delay gastric emptying and have not been studied in this population, potentially worsening symptoms significantly. 1

Pre-existing Gastroparesis

• GLP-1 receptor agonists are contraindicated in patients with pre-existing gastroparesis because they mechanistically slow gastric emptying by inhibiting gastric peristalsis while increasing pyloric tone through vagal nerve-mediated pathways 2, 1
• Delayed gastric emptying persists even with long-acting formulations like semaglutide, documented by scintigraphy studies, and can lead to prolonged gastric retention, increased fasting gastric volumes, and reduced gastric acid secretion 2
• Retained gastric contents occur in 24.2% of semaglutide users versus 5.1% of controls, even after 10-14 day discontinuation and 12-hour fasting, creating severe aspiration risk during anesthesia and worsening gastroparesis symptoms 3, 2

Irritable Bowel Syndrome (IBS)

• Mixed-type IBS patients show the highest rates of GLP-1 RA discontinuation (21.7%), followed by constipation-predominant IBS (11.7%) and diarrhea-predominant IBS (2.2%), indicating significant tolerability issues across IBS subtypes 4
• Symptom-related discontinuations (nausea, vomiting, diarrhea, constipation) increase steadily with successive GLP-1 RA trials, rising from 28% with the first agent to 48% with the third agent 4
• Semaglutide has significantly more discontinuations within 6 months compared to liraglutide (63.4% vs. 43%) in IBS patients, suggesting agent-specific tolerability differences 4
• IBS patients require careful agent selection and close monitoring, as 88.7% of IBS patients prescribed GLP-1 RAs trial 2-3 different agents due to intolerance 4

Inflammatory Bowel Disease (IBD)

• GLP-1 receptor agonists appear safe in IBD patients, with gastrointestinal side effects occurring in only 11.5% of patients, which is lower than expected given the underlying disease 5
• C-reactive protein levels decrease significantly after one year of GLP-1 RA therapy in IBD patients (P = 0.005), suggesting potential anti-inflammatory benefits 5
• No differences were observed in IBD-related hospitalizations or endoscopic scores, indicating that GLP-1 RAs do not worsen underlying IBD activity 5
• Preliminary data suggest GLP-1 RAs may modulate crucial IBD pathogenesis pathways, including chronic inflammation circuits, intestinal tight junctions, and gut microbiome dysbiosis, though human trials are needed 6

Short Bowel Syndrome (SBS)

• GLP-1 receptor agonists, specifically exenatide, may paradoxically benefit patients with short bowel syndrome by improving bowel frequency, nutritional status, and quality of life 7
• In five SBS patients with ≤90 cm of small bowel, exenatide produced immediate improvement in bowel frequency (from 6-15 bowel movements daily to normalized patterns) and allowed discontinuation of total parenteral nutrition in three patients 7
• Antroduodenal manometry revealed that exenatide normalized continuous low-amplitude gastric contractions during fasting in SBS patients 7
• This represents a unique exception where GLP-1 RAs may treat rather than exacerbate a GI condition, though more research is needed 7

Common GI Adverse Events Across All Patients

• Abdominal pain is the most common GI adverse event (57.6%), followed by diarrhea (32.7%), constipation (30.4%), and nausea/vomiting (23.4%) in real-world GLP-1 RA users 8
• Dulaglutide and liraglutide have significantly higher rates of abdominal pain, constipation, diarrhea, and nausea/vomiting compared to semaglutide and exenatide 8
• Gastroparesis occurs in 5.1% of GLP-1 RA users, with dulaglutide and liraglutide having higher odds of gastroparesis than semaglutide 8
• Pancreatitis occurs in 3.4% of users overall, with liraglutide (4.0%) and exenatide (3.8%) having the highest rates 8
• GI bleeding occurs in 15.9% of GLP-1 RA users, with no significant differences between agents 8

Serious Epigastric Complications

• Acute pancreatitis is a rare but serious complication, particularly with exenatide, requiring caution in patients with a history of pancreatitis 2
• GLP-1 receptor agonists increase the risk of gallbladder disease, including acute cholecystitis, cholelithiasis, and cholecystitis 3, 2
• Persistent severe abdominal pain requires immediate evaluation for pancreatitis or gallbladder disease, with discontinuation of the GLP-1 RA if either is suspected 3, 2

Practical Management Strategies

• Start at the lowest dose and titrate slowly every 4 weeks to minimize gastrointestinal adverse effects, which are dose-dependent and more frequent with short-acting than long-acting formulations 3, 2
• Reduce meal size, limit alcohol and carbonated drinks, and avoid high-fat diets to minimize GI symptoms 2
• Avoid GLP-1 receptor agonists entirely in patients with pre-existing gastroparesis and monitor closely for pancreatitis, especially in patients with risk factors 2, 1
• Consider temporary discontinuation before elective surgery requiring general anesthesia due to pulmonary aspiration risk from delayed gastric emptying 2
• For IBS patients, exenatide appears to have a safer GI profile than other GLP-1 RAs (except for gastroparesis risk), and agent selection should be individualized based on IBS subtype 8