Semaglutide Side Effects
The most common side effects of semaglutide are gastrointestinal symptoms—nausea, vomiting, and diarrhea—occurring in 15-20% of patients, though these are typically transient and manageable with slow dose titration. 1
Common Gastrointestinal Side Effects
Nausea, vomiting, and diarrhea are the most frequently reported adverse effects, occurring in a dose-dependent manner and more commonly with short-acting than long-acting formulations. 1 These symptoms:
- Usually abate over several weeks to months with continued use 1
- Can be mitigated by starting at low doses and titrating upward slowly 1
- Are managed by reducing meal size, limiting alcohol and carbonated drinks, and avoiding high-fat diets 1
Additional gastrointestinal effects include:
Serious Adverse Effects Requiring Monitoring
Pancreatitis
Acute pancreatitis has been reported but occurs at low rates (0.27-0.3 cases per 100 patient-years in semaglutide groups vs 0.2-0.33 in comparator groups). 2 The FDA label states that if pancreatitis is suspected, semaglutide should be discontinued immediately and not restarted if confirmed. 2 Semaglutide should be used with caution in patients with a history of pancreatitis. 1, 2
Diabetic Retinopathy Complications
In patients with type 2 diabetes and high cardiovascular risk, diabetic retinopathy complications occurred more frequently with semaglutide (3.0%) versus placebo (1.8%). 2 The risk is substantially higher in patients with pre-existing diabetic retinopathy (8.2% vs 5.2% placebo) compared to those without (0.7% vs 0.4% placebo). 2 This appears related to rapid glucose lowering rather than a direct drug effect. 2
Gallbladder Disease
Gallbladder disorders, including acute cholecystitis and cholelithiasis, occur with increased frequency. 1 While usually asymptomatic, this represents a recognized class effect of GLP-1 receptor agonists. 1
Acute Kidney Injury
Postmarketing reports document acute kidney injury and worsening chronic renal failure, sometimes requiring hemodialysis, particularly in patients experiencing severe gastrointestinal symptoms leading to dehydration. 2 Monitor renal function when initiating or escalating doses in patients with severe GI reactions. 2
Cardiovascular Effects
Heart rate typically increases by approximately 5 beats per minute but has not been associated with higher blood pressure or other adverse cardiovascular events. 1 If symptomatic cardiac arrhythmia or tachycardia develops, monitoring and consideration of beta-blockers may be warranted. 1
Contraindications and Black Box Warnings
Semaglutide is absolutely contraindicated in patients with:
- Personal or family history of medullary thyroid carcinoma (MTC) 1, 2
- Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 1, 2
- Known hypersensitivity to semaglutide or product components 2
The FDA black box warning highlights the risk of thyroid C-cell tumors observed in rodent studies, though human relevance remains undetermined. 1, 2 Counsel patients about symptoms of thyroid tumors (neck mass, dysphagia, dyspnea, persistent hoarseness). 2
Hypoglycemia Risk
Semaglutide does not cause hypoglycemia per se, but when combined with insulin or insulin secretagogues (e.g., sulfonylureas), the risk increases significantly. 1, 2 Doses of these concomitant medications should be reduced to mitigate hypoglycemia risk. 1, 2
Hypersensitivity Reactions
Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with GLP-1 receptor agonists. 2 If these occur, discontinue semaglutide immediately and treat per standard protocols. 2 Use caution in patients with prior anaphylaxis or angioedema to other GLP-1 receptor agonists. 2
Injection Site Reactions
Injection site reactions are rare (<1%) with subcutaneous administration. 1 An oral formulation is now available, eliminating this concern for patients who prefer non-injectable therapy. 1
Delayed Gastric Emptying
Semaglutide causes delayed gastric emptying, which has important perioperative implications. 1 This effect is more pronounced with acute or intermittent dosing compared to continuous exposure, and may persist despite chronic use. 1 This creates potential aspiration risk during anesthesia and should be considered in surgical planning. 1
Clinical Management Pearls
To minimize gastrointestinal side effects:
- Avoid use in patients with gastroparesis 1
- Start at the lowest dose (0.25 mg weekly for subcutaneous) and titrate slowly 1, 2
- Educate patients to reduce meal size 1
- Limit alcohol and carbonated beverages 1
Monitor carefully for: