What are the gastrointestinal (GI) complications of semaglutide (glucagon-like peptide-1 (GLP-1) receptor agonist)?

Gastrointestinal Complications of Semaglutide

Semaglutide causes frequent gastrointestinal side effects, with nausea, vomiting, diarrhea, and esophageal reflux being the most common, while serious complications include pancreatitis, gallbladder disease, severe constipation, and gastroparesis. 1

Common GI Side Effects

The most frequently reported gastrointestinal adverse effects are:

• Nausea and vomiting occur commonly and are typically transient, particularly with gradual dose escalation 1
• Diarrhea and esophageal reflux are reported frequently in clinical trials 1
• Abdominal pain was the most common GI adverse event in real-world data, affecting 57.6% of users 2
• Constipation affects approximately 30.4% of patients and can progress to severe forms 2

These symptoms are dose-dependent and generally most prevalent during the dose escalation period (baseline to week 12) 3. Importantly, the superior weight loss achieved with semaglutide is not primarily mediated by these GI symptoms—nausea and vomiting contributed less than 0.1 kg to the overall weight loss difference compared to other GLP-1 receptor agonists 3.

Mechanism of GI Effects

Semaglutide delays gastric emptying through vagal nerve-mediated pathways, which is a primary mechanism of its glucose-lowering effect 1:

• GLP-1 receptors on the myenteric plexus activate nitrergic pathways to inhibit vagal activity on the gut 1
• This leads to reduced phasic gastric contractions, delayed gastric emptying, reduced gastric acid secretion, and increased fasting and postprandial gastric volumes 1
• The delay in gastric emptying is more pronounced in people with normal rapid gastric emptying 1
• Tachyphylaxis may develop with continuous exposure, though delayed gastric emptying persists even after adaptation 1

Serious GI Complications

Pancreatitis

• Pancreatitis has been reported in clinical trials, though causality has not been definitively established 1
• The FDA and European Medicines Agency have not identified a causal link between GLP-1 receptor agonists and pancreatitis or pancreatic cancer 1
• Incidence in real-world data was 3.4%, with liraglutide and exenatide showing the highest rates (4.0% and 3.8% respectively) 2
• Discontinue semaglutide if pancreatitis is suspected 1

Gallbladder Disease

• GLP-1 receptor agonists increase the risk of cholelithiasis and cholecystitis 1
• This represents an established risk with the drug class 4
• Monitor for right upper quadrant pain and nausea as warning signs 5

Gastroparesis

• Semaglutide can cause or exacerbate gastroparesis through its mechanism of delayed gastric emptying 6, 7
• The American Gastroenterological Association lists GLP-1 receptor agonists as a potential cause of gastroparesis 6
• Real-world incidence was 5.1%, with dulaglutide and liraglutide showing higher odds compared to semaglutide 2
• Avoid in patients with pre-existing symptoms of nausea, bloating, or abdominal discomfort 7

Severe Constipation and Bowel Obstruction

• Severe constipation and small bowel obstruction/ileus progression can occur 1
• These complications may develop or persist even after stopping the medication 5
• Reported as serious adverse events in the SUSTAIN trials 1

Acute Kidney Injury

• Use caution in patients with kidney disease due to potential risk of acute kidney injury, particularly from gastrointestinal fluid losses 1
• Risk may persist after discontinuation, requiring continued monitoring 5

Risk Mitigation Strategies

To minimize GI complications:

• Gradual dose titration is essential to mitigate nausea and vomiting 1
• Reduce meal size and educate patients about portion control 1
• Avoid high-fat diets to help manage GI symptoms 6
• Start at low doses and titrate slowly for patients with risk factors 6

Perioperative Considerations

For elective surgery:

• Withhold semaglutide for at least three half-lives (approximately 5 weeks after last dose, given the ~1 week half-life) before elective procedures for patients using it for weight management 6, 8
• For patients with type 2 diabetes, prolonged cessation may worsen glycemic control—discuss with endocrinology 6
• The delayed gastric emptying and increased postprandial gastric volumes create aspiration risk 1

Medication Interactions

• Delayed absorption of oral medications may occur due to delayed gastric emptying 1
• Monitor medications with narrow therapeutic indices (e.g., warfarin) closely 1
• Oral hormonal contraception may be affected—use or add non-oral contraception for 4 weeks after initiation and dose escalations 1

Comparative Safety Profile

In the pooled analysis of SUSTAIN trials, semaglutide showed a 38% higher risk of serious adverse events compared to placebo (95% CI, 1.10–1.73), with examples including abdominal pain, constipation, diarrhea, nausea, vomiting, pancreatitis, cholelithiasis, cholecystitis, and gastroenteritis 1. However, the overall risk/benefit profile remains favorable given the significant metabolic and cardiovascular benefits 4.